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Tseng PT, Zeng BY, Hsu CW, Hung CM, Carvalho AF, Stubbs B, Chen YW, Chen TY, Lei WT, Chen JJ, Su KP, Shiue YL, Liang CS. The pharmacodynamics-based prophylactic benefits of GLP-1 receptor agonists and SGLT2 inhibitors on neurodegenerative diseases: evidence from a network meta-analysis. BMC Med 2025; 23:197. [PMID: 40189519 PMCID: PMC11974209 DOI: 10.1186/s12916-025-04018-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 03/18/2025] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a new generation of antihyperglycemic agents that operate through mechanisms distinct from conventional diabetes treatments. Beyond their metabolic effects, these medications have demonstrated neuroprotective properties in preclinical studies. While clinical trials have explored their therapeutic potential in established neurodegenerative conditions, their role in disease prevention remains unclear. We conducted a network meta-analysis (NMA) to comprehensively evaluate the prophylactic benefits of these agents across multiple neurodegenerative diseases and identify the most promising preventive strategies. METHODS We systematically searched PubMed, Embase, ClinicalKey, Cochrane CENTRAL, ProQuest, ScienceDirect, Web of Science, and ClinicalTrials.gov through October 24th, 2024, for randomized controlled trials (RCTs) of GLP-1 receptor agonists or SGLT2 inhibitors. Our primary outcome was the incidence of seven major neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, Lewy body dementia, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington's disease. Secondary outcomes included safety profiles assessed through dropout rates. We performed a frequentist-based NMA and evaluated risk of bias with Risk of Bias tool. The main result of the primary outcome in the current study would be re-affirmed via sensitivity test with Bayesian-based NMA. RESULTS Our analysis encompassed 22 RCTs involving 138,282 participants (mean age 64.8 years, 36.4% female). Among all investigated medications, only dapagliflozin demonstrated significant prophylactic benefits, specifically in preventing Parkinson's disease (odds ratio = 0.28, 95% confidence intervals = 0.09 to 0.93) compared to controls. Neither GLP-1 receptor agonists nor other SGLT2 inhibitors showed significant preventive effects for any of the investigated neurodegenerative conditions. Drop-out rates were comparable across all treatments. CONCLUSIONS This comprehensive NMA reveals a novel and specific prophylactic effect of dapagliflozin against Parkinson's disease, representing a potential breakthrough in preventive neurology. The specificity of dapagliflozin's protective effect to Parkinson's disease might rely on its highly selective inhibition to SGLT2. These findings provide important direction for future research and could inform preventive strategies for populations at risk of Parkinson's disease. TRIAL REGISTRATION PROSPERO CRD42021252381.
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Affiliation(s)
- Ping-Tao Tseng
- Institute of Precision Medicine, National Sun Yat-Sen University, 70 Lienhai Rd, Kaohsiung City, 80424, Taiwan.
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
- Prospect Clinic for Otorhinolaryngology & Neurology, No. 252, Nanzixin Road, Nanzi District, Kaohsiung City, 81166, Taiwan.
| | - Bing-Yan Zeng
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
- Department of Internal Medicine, E-Da Dachang Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Chih-Wei Hsu
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Ming Hung
- Division of General Surgery, Department of Surgery, E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Andre F Carvalho
- Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia
| | - Brendon Stubbs
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- Department of Sport, University of Vienna, Vienna, Austria
| | - Yen-Wen Chen
- Prospect Clinic for Otorhinolaryngology & Neurology, No. 252, Nanzixin Road, Nanzi District, Kaohsiung City, 81166, Taiwan
| | - Tien-Yu Chen
- Department of Psychiatry, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
| | - Wei-Te Lei
- Section of Immunology, Rheumatology, and Allergy Department of Pediatrics, Section of Immunology, Rheumatology, and Allergy Department of Pediatrics, Hsinchu Munipical MacKay Children's Hospital, Hsinchu City, Taiwan
- Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan
| | - Jiann-Jy Chen
- Prospect Clinic for Otorhinolaryngology & Neurology, No. 252, Nanzixin Road, Nanzi District, Kaohsiung City, 81166, Taiwan
- Department of Otorhinolaryngology, E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Kuan-Pin Su
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan
- College of Medicine, China Medical University, Taichung, Taiwan
- An-Nan Hospital, China Medical University, Tainan, Taiwan
| | - Yow-Ling Shiue
- Institute of Precision Medicine, National Sun Yat-Sen University, 70 Lienhai Rd, Kaohsiung City, 80424, Taiwan.
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
| | - Chih-Sung Liang
- Department of Psychiatry, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Beitou District, Beitou Branch, No. 60, Xinmin Road, Taipei City, 112, Taiwan.
- Department of Psychiatry, National Defense Medical Center, Taipei, Taiwan.
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Emanuelsson F, Jensen J, Omar M, Jürgens M, Kistorp C, Brandt-Jacobsen NH, Møller JE, Schou M, Bechmann LE, Larsen EL, Nordestgaard BG, Benn M. Effect of empagliflozin on plasma lipids and lipoproteins in type 2 diabetes and heart failure - Empire HF and SIMPLE. J Clin Lipidol 2025; 19:276-285. [PMID: 39843293 DOI: 10.1016/j.jacl.2024.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 12/19/2024] [Accepted: 12/20/2024] [Indexed: 01/24/2025]
Abstract
OBJECTIVE Beyond glucose-lowering, sodium-glucose co-transporter 2 (SGLT2) inhibitors have cardioprotective effects with unclear mechanisms. We examined changes in an extensive panel of plasma lipids, lipoproteins, and apolipoproteins and whether these changes were independent of weight loss, hemoglobin A1c, and hematocrit in patients treated with empagliflozin vs placebo to better understand the observed cardioprotective effects. METHODS Post-hoc analyses of 2 double-blind, placebo-controlled trials, the Empire HF trial including 190 patients with heart failure and reduced ejection fraction and the SIMPLE trial including 90 patients with type 2 diabetes randomized to, respectively, 10 mg and 25 mg empagliflozin daily or placebo for 12 weeks. RESULTS In studies combined, empagliflozin reduced age and sex adjusted body weight by 1.40 kg (SEM: 0.10; P < .001) and hemoglobin A1c by 2.71 mmol/mol (SEM: 0.24; P < .001); and increased hematocrit by 1.9% (SEM: 0.12; P < .001) compared to placebo. No mean changes were seen in concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, small dense LDL cholesterol, very low-density lipoprotein cholesterol, triglyceride rich lipoprotein cholesterol, non-high-density lipoprotein (non-HDL) cholesterol, apolipoprotein B, lipoprotein(a), HDL cholesterol, and triglycerides adjusted for body weight, hemoglobin A1c, and hematocrit with empagliflozin compared to placebo. CONCLUSION Empagliflozin treatment reduced body weight and hemoglobin A1c, and increased hematocrit. No changes were seen in concentrations of lipids and lipoproteins with empagliflozin compared to placebo. This suggests that the cardioprotective effects of SGLT2 inhibitors are independent of lipid and lipoprotein concentrations.
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Affiliation(s)
- Frida Emanuelsson
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Centre of Diagnostic Investigation, Copenhagen, Denmark (Emanuelsson, Bechmann, Larsen, Benn)
| | - Jesper Jensen
- Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark (Jensen, Schou)
| | - Massar Omar
- Department of Cardiology, Odense University Hospital, Odense, Denmark (Omar, Møller); Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark (Omar)
| | - Mikkel Jürgens
- Department of Endocrinology, Copenhagen University Hospital - Rigshospitalet, Centre for Cancer and Organ Diseases, Copenhagen, Denmark (Jürgens, Brandt-Jacobsen)
| | - Caroline Kistorp
- Clinical Institute, University of Southern Denmark, Odense, Denmark (Kistorp, Møller); Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Denmark (Kistorp, Brandt-Jacobsen, Schou, Nordestgaard, Benn)
| | - Niels H Brandt-Jacobsen
- Department of Endocrinology, Copenhagen University Hospital - Rigshospitalet, Centre for Cancer and Organ Diseases, Copenhagen, Denmark (Jürgens, Brandt-Jacobsen); Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Denmark (Kistorp, Brandt-Jacobsen, Schou, Nordestgaard, Benn)
| | - Jacob Eifer Møller
- Department of Cardiology, Odense University Hospital, Odense, Denmark (Omar, Møller); Clinical Institute, University of Southern Denmark, Odense, Denmark (Kistorp, Møller)
| | - Morten Schou
- Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark (Jensen, Schou); Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Denmark (Kistorp, Brandt-Jacobsen, Schou, Nordestgaard, Benn)
| | - Louise Ellegaard Bechmann
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Centre of Diagnostic Investigation, Copenhagen, Denmark (Emanuelsson, Bechmann, Larsen, Benn)
| | - Emil List Larsen
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Centre of Diagnostic Investigation, Copenhagen, Denmark (Emanuelsson, Bechmann, Larsen, Benn)
| | - Børge G Nordestgaard
- Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark (Nordestgaard); Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Denmark (Kistorp, Brandt-Jacobsen, Schou, Nordestgaard, Benn)
| | - Marianne Benn
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Centre of Diagnostic Investigation, Copenhagen, Denmark (Emanuelsson, Bechmann, Larsen, Benn); Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Denmark (Kistorp, Brandt-Jacobsen, Schou, Nordestgaard, Benn).
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Jaiswal V, Ang SP, Kumar D, Deb N, Jaiswal A, Joshi A, Nasir YM, Bandyopadhyay D, Michos ED, Benjamin EJ, Fonarow GC. Sodium-Glucose Cotransporter-2 Inhibitors and Arrhythmias: A Meta-Analysis of 38 Randomized Controlled Trials. JACC. ADVANCES 2025; 4:101615. [PMID: 39985887 PMCID: PMC11904486 DOI: 10.1016/j.jacadv.2025.101615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 01/07/2025] [Accepted: 01/11/2025] [Indexed: 02/24/2025]
Abstract
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown promising results in reducing hospitalizations from heart failure (HF) and cardiovascular mortality. However, their effect on arrhythmia and sudden cardiac death (SCD) is not well established. OBJECTIVES The authors sought to evaluate the association between SGLT2i and the risk of arrhythmias and SCD in patients with type 2 diabetes mellitus, HF, or chronic kidney disease. METHODS We performed a systematic literature search on PubMed, EMBASE, and Scopus for relevant randomized controlled trials from inception until February 10, 2023. ORs and 95% CIs were pooled using a random effect model. RESULTS A total of 38 randomized controlled trials with 88,704 patients (48,435 in the SGLT2i group and 40,269 in the control group) were included in the study. The mean age of patients among SGLT2i and control groups was 56.8 and 56.7 years, respectively. The mean follow-up duration was 1.6 years. Pooled analysis of primary and secondary outcomes showed that SGLT2i significantly reduced the risk of incident atrial arrhythmia (OR: 0.85 [95% CI: 0.75-0.98], P = 0.02), SCD (OR: 0.72 [95% CI: 0.55-0.94], P = 0.02) compared with placebo. However, the risk of ventricular arrhythmia (OR: 1.03 [95% CI: 0.84-1.26], P = 0.77) and cardiac arrest (OR: 0.94 [95% CI: 0.72-1.23] P = 0.67) was comparable between both groups of patients. CONCLUSIONS SGLT2i therapy was associated with an overall lower risk of atrial arrythmia and SCD in patients with type 2 diabetes mellitus and/or HF or chronic kidney disease. However, SGLT2i therapy was not associated with a lower risk of ventricular arrhythmia.
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Affiliation(s)
- Vikash Jaiswal
- Department of Cardiovascular Research, Larkin Community Hospital, South Miami, Florida, USA
| | - Song Peng Ang
- Department of Internal Medicine, Rutgers Health/Community Medical Center, Toms River, New Jersey, USA
| | - Danisha Kumar
- Dow University of Health Sciences, Karachi, Pakistan
| | - Novonil Deb
- North Bengal Medical College, West Bengal, India
| | - Akash Jaiswal
- Department of Geriatric Medicine, All India Institute of Medical Science, New Delhi, India
| | - Amey Joshi
- Michigan State University-Sparrow Hospital, Lansing, Michigan, USA
| | - Yusra Minahil Nasir
- Department of Internal Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA
| | | | - Erin D Michos
- Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Emelia J Benjamin
- Department of Medicine, Cardiovascular Medicine, Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA; Epidemiology Department, Boston University School of Public Health, Boston, Massachusetts, USA
| | - Gregg C Fonarow
- Ahmanson-UCLA Cardiomyopathy Center, Ronald Reagan UCLA Medical Center, Los Angeles, California, USA.
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Xu L, Wu Y, Li J, Ding Y, Chow J, Li L, Liu H, Wang Z, Gong T, Li Y, Ma G. Efficacy and safety of 11 sodium-glucose cotransporter-2 inhibitors at different dosages in type 2 diabetes mellitus patients inadequately controlled with metformin: a Bayesian network meta-analysis. BMJ Open 2025; 15:e088687. [PMID: 40010842 PMCID: PMC11877256 DOI: 10.1136/bmjopen-2024-088687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 02/07/2025] [Indexed: 02/28/2025] Open
Abstract
OBJECTIVES Assess the efficacy and safety profiles of different sodium-glucose cotransporter-2 inhibitors (SGLT2is) as an add-on to metformin in type 2 diabetes mellitus (T2DM) patients. DESIGN Bayesian network meta-analysis. DATA SOURCES PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov were searched before 18 December 2024. ELIGIBILITY CRITERIA Randomised controlled trials (RCTs) evaluating T2DM patients taking one of 12 SGLT2is as add-on therapy to metformin. Efficacy outcomes focused on glycated haemoglobin (HbA1c) reduction, fasting plasma glucose (FPG) reduction and weight loss (WL). Safety outcomes included adverse events (AEs), serious AEs (SAEs), hypoglycaemia, urinary tract infections (UTI) and genital infections (GI). DATA EXTRACTION AND SYNTHESIS Two investigators independently extracted data. The quality of the included studies was assessed using the Cochrane Risk of Bias Tool (V.2.0) for RCTs. RESULTS 23 RCTs involving 9144 patients and 11 SGLT2is were included. Compared with placebo, most SGLT2is reduced HbA1c (mean difference (MD), -0.45~-0.80%), FPG (MD, -0.78~-2.02 mmol/L) and body weight (MD, -0.88~-2.67 kg). Only 10 mg of henagliflozin increased the incidence of AEs, and none of the included interventions increased the risks of SAEs or UTIs. 50 mg of empagliflozin exhibited higher risks of hypoglycaemia. Only 10 mg of empagliflozin increased the risk of GI. According to the surface under the cumulative ranking values, SGLT2is with optimal efficacy and safety were 15 mg of ertugliflozin in HbA1c reduction, 300 mg of canagliflozin in FPG reduction, WL and hypoglycaemia, 400 mg of sotagliflozin in total AEs, 10 mg of ertugliflozin and 150 mg of ipragliflozin in SAEs, 12.5 mg of ipragliflozin in UTI and 1 mg of ertugliflozin in GI. CONCLUSIONS As add-on therapy, SGLT2is demonstrated favourable antidiabetic efficacy and acceptable safety. 300 mg of canagliflozin was the best option among the included interventions considering favourable glucose control and WL. Some novel SGLT2is (eg, henagliflozin) exhibited promising efficacy and safety profiles, but more research is needed to validate the findings.
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Affiliation(s)
- Leqing Xu
- Fudan University, Shanghai, Shanghai, China
| | - Yike Wu
- Fudan University, Shanghai, Shanghai, China
| | - Jiyifan Li
- Fudan University, Shanghai, Shanghai, China
| | - Yanan Ding
- Fudan University, Shanghai, Shanghai, China
| | | | | | | | - Zihan Wang
- Fudan University, Shanghai, Shanghai, China
| | | | - Yue Li
- Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Guo Ma
- Fudan University, Shanghai, Shanghai, China
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Vale C, Lourenço IM, Jordan G, Golovaty I, Torres H, Moin T, Buysschaert M, Neves JS, Bergman M. Early combination therapy with SGLT2i and GLP-1 RA or dual GIP/GLP-1 RA in type 2 diabetes. Diabetes Obes Metab 2025; 27:468-481. [PMID: 39604324 DOI: 10.1111/dom.16077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 10/31/2024] [Accepted: 11/06/2024] [Indexed: 11/29/2024]
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-Like peptide-1 receptor agonists (GLP-1 RA) are recommended in people with type 2 diabetes (T2D) for glycaemic control and for people with high cardiovascular risk. However, current guidelines do not specifically address the role of initial early combination therapy with SGLT2i and GLP-1 RA or dual gastric inhibitory polypeptide (GIP)/GLP-1 RA, but rather sequential initiation with either in T2D. This review synthesizes the available evidence on the use of SGLT2i and GLP-1-based therapies for T2D and provides a rationale for their combination. The combination of SGLT2i with GLP-1-based therapies addresses complementary pathophysiological mechanisms and enhances efficacy in achieving target haemoglobin A1C (HbA1c) levels. SGLT2i and GLP-1 RA also have been shown to prevent complications of T2D. While both classes reduce adverse cardiorenal events, SGLT2i has a predominant effect on prevention of kidney dysfunction and heart failure, whereas GLP-1 RA has a more marked effect on the risk of atherosclerotic cardiovascular disease. Both drug classes have favourable safety profiles. Finally, weight loss with combination therapy may have disease-modifying effects that may reverse T2D progression. We propose that the combination of SGLT2i with GLP-1 RA or dual GIP/GLP-1 RA should be considered for most patients with T2D who do not have contraindications.
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Affiliation(s)
- Catarina Vale
- Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Internal Medicine, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Inês Mariana Lourenço
- Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | | | - Ilya Golovaty
- General Medicine Service, VA Puget Sound Health Care System, Seattle, Washington, USA
- Division of General Internal Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Hugo Torres
- David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Tannaz Moin
- David Geffen School of Medicine, University of California, Los Angeles, California, USA
- HSR&D Center for the Study of Healthcare Innovation, Implementation & Policy, VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Martin Buysschaert
- Department of Endocrinology and Diabetology, Université Catholique de Louvain, University Clinic Saint-Luc, Brussels, Belgium
| | - João Sérgio Neves
- Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Michael Bergman
- Holman Division of Endocrinology, Diabetes and Metabolism, Departments of Medicine and Population Health, VA New York Harbor Healthcare System, New York University Grossman School of Medicine, New York, New York, USA
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Panda P, Mohapatra R, Samantaray B. Insightful Perspectives on Sodium-glucose Co-transporter 2 Inhibitors: Navigating Safety Updates and Beyond. Curr Drug Res Rev 2025; 17:19-32. [PMID: 40183146 DOI: 10.2174/0125899775332399240806101923] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/04/2024] [Accepted: 07/22/2024] [Indexed: 04/05/2025]
Abstract
SGLT2 (Sodium-Glucose Co-transporter 2) inhibitors, also known as gliflozin class, are a novel family of oral drugs being used to treat type 2 diabetes. SGLT2 inhibitors can work alone or in conjunction with other medications. This class includes five drugs, including canagliflozin, ertugliflozin, sotagliflozin, dapagliflozin, and empagliflozin. SGLT2 inhibitors inhibit the SGLT2 cotransporter in the proximal tubules of the kidney, reducing glucose and sodium reabsorption. It promotes the elimination of sugar in urine (diabetes mellitus) and lowers blood sugar levels. SGLT2 inhibitors also have pleiotropic effects on cardiac and renal function, broadening their therapeutic applications in heart failure. Despite the clinical benefits, regulators have placed secondary warnings in product information since the medications first hit the market. SGLT2 inhibitors, in particular, have had a significant impact on a variety of risk factors. This can lead to hypoglycaemia, urinary tract infections, diabetic ketoacidosis, lower limb amputation, and fractures. Although some of these events are uncommon, they can lead to severe and deadly consequences; therefore, patients must be closely monitored. In general, SLGT2 inhibitors are an efficient diabetes treatment with strong cardiovascular and renal protection and a favourable safety overview. This review sought to summarise the safety overview of commercially available SGLT2 inhibitors.
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Affiliation(s)
- Pratikeswar Panda
- Department of Pharmaceutics, School of Pharmaceutical Science, Siksha 'O' Anusandhan University, Bhubaneswar, Odisha, India
| | - Rajaram Mohapatra
- Department of Pharmaceutics, School of Pharmaceutical Science, Siksha 'O' Anusandhan University, Bhubaneswar, Odisha, India
| | - Biswajit Samantaray
- Department of Pharmaceutics, School of Pharmaceutical Science, Siksha 'O' Anusandhan University, Bhubaneswar, Odisha, India
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Geng L, Sun B, Chen Y. A meta-analysis of randomized controlled studies examining the effects of sodium-glucose co-transporter-2 inhibitors on peripheral artery disease and risk of amputations. Diabetes Obes Metab 2024; 26:5376-5389. [PMID: 39267269 DOI: 10.1111/dom.15901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 08/09/2024] [Accepted: 08/10/2024] [Indexed: 09/17/2024]
Abstract
AIM Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are used to maintain glycaemic control as well as for their beneficial cardiovascular and renal effects in diabetes patients. However, increased risk of amputation and peripheral artery disease (PAD) have been observed with the use of some SGLT-2is. A meta-analysis was conducted to understand the effect of SGLT-2is on amputation and PAD events using data from randomized controlled trials (RCT). MATERIALS AND METHODS A systematic literature review was conducted using Medline and Central databases for RCTs that involved the administration of SGLT-2is versus placebo/active comparators to diabetic patients. The primary outcome was amputation events and PAD. A random-effects model was used to calculate the pooled odds ratio, and subgroup analyses was performed. RESULTS A total of 51 RCTs were included in the meta-analysis with data from 97 589 patients. Meta-analysis of the data showed that there was a significant increase in PAD risk (p = 0.04) but no significant increase in amputation risk with SGLT-2i use versus placebo/active comparators (p = 0.43). Subgroup analyses demonstrated no significant difference between SGLT-2i type, duration of treatment or patient risk factors on amputation or PAD incidence. However, length of drug treatment (> 100 weeks) was associated with a significant increase in both PAD and amputation risks in the SGLT-2i treatment groups. CONCLUSIONS The results of the meta-analysis showed no significant association between SGLT-2i use and PAD and amputation risks in diabetic patients when used for shorter treatment durations.
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Affiliation(s)
- Li Geng
- Department of Vascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Bing Sun
- Department of Neurology, Changchun Central Hospital, Changchun, China
| | - Yan Chen
- Department of Endocrinology, The Second Hospital of Jilin University, Changchun, China
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Güdemann LM, Young KG, Thomas NJM, Hopkins R, Challen R, Jones AG, Hattersley AT, Pearson ER, Shields BM, Bowden J, Dennis JM, McGovern AP. Safety and effectiveness of SGLT2 inhibitors in a UK population with type 2 diabetes and aged over 70 years: an instrumental variable approach. Diabetologia 2024; 67:1817-1827. [PMID: 38836934 PMCID: PMC11410842 DOI: 10.1007/s00125-024-06190-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 03/11/2024] [Indexed: 06/06/2024]
Abstract
AIMS/HYPOTHESIS Older adults are under-represented in trials, meaning the benefits and risks of glucose-lowering agents in this age group are unclear. The aim of this study was to assess the safety and effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in people with type 2 diabetes aged over 70 years using causal analysis. METHODS Hospital-linked UK primary care data (Clinical Practice Research Datalink, 2013-2020) were used to compare adverse events and effectiveness in individuals initiating SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i). Analysis was age-stratified: <70 years (SGLT2i n=66,810, DPP4i n=76,172), ≥70 years (SGLT2i n=10,419, DPP4i n=33,434). Outcomes were assessed using the instrumental variable causal inference method and prescriber preference as the instrument. RESULTS Risk of diabetic ketoacidosis was increased with SGLT2i in those aged ≥70 (incidence rate ratio compared with DPP4i: 3.82 [95% CI 1.12, 13.03]), but not in those aged <70 (1.12 [0.41, 3.04]). However, incidence rates with SGLT2i in those ≥70 was low (29.6 [29.5, 29.7]) per 10,000 person-years. SGLT2i were associated with similarly increased risk of genital infection in both age groups (incidence rate ratio in those <70: 2.27 [2.03, 2.53]; ≥70: 2.16 [1.77, 2.63]). There was no evidence of an increased risk of volume depletion, poor micturition control, urinary frequency, falls or amputation with SGLT2i in either age group. In those ≥70, HbA1c reduction was similar between SGLT2i and DPP4i (-0.3 mmol/mol [-1.6, 1.1], -0.02% [0.1, 0.1]), but in those <70, SGLT2i were more effective (-4 mmol/mol [4.8, -3.1], -0.4% [-0.4, -0.3]). CONCLUSIONS/INTERPRETATION Causal analysis suggests SGLT2i are effective in adults aged ≥70 years, but increase risk for genital infections and diabetic ketoacidosis. Our study extends RCT evidence to older adults with type 2 diabetes.
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Affiliation(s)
- Laura M Güdemann
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK.
| | - Katie G Young
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Nicholas J M Thomas
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Rhian Hopkins
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Robert Challen
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Angus G Jones
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Andrew T Hattersley
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Ewan R Pearson
- Division of Molecular & Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
| | - Beverley M Shields
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Jack Bowden
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK
| | - John M Dennis
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Andrew P McGovern
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK
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9
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Mariani MV, Manzi G, Pierucci N, Laviola D, Piro A, D'Amato A, Filomena D, Matteucci A, Severino P, Miraldi F, Vizza CD, Lavalle C. SGLT2i effect on atrial fibrillation: A network meta-analysis of randomized controlled trials. J Cardiovasc Electrophysiol 2024; 35:1754-1765. [PMID: 38940255 DOI: 10.1111/jce.16344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 06/04/2024] [Accepted: 06/06/2024] [Indexed: 06/29/2024]
Abstract
INTRODUCTION Gliflozins are recommended as first-line treatment in patients with heart failure and/or cardiovascular comorbidities and are demonstrated to reduce atrial fibrillation (AF) occurrence. However, it is not well known which gliflozin yields the larger cardioprotection in terms of AF occurrence reduction. Hence, we aimed to compare data regarding AF recurrence associated with different gliflozins. METHODS An accurate search of online scientific libraries (from inception to June 1, 2023) was performed. Fifty-nine studies were included in the meta-analysis involving 108 026 patients, of whom 60 097 received gliflozins and 47 929 received placebo. RESULTS Gliflozins provided a statistically significant reduction of AF occurrence relative to standard of care therapy in the overall population (relative risks [RR]: 0.8880, 95% CI: [0.8059; 0.9784], p = .0164) and in patients with diabetes and cardiorenal diseases (RR: 0.8352, 95% CI: [0.7219; 0.9663], p = .0155). Dapagliflozin significantly decreased AF occurrence as compared to placebo (0.7259 [0.6337; 0.8316], p < .0001) in the overall population, in patients with diabetes (RR: 0.2482, 95% CI: [0.0682; 0.9033], p = .0345), with diabetes associated with cardiorenal diseases (RR: 0.7192, 95% CI: [0.5679; 0.9110], p = .0063) and in the subanalysis including studies with follow-up ≥1 year (RR: 0.7792, 95% CI: [0.6508; 0.9330], p = .0066). No significant differences in terms of AF protection were found among different gliflozins. CONCLUSIONS Dapagliflozin use was associated with significant reduction in AF risk as compared to placebo in overall population and patients with diabetes, whereas the use of other gliflozins did not significantly reduce AF occurrence.
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Affiliation(s)
- Marco Valerio Mariani
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Giovanna Manzi
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Nicola Pierucci
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Domenico Laviola
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Agostino Piro
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Andrea D'Amato
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Domenico Filomena
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Andrea Matteucci
- Clinical and Rehabilitation Cardiology Division, San Filippo Neri Hospital, Rome, Italy
| | - Paolo Severino
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Fabio Miraldi
- Cardio Thoracic-Vascular and Organ Transplantation Surgery Department, Policlinico Umberto I Hospital, Rome, Italy
| | - Carmine Dario Vizza
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Carlo Lavalle
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
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10
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Mondal S, Pramanik S, Khare VR, Fernandez CJ, Pappachan JM. Sodium glucose cotransporter-2 inhibitors and heart disease: Current perspectives. World J Cardiol 2024; 16:240-259. [PMID: 38817648 PMCID: PMC11135334 DOI: 10.4330/wjc.v16.i5.240] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 04/08/2024] [Accepted: 04/28/2024] [Indexed: 05/23/2024] Open
Abstract
Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are antidiabetic medications with remarkable cardiovascular (CV) benefits proven by multiple randomised controlled trials and real-world data. These drugs are also useful in the prevention of CV disease (CVD) in patients with diabetes mellitus (DM). Although DM as such is a huge risk factor for CVD, the CV benefits of SGLT-2i are not just because of antidiabetic effects. These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well. There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated. Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases. This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.
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Affiliation(s)
- Sunetra Mondal
- Department of Endocrinology, NRS Medical College, Kolkata 700020, West Bengal, India
| | - Subhodip Pramanik
- Department of Endocrinology, Neotia Getwel Multispecialty Hospitals, Siliguri 734010, West Bengal, India
| | - Vibhu Ranjan Khare
- Department of Endocrinology, NRS Medical College, Kolkata 700020, West Bengal, India
| | - Cornelius James Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, United Kingdom.
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11
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Zhang HD, Ding L, Mi LJ, Zhang AK, Zhang K, Jiang ZH, Yu FY, Yan XX, Shen YJ, Tang M. Sodium-glucose co-transporter-2 inhibitors for the prevention of atrial fibrillation: a systemic review and meta-analysis. Eur J Prev Cardiol 2024; 31:770-779. [PMID: 37966828 DOI: 10.1093/eurjpc/zwad356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 10/22/2023] [Accepted: 11/09/2023] [Indexed: 11/16/2023]
Abstract
AIMS Sodium-glucose co-transporter-2 (SGLT2) inhibitors are reported to have cardiac benefits. The effects of SGLT2 inhibitors on the prevention of atrial fibrillation (AF) remain inconclusive. We aimed to investigate whether SGLT2 inhibitors can prevent AF occurrence in patients with cardiometabolic diseases. METHODS AND RESULTS We searched MEDLINE, EMBASE, and the Cochrane CENTRAL database up to 1 July 2023. Randomized, placebo-controlled trials of SGLT2 inhibitors in patients with diabetes, heart failure, chronic kidney diseases (CKDs), or cardiometabolic risk factors were included. The primary outcome was AF occurrence. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated in the overall population and selected subgroups. Forty-six trials comprising 101 100 patients were included. Overall, no significant risk reduction of AF occurrence was observed with SGLT2 inhibitors, although there was a favourable trend (RR 0.90, 95% CI 0.80-1.01). In trials with follow-up durations of over 1 year, a similar result was achieved (RR 0.90, 95% CI 0.80-1.01). The results were consistent across different SGLT2 inhibitors, with RRs (95% CIs) of 0.82 (0.60-1.12) for canagliflozin, 0.87 (0.73-1.03) for dapagliflozin, 0.97 (0.78-1.22) for empagliflozin, 0.99 (0.66-1.50) for sotagliflozin, and 0.87 (0.58-1.29) for ertugliflozin. Analyses in different doses of SGLT2 inhibitors yielded similar results. The associations between SGLT2 inhibitors and AF occurrence were also absent in patients with diabetes, heart failure, and CKDs. CONCLUSION For patients with cardiometabolic diseases or risk factors, SGLT2 inhibitors did not decrease the risk of AF occurrence, regardless of follow-up duration, type or dose of the drug, or the patient population.
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Affiliation(s)
- Hong-Da Zhang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Lei Ding
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Li-Jie Mi
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Ai-Kai Zhang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Kuo Zhang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Zi-Han Jiang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Feng-Yuan Yu
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Xin-Xin Yan
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Yu-Jing Shen
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Min Tang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
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12
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Drake T, Landsteiner A, Langsetmo L, MacDonald R, Anthony M, Kalinowski C, Ullman K, Billington CJ, Kaka A, Sultan S, Wilt TJ. Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Systematic Review and Network Meta-analysis for the American College of Physicians. Ann Intern Med 2024; 177:618-632. [PMID: 38639549 DOI: 10.7326/m23-1490] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/20/2024] Open
Abstract
BACKGROUND Newer diabetes medications may have beneficial effects on mortality, cardiovascular outcomes, and renal outcomes. PURPOSE To evaluate the effectiveness, comparative effectiveness, and harms of sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, and long-acting insulins as monotherapy or combination therapy in adults with type 2 diabetes mellitus (T2DM). DATA SOURCES MEDLINE and EMBASE for randomized controlled trials (RCTs) published from 2010 through January 2023. STUDY SELECTION RCTs lasting at least 52 weeks that included at least 500 adults with T2DM receiving eligible medications and reported any outcomes of interest. DATA EXTRACTION Data were abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE) were done. DATA SYNTHESIS A total of 130 publications from 84 RCTs were identified. CoE was appraised using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria for direct, indirect, and network meta-analysis (NMA); the highest CoE was reported. Compared with usual care, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (high CoE) and major adverse cardiovascular events (MACE) (moderate to high CoE), SGLT2 inhibitors reduce progression of chronic kidney disease (CKD) and heart failure hospitalizations and GLP1 agonists reduce stroke (high CoE), and SGLT2 inhibitors reduce serious adverse events and severe hypoglycemia (high CoE). The threshold for minimally important differences, which was predefined with the American College of Physicians Clinical Guidelines Committee, was not met for these outcomes. Compared with usual care, insulin, tirzepatide, and DPP4 inhibitors do not reduce all-cause mortality (low to high CoE). Compared with insulin, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (low to moderate CoE). Compared with DPP4 inhibitors, GLP1 agonists reduce all-cause mortality (moderate CoE). Compared with DPP4 inhibitors and sulfonylurea (SU), SGLT2 inhibitors reduce MACE (moderate to high CoE). Compared with SU and insulin, SGLT2 inhibitors and GLP1 agonists reduce severe hypoglycemia (low to high CoE). LIMITATIONS Infrequent direct comparisons between drugs of interest; sparse data for NMA on most outcomes; possible incoherence due to differences in baseline patient characteristics and usual care; insufficient data on predefined subgroups, including demographic subgroups, patients with prior cardiovascular disease, and treatment-naive persons. CONCLUSION In adults with T2DM, SGLT2 inhibitors and GLP1 agonists (but not DPP4 inhibitors, insulin, or tirzepatide) reduce all-cause mortality and MACE compared with usual care. SGLT2 inhibitors reduce CKD progression and heart failure hospitalization and GLP1 agonists reduce stroke compared with usual care. Serious adverse events and severe hypoglycemia are less frequent with SGLT2 inhibitors and GLP1 agonists than with insulin or SU. PRIMARY FUNDING SOURCE American College of Physicians. (PROSPERO: CRD42022322129).
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Affiliation(s)
- Tyler Drake
- Department of Medicine, VA Health Care System, and Department of Medicine, University of Minnesota, Minneapolis, Minnesota (T.D., C.J.B., A.K.)
| | - Adrienne Landsteiner
- Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (A.L., R.M., M.A., C.K., K.U.)
| | - Lisa Langsetmo
- Department of Medicine, University of Minnesota; Center for Care Delivery & Outcomes Research, VA Health Care System; and Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota (L.L.)
| | - Roderick MacDonald
- Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (A.L., R.M., M.A., C.K., K.U.)
| | - Maylen Anthony
- Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (A.L., R.M., M.A., C.K., K.U.)
| | - Caleb Kalinowski
- Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (A.L., R.M., M.A., C.K., K.U.)
| | - Kristen Ullman
- Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (A.L., R.M., M.A., C.K., K.U.)
| | - Charles J Billington
- Department of Medicine, VA Health Care System, and Department of Medicine, University of Minnesota, Minneapolis, Minnesota (T.D., C.J.B., A.K.)
| | - Anjum Kaka
- Department of Medicine, VA Health Care System, and Department of Medicine, University of Minnesota, Minneapolis, Minnesota (T.D., C.J.B., A.K.)
| | - Shahnaz Sultan
- Department of Medicine, University of Minnesota, and Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (S.S.)
| | - Timothy J Wilt
- Department of Medicine, VA Health Care System; Department of Medicine, University of Minnesota; Center for Care Delivery & Outcomes Research, VA Health Care System; and Division of Health Policy & Management, School of Public Health, University of Minnesota, Minneapolis, Minnesota (T.J.W.)
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13
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Preda A, Montecucco F, Carbone F, Camici GG, Lüscher TF, Kraler S, Liberale L. SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits. Cardiovasc Res 2024; 120:443-460. [PMID: 38456601 PMCID: PMC12001887 DOI: 10.1093/cvr/cvae047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 01/03/2024] [Accepted: 02/05/2024] [Indexed: 03/09/2024] Open
Abstract
An increasing number of individuals are at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and eventually premature death. The sodium-glucose co-transporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated overview of the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With landmark randomized controlled trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (i.e. at systemic, vascular, cardiac, and renal levels), we provide insights into the key mechanisms that may underlie their beneficial effects, including gliflozins' role in the modulation of inflammation, oxidative stress, cellular energy metabolism, and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, collectively contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrhythmias are presented and potential implications for future research and clinical practice are comprehensively reviewed.
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Affiliation(s)
- Alberto Preda
- Department of Clinical Cardiology, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, Genoa, Italy
| | - Federico Carbone
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, Genoa, Italy
| | - Giovanni G Camici
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Department of Research and Education, University Hospital Zurich, Zurich, Switzerland
| | - Thomas F Lüscher
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Royal Brompton and Harefield Hospitals and Imperial College and King’s College, London, United Kingdom
| | - Simon Kraler
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Department of Internal Medicine, Cantonal Hospital Baden, Baden, Switzerland
| | - Luca Liberale
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, Genoa, Italy
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14
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Cai Y, Zou H, Hu R, Chen H, Yang G, Gong L. A comprehensive meta-analysis on safety outcomes reveals the novel potentials of SGLT2is, especially preventing respiratory diseases. Front Endocrinol (Lausanne) 2024; 15:1376446. [PMID: 38742192 PMCID: PMC11089104 DOI: 10.3389/fendo.2024.1376446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 04/15/2024] [Indexed: 05/16/2024] Open
Affiliation(s)
- YuJun Cai
- Department of Respiratory and Critical Care Medicine, Dianjiang People’s Hospital of Chongqing, Chongqing, China
| | - HaiTao Zou
- Department of Respiratory and Critical Care Medicine, Dianjiang People’s Hospital of Chongqing, Chongqing, China
| | - Rong Hu
- Department of Respiratory and Critical Care Medicine, Dianjiang People’s Hospital of Chongqing, Chongqing, China
| | - Hao Chen
- Department of Respiratory and Critical Care Medicine, Dianjiang People’s Hospital of Chongqing, Chongqing, China
| | - GuoHuan Yang
- Department of Respiratory and Critical Care Medicine, Dianjiang People’s Hospital of Chongqing, Chongqing, China
| | - LiDan Gong
- Department of Pharmacy, Dianjiang People’s Hospital of Chongqing, Chongqing, China
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15
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Wang Y, Zhou X. The relationship between use of SGLT2is and incidence of respiratory and infectious diseases and site-specific fractures: a meta-analysis based on 32 large RCTs. Eur J Clin Pharmacol 2024; 80:563-573. [PMID: 38267688 DOI: 10.1007/s00228-024-03631-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 01/17/2024] [Indexed: 01/26/2024]
Abstract
OBJECTIVES We aimed to evaluate the relationship between use of sodium-glucose cotransporter-2 inhibitors (SGLT2is) and incidence of various respiratory and infectious diseases and site-specific fractures. METHODS Large randomized controlled trials (RCTs) of SGLT2is enrolling more than 400 subjects were included. Outcomes of interest were various serious adverse events regarding to respiratory and infectious disorders and site-specific fractures. Meta-analysis was done using risk ratio (RR) and 95% confidence interval (CI) as effect size. RESULTS Thirty-two large RCTs were included in this meta-analysis. Use of SGLT2is was significantly associated with the lower incidences of 6 kinds of noninfectious respiratory diseases {e.g., Asthma (RR 0.64, 95% CI 0.43-0.96; P = 0.0299), Chronic obstructive pulmonary disease [COPD] (RR 0.75, 95% CI 0.62-0.91; P = 0.0027), and Respiratory failure (RR 0.78, 95% CI 0.61-0.99; P = 0.0447)} and 4 kinds of infectious respiratory diseases {e.g., Bronchitis (RR 0.61, 95% CI 0.46-0.81; P = 0.0007), and Pneumonia (RR 0.85, 95% CI 0.78-0.93; P = 0.0002)}. Use of SGLT2is was not significantly associated with the incidences of 31 kinds of site-specific fractures (e.g., Hip fracture, Femoral neck fracture, and Spinal fracture; P > 0.05). CONCLUSIONS Our meta-analysis confirmed the benefits of SGLT2is against 6 kinds of noninfectious respiratory diseases (e.g., Asthma, COPD, and Respiratory failure) and 4 kinds of infectious respiratory diseases (e.g., Bronchitis, and Pneumonia). These findings suggest a likelihood that SGLT2is might be used to prevent or treat these respiratory diseases. Moreover, our meta-analysis for the first time revealed no association between use of SGLT2is and incidence of various site-specific fractures.
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Affiliation(s)
- Yueping Wang
- Department of Infectious Disease, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570102, China.
| | - Xian Zhou
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan Province, China
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Hong Y, Jeon Y, Choi Y, Chung TK, Lee H. Effectiveness and Safety of Sodium-Glucose Cotransporter 2 Inhibitors Added to Dual or Triple Treatment in Patients with Type 2 Diabetes Mellitus. Diabetes Ther 2024; 15:487-496. [PMID: 38114614 PMCID: PMC10838879 DOI: 10.1007/s13300-023-01518-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 12/05/2023] [Indexed: 12/21/2023] Open
Abstract
INTRODUCTION We evaluated the effectiveness and safety of sodium-glucose cotransporter 2 inhibitor (SGLT2i) add-on treatment in patients with type 2 diabetes mellitus (T2DM) in the real-world setting. METHODS This single-center retrospective study used the clinical database of Seoul National University Hospital in South Korea. Patients who received metformin monotherapy or combination therapy with ≥ 1 other oral hypoglycemic medication and had a baseline glycosylated hemoglobin (HbA1c) between 7.0% and 10.5% were included. Propensity score matching was applied between patients treated with and without SGLT2 inhibitors (SGLT2i and non-SGLT2i groups, respectively). Changes in HbA1c from baseline to week 26 were compared between the SGLT2i and non-SGLT2i groups, and risk of adverse events (AE) were also assessed. RESULTS A total of 1106 patients were included. At week 26, HbA1c was significantly more reduced by 0.35 percentage points in the SGLT2i group than in the non-SGLT2i group (95% CI 0.30-0.41, P < 0.001). Likewise, the proportion of patients achieving HbA1c < 7% was also significantly higher (51.9% vs. 37.6%, P < 0.05) in the SGLT2i group than in the non-SGLT2i group. The risk of adverse events in the SGLT2i group was mostly comparable with those in the non-SGLT2i group except for diseases of the liver, pain, hypertensive diseases, and metabolic disorders, which showed significantly higher odds in the SGLT2i group. CONCLUSIONS SGLT2i add-on treatment is an effective and safe therapeutic option for patients with T2DM in the real-world practice setting.
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Affiliation(s)
- Yesol Hong
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea
| | - Yoomin Jeon
- Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea
- Center for Convergence Approaches in Drug Development, Seoul, South Korea
| | - Yoona Choi
- Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea
- Center for Convergence Approaches in Drug Development, Seoul, South Korea
| | - Tae Kyu Chung
- Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea
- Center for Convergence Approaches in Drug Development, Seoul, South Korea
| | - Howard Lee
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea.
- Center for Convergence Approaches in Drug Development, Seoul, South Korea.
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17
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Luo Y, Bai R, Zhang W, Qin G. Selective sodium-glucose cotransporter-2 inhibitors in the improvement of hemoglobin and hematocrit in patients with type 2 diabetes mellitus: a network meta-analysis. Front Endocrinol (Lausanne) 2024; 15:1333624. [PMID: 38362282 PMCID: PMC10867125 DOI: 10.3389/fendo.2024.1333624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 01/16/2024] [Indexed: 02/17/2024] Open
Abstract
Objective To compare the effects of different selective sodium-glucose cotransporter-2 inhibitors (SGLT2i) on hemoglobin and hematocrit in patients with type 2 diabetes mellitus (T2DM) with a network meta-analysis (NMA). Methods Randomized controlled trials (RCTs) on SGLT2i for patients with T2DM were searched in PubMed, Embase, Cochrane Library, and Web of Science from inception of these databases to July 1, 2023. The risk of bias (RoB) tool was used to evaluate the quality of the included studies, and R software was adopted for data analysis. Results Twenty-two articles were included, involving a total of 14,001 T2DM patients. SGLT2i included empagliflozin, dapagliflozin, and canagliflozin. The NMA results showed that compared with placebo, canagliflozin 100mg, canagliflozin 300mg, dapagliflozin 10mg, dapagliflozin 2mg, dapagliflozin 50mg, dapagliflozin 5mg, empagliflozin 25mg, and dapagliflozin 20mg increased hematocrit in patients with T2DM, while canagliflozin 100mg, canagliflozin 200mg, canagliflozin 300mg increased hemoglobin in patients with T2DM. In addition, the NMA results indicated that canagliflozin 100mg had the best effect on the improvement of hematocrit, and canagliflozin 200mg had the best effect on the improvement of hemoglobin. Conclusion Based on the existing studies, we concluded that SGLT2i could increase hematocrit and hemoglobin levels in patients with T2DM, and canagliflozin 100mg had the best effect on the improvement of hematocrit, while canagliflozin 200mg had the best effect on the improvement of hemoglobin. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/#loginpage, identifier PROSPERO (CRD42023477103).
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Affiliation(s)
- Yuanyuan Luo
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Ruojing Bai
- Department of Geriatric Medicine, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Wei Zhang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Guijun Qin
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
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18
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Xie X, Wu C, Hao Y, Wang T, Yang Y, Cai P, Zhang Y, Huang J, Deng K, Yan D, Lin H. Benefits and risks of drug combination therapy for diabetes mellitus and its complications: a comprehensive review. Front Endocrinol (Lausanne) 2023; 14:1301093. [PMID: 38179301 PMCID: PMC10766371 DOI: 10.3389/fendo.2023.1301093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/27/2023] [Indexed: 01/06/2024] Open
Abstract
Diabetes is a chronic metabolic disease, and its therapeutic goals focus on the effective management of blood glucose and various complications. Drug combination therapy has emerged as a comprehensive treatment approach for diabetes. An increasing number of studies have shown that, compared with monotherapy, combination therapy can bring significant clinical benefits while controlling blood glucose, weight, and blood pressure, as well as mitigating damage from certain complications and delaying their progression in diabetes, including both type 1 diabetes (T1D), type 2 diabetes (T2D) and related complications. This evidence provides strong support for the recommendation of combination therapy for diabetes and highlights the importance of combined treatment. In this review, we first provided a brief overview of the phenotype and pathogenesis of diabetes and discussed several conventional anti-diabetic medications currently used for the treatment of diabetes. We then reviewed several clinical trials and pre-clinical animal experiments on T1D, T2D, and their common complications to evaluate the efficacy and safety of different classes of drug combinations. In general, combination therapy plays a pivotal role in the management of diabetes. Integrating the effectiveness of multiple drugs enables more comprehensive and effective control of blood glucose without increasing the risk of hypoglycemia or other serious adverse events. However, specific treatment regimens should be tailored to individual patients and implemented under the guidance of healthcare professionals.
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Affiliation(s)
- Xueqin Xie
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Changchun Wu
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuduo Hao
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Tianyu Wang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuhe Yang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Peiling Cai
- School of Basic Medical Sciences, Chengdu University, Chengdu, China
| | - Yang Zhang
- Innovative Institute of Chinese Medicine and Pharmacy, Academy for Interdiscipline, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jian Huang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Kejun Deng
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Dan Yan
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hao Lin
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
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19
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Tomlinson B, Li YH. Canagliflozin + metformin ER for the treatment of type 2 diabetes: the evidence to date. Expert Opin Pharmacother 2023; 24:1937-1947. [PMID: 37881952 DOI: 10.1080/14656566.2023.2276180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 10/24/2023] [Indexed: 10/27/2023]
Abstract
INTRODUCTION Patients with type 2 diabetes (T2D) usually show progressive deterioration in glycemic control and sequential additions of therapy are generally needed. Many new options for glucose lowering therapy have been introduced recently and it is becoming common practice to use fixed-dose combinations (FDCs) of glucose lowering agents from different classes. This article reviews the FDC of canagliflozin with metformin extended release. AREAS COVERED A literature search was performed to identify publications describing the efficacy and safety of canagliflozin and metformin when used separately and in combinations. EXPERT OPINION Canagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor which has shown benefits in reducing progression of renal disease and heart failure in patients with T2D. There was an increased incidence of amputation with canagliflozin in one study, but canagliflozin results in weight loss and reduction of blood pressure which contribute to the overall benefit. Metformin has been the first line oral hypoglycemic agent for many years and is thought to have many advantages, but it should be avoided in patients with severely decreased renal function because of the risk of lactic acidosis. The combination in a single tablet given once daily should help to simplify therapy and improve medication adherence in T2D.
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Affiliation(s)
- Brian Tomlinson
- Faculty of Medicine, Macau University of Science and Technology, Macau, China
| | - Yan-Hong Li
- The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
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20
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Venkatasubramaniam A, Mateen BA, Shields BM, Hattersley AT, Jones AG, Vollmer SJ, Dennis JM. Comparison of causal forest and regression-based approaches to evaluate treatment effect heterogeneity: an application for type 2 diabetes precision medicine. BMC Med Inform Decis Mak 2023; 23:110. [PMID: 37328784 PMCID: PMC10276367 DOI: 10.1186/s12911-023-02207-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 06/01/2023] [Indexed: 06/18/2023] Open
Abstract
OBJECTIVE Precision medicine requires reliable identification of variation in patient-level outcomes with different available treatments, often termed treatment effect heterogeneity. We aimed to evaluate the comparative utility of individualized treatment selection strategies based on predicted individual-level treatment effects from a causal forest machine learning algorithm and a penalized regression model. METHODS Cohort study characterizing individual-level glucose-lowering response (6 month reduction in HbA1c) in people with type 2 diabetes initiating SGLT2-inhibitor or DPP4-inhibitor therapy. Model development set comprised 1,428 participants in the CANTATA-D and CANTATA-D2 randomised clinical trials of SGLT2-inhibitors versus DPP4-inhibitors. For external validation, calibration of observed versus predicted differences in HbA1c in patient strata defined by size of predicted HbA1c benefit was evaluated in 18,741 patients in UK primary care (Clinical Practice Research Datalink). RESULTS Heterogeneity in treatment effects was detected in clinical trial participants with both approaches (proportion predicted to have a benefit on SGLT2-inhibitor therapy over DPP4-inhibitor therapy: causal forest: 98.6%; penalized regression: 81.7%). In validation, calibration was good with penalized regression but sub-optimal with causal forest. A strata with an HbA1c benefit > 10 mmol/mol with SGLT2-inhibitors (3.7% of patients, observed benefit 11.0 mmol/mol [95%CI 8.0-14.0]) was identified using penalized regression but not causal forest, and a much larger strata with an HbA1c benefit 5-10 mmol with SGLT2-inhibitors was identified with penalized regression (regression: 20.9% of patients, observed benefit 7.8 mmol/mol (95%CI 6.7-8.9); causal forest 11.6%, observed benefit 8.7 mmol/mol (95%CI 7.4-10.1). CONCLUSIONS Consistent with recent results for outcome prediction with clinical data, when evaluating treatment effect heterogeneity researchers should not rely on causal forest or other similar machine learning algorithms alone, and must compare outputs with standard regression, which in this evaluation was superior.
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Affiliation(s)
| | - Bilal A Mateen
- The Alan Turing Institute, British Library, 96 Euston Road, London, NW1 2DB, UK
- University College London, Institute of Health Informatics, 222 Euston Rd, London, NW1 2DA, UK
| | - Beverley M Shields
- University of Exeter Medical School, Institute of Biomedical & Clinical Science, RILD Building, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK
| | - Andrew T Hattersley
- University of Exeter Medical School, Institute of Biomedical & Clinical Science, RILD Building, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK
| | - Angus G Jones
- University of Exeter Medical School, Institute of Biomedical & Clinical Science, RILD Building, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK
| | | | - John M Dennis
- University of Exeter Medical School, Institute of Biomedical & Clinical Science, RILD Building, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
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21
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Yang S, Liu Y, Zhang S, Wu F, Liu D, Wu Q, Zheng H, Fan P, Su N. Risk of diabetic ketoacidosis of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and network meta-analysis of randomized controlled trials. Front Pharmacol 2023; 14:1145587. [PMID: 37397500 PMCID: PMC10311413 DOI: 10.3389/fphar.2023.1145587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 05/23/2023] [Indexed: 07/04/2023] Open
Abstract
Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have proven to be effective in improving glycemic control in patients with type 2 diabetes mellitus (T2DM). However, the risk of diabetic ketoacidosis (DKA) in patients remains unclear. The purpose of this study is to conduct this systematic review and network meta-analysis for the risk of DKA of SGLT2 inhibitors in patients with T2DM. Methods: We searched for randomized controlled trials (RCTs) concerning SGLT2 inhibitors in patients with T2DM in PubMed, EMBASE (Ovid SP), Cochrane Central Register of Controlled Trials (Ovid SP), and ClinicalTrials.gov from inception to January 2022. The primary outcomes were the risk of DKA. We assessed the sparse network with a fixed-effect model and consistency model in a frequentist framework with a graph-theoretical method by the netmeta package in R. We assessed the evidence quality of evidence of outcomes according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results: In total, 36 studies involving 52,264 patients were included. The network showed that there was no significant difference observed among SGLT2 inhibitors, other active antidiabetic drugs, and placebo in the risk of DKA. There was no significant difference in the DKA risk between different doses of SGLT2 inhibitors. The certainty of the evidence ranged from very low to moderate. The probabilities of rankings and P-score showed that compared to placebo, SGLT2 inhibitors might increase the risk of DKA (P-score = 0.5298). Canagliflozin might have a higher DKA risk than other SGLT2 inhibitors (P-score = 0.7388). Conclusion: Neither SGLT2 inhibitors nor other active antidiabetic drugs were associated with an increased risk of DKA compared to placebo, and the risk of DKA with SGLT2 inhibitors was not found to be dose-dependent. In addition, the use of canagliflozin was less advisable than other SGLT2 inhibitors according to the rankings and P-score. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier PROSPERO, CRD42021297081.
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Affiliation(s)
- Shiwen Yang
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Ying Liu
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Shengzhao Zhang
- Department of Pharmacy, Karamay Central Hospital, Karamay, China
| | - Fengbo Wu
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Dan Liu
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China
| | - Qingfang Wu
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Hanrui Zheng
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Ping Fan
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
| | - Na Su
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China
- West China School of Pharmacy, Sichuan University, Chengdu, China
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22
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Samkari MM, Bokhari NS, Alhajaji R, Ahmed ME, Al Raddadi A, Bahget AK, Saleh SF, Aljehani F, Alzahrani SH, Alsifyani SS, Samkari MM, Badr AF, Alalawi M, Al Sulaiman K. Safety and tolerability of Empagliflozin use during the holy month of Ramadan by fasting patients with type 2 diabetes: A prospective cohort study. Saudi Pharm J 2023; 31:972-978. [PMID: 37234349 PMCID: PMC10205764 DOI: 10.1016/j.jsps.2023.04.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 04/22/2023] [Indexed: 05/27/2023] Open
Abstract
Background Type 2 Diabetes Mellitus (T2DM) patients are exposed to a 7.5 times higher risk of hypoglycemia while fasting during Ramadan. Relevant diabetes guidelines prioritize the use of SGLT2 inhibitors over other classes. There is a great need to enrich data on their safe and effective use by fasting patients at greater risk of hypoglycemia. Therefore, this study aims to assess the safety and tolerability of Empagliflozin in T2DM Muslim patients during Ramadan. Methodology A prospective cohort study was conducted for adult Muslim T2DM patients. Patients who met the inclusion criteria were categorized into two sub-cohorts based on Empagliflozin use during Ramadan (Control versus Empagliflozin). The primary outcomes were the incidence of hypoglycemia symptoms and confirmed hypoglycemia. Other outcomes were secondary. All patients were followed up to eight weeks post-Ramadan. A propensity score (PS) matching and Risk Ratio (RR) were used to report the outcomes. Results Among 1104 patients with T2DM who were screened, 220 patients were included, and Empagliflozin was given to 89 patients as an add-on to OHDs. After matching with PS (1:1 ratio), the two groups were comparable. The use of other OHDs, such as sulfonylurea, DPP4 inhibitors, and Biguanides, was not statistically different between the two groups. The risk of hypoglycemia symptoms during Ramadan was lower in patients who received Empagliflozin than in the control group (RR 0.48 CI 0.26, 0.89; p-value = 0.02). Additionally, the risk of confirmed hypoglycemia was not statistically significant between the two groups (RR 1.09 CI 0.37, 3.22; p-value = 0.89). Conclusion Empagliflozin use during Ramadan fasting was associated with a lower risk of hypoglycemia symptoms and higher tolerability. Further randomized control trials are required to confirm these findings.
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Affiliation(s)
- Mayada M. Samkari
- Diabetic and Endocrine Center, Al-Noor Specialist Hospital, Makkah Healthcare Cluster, Makkah, Saudi Arabia
| | - Neda'a S. Bokhari
- Diabetic and Endocrine Center, Al-Noor Specialist Hospital, Makkah Healthcare Cluster, Makkah, Saudi Arabia
| | - Raghad Alhajaji
- Health Programs Administration, Makkah Health Affairs, Ministry of Health, Makkah, Saudi Arabia
- Al-Magrah Primary Health Care, Primary Care Administration, Makkah Healthcare Cluster, Makkah, Saudi Arabia
| | - Malaz E. Ahmed
- Health Programs Administration, Makkah Health Affairs, Ministry of Health, Makkah, Saudi Arabia
| | - Ahmad Al Raddadi
- Diabetic and Endocrine Center, Al-Noor Specialist Hospital, Makkah Healthcare Cluster, Makkah, Saudi Arabia
| | - Alaa K. Bahget
- Diabetic and Endocrine Center, Al-Noor Specialist Hospital, Makkah Healthcare Cluster, Makkah, Saudi Arabia
| | - Sarah F. Saleh
- Diabetic and Endocrine Center, Al-Noor Specialist Hospital, Makkah Healthcare Cluster, Makkah, Saudi Arabia
| | - Faisal Aljehani
- College of Medicine, Department of Internal Medicine, University of Jeddah, Jeddah, Saudi Arabia
| | - Saud H. Alzahrani
- Public Health Administration, Makkah Health Affairs, Ministry of Health, Makkah, Saudi Arabia
| | | | - May M. Samkari
- Health Programs Administration, Jeddah Health Affairs, Ministry of Health, Jeddah, Saudi Arabia
| | - Aisha F. Badr
- Pharmacy Practice Department, King Abdulaziz University Faculty of Pharmacy, Jeddah, Saudi Arabia
| | - Mai Alalawi
- Department of Pharmaceutical Sciences, Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia
- Pharmaceutical Care Department, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - Khalid Al Sulaiman
- Pharmaceutical Care Department, King Abdulaziz Medical City (KAMC)-Ministry of National Guard Health Affairs (MNGHA), Riyadh, Saudi Arabia
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, PO Box 22490, Riyadh k426, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- Saudi Critical Care Pharmacy Research (SCAPE) Platform, Riyadh, Saudi Arabia
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23
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Corremans R, Vervaet BA, Dams G, D'Haese PC, Verhulst A. Metformin and Canagliflozin Are Equally Renoprotective in Diabetic Kidney Disease but Have No Synergistic Effect. Int J Mol Sci 2023; 24:ijms24109043. [PMID: 37240387 DOI: 10.3390/ijms24109043] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 05/12/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
Diabetic Kidney Disease (DKD) is a major microvascular complication for diabetic patients and is the most common cause of chronic kidney disease (CKD) and end-stage renal disease. Antidiabetic drugs, such as metformin and canagliflozin, have been shown to exert renoprotective effects. Additionally, quercetin recently showed promising results for the treatment of DKD. However, the molecular pathways through which these drugs exert their renoprotective effects remain partly unknown. The current study compares the renoprotective potential of metformin, canagliflozin, metformin + canagliflozin, and quercetin in a preclinical rat model of DKD. By combining streptozotocin (STZ) and nicotinamide (NAD) with daily oral N(ω)-Nitro-L-Arginine Methyl Ester (L-NAME) administration, DKD was induced in male Wistar Rats. After two weeks, rats were assigned to five treatment groups, receiving vehicle, metformin, canagliflozin, metformin + canagliflozin, or quercetin for a period of 12 weeks by daily oral gavage. Non-diabetic vehicle-treated control rats were also included in this study. All rats in which diabetes was induced developed hyperglycemia, hyperfiltration, proteinuria, hypertension, renal tubular injury and interstitial fibrosis, confirming DKD. Metformin and canagliflozin, alone or together, exerted similar renoprotective actions and similar reductions in tubular injury and collagen accumulation. Renoprotective actions of canagliflozin correlated with reduced hyperglycemia, while metformin was able to exert these effects even in the absence of proper glycemic control. Gene expression revealed that the renoprotective pathways may be traced back to the NF-κB pathway. No protective effect was seen with quercetin. In this experimental model of DKD, metformin and canagliflozin were able to protect the kidney against DKD progression, albeit in a non-synergistic way. These renoprotective effects may be attributable to the inhibition of the NF-κB pathway.
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Affiliation(s)
- Raphaëlle Corremans
- Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium
| | - Benjamin A Vervaet
- Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium
| | - Geert Dams
- Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium
| | - Patrick C D'Haese
- Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium
| | - Anja Verhulst
- Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium
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24
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Liu M, Liu J, Wang Q, Song P, Li H, Wu S, Gong J. Quantitative analysis of low content polymorphic impurities in canagliflozin tablets by PXRD, NIR, ATR-FITR and Raman solid-state analysis techniques combined with stoichiometry. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2023; 293:122458. [PMID: 36801728 DOI: 10.1016/j.saa.2023.122458] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/31/2023] [Accepted: 02/04/2023] [Indexed: 06/18/2023]
Abstract
Canagliflozin (CFZ) was a commercially new class of anti-diabetic drug, which had various anhydrate crystal forms and two hydrate crystal forms (Canagliflozin hemihydrate (Hemi-CFZ) and Canagliflozin monohydrate (Mono-CFZ) crystal form). Commercially available CFZ tablets' active pharmaceutical ingredient (API) was Hemi-CFZ, which was easy conversion to CFZ or Mono-CFZ under the influence of temperature, pressure, humidity and other factors in tablets processing, storage, and transportation, thus affected bioavailability and efficacy of tablets. Therefore, quantitative analysis low content of CFZ and Mono-CFZ in tablets was essential to control tablets' quality. The main objective of this study was to examine the feasibility of Powder X-ray Diffraction (PXRD), Near Infrared Spectroscopy (NIR), Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) and Raman for quantitative analysis the low content of CFZ or Mono-CFZ in ternary mixtures. PLSR calibration models for low content of CFZ and Mono-CFZ were established by the solid analysis techniques of PXRD, NIR, ATR-FTIR and Raman combined with various pretreatments (such as Multiplicative Scatter Correction (MSC), Standard Normal Variate (SNV), Savitzky-Golay First Derivative (SG1st), Savitzky-Golay Second Derivative (SG2nd) and Wavelet Transform (WT)), and the correction models were verified. However, compared with PXRD, ATR-FTIR and Raman, NIR due to its water sensitivity was the most suitable for the quantitative analysis low content of CFZ or Mono-CFZ in tablets. Partial Least Squares Regression (PLSR) model for quantitative analysis low content of CFZ in tablets was as follow: Y = 0.0480 + 0.9928 X, R2 = 0.9986, LOD = 0.1596 %, LOQ = 0.4838 %, SG1st + WT pretreated. And that of Mono-CFZ were Y = 0.0050 + 0.9996 X, R2 = 0.9996, LOD = 0.0164 %, LOQ = 0.0498 %, MSC + WT pretreated and Y = 0.0051 + 0.9996 X, R2 = 0.9996, LOD = 0.0167 %, LOQ = 0.0505 %, SNV + WT pretreated, respectively. That can be used for quantitative analysis of impurity crystal content in drug production to ensure drug quality.
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Affiliation(s)
- Mingdi Liu
- State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, PR China; College of Chemistry and Chemical Engineering, Qinghai Minzu University, Xining 810007, PR China; Key Laboratory of Resource Chemistry and Eco-environmental Protection in Tibetan Plateau, State Ethnic Affairs Commission, Xining 810007, PR China
| | - Jichao Liu
- College of Chemistry and Chemical Engineering, Qinghai Minzu University, Xining 810007, PR China; Key Laboratory of Resource Chemistry and Eco-environmental Protection in Tibetan Plateau, State Ethnic Affairs Commission, Xining 810007, PR China
| | - Qiuhong Wang
- College of Chemistry and Chemical Engineering, Qinghai Minzu University, Xining 810007, PR China; Key Laboratory of Resource Chemistry and Eco-environmental Protection in Tibetan Plateau, State Ethnic Affairs Commission, Xining 810007, PR China
| | - Ping Song
- College of Chemistry and Chemical Engineering, Qinghai Minzu University, Xining 810007, PR China; Key Laboratory of Resource Chemistry and Eco-environmental Protection in Tibetan Plateau, State Ethnic Affairs Commission, Xining 810007, PR China
| | - Haichao Li
- College of Chemistry and Chemical Engineering, Qinghai Minzu University, Xining 810007, PR China; Key Laboratory of Resource Chemistry and Eco-environmental Protection in Tibetan Plateau, State Ethnic Affairs Commission, Xining 810007, PR China
| | - Songgu Wu
- State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, PR China; College of Chemistry and Chemical Engineering, Qinghai Minzu University, Xining 810007, PR China.
| | - Junbo Gong
- State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, PR China; College of Chemistry and Chemical Engineering, Qinghai Minzu University, Xining 810007, PR China
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Artasensi A, Mazzolari A, Pedretti A, Vistoli G, Fumagalli L. Obesity and Type 2 Diabetes: Adiposopathy as a Triggering Factor and Therapeutic Options. Molecules 2023; 28:molecules28073094. [PMID: 37049856 PMCID: PMC10095867 DOI: 10.3390/molecules28073094] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 03/22/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
Obesity and type 2 diabetes (T2DM) are major public health concerns associated with serious morbidity and increased mortality. Both obesity and T2DM are strongly associated with adiposopathy, a term that describes the pathophysiological changes of the adipose tissue. In this review, we have highlighted adipose tissue dysfunction as a major factor in the etiology of these conditions since it promotes chronic inflammation, dysregulated glucose homeostasis, and impaired adipogenesis, leading to the accumulation of ectopic fat and insulin resistance. This dysfunctional state can be effectively ameliorated by the loss of at least 15% of body weight, that is correlated with better glycemic control, decreased likelihood of cardiometabolic disease, and an improvement in overall quality of life. Weight loss can be achieved through lifestyle modifications (healthy diet, regular physical activity) and pharmacotherapy. In this review, we summarized different effective management strategies to address weight loss, such as bariatric surgery and several classes of drugs, namely metformin, GLP-1 receptor agonists, amylin analogs, and SGLT2 inhibitors. These drugs act by targeting various mechanisms involved in the pathophysiology of obesity and T2DM, and they have been shown to induce significant weight loss and improve glycemic control in obese individuals with T2DM.
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Tsai PC, Chuang WJ, Ko AMS, Chen JS, Chiu CH, Chen CH, Yeh YH. Neutral effects of SGLT2 inhibitors in acute coronary syndromes, peripheral arterial occlusive disease, or ischemic stroke: a meta-analysis of randomized controlled trials. Cardiovasc Diabetol 2023; 22:57. [PMID: 36915157 PMCID: PMC10012509 DOI: 10.1186/s12933-023-01789-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 03/03/2023] [Indexed: 03/15/2023] Open
Abstract
BACKGROUND Patients with type 2 diabetes are at increased risk for cardiovascular diseases. Sodium-glucose transport 2 inhibitors (SGLT2i) have been shown to enhance cardiovascular health since their debut as a second-line therapy for diabetes. Acute coronary syndrome (ACS), peripheral arterial occlusive disease (PAOD), and ischemic stroke (IS) are types of atherosclerotic cardiovascular disease (ASCVD), although the benefits of treating these disorders have not been shown consistently. METHODS We searched four databases (PubMed, Embase, the Cochrane library, and clinicaltrial.gov) for randomized clinical trials (RCTs) until November of 2022. Comparisons were made between SGLT2i-treated and control individuals with type 2 diabetes. Primary outcomes were ACS, PAOD, and IS; secondary outcomes included cardiovascular mortality and all-cause mortality. Risk ratio (RR) and 95% confidence intervals (CI) were determined using a fixed effects model. Cochrane's risk-of-bias (RoB2) instrument was used to assess the validity of each study that met the inclusion criteria. RESULTS We enrolled 79,504 patients with type 2 diabetes from 43 RCTs. There was no difference in the risk of ACS (RR = 0.97, 95% CI 0.89-1.05), PAOD (RR = 0.98, 95% CI 0.78-1.24), or IS (RR = 0.95, 95% CI 0.79-1.14) among patients who took an SGLT2i compared to those who took a placebo or oral hypoglycemic drugs. Subgroup analysis revealed that none of the SGLT2i treatments (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) significantly altered outcomes when analyzed separately. Consistent with prior findings, SGLT2i reduced the risk of cardiovascular mortality (RR = 0.85, 95% CI 0.77-0.93) and all-cause mortality (RR = 0.88, 95% CI 0.82-0.94). CONCLUSION Our results appear to contradict the mainstream concepts regarding the cardiovascular effects of SGLT2i since we found no significant therapeutic benefits in SGLT2i to reduce the incidence of ACS, PAOD, or IS when compared to placebo or oral hypoglycemic drugs.
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Affiliation(s)
- Pei-Chien Tsai
- Department and Graduate Institute of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
- Master's Program in Clinical Trials and Assessment, Department of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
- Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, No. 5, Fuxing st., Guishan Dist., Taoyuan City, 333, Taiwan
- Healthy Aging Research Center, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
| | - Wei-Jung Chuang
- Master's Program in Clinical Trials and Assessment, Department of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
| | - Albert Min-Shan Ko
- Department and Graduate Institute of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
- Master's Program in Clinical Trials and Assessment, Department of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
- Healthy Aging Research Center, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
- Cardiovascular Department, Chang Gung Memorial Hospital, No. 5, Fuxing st., Guishan Dist., Taoyuan City, 333, Taiwan
| | - Jui-Shuan Chen
- Master's Program in Clinical Trials and Assessment, Department of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
| | - Cheng-Hsun Chiu
- Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, No. 5, Fuxing st., Guishan Dist., Taoyuan City, 333, Taiwan
- Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, No. 5, Fuxing st., Guishan Dist., Taoyuan City, 333, Taiwan
| | - Chun-Han Chen
- Master's Program in Clinical Trials and Assessment, Department of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
| | - Yung-Hsin Yeh
- Cardiovascular Department, Chang Gung Memorial Hospital, No. 5, Fuxing st., Guishan Dist., Taoyuan City, 333, Taiwan.
- School of Medicine, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan.
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Gao L, Cheng Z, Su B, Su X, Song W, Guo Y, Liao L, Chen X, Li J, Tan X, Xu F, Pang S, Wang K, Ye J, Wang Y, Chen L, Sun J, Ji L. Efficacy and safety of janagliflozin as add-on therapy to metformin in Chinese patients with type 2 diabetes inadequately controlled with metformin alone: A multicentre, randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Obes Metab 2023; 25:785-795. [PMID: 36433709 DOI: 10.1111/dom.14926] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 11/18/2022] [Accepted: 11/20/2022] [Indexed: 11/27/2022]
Abstract
AIM To evaluate the efficacy and safety of janagliflozin in Chinese patients with type 2 diabetes (T2D) inadequately controlled with metformin monotherapy. MATERIALS AND METHODS This multicentre phase 3 trial included a 24-week, randomized, double-blind, placebo-controlled period, followed by a 28-week extension period. Patients (N = 421) with HbA1c of 7.0% or higher and 10.5% or less were randomized (1:1:1) to receive once-daily placebo, janagliflozin 25 or 50 mg. After the 24-week treatment period, patients on placebo were re-randomized (1:1) to janagliflozin 25 or 50 mg for the additional 28-week treatment, whereas patients on janagliflozin maintained the same therapy. The primary endpoint was the change from baseline in HbA1c to week 24. RESULTS At week 24, the placebo-adjusted least squares mean changes of HbA1c were -0.58% and -0.58% with janagliflozin 25 and 50 mg, respectively (P < .0001 for both). The proportion of patients achieving HbA1c less than 7.0% was higher with janagliflozin 25 and 50 mg compared with placebo (41.8%, 41.7% and 28.0%, respectively). Both janagliflozin doses provided significant reductions in fasting plasma glucose, 2-hour postprandial glucose, body weight and systolic blood pressure, and improvements in high-density lipoprotein cholesterol and insulin sensitivity compared with placebo (P < .05 for all). The trends in improvement of these variables were retained during the 28-week extension period. No severe hypoglycaemia occurred throughout the whole 52-week treatment. CONCLUSIONS Janagliflozin 25 or 50 mg once-daily added to metformin therapy significantly improved glycaemic control, reduced body weight and systolic blood pressure, improved high-density lipoprotein cholesterol and insulin sensitivity, and was generally well-tolerated by Chinese T2D patients who had poor glycaemic control with metformin monotherapy.
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Affiliation(s)
- Leili Gao
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Zhifeng Cheng
- Department of Endocrinology, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Benli Su
- Department of Endocrinology, The Second Hospital of Dalian Medical University, Dalian, China
| | - Xiuhai Su
- Department of Endocrinology, Cangzhou Hospital of Integrated TCM-WM Hebei, Cangzhou, China
| | - Weihong Song
- Department of Endocrinology, Chenzhou First People's Hospital, Chenzhou, China
| | - Yushan Guo
- Department of Endocrinology, The Affiliated Hospital of Beihua University, Jilin, China
| | - Lin Liao
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Xiaowen Chen
- Department of Endocrinology, Huangshi Central Hospital, Huangshi, China
| | - Jiarui Li
- Department of Endocrinology, Cangzhou Central Hospital, Cangzhou, China
| | - Xingrong Tan
- Department of Endocrinology, The Ninth People's Hospital of Chongqing, Chongqing, China
| | - Fangjiang Xu
- Department of Endocrinology, Linyi Central Hospital, Linyi, China
| | - Shuguang Pang
- Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
| | - Kun Wang
- Department of Endocrinology, Nanjing Jiangning Hospital, Nanjing, China
| | - Jun Ye
- Department of Endocrinology, The Second People's Hospital of Hefei, Hefei, China
| | - Yuan Wang
- Department of Endocrinology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lili Chen
- Department of Endocrinology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jingfang Sun
- Jilin Huisheng Bio-pharmaceutical Co., Ltd, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
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Yao M, Wang Y, Mei F, Zou K, Li L, Sun X. Methods for the Inclusion of Real-World Evidence in a Rare Events Meta-Analysis of Randomized Controlled Trials. J Clin Med 2023; 12:jcm12041690. [PMID: 36836227 PMCID: PMC9964527 DOI: 10.3390/jcm12041690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/10/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
BACKGROUND Many rare events meta-analyses of randomized controlled trials (RCTs) have lower statistical power, and real-world evidence (RWE) is becoming widely recognized as a valuable source of evidence. The purpose of this study is to investigate methods for including RWE in a rare events meta-analysis of RCTs and the impact on the level of uncertainty around the estimates. METHODS Four methods for the inclusion of RWE in evidence synthesis were investigated by applying them to two previously published rare events meta-analyses: the naïve data synthesis (NDS), the design-adjusted synthesis (DAS), the use of RWE as prior information (RPI), and the three-level hierarchical models (THMs). We gauged the effect of the inclusion of RWE by varying the degree of confidence placed in RWE. RESULTS This study showed that the inclusion of RWE in a rare events meta-analysis of RCTs could increase the precision of the estimates, but this depended on the method of inclusion and the level of confidence placed in RWE. NDS cannot consider the bias of RWE, and its results may be misleading. DAS resulted in stable estimates for the two examples, regardless of whether we placed high- or low-level confidence in RWE. The results of the RPI approach were sensitive to the confidence level placed in RWE. The THM was effective in allowing for accommodating differences between study types, while it had a conservative result compared with other methods. CONCLUSION The inclusion of RWE in a rare events meta-analysis of RCTs could increase the level of certainty of the estimates and enhance the decision-making process. DAS might be appropriate for inclusion of RWE in a rare event meta-analysis of RCTs, but further evaluation in different scenarios of empirical or simulation studies is still warranted.
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Affiliation(s)
- Minghong Yao
- Chinese Evidence-Based Medicine Center and MAGIC China Center, West China Hospital, Sichuan University, Chengdu 610041, China
- NMPA Key Laboratory for Real World Data Research and Evaluation in Hainan, Chengdu 610041, China
- Sichuan Center of Technology Innovation for Real World Data, Chengdu 610041, China
| | - Yuning Wang
- Chinese Evidence-Based Medicine Center and MAGIC China Center, West China Hospital, Sichuan University, Chengdu 610041, China
- NMPA Key Laboratory for Real World Data Research and Evaluation in Hainan, Chengdu 610041, China
- Sichuan Center of Technology Innovation for Real World Data, Chengdu 610041, China
| | - Fan Mei
- Chinese Evidence-Based Medicine Center and MAGIC China Center, West China Hospital, Sichuan University, Chengdu 610041, China
- NMPA Key Laboratory for Real World Data Research and Evaluation in Hainan, Chengdu 610041, China
- Sichuan Center of Technology Innovation for Real World Data, Chengdu 610041, China
| | - Kang Zou
- Chinese Evidence-Based Medicine Center and MAGIC China Center, West China Hospital, Sichuan University, Chengdu 610041, China
- NMPA Key Laboratory for Real World Data Research and Evaluation in Hainan, Chengdu 610041, China
- Sichuan Center of Technology Innovation for Real World Data, Chengdu 610041, China
| | - Ling Li
- Chinese Evidence-Based Medicine Center and MAGIC China Center, West China Hospital, Sichuan University, Chengdu 610041, China
- NMPA Key Laboratory for Real World Data Research and Evaluation in Hainan, Chengdu 610041, China
- Sichuan Center of Technology Innovation for Real World Data, Chengdu 610041, China
- Correspondence: (L.L.); (X.S.); Tel.: +86-02885164187 (L.L.)
| | - Xin Sun
- Chinese Evidence-Based Medicine Center and MAGIC China Center, West China Hospital, Sichuan University, Chengdu 610041, China
- NMPA Key Laboratory for Real World Data Research and Evaluation in Hainan, Chengdu 610041, China
- Sichuan Center of Technology Innovation for Real World Data, Chengdu 610041, China
- Correspondence: (L.L.); (X.S.); Tel.: +86-02885164187 (L.L.)
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Butt MI, Aljamei H, Riazuddin M, AlHaqbani L, Albalwi R, Abothenain FFM, Alagla NAM, Waheed N. Efficacy and safety of empagliflozin: a "real-world" experience from Saudi Arabia. Ann Saudi Med 2023; 43:50-56. [PMID: 36739502 PMCID: PMC9899336 DOI: 10.5144/0256-4947.2023.50] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors are new agents for treating type 2 diabetes. In addition to the glycemic benefits, these agents provide cardiorenal protection in patients with diabetes and without diabetes. There is consistent evidence that these agents increase the risk of genitourinary infections and dehydration, but randomized controlled trials have not included patients from the Middle East. OBJECTIVES Determine the efficacy and safety of empagliflozin, specifically whether the genitourinary infection risk differs in our population and whether there is an increased risk of dehydration, ketoacidosis, hypoglycemia, and hospitalization with fasting. DESIGN Retrospective review of medical records. SETTINGS Department of medicine at tertiary care center. PATIENTS AND METHODS We reviewed the electronic records of patients with type 2 diabetes who took empagliflozin from 1 December 2018 to 30 November 2019. We collected safety and efficacy data for 12 months from the initiation of treatment. MAIN OUTCOMES MEASURES Glycemic and weight loss efficacy, risk of hospitalization due to hypoglycemia, dehydration, and genitourinary infections. SAMPLE SIZE 637 patients. RESULTS We observed an improvement in glycated hemoglobin, a 4.2% weight loss, improved left ventricular function, stable serum creatinine, and reduced albuminuria. Our patients did not have an increased risk of genitourinary infections, hypoglycemia, dehydration, ketoacidosis, or hospitalizations. Fasting did not increase the incidence of adverse events. CONCLUSIONS Empagliflozin is safe and effective in our local population. We hypothesize that glycosuria induced by empagliflozin is not the sole contributor to the increased risk of genitourinary infections. Local hygiene and circumcision might reduce this risk. Empagliflozin can be used safely during fasting. LIMITATIONS Retrospective design. CONFLICT OF INTEREST None.
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Affiliation(s)
- Muhammad Imran Butt
- From the Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Hadeel Aljamei
- From the Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Muhammad Riazuddin
- From the Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Lamia AlHaqbani
- From the Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Roaa Albalwi
- From the Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | | | | | - Najeeb Waheed
- From the Department of Endocrinology, Imperial College London Diabetes Centre, Al Ain, United Arab Emirates
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Loiseau N, Trichelair P, He M, Andreux M, Zaslavskiy M, Wainrib G, Blum MGB. External control arm analysis: an evaluation of propensity score approaches, G-computation, and doubly debiased machine learning. BMC Med Res Methodol 2022; 22:335. [PMID: 36577946 PMCID: PMC9795588 DOI: 10.1186/s12874-022-01799-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 11/21/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND An external control arm is a cohort of control patients that are collected from data external to a single-arm trial. To provide an unbiased estimation of efficacy, the clinical profiles of patients from single and external arms should be aligned, typically using propensity score approaches. There are alternative approaches to infer efficacy based on comparisons between outcomes of single-arm patients and machine-learning predictions of control patient outcomes. These methods include G-computation and Doubly Debiased Machine Learning (DDML) and their evaluation for External Control Arms (ECA) analysis is insufficient. METHODS We consider both numerical simulations and a trial replication procedure to evaluate the different statistical approaches: propensity score matching, Inverse Probability of Treatment Weighting (IPTW), G-computation, and DDML. The replication study relies on five type 2 diabetes randomized clinical trials granted by the Yale University Open Data Access (YODA) project. From the pool of five trials, observational experiments are artificially built by replacing a control arm from one trial by an arm originating from another trial and containing similarly-treated patients. RESULTS Among the different statistical approaches, numerical simulations show that DDML has the smallest bias followed by G-computation. In terms of mean squared error, G-computation usually minimizes mean squared error. Compared to other methods, DDML has varying Mean Squared Error performances that improves with increasing sample sizes. For hypothesis testing, all methods control type I error and DDML is the most conservative. G-computation is the best method in terms of statistical power, and DDML has comparable power at [Formula: see text] but inferior ones for smaller sample sizes. The replication procedure also indicates that G-computation minimizes mean squared error whereas DDML has intermediate performances in between G-computation and propensity score approaches. The confidence intervals of G-computation are the narrowest whereas confidence intervals obtained with DDML are the widest for small sample sizes, which confirms its conservative nature. CONCLUSIONS For external control arm analyses, methods based on outcome prediction models can reduce estimation error and increase statistical power compared to propensity score approaches.
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Rong X, Zhu Y, Wen B, Liu K, Li X, Gou Q, Chen X. Risk of hypovolemia associated with sodium-glucose cotransporter-2 inhibitors treatment: A meta-analysis of randomized controlled trials. Front Cardiovasc Med 2022; 9:973129. [PMID: 36451919 PMCID: PMC9701837 DOI: 10.3389/fcvm.2022.973129] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 10/26/2022] [Indexed: 01/26/2024] Open
Abstract
AIM OF THE REVIEW To assess the risk of hypovolemia for sodium-glucose cotransporter-2 (SGLT2) inhibitors treatment. METHOD A systematic literature retrieval was performed in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and Scopus from inception up to 4 October 2022, Data for study characteristics and outcomes of interest were extracted from each eligible study. Risk ratios (RRs) with a 95% confidence interval (CI) for hypovolemia were calculated using a random-effect model. RESULTS A total of 57 studies (n = 68,622) were included in our meta-analysis, with a result of 1,972 hypovolemia incidents (1,142 in the SGLT2 inhibitors group and 830 in the control group). The pooled RR was 1.12 (95% CI: 1.02-1.22). It is evident that receiving SGLT2 inhibitors increased the risk of hypovolemia. When stratified by category of SGLT2 inhibitors the result was consistent; when the subgroup was analyzed by age, the pooled RR was 1.07 (95% CI: 0.94-1.23) in patients aged ≥65 years and 1.14 (95% CI: 1.02-1.28) in those aged <65 years. When comparing the baseline estimated glomerular filtration rate (eGFR) of less than or equal to 60 mL/min/1.73 m2 with a baseline eGFR greater than 60 mL/min/1.73 m2, the pooled RR was 1.21, (95% CI: 1.00-1.46) and 1.08, (95%CI: 0.98-1.20), respectively. CONCLUSION Our meta-analysis has demonstrated that SGLT2 inhibitors increased the risk of hypovolemia in patients with Type 2 Diabetes Mellitus (T2DM). It is necessary to pay attention to the risk of hypovolemia associated with SGLT2 inhibitors, especially in older individuals and those with moderate renal impairment. SYSTEMATIC REVIEW REGISTRATION [https://www.crd.york.ac.uk/prospero/], identifier [CRD42020156254].
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Affiliation(s)
- Xi Rong
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China
| | - Yawen Zhu
- Department of General Practice, West China Hospital, Sichuan University, Chengdu, China
| | - Bo Wen
- dMed Biopharmaceutical Company Limited, Shanghai, China
| | - Kai Liu
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
| | - Xinran Li
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
| | - Qiling Gou
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoping Chen
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
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Alser M, Elrayess MA. From an Apple to a Pear: Moving Fat around for Reversing Insulin Resistance. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph192114251. [PMID: 36361131 PMCID: PMC9659102 DOI: 10.3390/ijerph192114251] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 10/19/2022] [Indexed: 06/02/2023]
Abstract
Type 2 diabetes (T2D) is a chronic condition where the body is resistant to insulin, leading to an elevated blood glucose state. Obesity is a main factor leading to T2D. Many clinical studies, however, have described a proportion of obese individuals who express a metabolically healthy profile, whereas some lean individuals could develop metabolic disorders. To study obesity as a risk factor, body fat distribution needs to be considered rather than crude body weight. Different individuals' bodies favor storing fat in different depots; some tend to accumulate more fat in the visceral depot, while others tend to store it in the femoral depot. This tendency relies on different factors, including genetic background and lifestyle. Consuming some types of medications can cause a shift in this tendency, leading to fat redistribution. Fat distribution plays an important role in the progression of risk of insulin resistance (IR). Apple-shaped individuals with enhanced abdominal obesity have a higher risk of IR compared to BMI-matched pear-shaped individuals, who store their fat in the gluteal-femoral depots. This is related to the different adipose tissue physiology between these two depots. In this review, we will summarize the recent evidence highlighting the underlying protective mechanisms in gluteal-femoral subcutaneous adipose tissues compared to those associated with abdominal adipose tissue, and we will revise the recent evidence showing antidiabetic drugs that impact fat distribution as they manage the T2D condition.
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Affiliation(s)
- Maha Alser
- Biomedical Research Center, Qatar University, Doha P.O. Box 2713, Qatar
| | - Mohamed A. Elrayess
- Biomedical Research Center, Qatar University, Doha P.O. Box 2713, Qatar
- College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
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Davidson JA, Sukor N, Hew F, Mohamed M, Hussein Z. Safety of sodium-glucose cotransporter 2 inhibitors in Asian type 2 diabetes populations. J Diabetes Investig 2022; 14:167-182. [PMID: 36260389 PMCID: PMC9889611 DOI: 10.1111/jdi.13915] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 09/02/2022] [Accepted: 09/10/2022] [Indexed: 02/04/2023] Open
Abstract
The prevalence of type 2 diabetes mellitus continues to increase in many Asian countries, with possible contributing factors, such as younger-onset disease, diabetes development at lower body mass index, higher visceral fat accumulation and poorer β-cell function, among Asian populations. Sodium-glucose cotransporter 2 inhibitors have been shown to confer favorable effects in type 2 diabetes mellitus patients, such as improved glycemic control, weight and blood pressure reduction, and importantly, cardiorenal benefits. Sodium-glucose cotransporter 2 inhibitors are generally well-tolerated, and have a well-defined safety profile based on evidence from numerous clinical trials and post-marketing pharmacovigilance reporting. To our knowledge, this review is the first to provide a comprehensive coverage of the adverse events of sodium-glucose cotransporter 2 inhibitors, as well as their management and counseling aspects for Asian type 2 diabetes mellitus populations.
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Affiliation(s)
- Jaime A Davidson
- Touchstone Diabetes CenterThe University of Texas Southwestern Medical CenterDallasTexasUSA
| | - Norlela Sukor
- Universiti Kebangsaan Malaysia Medical CentreKuala LumpurMalaysia
| | - Fen‐Lee Hew
- Subang Jaya Medical CentreSubang JayaSelangorMalaysia
| | - Mafauzy Mohamed
- School of Medical SciencesUniversiti Sains MalaysiaKelantanMalaysia
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Gouraud H, Wallach JD, Boussageon R, Ross JS, Naudet F. Vibration of effect in more than 16 000 pooled analyses of individual participant data from 12 randomised controlled trials comparing canagliflozin and placebo for type 2 diabetes mellitus: multiverse analysis. BMJ MEDICINE 2022; 1:e000154. [PMID: 36936564 PMCID: PMC9978683 DOI: 10.1136/bmjmed-2022-000154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 08/23/2022] [Indexed: 11/04/2022]
Abstract
Objective To evaluate the impact of conducting all possible pooled analyses across different combinations of randomised controlled trials and endpoints. Design Multiverse analysis, consisting of numerous pooled analyses of individual participant data. Setting Individual patient data from 12 randomised controlled trials comparing canagliflozin treatment with placebo, shared on the Yale University Open Data Access project (https://yoda.yale.edu/) platform, up to 16 April 2021. Participants 15 094 people with type 2 diabetes mellitus. Main outcome measures Pooled analyses estimated changes in serum glycated haemoglobin (HbA1c), major adverse cardiovascular events, and serious adverse events at weeks 12, 18, 26, and 52. The distribution of effect estimates was calculated for all possible combinations, and the direction and magnitude of the first and 99th centiles of effect estimates were compared. Results Across 16 332 distinct pooled analyses comparing canagliflozin with placebo for changes in HbA1c, standardised effect estimates were in favour of canagliflozin treatment at both the first centile (-0.75%) and 99th centile (-0.48%); 15 994 (97.93%) analyses showed significant results (P<0.05) in favour of canagliflozin. For major adverse cardiovascular events, estimated hazard ratios were 0.20 at the first centile and 0.90 at the 99th centile; 2705 of 8144 analyses (33.21%) were significant, all of which were in favour of canagliflozin treatment. For serious adverse events, estimated hazard ratios were 0.59 at the first centile and 1.14 at the 99th centile; 5793 of 16 332 (35.47%) analyses were significant, with 5754 in favour of canagliflozin and 39 in favour of placebo. Conclusion Results from pooled analyses can be subject to vibration of effects and should be critically appraised, especially regarding the risk for selection and availability bias in individual participant data retrieved.
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Affiliation(s)
- Henri Gouraud
- Inserm, CIC 1414 (Centre d’Investigation Clinique de Rennes), Rennes 1 University, Rennes, France
- Inserm, Irset (Institut de recherche en santé, environnement et travail), Rennes 1 University, Rennes, France
| | - Joshua D Wallach
- Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, CT, USA
| | - Rémy Boussageon
- UCBL, CNRS, UMR 5558, LBBE, EMET, University Claude Bernard Lyon 1, Villeurbanne, France
| | - Joseph S Ross
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Florian Naudet
- Inserm, CIC 1414 (Centre d’Investigation Clinique de Rennes), Rennes 1 University, Rennes, France
- Inserm, Irset (Institut de recherche en santé, environnement et travail), Rennes 1 University, Rennes, France
- Institut Universitaire de France, Paris, France
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Mechanism of canagliflozin-induced vasodilation in resistance mesenteric arteries and the regulation of systemic blood pressure. J Pharmacol Sci 2022; 150:211-222. [DOI: 10.1016/j.jphs.2022.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 08/18/2022] [Accepted: 09/21/2022] [Indexed: 11/21/2022] Open
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Zou X, Huang Q, Luo Y, Ren Q, Han X, Zhou X, Ji L. The efficacy of canagliflozin in diabetes subgroups stratified by data-driven clustering or a supervised machine learning method: a post hoc analysis of canagliflozin clinical trial data. Diabetologia 2022; 65:1424-1435. [PMID: 35802168 DOI: 10.1007/s00125-022-05748-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 04/29/2022] [Indexed: 11/28/2022]
Abstract
AIMS/HYPOTHESIS Data-driven diabetes subgroups have shown distinct clinical characteristics and disease progression, although there is a lack of evidence that this information can guide clinical decisions. We aimed to investigate whether diabetes subgroups, identified by data-driven clustering or supervised machine learning methods, respond differently to canagliflozin. METHODS We pooled data from five randomised, double-blinded clinical trials of canagliflozin at an individual level. We applied the coordinates from the All New Diabetics in Scania (ANDIS) study to form four subgroups: mild age-related diabetes (MARD); severe insulin-deficient diabetes (SIDD); mild obesity-related diabetes (MOD) and severe insulin-resistant diabetes (SIRD). Machine learning models for HbA1c lowering (ML-A1C) and albuminuria progression (ML-ACR) were developed. The primary efficacy endpoint was reduction in HbA1c at 52 weeks. Concordance of a model was defined as the difference between predicted HbA1c and actual HbA1c decline less than 3.28 mmol/mol (0.3%). RESULTS The decline in HbA1c resulting from treatment was different among the four diabetes clusters (pinteraction=0.004). In MOD, canagliflozin showed a robust glucose-lowering effect at week 52, compared with other drugs, with least-squares mean of HbA1c decline [95% CI] being 6.6 mmol/mol (4.1, 9.2) (0.61% [0.38, 0.84]) for sitagliptin, 7.1 mmol/mol (4.7, 9.5) (0.65% [0.43, 0.87]) for glimepiride, and 9.8 mmol/mol (9.0, 10.5) (0.90% [0.83, 0.96]) for canagliflozin. This superiority persisted until 104 weeks. The proportion of individuals who achieved HbA1c <53 mmol/mol (<7.0%) was highest in sitagliptin-treated individuals with MARD but was similar among drugs in individuals with MOD. The ML-A1C model and the cluster algorithm showed a similar concordance rate in predicting HbA1c lowering (31.5% vs 31.4%, p=0.996). Individuals were divided into high-risk and low-risk groups using ML-ACR model according to their predicted progression risk for albuminuria. The effect of canagliflozin vs placebo on albuminuria progression differed significantly between the high-risk (HR 0.67 [95% CI 0.57, 0.80]) and low-risk groups (HR 0.91 [0.75, 1.11]) (pinteraction=0.016). CONCLUSIONS/INTERPRETATION Data-driven clusters of individuals with diabetes showed different responses to canagliflozin in glucose lowering but not renal outcome prevention. Canagliflozin reduced the risk of albumin progression in high-risk individuals identified by supervised machine learning. Further studies with larger sample sizes for external replication and subtype-specific clinical trials are necessary to determine the clinical utility of these stratification strategies in sodium-glucose cotransporter 2 inhibitor treatment. DATA AVAILABILITY The application for the clinical trial data source is available on the YODA website ( http://yoda.yale.edu/ ).
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Affiliation(s)
- Xiantong Zou
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
| | - Qi Huang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Yingying Luo
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Qian Ren
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xueyao Han
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xianghai Zhou
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
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He L, Wang J, Ping F, Yang N, Huang J, Li W, Xu L, Zhang H, Li Y. Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trials. BMJ 2022; 377:e068882. [PMID: 35764326 PMCID: PMC9237836 DOI: 10.1136/bmj-2021-068882] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To examine the association between dipeptidyl peptidase-4 inhibitors and gallbladder or biliary diseases. DESIGN Systematic review and pairwise and network meta-analysis. DATA SOURCES PubMed, EMBASE, Web of Science, and CENTRAL from inception until 31 July 2021. ELIGIBILITY CRITERIA Randomised controlled trials of adult patients with type 2 diabetes who received dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors compared with placebo or other antidiabetes drugs. MAIN OUTCOME MEASURES Composite of gallbladder or biliary diseases, cholecystitis, cholelithiasis, and biliary diseases. DATA EXTRACTION AND DATA SYNTHESIS Two reviewers independently extracted the data and assessed the quality of the studies. The quality of the evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development and Evaluations framework (GRADE) approach. The meta-analysis used pooled odds ratios and 95% confidence intervals. RESULTS A total of 82 randomised controlled trials with 104 833 participants were included in the pairwise meta-analysis. Compared with placebo or non-incretin drugs, dipeptidyl peptidase-4 inhibitors were significantly associated with an increased risk of the composite of gallbladder or biliary diseases (odds ratio 1.22 (95%confidence interval 1.04 to 1.43); risk difference 11 (2 to 21) more events per 10 000 person years) and cholecystitis (odds ratio 1.43 (1.14 to 1.79); risk difference 15 (5 to 27) more events per 10 000 person years) but not with the risk of cholelithiasis and biliary diseases. The associations tended to be observed in patients with a longer duration of dipeptidyl peptidase-4 inhibitor treatment. In the network meta-analysis of 184 trials, dipeptidyl peptidase-4 inhibitors increased the risk of the composite of gallbladder or biliary diseases and cholecystitis compared with sodium-glucose cotransporter-2 inhibitors but not compared with glucagon-like peptide-1 receptor agonists. CONCLUSIONS Dipeptidyl peptidase-4 inhibitors increased the risk of cholecystitis in randomised controlled trials, especially with a longer treatment duration, which requires more attention from physicians in clinical practice. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42021271647.
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Affiliation(s)
- Liyun He
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jialu Wang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fan Ping
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Na Yang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jingyue Huang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Li
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lingling Xu
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huabing Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuxiu Li
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Singh AK, Singh R. Relook at DPP-4 inhibitors in the era of SGLT-2 inhibitors. World J Diabetes 2022; 13:466-470. [PMID: 35800411 PMCID: PMC9210541 DOI: 10.4239/wjd.v13.i6.466] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/19/2022] [Accepted: 05/23/2022] [Indexed: 02/06/2023] Open
Abstract
SGLT-2 inhibitors (SGLT-2Is) have significantly improved cardio-renal outcomes and are preferred agents in people with cardiovascular diseases, heart failure, and diabetic kidney disease. Similarly, GLP-1 receptor agonists (GLP-1RAs) have significantly improved atherosclerotic cardiovascular outcomes. To this end, DPP-4 inhibitors (DPP-4Is) are cardiac-neutral drugs. While long-acting GLP-1RAs have shown a favorable HbA1c lowering compared to DPP-4Is, there is no clinically meaningful HbA1c lowering difference between SGLT-2Is vs DPP-4Is. Moreover, the glucose-lowering potential of SGLT-2Is gets compromised with a progressive decline in renal functions, unlike DPP-4Is. Furthermore, the HbA1c lowering potential of DPP-4Is is favorable in people with T2DM having a modest baseline HbA1c (8.0%-8.5%) compared with SGLT-2Is which lowers HbA1c larger in a background of higher baseline HbA1c (> 8.5%-9.0%). These findings suggest that the role of DPP-4Is in the management of type 2 diabetes mellitus cannot be completely ignored even in the era of SGLT-2Is.
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Affiliation(s)
- Awadhesh Kumar Singh
- Department of Diabetes & Endocrinology, G.D Hospital & Diabetes Institute, Kolkata 700013, West Bengal, India
| | - Ritu Singh
- Department of Diabetes & Endocrinology, G.D Hospital & Diabetes Institute, Kolkata 700013, West Bengal, India
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Real-world evaluation of sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors for managing type 2 diabetes mellitus: a retrospective multi-ethnic cohort study. J Diabetes Metab Disord 2022; 21:521-555. [PMID: 35673518 PMCID: PMC9167339 DOI: 10.1007/s40200-022-01004-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 02/07/2022] [Indexed: 11/29/2022]
Abstract
Abstract Purpose Sodium-glucose co-transporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors are increasingly used as second-line therapies in patients with type 2 diabetes. The aim of this study was to assess the real-world effects of SGLT2 inhibitors in a multi-ethnic population in Singapore. Methods This retrospective cohort study examined patients diagnosed with and treated for diabetes from the Ministry of Health’s administrative database. Differences in outcomes between treatment groups were assessed using Poisson regression. Demographics, clinical characteristics, previous diagnoses and hospitalisations, and diabetes medication history were used for propensity score matching. Subgroup analyses by ethnicity were performed. Effect size was estimated using risk ratios (RRs) with 95% confidence intervals (CIs). Results Patients initiating SGLT2 inhibitors were more likely to achieve glycaemic control target than DPP4 inhibitor-treated patients (RR 1.09; 95% CI 1.04, 1.14). This was observed only in patients of Chinese ethnicity. A higher risk of diabetic ketoacidosis in SGLT2 inhibitor initiators was not observed. SGLT2 inhibitors were associated with reduced risk of hypoglycaemia (RR 0.69; 95% CI 0.59, 0.82) and urinary tract infection (RR 0.52; 95% CI 0.43, 0.63) but was not statistically significant for hypoglycaemia in Malay patients. Compared to DPP4 inhibitors, SGLT2 inhibitors were associated with 12% and 34% reduction in any-cause hospitalisation and all-cause mortality, respectively, potentially resulting in more than $50 million savings over 10 years. Conclusion SGLT2 inhibitors were associated with improvements in glycaemic control, reduced risk of complications, and was well tolerated. Ethnicity also plays a role and should be considered in future studies.
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Xu B, Li S, Kang B, Zhou J. The current role of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus management. Cardiovasc Diabetol 2022; 21:83. [PMID: 35614469 PMCID: PMC9134641 DOI: 10.1186/s12933-022-01512-w] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic, complex metabolic disease characterized by chronic hyperglycemia causing from insufficient insulin signaling because of insulin resistance or defective insulin secretion, and may induce severe complications and premature death. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are oral drugs used to reduce hyperglycemia in patients with T2DM, including empagliflozin, ertugliflozin, dapagliflozin and canagliflozin. The primary objective of this article is to examine the clinical benefit, safety, and tolerability of the four SGLT2 inhibitors approved by the US FDA. SGLT2 inhibitors increase urinary glucose excretion via inhibiting SGLT2 to decrease renal reabsorption of filtered glucose and reduce the renal threshold for glucose. Rather than stimulating insulin release, SGLT2 inhibitors improve β-cell function by improving glucotoxicity, as well as reduce insulin resistance and increase insulin sensitivity. Early clinical trials have confirmed the beneficial effects of SGLT2 in T2DM with acceptable safety and excellent tolerability. In recent years, SGLT2 inhibitors has been successively approved by the FDA to decrease cardiovascular death and decrease the risk of stroke and cardiac attack in T2DM adults who have been diagnosed with cardiovascular disease, treating heart failure (HF) with reduced ejection fraction and HF with preserved ejection fraction, and treat diabetic kidney disease (DKD), decrease the risk of hospitalization for HF in T2DM and DKD patients. SGLT2 inhibitors are expected to be an effective treatment for T2DM patients with non alcoholic fatty liver disease. SGLT2 inhibitors have a similar safety profile to placebo or other active control groups, with major adverse events such as Ketoacidosis or hypotension and genital or urinary tract infections.
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Affiliation(s)
- Bo Xu
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Shaoqian Li
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Bo Kang
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Jiecan Zhou
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
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Xie L, Xiao Y, Tai S, Yang H, Zhou S, Zhou Z. Emerging Roles of Sodium Glucose Cotransporter 2 (SGLT-2) Inhibitors in Diabetic Cardiovascular Diseases: Focusing on Immunity, Inflammation and Metabolism. Front Pharmacol 2022; 13:836849. [PMID: 35295328 PMCID: PMC8920092 DOI: 10.3389/fphar.2022.836849] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/07/2022] [Indexed: 11/29/2022] Open
Abstract
Diabetes mellitus (DM) is one of the most fast evolving global issues characterized by hyperglycemia. Patients with diabetes are considered to face with higher risks of adverse cardiovascular events. Those are the main cause of mortality and disability in diabetes patients. There are novel antidiabetic agents that selectively suppress sodium-glucose cotransporter-2 (SGLT-2). They work by reducing proximal tubule glucose reabsorption. Although increasing evidence has shown that SGLT-2 inhibitors can contribute to a series of cardiovascular benefits in diabetic patients, including a reduced incidence of major adverse cardiovascular events and protection of extracardiac organs, the potential mechanisms of SGLT2 inhibitors’ cardiovascular protective effects are still not fully elucidated. Given the important role of inflammation and metabolism in diabetic cardiovascular diseases, this review is intended to rationally compile the multifactorial mechanisms of SGLT-2 inhibitors from the point of immunity, inflammation and metabolism, depicting the fundamental cellular and molecular processing of SGLT-2 inhibitors exerting regulating immunity, inflammation and metabolism. Finally, future directions and perspectives to prevent or delay cardiovascular complications in DM by SGLT-2 inhibitors are presented.
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Affiliation(s)
- Lingxiang Xie
- Key Laboratory of Diabetes Immunology, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yang Xiao
- Key Laboratory of Diabetes Immunology, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shi Tai
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Huijie Yang
- Key Laboratory of Diabetes Immunology, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shenghua Zhou
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguang Zhou
- Key Laboratory of Diabetes Immunology, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
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Pinto LC, Rados DV, Remonti LR, Viana MV, Leitão CB, Gross JL. Dose-ranging effects of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2022; 66:68-76. [PMID: 35263050 PMCID: PMC9991024 DOI: 10.20945/2359-3997000000440] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 10/25/2021] [Indexed: 11/23/2022]
Abstract
The lowest dosage of empagliflozin (10 mg) showed similar benefits on glycated hemoglobin (HbA1c) level, body weight, blood pressure, and total and cardiovascular mortality in comparison with the highest available dose (25 mg) in the EMPAREG trial. These findings have not been clearly demonstrated for canagliflozin and dapagliflozin. The objective was to compare the effect of different doses of SGLT2 inhibitors commercially available in Brazil on HbA1c and body weight of patients with type 2 diabetes. MEDLINE, Cochrane and Embase databases were searched from inception until 11th October 2021 for randomized controlled trials of SGLT2 inhibitors in type 2 diabetes patients, lasting at least 12 weeks. HbA1c and body weight variations were described using standard mean difference. We performed direct and indirect meta-analysis, as well as a meta-regression with medication doses as covariates. Eighteen studies were included, comprising 16,095 patients. In the direct meta-analysis, SGLT2 inhibitors reduced HbA1c by 0.62% (95% CI -0.66 to -0.59) and body weight by 0.60 kg (95% CI -0.64 to -0.55). In the indirect meta-analysis, canagliflozin 300 mg ranked the highest regarding reductions in HbA1c and body weight. The remaining medications and dosages were clinically similar, despite some statistically significant differences among them. Canagliflozin 300 mg seems to be more potent in reducing HbA1c and body weight in patients with type 2 diabetes. The remaining SGLT2 inhibitors at different doses lead to similar effects for both outcomes. Whether these glycemic and weight effects are reflected in lower mortality and cardiovascular events is still uncertain and may be a topic for further studies.
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Affiliation(s)
- Lana C Pinto
- Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil,
| | - Dimitris V Rados
- Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil
| | - Luciana R Remonti
- Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil
| | - Marina V Viana
- Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil
| | - Cristiane B Leitão
- Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil
| | - Jorge L Gross
- Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil
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SGLT2 Inhibitors in Type 2 Diabetes Mellitus and Heart Failure-A Concise Review. J Clin Med 2022; 11:jcm11061470. [PMID: 35329796 PMCID: PMC8952302 DOI: 10.3390/jcm11061470] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 02/28/2022] [Accepted: 03/06/2022] [Indexed: 01/25/2023] Open
Abstract
The incidence of both diabetes mellitus type 2 and heart failure is rapidly growing, and the diseases often coexist. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a new antidiabetic drug class that mediates epithelial glucose transport at the renal proximal tubules, inhibiting glucose absorption—resulting in glycosuria—and therefore improving glycemic control. Recent trials have proven that SGLT2i also improve cardiovascular and renal outcomes, including reduced cardiovascular mortality and fewer hospitalizations for heart failure. Reduced preload and afterload, improved vascular function, and changes in tissue sodium and calcium handling may also play a role. The expected paradigm shift in treatment strategies was reflected in the most recent 2021 guidelines published by the European Society of Cardiology, recommending dapagliflozin and empagliflozin as first-line treatment for heart failure patients with reduced ejection fraction. Moreover, the recent results of the EMPEROR-Preserved trial regarding empagliflozin give us hope that there is finally an effective treatment for patients with heart failure with preserved ejection fraction. This review aims to assess the efficacy and safety of these new anti-glycemic oral agents in the management of diabetic and heart failure patients.
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Cai M, Shao X, Xing F, Zhang Y, Gao X, Zeng Q, Dilimulati D, Qu S, Zhang M. Efficacy of canagliflozin versus metformin in women with polycystic ovary syndrome: A randomized, open-label, noninferiority trial. Diabetes Obes Metab 2022; 24:312-320. [PMID: 34726324 DOI: 10.1111/dom.14583] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/07/2021] [Accepted: 10/20/2021] [Indexed: 01/10/2023]
Abstract
OBJECTIVES To determine the safety and efficacy of canagliflozin in comparison to metformin in polycystic ovary syndrome (PCOS) patients with insulin resistance (IR). METHODS A single-centre, prospective, randomized open-label (ratio 1:1) noninferiority trial was conducted at the Department of Endocrinology, Shanghai Tenth People's Hospital, between July 2019 and April 2021. Women aged 18 to 45 years with PCOS and IR were enrolled and randomly assigned to either 100 mg (n = 33) canagliflozin daily or 1500 to 2000 mg metformin daily (n = 35) for 12 weeks. The primary outcome was changes in homeostatic model assessment (HOMA)-IR after 12 weeks of treatment. The secondary outcomes included changes in anthropometric measurements, menstrual frequency, sex hormone levels, metabolic variables and body fat distribution. RESULTS For lowering of HOMA-IR after 12 weeks of treatment, canagliflozin was found to be noninferior to metformin (least-squares mean difference -0.81% [95% confidence interval -2.13 to 0.51]). Both canagliflozin and metformin significantly improved menstrual pattern, reduced body weight and total fat mass, and decreased triglyceride levels. Compared with metformin, canagliflozin had significant advantages in reducing uric acid and dehydroepiandrosterone sulphate levels. Pruritus vulvae (9.09%) and gastrointestinal reaction (55.55%) were the main adverse events in the metformin group and canagliflozin group, respectively. CONCLUSION This study demonstrates that canagliflozin was not inferior to metformin in PCOS patients with IR, which suggests that sodium-glucose cotransporter-2 inhibitors should be considered as effective drugs in the treatment of PCOS patients with IR.
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Affiliation(s)
- Meili Cai
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaowen Shao
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Feng Xing
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuqin Zhang
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xinyu Gao
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qiongjing Zeng
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Diliqingna Dilimulati
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- National Metabolic Management Center, Shanghai Tenth People's Hospital, Shanghai, China
| | - Manna Zhang
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- National Metabolic Management Center, Shanghai Tenth People's Hospital, Shanghai, China
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Zhong J, Wen MJ, Cheung SH, Poon WY. Simultaneous tests of non inferiority and superiority in three-arm clinical studies with heterogeneous variance. COMMUN STAT-THEOR M 2022. [DOI: 10.1080/03610926.2020.1747082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Junjiang Zhong
- School of Applied Mathematics, Xiamen University of Technology, Xiamen, China
| | - Miin-Jye Wen
- Department of Statistics, Institute of Data Science, and Institute of International Management, National Cheng Kung University, Tainan, Taiwan
| | - Siu Hung Cheung
- Department of Statistics and Data Science, Southern University of Science and Technology, Shenzhen, China
| | - Wai-Yin Poon
- Department of Statistics, The Chinese University of Hong Kong, Hong Kong, China
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Zhou B, Shi Y, Fu R, Ni H, Gu L, Si Y, Zhang M, Jiang K, Shen J, Li X, Sun X. Relationship Between SGLT-2i and Ocular Diseases in Patients With Type 2 Diabetes Mellitus: A Meta-Analysis of Randomized Controlled Trials. Front Endocrinol (Lausanne) 2022; 13:907340. [PMID: 35692406 PMCID: PMC9178099 DOI: 10.3389/fendo.2022.907340] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 04/25/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND This meta-analysis was conducted to explore the association between sodium-glucose cotransporter 2 inhibitors (SGLT-2is) and ocular diseases in type 2 diabetes mellitus (T2DM) patients. METHODS PubMed, Cochrane Central Registry of Controlled Trials, Web of Science and Springer were searched for articles on randomized controlled trials (RCTs) involving T2DM patients treated with SGLT-2i versus placebo or other hypoglycemic agents published prior to August 2021. The primary outcome of this meta-analysis was incidence of ocular diseases, which was assessed using risk ratios (RR) and 95% confidence intervals (CI). We reviewed 47 papers and compared the effect of SGLT-2i with the effect of the control groups (placebo and other hypoglycemic drugs) on the incidence of ocular diseases. RESULTS Compared with controls, overall SGLT-2i use in T2DM patients was not associated with incidences of cataract, glaucoma, retinal disease and vitreous disease. Ertugliflozin (RR=0.47, P=0.01) reduced the risk for retinal disease, while empagliflozin (RR=0.44, P=0.05) reduced the risk for diabetic retinopathy (DR) compared with controls. SGLT-2i (RR=0.50, P=0.02), perhaps empagliflozin (RR=0.47, P=0.06), reduced the risk of retinal disease compared with active hypoglycemic agents. Canagliflozin (RR=4.50, P=0.03) increased the risk for vitreous disease compared with placebo. CONCLUSIONS There was no significant correlation between overall SGLT-2i and ocular diseases (cataract, glaucoma, retinal disease, vitreous disease, corneal disease, conjunctival disease, uveal disease, eye haemorrhage and vision problems) in T2DM patients. Ertugliflozin and empagliflozin may protect against ocular diseases, but canagliflozin may promote ocular diseases.
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Affiliation(s)
- Bin Zhou
- Department of General Surgery, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China
| | - Yetan Shi
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Rongrong Fu
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Haixiang Ni
- The Department of Endocrinology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Lihu Gu
- Department of General Surgery, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China
| | - Yuexiu Si
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Mengting Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ke Jiang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jingyi Shen
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiangyuan Li
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xing Sun
- Department of General Surgery, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
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Riyaphan J, Pham DC, Leong MK, Weng CF. In Silico Approaches to Identify Polyphenol Compounds as α-Glucosidase and α-Amylase Inhibitors against Type-II Diabetes. Biomolecules 2021; 11:1877. [PMID: 34944521 PMCID: PMC8699780 DOI: 10.3390/biom11121877] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 12/08/2021] [Accepted: 12/09/2021] [Indexed: 01/01/2023] Open
Abstract
Type-II diabetes mellitus (T2DM) results from a combination of genetic and lifestyle factors, and the prevalence of T2DM is increasing worldwide. Clinically, both α-glucosidase and α-amylase enzymes inhibitors can suppress peaks of postprandial glucose with surplus adverse effects, leading to efforts devoted to urgently seeking new anti-diabetes drugs from natural sources for delayed starch digestion. This review attempts to explore 10 families e.g., Bignoniaceae, Ericaceae, Dryopteridaceae, Campanulaceae, Geraniaceae, Euphorbiaceae, Rubiaceae, Acanthaceae, Rutaceae, and Moraceae as medicinal plants, and folk and herb medicines for lowering blood glucose level, or alternative anti-diabetic natural products. Many natural products have been studied in silico, in vitro, and in vivo assays to restrain hyperglycemia. In addition, natural products, and particularly polyphenols, possess diverse structures for exploring them as inhibitors of α-glucosidase and α-amylase. Interestingly, an in silico discovery approach using natural compounds via virtual screening could directly target α-glucosidase and α-amylase enzymes through Monte Carto molecular modeling. Autodock, MOE-Dock, Biovia Discovery Studio, PyMOL, and Accelrys have been used to discover new candidates as inhibitors or activators. While docking score, binding energy (Kcal/mol), the number of hydrogen bonds, or interactions with critical amino acid residues have been taken into concerning the reliability of software for validation of enzymatic analysis, in vitro cell assay and in vivo animal tests are required to obtain leads, hits, and candidates in drug discovery and development.
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Affiliation(s)
| | - Dinh-Chuong Pham
- Biomaterials and Nanotechnology Research Group, Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam;
| | - Max K. Leong
- Department of Chemistry, National Dong Hwa University, Hualien 97401, Taiwan
| | - Ching-Feng Weng
- Functional Physiology Section, Department of Basic Medical Science, Xiamen Medical College, Xiamen 361023, China
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Täger T, Atar D, Agewall S, Katus HA, Grundtvig M, Cleland JGF, Clark AL, Fröhlich H, Frankenstein L. Comparative efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for cardiovascular outcomes in type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials. Heart Fail Rev 2021; 26:1421-1435. [PMID: 32314085 PMCID: PMC8510986 DOI: 10.1007/s10741-020-09954-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2D). The comparative efficacy of individual SGLT2i remains unclear. We searched PubMed, www.clinicaltrials.gov and the Cochrane Central Register of Controlled Trials for randomised controlled trials exploring the use of canagliflozin, dapagliflozin, empagliflozin or ertugliflozin in patients with T2D. Comparators included placebo or any other active treatment. The primary endpoint was all-cause mortality. Secondary endpoints were cardiovascular mortality and worsening heart failure (HF). Evidence was synthesised using network meta-analysis (NMA). Sixty-four trials reporting on 74,874 patients were included. The overall quality of evidence was high. When compared with placebo, empagliflozin and canagliflozin improved all three endpoints, whereas dapagliflozin improved worsening HF. When compared with other SGLT2i, empagliflozin was superior for all-cause and cardiovascular mortality reduction. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Ertugliflozin had no effect on any of the three endpoints investigated. Sensitivity analyses including extension periods of trials or excluding studies with a treatment duration of < 52 weeks confirmed the main results. Similar results were obtained when restricting mortality analyses to patients included in cardiovascular outcome trials (n = 38,719). Empagliflozin and canagliflozin improved survival with empagliflozin being superior to the other SGLT2i. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Prospective head-to-head comparisons would be needed to confirm these results.
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Affiliation(s)
- Tobias Täger
- Department of Cardiology, Angiology, and Pulmonology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Dan Atar
- Department of Cardiology, Oslo University Hospital, Ulleval and Institute of Clinical Sciences, University of Oslo, Oslo, Norway
| | - Stefan Agewall
- Department of Cardiology, Oslo University Hospital, Ulleval and Institute of Clinical Sciences, University of Oslo, Oslo, Norway
| | - Hugo A Katus
- Department of Cardiology, Angiology, and Pulmonology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Morten Grundtvig
- Medical Department, Innlandet Hospital Trust Division Lillehammer, Lillehammer, Norway
| | - John G F Cleland
- National Heart & Lung Institute, Royal Brompton & Harefield Hospitals, Imperial College, London, and Robertson Centre for Biostatistics & Clinical Trials, Glasgow, UK
| | - Andrew L Clark
- Castle Hill Hospital of the University of Hull, Cottingham, UK
| | - Hanna Fröhlich
- Department of Cardiology, Angiology, and Pulmonology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Lutz Frankenstein
- Department of Cardiology, Angiology, and Pulmonology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
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Odutayo A, da Costa BR, Pereira TV, Garg V, Iskander S, Roble F, Lalji R, Hincapié CA, Akingbade A, Rodrigues M, Agarwal A, Lawendy B, Saadat P, Udell JA, Cosentino F, Grant PJ, Verma S, Jüni P. Sodium-Glucose Cotransporter 2 Inhibitors, All-Cause Mortality, and Cardiovascular Outcomes in Adults with Type 2 Diabetes: A Bayesian Meta-Analysis and Meta-Regression. J Am Heart Assoc 2021; 10:e019918. [PMID: 34514812 PMCID: PMC8649541 DOI: 10.1161/jaha.120.019918] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Background This study aimed to assess the effectiveness of sodium‐glucose cotransporter 2 inhibitors in reducing the incidence of mortality and cardiovascular outcomes in adults with type 2 diabetes. Methods and Results We conducted a Bayesian meta‐analysis of randomized controlled trials comparing sodium‐glucose cotransporter 2 inhibitors with placebo. We used meta‐regression to examine the association between treatment effects and control group event rates as measures of cardiovascular baseline risk. Fifty‐three randomized controlled trials were included in our synthesis. Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all‐cause mortality (empagliflozin: rate ratio [RR], 0.79; 95% credibility interval [CrI], 0.63–0.97; canagliflozin: RR, 0.86; 95% CrI, 0.69–1.05; dapagliflozin: RR, 0.86; 95% CrI, 0.72–1.01) and cardiovascular mortality (empagliflozin: RR, 0.78; 95% CrI, 0.61–1.00; canagliflozin: RR, 0.83; 95% CrI, 0.63–1.05; dapagliflozin: RR, 0.88; 95% CrI, 0.71–1.08), with a 90.1% to 98.7% probability for the true RR to be <1.00 for both outcomes. There was little evidence for ertugliflozin and sotagliflozin versus placebo for reducing all‐cause and cardiovascular mortality. There was no association between treatment effects for all‐cause and cardiovascular mortality and the control group event rates. There was evidence for a reduction in the incidence of heart failure for empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin versus placebo (probability RR <1.00 of ≥99.3%) and weaker, albeit positive, evidence for acute myocardial infarction for the first 3 agents (probability RR <1.00 of 89.0%–95.2%). There was little evidence of any agent except canagliflozin for reducing the incidence of stroke. Conclusions Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all‐cause and cardiovascular mortality versus placebo. Treatment effects of sodium‐glucose cotransporter 2 inhibitors versus placebo do not vary by baseline risk.
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Affiliation(s)
- Ayodele Odutayo
- Department of Medicine and Institute of Health Policy, Management and Evaluation Applied Health Research Centre (AHRC) Li Ka Shing Knowledge Institute of St. Michael's HospitalUniversity of Toronto Canada
| | - Bruno R da Costa
- Department of Medicine and Institute of Health Policy, Management and Evaluation Applied Health Research Centre (AHRC) Li Ka Shing Knowledge Institute of St. Michael's HospitalUniversity of Toronto Canada
| | - Tiago V Pereira
- Department of Medicine and Institute of Health Policy, Management and Evaluation Applied Health Research Centre (AHRC) Li Ka Shing Knowledge Institute of St. Michael's HospitalUniversity of Toronto Canada.,Department of Health Sciences University of Leicester UK
| | - Vinay Garg
- Faculty of Medicine Department of Medicine University of Toronto Ontario Canada
| | - Samir Iskander
- Department of Medicine and Institute of Health Policy, Management and Evaluation Applied Health Research Centre (AHRC) Li Ka Shing Knowledge Institute of St. Michael's HospitalUniversity of Toronto Canada
| | - Fatimah Roble
- Faculty of Medicine Department of Medicine University of Toronto Ontario Canada
| | - Rahim Lalji
- Department of Chiropractic Medicine Faculty of Medicine University of Zurich and Balgrist University Hospital Zurich Switzerland.,Epidemiology, Biostatistics and Prevention Institute University of Zurich Zurich Switzerland
| | - Cesar A Hincapié
- Department of Medicine and Institute of Health Policy, Management and Evaluation Applied Health Research Centre (AHRC) Li Ka Shing Knowledge Institute of St. Michael's HospitalUniversity of Toronto Canada.,Department of Chiropractic Medicine Faculty of Medicine University of Zurich and Balgrist University Hospital Zurich Switzerland.,Epidemiology, Biostatistics and Prevention Institute University of Zurich Zurich Switzerland
| | | | - Myanca Rodrigues
- Health Research Methodology Graduate Program Department of Health Research Methods, Evidence & Impact Faculty of Health Sciences McMaster University Hamilton Ontario Canada
| | - Arnav Agarwal
- Faculty of Medicine Department of Medicine University of Toronto Ontario Canada
| | - Bishoy Lawendy
- Faculty of Medicine Department of Medicine University of Toronto Ontario Canada
| | - Pakeezah Saadat
- Department of Medicine and Institute of Health Policy, Management and Evaluation Applied Health Research Centre (AHRC) Li Ka Shing Knowledge Institute of St. Michael's HospitalUniversity of Toronto Canada
| | - Jacob A Udell
- Faculty of Medicine Department of Medicine University of Toronto Ontario Canada
| | - Francesco Cosentino
- Cardiology Unit Department of Medicine Solna Karolinska Institute &Karolinska University Hospital Stockholm Sweden
| | - Peter J Grant
- Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds/Leeds Teaching Hospitals NHS TrustLIGHT Laboratories Leeds UK
| | - Subodh Verma
- Departments of Surgery, and Pharmacology and Toxicology University of Toronto Ontario Canada
| | - Peter Jüni
- Department of Medicine and Institute of Health Policy, Management and Evaluation Applied Health Research Centre (AHRC) Li Ka Shing Knowledge Institute of St. Michael's HospitalUniversity of Toronto Canada
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50
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Coelho FDS, Borges-Canha M, von Hafe M, Neves JS, Vale C, Leite AR, Carvalho D, Leite-Moreira A. Effects of sodium-glucose co-transporter 2 inhibitors on liver parameters and steatosis: A meta-analysis of randomized clinical trials. Diabetes Metab Res Rev 2021; 37:e3413. [PMID: 33010191 DOI: 10.1002/dmrr.3413] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/12/2020] [Accepted: 08/23/2020] [Indexed: 12/17/2022]
Abstract
AIMS Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in Western countries and a common comorbidity with type 2 diabetes (T2D). It lacks effective pharmacotherapy. We aimed to summarize the evidence on the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on liver structure and function. MATERIALS AND METHODS Meta-analysis of randomized clinical trials in PubMed, Web of Science and ClinicalTrials.gov from their inception to April 2019. Trials evaluating liver function and/or structure and comparing SGLT2 inhibitors with placebo or other oral antidiabetic drugs in patients with T2D were included. Twenty studies (from 3033) were included. A total of 1950 patients with T2D, with or without NAFLD, were treated with SGLT2 inhibitors for at least 8 weeks, and 1900 patients were used as controls. Independent extraction was carried out by two observers. This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis. RESULTS SGLT2 inhibitors induced a significant decrease in serum alanine (-7.43U/L, [95%CI -12.14, -2.71], p < 0.01), in aspartate aminotransferases (-2.83U/L, [-4.71, -0.95], p < 0.01), as well as in gamma glutamyl transferase (-8.21U/L, [-9.52, -6.91], p < 0.01), and an increase in total plasma bilirubin (8.19% [0.79, 15.59], p < 0.01), comparing with placebo or other oral antidiabetic drugs. SGLT2 inhibitors treatment was associated with a decrease in liver steatosis (-3.39% [-6.01, -0.77], p < 0.0.1). CONCLUSIONS Treatment with SGLT2 inhibitors improves liver structure and function in patients with T2D. This meta-analysis suggests that SGLT2 inhibitors are a promising pharmacological approach for treatment of NAFLD.
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Affiliation(s)
- Francisca Dos Santos Coelho
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Marta Borges-Canha
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Madalena von Hafe
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - João Sérgio Neves
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Catarina Vale
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Ana Rita Leite
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Davide Carvalho
- Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário de São João, Porto, Portugal
- Instituto de Investigação e Inovação em Saúde (i3s), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Adelino Leite-Moreira
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Cardiovascular Research Centre (UnIC), Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Serviço de Cirurgia Cardiotorácica, Centro Hospitalar Universitário de São João, Porto, Portugal
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