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AL-Noshokaty TM, Abdelhamid R, Abdelmaksoud NM, Khaled A, Hossam M, Ahmed R, Saber T, Khaled S, Elshaer SS, Abulsoud AI. Unlocking the multifaceted roles of GLP-1: Physiological functions and therapeutic potential. Toxicol Rep 2025; 14:101895. [PMID: 39911322 PMCID: PMC11795145 DOI: 10.1016/j.toxrep.2025.101895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 02/07/2025] Open
Abstract
Glucagon (GCG) like peptide 1 (GLP-1) has emerged as a powerful player in regulating metabolism and a promising therapeutic target for various chronic diseases. This review delves into the physiological roles of GLP-1, exploring its impact on glucose homeostasis, insulin secretion, and satiety. We examine the compelling evidence supporting GLP-1 receptor agonists (GLP-1RAs) in managing type 2 diabetes (T2D), obesity, and other diseases. The intricate molecular mechanisms underlying GLP-1RAs are explored, including their interactions with pathways like extracellular signal-regulated kinase 1/2 (ERK1/2), activated protein kinase (AMPK), cyclic adenine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC). Expanding our understanding, the review investigates the potential role of GLP-1 in cancers. Also, microribonucleic acid (RNA) (miRNAs), critical regulators of gene expression, are introduced as potential modulators of GLP-1 signaling. We delve into the link between miRNAs and T2D obesity and explore specific miRNA examples influencing GLP-1R function. Finally, the review explores the rationale for seeking alternatives to GLP-1RAs and highlights natural products with promising GLP-1 modulatory effects.
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Affiliation(s)
- Tohada M. AL-Noshokaty
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Rehab Abdelhamid
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | | | - Aya Khaled
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mariam Hossam
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Razan Ahmed
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Toka Saber
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Shahd Khaled
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Shereen Saeid Elshaer
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, Egypt
| | - Ahmed I. Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11231, Egypt
- Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
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Zhou ZD, Yi L, Popławska-Domaszewicz K, Chaudhuri KR, Jankovic J, Tan EK. Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges. Pharmacol Res 2025; 216:107770. [PMID: 40344943 DOI: 10.1016/j.phrs.2025.107770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 04/10/2025] [Accepted: 05/07/2025] [Indexed: 05/11/2025]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists (GRA) belong to a class of compounds that reduce blood glucose and energy intake by simulating actions of endogenous incretin hormone GLP-1 after it is released by the gut following food consumption. They are used to treat type 2 diabetes mellitus (T2DM) and obesity and have systemic effects on various organs, including the brain, liver, pancreas, heart, and the gut. Patients with T2DM have a higher risk of developing neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), accompanied by more severe motor deficits and faster disease progression, suggesting dysregulation of insulin signaling in these diseases. Experimental studies have shown that GRA have protective effects to modulate neuroinflammation, oxidative stress, mitochondrial and autophagic functions, and protein misfolding. Hence the compounds have generated enormous interest as novel therapeutic agents against NDs. To date, clinical trials have shown that three GRA, exenatide, liraglutide and lixisenatide can improve motor deficits as an add-on therapy in PD patients and liraglutide can improve cognitive function in AD patients. The neuroprotective effects of these and other GRA, such as PT320 (a sustained-released exenatide) and semaglutide, are still under investigation. The dual GLP-1/gastric inhibitory polypeptide (GIP) receptor agonists have been demonstrated to have beneficial effects in AD and PD mice models. Overall, GRA are highly promising novel drugs, but future clinical studies should identify which subsets of patients should be targeted as potential candidates for their symptomatic and/or neuroprotective benefits, investigate whether combinations with other classes of drugs can further augment their efficacy, and evaluate their long-term disease-modifying and adverse effects.
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Affiliation(s)
- Zhi Dong Zhou
- National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, 308433, Singapore; Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, 169857, Singapore.
| | - Lingxiao Yi
- National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, 308433, Singapore.
| | - Karolina Popławska-Domaszewicz
- Department of Neurology, Poznan University of Medical Sciences, Poznan 60-355, Poland; Parkinson's Foundation Centre of Excellence, King's College Hospital, Denmark Hill, London SE5 9RS, UK.
| | - Kallol Ray Chaudhuri
- Department of Basic and Clinical Neuroscience, The Maurice Wohl Clinical Neuroscience Institute, King's College London, Cutcombe Road, London SE5 9RT, UK.
| | - Joseph Jankovic
- Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
| | - Eng King Tan
- National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, 308433, Singapore; Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, 169857, Singapore.
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Natale P, Green SC, Tunnicliffe DJ, Pellegrino G, Toyama T, Strippoli GF. Glucagon-like peptide 1 (GLP-1) receptor agonists for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev 2025; 2:CD015849. [PMID: 39963952 PMCID: PMC11834151 DOI: 10.1002/14651858.cd015849.pub2] [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] [Indexed: 02/21/2025]
Abstract
BACKGROUND Approximately 40% of people with diabetes develop kidney failure and experience an accelerated risk of cardiovascular complications. Glucagon-like peptide 1 (GLP-1) receptor agonists are glucose-lowering agents that manage glucose and weight control. OBJECTIVES We assessed the benefits and harms of GLP-1 receptor agonists in people with chronic kidney disease (CKD) and diabetes. SEARCH METHODS The Cochrane Kidney and Transplant Register of Studies was searched to 10 September 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA Randomised controlled studies were eligible if participants with diabetes and CKD were randomly allocated to a GLP-1 receptor agonist, placebo, standard care or a second glucose-lowering agent. CKD included all stages (from 1 to 5). DATA COLLECTION AND ANALYSIS Three authors independently extracted data and assessed the risk of bias using the risk of bias assessment tool 2. Pooled analyses using summary estimates of effects were obtained using a random-effects model, and results were expressed as risk ratios (RR) and/or hazard ratio (HR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. The primary outcomes included death (all-cause and cardiovascular), 3- and 4-point major adverse cardiovascular events (MACE), kidney failure, composite kidney outcome, and severe hypoglycaemia. The secondary outcomes included non-fatal or fatal myocardial infarction (MI) or stroke, non-fatal peripheral arterial events, heart failure, hospitalisation due to heart failure, estimated glomerular filtration rate or creatinine clearance, doubling of serum creatinine, urine albumin-to-creatinine ratio, albuminuria progression, vascular access outcomes, body weight, body mass index, fatigue, life participation, peritoneal dialysis infection, peritoneal dialysis failure, adverse events, serious adverse events, withdrawal due to adverse events, HbA1c, sudden death, acute MI, ischaemic stroke, and coronary revascularisation. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS Forty-two studies involving 48,148 participants were included. All studies were conducted on people with type 2 diabetes, and no studies were carried out on children. The median study age was 66 years. The median study follow-up was 26 weeks. Six studies were conducted in people with CKD stages 1-2, 11 studies in people with CKD stages 3-5, one study in people on dialysis, and the remaining studies included people with both CKD stages 1-2 and 3-5. Risks of bias in the included studies for all the primary outcomes in studies that compared GLP-1 receptor agonists to placebo were low in most methodological domains, except one study that was assessed at high risk of bias due to missing outcome data for death (all-cause and cardiovascular). The overall risk of bias for all-cause and cardiovascular death in studies that reported the treatment effects of GLP-1 receptor agonists compared to standard care, dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter 2 (SGLT2) inhibitors were assessed as unclear or at high risk of bias due to deviations from intended interventions or missing data. For GLP-1 receptor agonists compared to insulin or another GLP-1 receptor agonist, the risk of bias for all-cause and cardiovascular death was low or unclear. Compared to placebo, GLP-1 receptor agonists probably reduced the risk of all-cause death (RR 0.85, 95% CI 0.74 to 0.98; I2 = 23%; 8 studies, 17,861 participants; moderate-certainty evidence), but may have little or no effect on cardiovascular death (RR 0.84, 95% CI 0.68 to 1.05; I2 = 42%; 7 studies, 17,801 participants; low-certainty evidence). Compared to placebo, GLP-1 receptor agonists probably decreased 3-point MACE (RR 0.84, 95% CI 0.73 to 0.98; I² = 65%; 4 studies, 19,825 participants; moderate-certainty evidence), and 4-point MACE compared to placebo (RR 0.77, 95% CI 0.67 to 0.89; 1 study, 2,158 participants; moderate-certainty evidence). Based on absolute risks of clinical outcomes, it is likely that GLP-1 receptor agonists prevent all-cause death in 52 people with CKD stages 1-2 and 116 in CKD stages 3-5, cardiovascular death in 34 people with CKD stages 1-2 and 71 in CKD stages 3-5, while 95 CKD stages 1-2 and 153 in CKD stages 3-5 might experience a major cardiovascular event for every 1000 people treated over 1 year. Compared to placebo, GLP-1 receptor agonists probably had little or no effect on kidney failure, defined as starting dialysis or kidney transplant (RR 0.86, 95% CI 0.66 to 1.13; I2 = 0%; 3 studies, 4,134 participants; moderate-certainty evidence), or on composite kidney outcomes (RR 0.89, 95% CI 0.78 to 1.02; I2 = 0%; 2 studies, 16,849 participants; moderate-certainty evidence). Compared to placebo, GLP-1 receptor agonists may have little or no effect on the risk of severe hypoglycaemia (RR 0.82, 95% CI 0.54 to 1.25; I2 = 44%; 4 studies, 6,292 participants; low-certainty evidence). The effects of GLP-1 receptor agonists compared to standard care or other hypoglycaemic agents were uncertain. No studies evaluated treatment on risks of fatigue, life participation, amputation or fracture. AUTHORS' CONCLUSIONS GLP-1 receptor agonists probably reduced all-cause death but may have little or no effect on cardiovascular death in people with CKD and diabetes. GLP-1 receptor agonists probably lower major cardiovascular events, probably have little or no effect on kidney failure and composite kidney outcomes, and may have little or no effect on the risk of severe hypoglycaemia in people with CKD and diabetes.
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Affiliation(s)
- Patrizia Natale
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari Aldo Moro, Bari, Italy
| | - Suetonia C Green
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
| | | | - Giovanni Pellegrino
- Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari Aldo Moro, Bari, Italy
| | - Tadashi Toyama
- Department of Nephrology, Kanazawa University, Kanazawa, Japan
- Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan
| | - Giovanni Fm Strippoli
- Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari Aldo Moro, Bari, Italy
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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Mehta P, Rogers NM. Research Highlights. Transplantation 2024; 108:2153-2156. [PMID: 39760994 DOI: 10.1097/tp.0000000000005247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2025]
Affiliation(s)
- Paulomi Mehta
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Natasha M Rogers
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
- Sydney Medical School, Faculty of Health and Medicine, University of Sydney, Camperdown, Sydney, NSW, Australia
- Department of Renal Medicine, Westmead Hospital, Westmead, NSW, Australia
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Gutgesell RM, Nogueiras R, Tschöp MH, Müller TD. Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes. Diabetes Ther 2024; 15:1069-1084. [PMID: 38573467 PMCID: PMC11043266 DOI: 10.1007/s13300-024-01566-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: 02/09/2024] [Accepted: 03/12/2024] [Indexed: 04/05/2024] Open
Abstract
The discovery of long-acting incretin receptor agonists represents a major stride forward in tackling the dual epidemic of obesity and diabetes. Here we outline the evolution of incretin-based pharmacotherapy, from exendin-4 to the discovery of the multi-incretin hormone receptor agonists that look set to be our next step toward curing diabetes and obesity. We discuss the multiagonists currently in clinical trials and the improvement in efficacy each new generation of these drugs bring. The success of these agents in preclinical models and clinical trials suggests a promising future for multiagonists in the treatment of metabolic diseases, with the most recent glucose-dependent insulinotropic peptide receptor:glucagon-like peptide 1 receptor:glucagon receptor (GIPR:GLP-1R:GCGR) triagonists rivaling the efficacy of bariatric surgery. However, further research is needed to fully understand how these therapies exert their effect on body weight and in the last section we cover open questions about the potential mechanisms of multiagonist drugs, and the understanding of how gut-brain communication can be leveraged to achieve sustained body weight loss without adverse effects.
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Affiliation(s)
- Robert M Gutgesell
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Rubén Nogueiras
- CIBER Physiopathology of Obesity and Nutrition (CIBERobn), ISCIII, Madrid, Spain
- Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
| | - Matthias H Tschöp
- Helmholtz Munich, Neuherberg, Germany
- Division of Metabolic Diseases, Department of Medicine, Technical University of Munich, Munich, Germany
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
- Walther-Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians University, Munich, Germany.
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Sheng L, Deng M, Li X, Wan H, Lei C, Prabahar K, Hernández-Wolters B, Kord-Varkaneh H. The effect of subcutaneous Lixisenatide on weight loss in patients with type 2 Diabetes Mellitus: Systematic review and Meta-Analysis of randomized controlled trials. Diabetes Res Clin Pract 2024; 210:111617. [PMID: 38490492 DOI: 10.1016/j.diabres.2024.111617] [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: 12/17/2023] [Revised: 02/29/2024] [Accepted: 03/12/2024] [Indexed: 03/17/2024]
Abstract
BACKGROUND The impacts of subcutaneous Lixisenatide on body weight in patients with type 2 DM, remain inadequately understood; consequently, this systematic review and meta-regression analysis of randomized controlled trials (RCTs) was conducted to evaluate the influence of subcutaneous Lixisenatide administration on BW and BMI values in individuals with Type 2 diabetes. METHODS A comprehensive literature search was conducted across four databases, spanning from their inception to February 2023. We computed effect sizes employing the random-effects model and reported results in terms of weighted mean differences (WMD) along with their corresponding 95% confidence intervals (CI). RESULTS 23 articles with 26 RCT arms were included in the meta-analysis. The combined findings from a random-effects model demonstrated a significant reduction in body weight (WMD: -0.97 kg, 95 % CI: -1.10, -0.83, p < 0.001) and BMI (WMD: -0.48 kg/m2, 95 % CI: -0.67, -0.29, P < 0.001) after subcutaneous administration of Lixisenatide. Furthermore, a more pronounced reduction in body weight was discovered in RCTs lasting less than 24 weeks (WMD: -1.56 kg, 95 % CI: -2.91, -0.20, p < 0.001), employing a daily dosage of subcutaneous Lixisenatide lower than 19 µg per day (WMD: -1.94 kg, 95 % CI: -2.54, -1.34, p < 0.001) and with a mean participant age of 60 years or more (WMD: -1.86 kg, 95 % CI: -3.16, -0.57, p = 0.005). CONCLUSIONS Lixisenatide was found to significantly decrease BW and BMI in patients with type 2 DM and could be considered as a therapeutic option for those suffering from weight gain caused by other anti-diabetic agents. However, while prescribing Lixisenatide, careful consideration of patient-specific factors is recommended.
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Affiliation(s)
- Lei Sheng
- Department of Health Management Center, the Fifth Hospital of Wuhan, Wuhan, Hubei 430050, China
| | - Meixian Deng
- Department of Gynecology, the Fifth Hospital of Wuhan, Wuhan, Hubei 430050, China
| | - Xin Li
- Department of Neurology, the Fifth Hospital of Wuhan, Wuhan, Hubei 430050, China
| | - Huan Wan
- Department of Neurology, the Fifth Hospital of Wuhan, Wuhan, Hubei 430050, China; Department of Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China.
| | - Changjiang Lei
- Department of Oncology, the Fifth Hospital of Wuhan, Wuhan, Hubei 430050, China.
| | - Kousalya Prabahar
- Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | | | - Hamed Kord-Varkaneh
- Department of Nutrition and Food Hygiene, School of Medicine, Nutrition Health Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
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Deng W, Zhao Z, Zou T, Kuang T, Wang J. Research Advances in Fusion Protein-Based Drugs for Diabetes Treatment. Diabetes Metab Syndr Obes 2024; 17:343-362. [PMID: 38288338 PMCID: PMC10823413 DOI: 10.2147/dmso.s421527] [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: 07/10/2023] [Accepted: 12/22/2023] [Indexed: 01/31/2024] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disease characterized by elevated blood glucose levels, resulting in multi-organ dysfunction and various complications. Fusion proteins can form multifunctional complexes by combining the target proteins with partner proteins. It has significant advantages in improving the performance of the target proteins, extending their biological half-life, and enhancing patient drug compliance. Fusion protein-based drugs have emerged as promising new drugs in diabetes therapeutics. However, there has not been a systematic review of fusion protein-based drugs for diabetes therapeutics. Hence, we conducted a comprehensive review of published literature on diabetic fusion protein-based drugs for diabetes, with a primary focus on immunoglobulin G (IgG) fragment crystallizable (Fc) region, albumin, and transferrin (TF). This review aims to provide a reference for the subsequent development and clinical application of fusion protein-based drugs in diabetes therapeutics.
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Affiliation(s)
- Wenying Deng
- School of Basic Medical Sciences, University of South China, Hengyang, Hunan Province, 421001, People’s Republic of China
| | - Zeyi Zhao
- School of Basic Medical Sciences, University of South China, Hengyang, Hunan Province, 421001, People’s Republic of China
| | - Tao Zou
- Department of Cardiovascular Medicine, First Affiliated Hospital of University of South China, Hengyang, Hunan Province, 421001, People’s Republic of China
| | - Tongdong Kuang
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi Province, 541199, People’s Republic of China
| | - Jing Wang
- School of Basic Medical Sciences, University of South China, Hengyang, Hunan Province, 421001, People’s Republic of China
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Venkatesan K, Haroon NN. Management of Metabolic-Associated Fatty Liver Disease. Endocrinol Metab Clin North Am 2023; 52:547-557. [PMID: 37495344 DOI: 10.1016/j.ecl.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/28/2023]
Abstract
Metabolic-associated fatty liver disease (MAFLD), previously known as nonalcoholic fatty liver disease (NAFLD), is the most common cause of liver disease in the world. Its prevalence is over 30% and is becoming the most common cause of liver transplants. Rates are rising along with obesity-related diseases. Risk factors for MAFLD include adverse lifestyles, genetic variations, advancing age, male sex, and alterations in the gut microbiota. Extrahepatic complications include cardiovascular disease, renal dysfunction, and colorectal cancer. As there are no currently approved medications for MAFLD, management mainly focuses on lifestyle modifications.
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Affiliation(s)
- Kirthika Venkatesan
- Caribbean Medical University School of Medicine, 25 Pater Euwensweg, Willemstad, Curaçao; Walden University, 650 South Exerter Street, Baltimore, MD 21202, USA
| | - Nisha Nigil Haroon
- Clinical Sciences Division, Northern Ontario School of Medicine, Sudbury, Ontario, Canada; Health Sciences North Research Institute, Sudbury, Ontario, Canada.
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Popoviciu MS, Păduraru L, Yahya G, Metwally K, Cavalu S. Emerging Role of GLP-1 Agonists in Obesity: A Comprehensive Review of Randomised Controlled Trials. Int J Mol Sci 2023; 24:10449. [PMID: 37445623 DOI: 10.3390/ijms241310449] [Citation(s) in RCA: 94] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 06/13/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Obesity is a chronic disease with high prevalence and associated comorbidities, making it a growing global concern. These comorbidities include type 2 diabetes, hypertension, ventilatory dysfunction, arthrosis, venous and lymphatic circulation diseases, depression, and others, which have a negative impact on health and increase morbidity and mortality. GLP-1 agonists, used to treat type 2 diabetes, have been shown to be effective in promoting weight loss in preclinical and clinical studies. This review summarizes numerous studies conducted on the main drugs in the GLP-1 agonists class, outlining the maximum achievable weight loss. Our aim is to emphasize the active role and main outcomes of GLP-1 agonists in promoting weight loss, as well as in improving hyperglycemia, insulin sensitivity, blood pressure, cardio-metabolic, and renal protection. We highlight the pleiotropic effects of these medications, along with their indications, contraindications, and precautions for both diabetic and non-diabetic patients, based on long-term follow-up studies.
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Affiliation(s)
- Mihaela-Simona Popoviciu
- Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410073 Oradea, Romania
| | - Lorena Păduraru
- Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410073 Oradea, Romania
| | - Galal Yahya
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Al Sharqia 44519, Egypt
- Department of Molecular Genetics, Faculty of Biology, Technical University of Kaiserslautern, Paul-Ehrlich Str. 24, 67663 Kaiserslautern, Germany
| | - Kamel Metwally
- Department of Medicinal Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia
- Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | - Simona Cavalu
- Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410073 Oradea, Romania
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Haddad F, Dokmak G, Bader M, Karaman R. A Comprehensive Review on Weight Loss Associated with Anti-Diabetic Medications. Life (Basel) 2023; 13:1012. [PMID: 37109541 PMCID: PMC10144237 DOI: 10.3390/life13041012] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/11/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
Obesity is a complex metabolic condition that can have a negative impact on one's health and even result in mortality. The management of obesity has been addressed in a number of ways, including lifestyle changes, medication using appetite suppressants and thermogenics, and bariatric surgery for individuals who are severely obese. Liraglutide and semaglutide are two of the five Food and Drug Administration (FDA)-approved anti-obesity drugs that are FDA-approved agents for the treatment of type 2 diabetes mellitus (T2DM) patients. In order to highlight the positive effects of these drugs as anti-obesity treatments, we analyzed the weight loss effects of T2DM agents that have demonstrated weight loss effects in this study by evaluating clinical studies that were published for each agent. Many clinical studies have revealed that some antihyperglycemic medications can help people lose weight, while others either cause weight gain or neutral results. Acarbose has mild weight loss effects and metformin and sodium-dependent glucose cotransporter proteins-2 (SGLT-2) inhibitors have modest weight loss effects; however, some glucagon-like peptide-1 (GLP-1) receptor agonists had the greatest impact on weight loss. Dipeptidyl peptidase 4 (DPP-4) inhibitors showed a neutral or mild weight loss effect. To sum up, some of the GLP-1 agonist drugs show promise as weight-loss treatments.
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Affiliation(s)
- Fatma Haddad
- Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem 9103401, Palestine; (F.H.); (G.D.); (M.B.)
- Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK
| | - Ghadeer Dokmak
- Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem 9103401, Palestine; (F.H.); (G.D.); (M.B.)
| | - Maryam Bader
- Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem 9103401, Palestine; (F.H.); (G.D.); (M.B.)
| | - Rafik Karaman
- Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem 9103401, Palestine; (F.H.); (G.D.); (M.B.)
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy
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Austin GO, Tomas A. Variation in responses to incretin therapy: Modifiable and non-modifiable factors. Front Mol Biosci 2023; 10:1170181. [PMID: 37091864 PMCID: PMC10119428 DOI: 10.3389/fmolb.2023.1170181] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 03/28/2023] [Indexed: 04/25/2023] Open
Abstract
Type 2 diabetes (T2D) and obesity have reached epidemic proportions. Incretin therapy is the second line of treatment for T2D, improving both blood glucose regulation and weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-stimulated insulinotropic polypeptide (GIP) are the incretin hormones that provide the foundations for these drugs. While these therapies have been highly effective for some, the results are variable. Incretin therapies target the class B G protein-coupled receptors GLP-1R and GIPR, expressed mainly in the pancreas and the hypothalamus, while some therapeutical approaches include additional targeting of the related glucagon receptor (GCGR) in the liver. The proper functioning of these receptors is crucial for incretin therapy success and here we review several mechanisms at the cellular and molecular level that influence an individual's response to incretin therapy.
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Affiliation(s)
| | - Alejandra Tomas
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
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12
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Wang JY, Wang QW, Yang XY, Yang W, Li DR, Jin JY, Zhang HC, Zhang XF. GLP-1 receptor agonists for the treatment of obesity: Role as a promising approach. Front Endocrinol (Lausanne) 2023; 14:1085799. [PMID: 36843578 PMCID: PMC9945324 DOI: 10.3389/fendo.2023.1085799] [Citation(s) in RCA: 99] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 01/02/2023] [Indexed: 02/04/2023] Open
Abstract
Obesity is a complex disease characterized by excessive fat accumulation which is caused by genetic, environmental and other factors. In recent years, there has been an increase in the morbidity, disability rate,and mortality due to obesity, making it great threat to people's health and lives, and increasing public health care expenses. Evidence from previous studies show that weight loss can significantly reduce the risk of obesity-related complications and chronic diseases. Diet control, moderate exercise, behavior modification programs, bariatric surgery and prescription drug treatment are the major interventions used to help people lose weight. Among them, anti-obesity drugs have high compliance rates and cause noticeable short-term effects in reducing obese levels. However, given the safety or effectiveness concerns of anti-obesity drugs, many of the currently used drugs have limited clinical use. Glucagon-like peptide-1 receptor (GLP-1R) agonists are a group of drugs that targets incretin hormone action, and its receptors are widely distributed in nerves, islets, heart, lung, skin, and other organs. Several animal experiments and clinical trials have demonstrated that GLP-1R agonists are more effective in treating or preventing obesity. Therefore, GLP-1R agonists are promising agents for the treatment of obese individuals. This review describes evidence from previous research on the effects of GLP-1R agonists on obesity. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop obesity treatments based on GLP-1R agonists.
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Affiliation(s)
- Jing-Yue Wang
- Department of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun, China
| | - Quan-Wei Wang
- Department of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun, China
| | - Xin-Yu Yang
- Department of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun, China
| | - Wei Yang
- Department of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun, China
| | - Dong-Rui Li
- Department of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun, China
| | - Jing-Yu Jin
- Department of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun, China
| | - Hui-Cong Zhang
- Department of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun, China
| | - Xian-Feng Zhang
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
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13
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Jeeyavudeen MS, Khan SKA, Fouda S, Pappachan JM. Management of metabolic-associated fatty liver disease: The diabetology perspective. World J Gastroenterol 2023; 29:126-143. [PMID: 36683717 PMCID: PMC9850951 DOI: 10.3748/wjg.v29.i1.126] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/26/2022] [Accepted: 12/13/2022] [Indexed: 01/04/2023] Open
Abstract
The metabolic syndrome as a consequence of the obesity pandemic resulted in a substantial increase in the prevalence of metabolic-associated fatty live disease (MAFLD) and type 2 diabetes mellitus (T2DM). Because of the similarity in pathobiology shared between T2DM and MAFLD, both disorders coexist in many patients and may potentiate the disease-related outcomes with rapid progression and increased complications of the individual diseases. In fact, awareness about this coexistence and the risk of complications are often overlooked by both hepatologists and diabetologists. Management of these individual disorders in a patient should be addressed wholistically using an appropriate multidisciplinary team approach involving both the specialists and, when necessary, liaising with dieticians and surgeons. This comprehensive review is to compile the current evidence from a diabetologist's perspective on MAFLD and T2DM and to suggest optimal management strategies.
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Affiliation(s)
- Mohammad Sadiq Jeeyavudeen
- Department of Endocrinology and Metabolism, University Hospitals of Edinburgh, Edinburgh EH4 2XU, United Kingdom
| | - Shahanas K A Khan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
| | - Sherouk Fouda
- School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC 3046, Australia
| | - 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, University of Manchester, Manchester M13 9PL, United Kingdom
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14
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Choice of Glucose-Lowering Drugs as Initial Monotherapy for Type 2 Diabetes Patients with Contraindications or Intolerance to Metformin: A Systematic Review and Meta-Analysis. J Clin Med 2022; 11:jcm11237094. [PMID: 36498669 PMCID: PMC9740076 DOI: 10.3390/jcm11237094] [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: 10/31/2022] [Revised: 11/24/2022] [Accepted: 11/27/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND There are multiple glucose-lowering drugs available as alternative initial monotherapy for type 2 diabetes patients with contraindications or intolerance to metformin. However, little comparative and systematic data are available for them as initial monotherapy. This study estimated and compared the treatment effects of glucose-lowering drugs as initial monotherapy for type 2 diabetes. METHODS PubMed, Web of Science, Embase, CNKI, Chongqing VIP, and WanFang Data from 1 January 1990 until 31 December 2020 were searched for randomized controlled trials which compared a glucose-lowering drug with placebo/lifestyle-intervention for type 2 diabetes. Drug classes included metformin, sulfonylureas (SUs), thiazolidinediones (TZDs), glinides (NIDEs), α-glucosidase inhibitors (AGIs), dipeptidyl peptidase-4 inhibitors (DPP-4is), sodium-glucose cotransporter-2 inhibitors (SGLT2is), insulins (INSs), and glucagon-like peptide-1 receptor agonists (GLP-1RAs). RESULTS A total of 185 trials were included, identifying 38,376 patients from 56 countries across six continents. When choosing an initial drug monotherapy alternative to metformin, SUs were most efficacious in reducing HbA1c (-1.39%; 95% CI -1.63, -1.16) and FPG (-2.70 mmol/L; 95% CI -3.18, -2.23), but increased hypoglycemia risks (5.44; 95% CI 2.11, 14.02). GLP-1RAs were most efficacious in reducing BMI (-1.05 kg/m2; 95% CI -1.81, -0.29) and TC (-0.42 mmol/L; 95% CI -0.61, -0.22). TZDs were most efficacious in increasing HDL-C (0.12 mmol/L; 95% CI 0.07, 0.17). SGLT2is were most efficacious in lowering SBP (-4.18 mmHg; 95% CI -4.84, -3.53). While AGIs conferred higher risk of AE-induced discontinuations (2.57; 95% CI 1.64, 4.03). Overall, only GLP-1RAs showed an integrated beneficial effect on all outcomes. Our results also confirmed the intraclass differences in treatment effects across drugs. Most trials were short-term, and no significant differences in mortality, total vascular events, myocardial infarction, heart failure, stroke, or diabetic nephropathy were observed across drug classes. CONCLUSIONS Our results suggest a potential treatment hierarchy for decision-makers, with GLP-1RAs being the preferred alternative therapy to metformin regarding their favorable efficacy and safety profiles.
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Abe M, Matsuoka T, Kawamoto S, Miyasato K, Kobayashi H. Toward Revision of the ‘Best Practice for Diabetic Patients on Hemodialysis 2012’. KIDNEY AND DIALYSIS 2022; 2:495-511. [DOI: 10.3390/kidneydial2040045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Diabetic nephropathy is the leading cause of dialysis therapy worldwide. The number of diabetes patients on dialysis in clinical settings has been increasing in Japan. In 2013, the Japanese Society for Dialysis Therapy (JSDT) published the “Best Practice for Diabetic Patients on Hemodialysis 2012”. While glycated hemoglobin (HbA1c) is used mainly as a glycemic control index for dialysis patients overseas, Japan is the first country in the world to use glycated albumin (GA) for assessment. According to a survey conducted by the JSDT in 2018, the number of facilities measuring only HbA1c has decreased compared with 2013, while the number of facilities measuring GA or both has significantly increased. Ten years have passed since the publication of the first edition of the guidelines, and several clinical studies regarding the GA value and mortality of dialysis patients have been reported. In addition, novel antidiabetic agents have appeared, and continuous glucose monitoring of dialysis patients has been adopted. On the other hand, Japanese dialysis patients are rapidly aging, and the proportion of patients with malnutrition is increasing. Therefore, there is great variation among diabetes patients on dialysis with respect to their backgrounds and characteristics. This review covers the indices and targets of glycemic control, the treatment of hyperglycemia, and diet recommendations for dialysis patients with diabetes.
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Affiliation(s)
- Masanori Abe
- Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Tomomi Matsuoka
- Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Shunsuke Kawamoto
- Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Kota Miyasato
- Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Hiroki Kobayashi
- Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan
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16
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Blonde L, Umpierrez GE, Reddy SS, McGill JB, Berga SL, Bush M, Chandrasekaran S, DeFronzo RA, Einhorn D, Galindo RJ, Gardner TW, Garg R, Garvey WT, Hirsch IB, Hurley DL, Izuora K, Kosiborod M, Olson D, Patel SB, Pop-Busui R, Sadhu AR, Samson SL, Stec C, Tamborlane WV, Tuttle KR, Twining C, Vella A, Vellanki P, Weber SL. American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. Endocr Pract 2022; 28:923-1049. [PMID: 35963508 PMCID: PMC10200071 DOI: 10.1016/j.eprac.2022.08.002] [Citation(s) in RCA: 234] [Impact Index Per Article: 78.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers. METHODS The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RESULTS This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes. CONCLUSIONS This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.
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Affiliation(s)
| | | | - S Sethu Reddy
- Central Michigan University, Mount Pleasant, Michigan
| | | | | | | | | | | | - Daniel Einhorn
- Scripps Whittier Diabetes Institute, La Jolla, California
| | | | | | - Rajesh Garg
- Lundquist Institute/Harbor-UCLA Medical Center, Torrance, California
| | | | | | | | | | | | - Darin Olson
- Colorado Mountain Medical, LLC, Avon, Colorado
| | | | | | - Archana R Sadhu
- Houston Methodist; Weill Cornell Medicine; Texas A&M College of Medicine; Houston, Texas
| | | | - Carla Stec
- American Association of Clinical Endocrinology, Jacksonville, Florida
| | | | - Katherine R Tuttle
- University of Washington and Providence Health Care, Seattle and Spokane, Washington
| | | | | | | | - Sandra L Weber
- University of South Carolina School of Medicine-Greenville, Prisma Health System, Greenville, South Carolina
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Pang J, Feng JN, Ling W, Jin T. The anti-inflammatory feature of glucagon-like peptide-1 and its based diabetes drugs—Therapeutic potential exploration in lung injury. Acta Pharm Sin B 2022; 12:4040-4055. [PMID: 36386481 PMCID: PMC9643154 DOI: 10.1016/j.apsb.2022.06.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/25/2022] [Accepted: 06/01/2022] [Indexed: 12/02/2022] Open
Abstract
Since 2005, GLP-1 receptor (GLP-1R) agonists (GLP-1RAs) have been developed as therapeutic agents for type 2 diabetes (T2D). GLP-1R is not only expressed in pancreatic islets but also other organs, especially the lung. However, controversy on extra-pancreatic GLP-1R expression still needs to be further resolved, utilizing different tools including the use of more reliable GLP-1R antibodies in immune-staining and co-immune-staining. Extra-pancreatic expression of GLP-1R has triggered extensive investigations on extra-pancreatic functions of GLP-1RAs, aiming to repurpose them into therapeutic agents for other disorders. Extensive studies have demonstrated promising anti-inflammatory features of GLP-1RAs. Whether those features are directly mediated by GLP-1R expressed in immune cells also remains controversial. Following a brief review on GLP-1 as an incretin hormone and the development of GLP-1RAs as therapeutic agents for T2D, we have summarized our current understanding of the anti-inflammatory features of GLP-1RAs and commented on the controversy on extra-pancreatic GLP-1R expression. The main part of this review is a literature discussion on GLP-1RA utilization in animal models with chronic airway diseases and acute lung injuries, including studies on the combined use of mesenchymal stem cell (MSC) based therapy. This is followed by a brief summary.
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18
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Terauchi Y, Usami M, Inoue T. The Durable Safety and Effectiveness of Lixisenatide in Japanese People with Type 2 Diabetes: The Post-Marketing Surveillance PRANDIAL Study. Adv Ther 2022; 39:2873-2888. [PMID: 35449321 PMCID: PMC9122860 DOI: 10.1007/s12325-022-02121-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 03/09/2022] [Indexed: 11/30/2022]
Abstract
Introduction Real-world evidence on lixisenatide in Japanese people with type 2 diabetes (T2D) is lacking. Therefore, the 3-year post-marketing PRANDIAL study was conducted to evaluate the safety (primary objective) and effectiveness (secondary objective) of lixisenatide in Japanese people with T2D during routine clinical practice. Methods This prospective, observational, multicenter, open-label study was conducted in Japanese individuals with T2D who initiated lixisenatide treatment between March 2014 and June 2017. Using electronic case report forms, investigators collected baseline demographic and clinical information and data on medications, safety and effectiveness up to 3 years after initiation of lixisenatide. Results Overall, 3046 participants were analyzed; their mean ± standard deviation (SD) age was 58.9 ± 13.1 years, and 53.7% were male. Mean ± SD duration of T2D was 12.8 ± 8.6 years, and baseline glycated hemoglobin (HbA1c) was 8.7% ± 1.7%. Most participants (93.9%) were receiving concomitant antidiabetic medications when they initiated lixisenatide. Median (range) lixisenatide treatment duration was 382 (1–1096) days. Adverse drug reactions (ADRs) were reported in 604 participants (19.8%) and serious ADRs in 22 (0.7%). The most common ADR was nausea (9.0%). Of ADRs of special interest, hypoglycemia occurred in 2.9% of participants, injection site reactions in 0.9%, and hypoglycemic unconsciousness in 0.03%. Baseline characteristics associated with an increased risk of ADRs (p < 0.05) were history of treatment for cardiovascular disease, hepatic dysfunction, and other complications. Effectiveness was analyzed in 2675 participants; HbA1c, fasting plasma glucose, postprandial glucose, and body weight all decreased significantly at last observation (all p < 0.0001 vs. baseline). Conclusions Lixisenatide was well tolerated, with no unexpected ADRs or new safety signals identified, and showed effective glycemic control and weight reduction up to 3 years, supporting the use of lixisenatide as a safe and effective treatment option for T2D in routine clinical practice in Japan. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-022-02121-5. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are antidiabetic drugs that lower blood glucose levels by stimulating the release of insulin and suppressing glucagon, the key hormones involved in controlling blood glucose levels in the body. The selective GLP-1RA lixisenatide was approved for the management of adults with type 2 diabetes (T2D) in Japan based on data from randomized clinical trials. However, these studies may not be representative of the safety and effectiveness of the drug when used in routine clinical practice. Therefore, we conducted the 3-year post-marketing PRANDIAL study to assess the safety and effectiveness of lixisenatide in 3046 Japanese individuals with T2D who started the drug between March 2014 and June 2017. Adverse drug reactions (adverse events for which lixisenatide causality could not be excluded) occurred in 19.8% of participants, with the most common adverse drug reaction being nausea. Hypoglycemia (abnormally low blood glucose levels) was reported in 2.9%. Individuals with a history of treatment for cardiovascular disease, hepatic dysfunction, and other complications had an increased risk of adverse drug reactions. Lixisenatide provided significant improvements in blood glucose control, with significant decreases in glycated hemoglobin (a marker of blood glucose control), fasting plasma glucose, and postprandial glucose levels from baseline, as well as significant reductions in body weight. In this real-world post-marketing surveillance study, lixisenatide was well tolerated, raising no new safety concerns, and provided durable effective blood glucose control and weight reduction. These results support the use of lixisenatide in Japanese individuals with T2D in routine clinical practice.
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Affiliation(s)
- Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Makiko Usami
- Post-Authorization Regulatory Studies, Sanofi K.K., Opera City Tower, 3-20-2 Nishi-Shinjuku, Shinjuku-ku, Tokyo, 163-1488, Japan.
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Abdelhaleem IA, Abd-Elhamied MA, Morsi AE, Kenawy S. Efficacy and safety of efpeglenatide in adults with obesity and its associated metabolic disturbance: A systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab 2022; 24:555-560. [PMID: 34766431 DOI: 10.1111/dom.14602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/26/2021] [Accepted: 11/06/2021] [Indexed: 11/28/2022]
Affiliation(s)
- Ibrahim A Abdelhaleem
- Faculty of Medicine, Zagazig University, Zagazig, Egypt
- Zagazig Medical Research Society, Zagazig, Egypt
| | - Mohamed A Abd-Elhamied
- Faculty of Medicine, Zagazig University, Zagazig, Egypt
- Zagazig Medical Research Society, Zagazig, Egypt
| | - Ahmed E Morsi
- Faculty of Medicine, Zagazig University, Zagazig, Egypt
- Zagazig Medical Research Society, Zagazig, Egypt
| | - Samar Kenawy
- Zagazig Medical Research Society, Zagazig, Egypt
- Resident physician, Primary Health Sector, Ministry of Health and Population, Cairo, Egypt
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Tan Q, Akindehin SE, Orsso CE, Waldner RC, DiMarchi RD, Müller TD, Haqq AM. Recent Advances in Incretin-Based Pharmacotherapies for the Treatment of Obesity and Diabetes. Front Endocrinol (Lausanne) 2022; 13:838410. [PMID: 35299971 PMCID: PMC8921987 DOI: 10.3389/fendo.2022.838410] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/07/2022] [Indexed: 01/01/2023] Open
Abstract
The incretin hormone glucagon-like peptide-1 (GLP-1) has received enormous attention during the past three decades as a therapeutic target for the treatment of obesity and type 2 diabetes. Continuous improvement of the pharmacokinetic profile of GLP-1R agonists, starting from native hormone with a half-life of ~2-3 min to the development of twice daily, daily and even once-weekly drugs highlight the pharmaceutical evolution of GLP-1-based medicines. In contrast to GLP-1, the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) received little attention as a pharmacological target, because of conflicting observations that argue activation or inhibition of the GIP receptor (GIPR) provides beneficial effects on systemic metabolism. Interest in GIPR agonism for the treatment of obesity and diabetes was recently propelled by the clinical success of unimolecular dual-agonists targeting the receptors for GIP and GLP-1, with reported significantly improved body weight and glucose control in patients with obesity and type II diabetes. Here we review the biology and pharmacology of GLP-1 and GIP and discuss recent advances in incretin-based pharmacotherapies.
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Affiliation(s)
- Qiming Tan
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Seun E. Akindehin
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Germany and German Center for Diabetes Research (DZD), Munich, Germany
| | - Camila E. Orsso
- Department of Agricultural Food & Nutritional Science, University of Alberta, Edmonton, AB, Canada
| | | | | | - Timo D. Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Germany and German Center for Diabetes Research (DZD), Munich, Germany
- *Correspondence: Timo D. Müller, ; Andrea M. Haqq,
| | - Andrea M. Haqq
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
- Department of Agricultural Food & Nutritional Science, University of Alberta, Edmonton, AB, Canada
- *Correspondence: Timo D. Müller, ; Andrea M. Haqq,
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Rosenberg J, Jacob J, Desai P, Park J, Donovan L, Kim JY. Incretin Hormones: Pathophysiological Risk Factors and Potential Targets for Type 2 Diabetes. J Obes Metab Syndr 2021; 30:233-247. [PMID: 34521773 PMCID: PMC8526293 DOI: 10.7570/jomes21053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 07/11/2021] [Accepted: 07/14/2021] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes (T2D) is a multifaceted metabolic disorder associated with distinctive pathophysiological disturbances. One of the pathophysiological risk factors observed in T2D is dysregulation of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Both hormones stimulate insulin secretion by acting postprandially on pancreatic β-cell receptors. Oral glucose administration stimulates increased insulin secretion in comparison with isoglycemic intravenous glucose administration, a phenomenon known as the incretin effect. While the evidence for incretin defects in individuals with T2D is growing, the etiology behind this attenuated incretin effect in T2D is not clearly understood. Given their central role in T2D pathophysiology, incretins are promising targets for T2D therapeutics. The present review synthesizes the recent attempts to explain the biological importance of incretin hormones and explore potential pharmacological approaches that target the incretins.
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Affiliation(s)
- Jared Rosenberg
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Jordan Jacob
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Priya Desai
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Jeremy Park
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Lorin Donovan
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Joon Young Kim
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
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22
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Liu F, Liu Y, Liu M, Wu G, Zhang M, Zhang X, Cui N, Yin H, Chen L. Efficacy of once-daily glucagon-like peptide-1 receptor agonist lixisenatide as an add-on treatment to basal insulin in Asian and white adults with type 2 diabetes mellitus: An individual-level pooled analysis of phase III studies. J Diabetes Investig 2021; 12:1386-1394. [PMID: 33475222 PMCID: PMC8354505 DOI: 10.1111/jdi.13504] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 12/11/2020] [Accepted: 01/01/2021] [Indexed: 11/29/2022] Open
Abstract
AIMS/INTRODUCTION The prevalence and pathophysiological background of type 2 diabetes mellitus vary across ethnicities, and can affect treatment responses. Adding lixisenatide to basal insulin (BI) in type 2 diabetes mellitus patients has shown improvements in glycated hemoglobin (HbA1c) and postprandial glycemic (PPG) excursions, without increasing hypoglycemic events. We aim to compare the efficacy of lixisenatide in Asian and white patients inadequately controlled with basal insulin. MATERIALS AND METHODS An individual-level pooled analysis of two multi-national phase III studies, GetGoal-L and GetGoal-L-C, was carried out to assess the efficacy of lixisenatide versus placebo as an add-on treatment to BI ± metformin in Asian and white patients with type 2 diabetes mellitus. Change in HbA1c, 2-h PPG and PPG excursion were analyzed, along with possible predictors of glycemic control. RESULTS Pooled data showed that baseline characteristics were similar between Asian and white patients with the exception of bodyweight, body mass index and BI dose being higher in white patients. After 24 weeks, lixisenatide reduced HbA1c in both ethnic groups, with no statistically significant difference between the two groups (Asian patients least squares mean difference -0.49, 95% confidence interval -0.68 to - 0.30 and white patients least squares mean difference -0.45, 95% confidence interval -0.63 to - 0.26; P = 0.6287). Similarly, no significant difference was found in 2-h PPG reduction between both groups (least squares mean difference for Asian vs white patients: -3.37 vs -3.93; P = 0.3203). Treatment with lixisenatide contributed to HbA1c reduction of -0.56% after adjustment of baseline HbA1c level in Asian patients, and -0.41% in white patients. CONCLUSIONS Adding lixisenatide to BI significantly reduced HbA1c and 2-h PPG levels in both Asian and white participants with type 2 diabetes mellitus. No differences in treatment effect were observed between the two populations.
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Affiliation(s)
- Fuqiang Liu
- Department of EndocrinologyQilu Hospital of Shandong UniversityJinanChina
| | - Yuan Liu
- Department of EndocrinologyQilu Hospital of Shandong UniversityJinanChina
| | - Minzhi Liu
- BDM Consulting, Inc.SomersetNew JerseyUSA
| | - Guangyu Wu
- Sanofi Investment Co., Ltd.ShanghaiChina
| | | | - Xia Zhang
- Sanofi Investment Co., Ltd.ShanghaiChina
| | - Nan Cui
- Sanofi Investment Co., Ltd.ShanghaiChina
| | - Huiqiu Yin
- Sanofi Investment Co., Ltd.ShanghaiChina
| | - Li Chen
- Department of EndocrinologyQilu Hospital of Shandong UniversityJinanChina
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23
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González-González JG, Díaz González-Colmenero A, Millán-Alanís JM, Lytvyn L, Solis RC, Mustafa RA, Palmer SC, Li S, Hao Q, Alvarez-Villalobos NA, Vandvik PO, Rodríguez-Gutiérrez R. Values, preferences and burden of treatment for the initiation of GLP-1 receptor agonists and SGLT-2 inhibitors in adult patients with type 2 diabetes: a systematic review. BMJ Open 2021; 11:e049130. [PMID: 34244276 PMCID: PMC8273479 DOI: 10.1136/bmjopen-2021-049130] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 03/19/2021] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES Assess values, preferences and burden of treatment that patients with type 2 diabetes consider when initiating glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared with other glucose-lowering options. METHODS Paired reviewers independently included studies reporting quantitative or qualitative methods to assess values, preferences and burden of treatment reported by patients with type 2 diabetes regarding the initiation of GLP-1 RA or SGLT-2i over other alternatives. A systematic search in MEDLINE, Scopus, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials from inception until May 2020 was performed by an experienced librarian. Risk of bias was assessed with a specifically designed tool for values and preferences studies. RESULTS 17 studies (7296 patients) proved eligible. Studies fulfilling criteria for SGLT-2i were not identified. Five studies (2662 patients) evaluated preferences for GLP-1 RA compared with other glucose-lowering medications. 12 studies (4634 patients) evaluated preferences between, at least, two kinds of GLP-1 RA or their injection devices based on the following attributes: efficacy, dose, application frequency, device characteristics. Among studies comparing GLP-1 RA to other glucose-lowering medications, some preferences were observed for dypeptil peptidase-4 inhibitors compared with once daily liraglutide. Comparing different attributes of GLP-1 RA drugs and devices, cardiovascular risk reduction, glucose lowering potential, once weekly and simple administered regimens were the most preferred. CONCLUSIONS As no evidence for preferences on SGLT-2i was available, only preferences for GLP-1 RA were assessed; however, evidence is still limited for the latter. Studies comparing preferences for GLP1-RA to other glucose-lowering alternatives only included twice daily or once daily injection regimens of GLP-1 RA drugs. According to our findings, once weekly alternatives are widely preferred than the formers. The extent to which patients with type 2 diabetes value reduced adverse cardiovascular and kidney outcomes, weighed benefits against harms and burden of treatment is limited and with very low certainty. PROSPERO REGISTRATION NUMBER CRD42020159284.
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Affiliation(s)
- José Gerardo González-González
- Plataforma INVEST Medicina UANL-KER Unit Mayo Clinic (KER Unit Mexico), Universidad Autonoma de Nuevo Leon Facultad de Medicina, Monterrey, Nuevo León, Mexico
- Endocrinology Division, Department of Internal Medicine, Hospital Universitario Dr José Eleuterio González, Monterrey, Nuevo León, Mexico
| | - Alejandro Díaz González-Colmenero
- Plataforma INVEST Medicina UANL-KER Unit Mayo Clinic (KER Unit Mexico), Universidad Autonoma de Nuevo Leon Facultad de Medicina, Monterrey, Nuevo León, Mexico
| | - Juan Manuel Millán-Alanís
- Plataforma INVEST Medicina UANL-KER Unit Mayo Clinic (KER Unit Mexico), Universidad Autonoma de Nuevo Leon Facultad de Medicina, Monterrey, Nuevo León, Mexico
| | - Lyubov Lytvyn
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Ricardo Cesar Solis
- Plataforma INVEST Medicina UANL-KER Unit Mayo Clinic (KER Unit Mexico), Universidad Autonoma de Nuevo Leon Facultad de Medicina, Monterrey, Nuevo León, Mexico
| | - Reem A Mustafa
- Internal Medicine, Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Suetonia C Palmer
- Department of Medicine, University of Otago, Christchurch, Christchurch, New Zealand
| | - Sheyu Li
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Division of Population Health and Genomics, Ninewells Hospital and School of Medicine, University of Dundee, Dundee, UK
| | - Qiukui Hao
- The center of Gerontology and Geriatrics, National Center for Geriatric Clinical Research, Sichuan University, Chengdu, Sichuan, China
| | - Neri Alejandro Alvarez-Villalobos
- Plataforma INVEST Medicina UANL-KER Unit Mayo Clinic (KER Unit Mexico), Universidad Autonoma de Nuevo Leon Facultad de Medicina, Monterrey, Nuevo León, Mexico
| | - Per Olav Vandvik
- Department of Medicine, Lovisenberg Diakonale Hospital, Oslo, Norway
| | - René Rodríguez-Gutiérrez
- Plataforma INVEST Medicina UANL-KER Unit Mayo Clinic (KER Unit Mexico), Universidad Autonoma de Nuevo Leon Facultad de Medicina, Monterrey, Nuevo León, Mexico
- Endocrinology Division, Department of Internal Medicine, Hospital Universitario Dr José Eleuterio González, Monterrey, Nuevo León, Mexico
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Tarazi MS, Touhamy S, Tchang BG, Shukla AP. Combined medical strategies for the management of type 2 diabetes mellitus and obesity in adults. Expert Opin Pharmacother 2021; 22:2199-2220. [PMID: 34165376 DOI: 10.1080/14656566.2021.1942841] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Given the relationship between the pathogenesis of obesity and type 2 diabetes mellitus (T2DM) as well as their significant health consequences, treatment strategies that can induce weight loss while achieving glycemic control are needed. Novel weight-reducing anti-diabetic agents along with anti-obesity medications (AOMs) can help medical providers address both conditions simultaneously and effectively. AREAS COVERED This review summarizes and compares weight loss efficacy and glycemic control of weight-reducing anti-diabetic medications, AOMs and emerging pharmacologic agents that help treat both obesity and T2DM. EXPERT OPINION Management of obesity and T2DM can be challenging to achieve and sustain in the presence of obesogenic anti-diabetic agents. Utilizing weight-reducing anti-diabetic agents, AOMs, and endobariatric or surgical procedures, either separately or in combination, can help achieve better clinical outcomes in patients with obesity and T2DM. Some agents in development, such as tirzepatide and bimagrumab, are promising pharmacotherapy options that may change the standards of care for cardiometabolic disease management.
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Affiliation(s)
- Mohamad Sirri Tarazi
- Weill Cornell Medical College, Comprehensive Weight Control Center, Division of Endocrinology, Diabetes & Metabolism, New York, NY, United States
| | - Samir Touhamy
- Weill Cornell Medical College, Comprehensive Weight Control Center, Division of Endocrinology, Diabetes & Metabolism, New York, NY, United States
| | - Beverly G Tchang
- New York Presbyterian Weill-Cornell Medical Center, Department of Medicine, 525 E 68th St., New York, NY, United States
| | - Alpana P Shukla
- Weill Cornell Medical College, Comprehensive Weight Control Center, Division of Endocrinology, Diabetes & Metabolism, New York, NY, United States
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25
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Druzhilov MA, Kuznetsova TY, Chumakova GA. Promising areas of pharmacotherapy for obesity. RUSSIAN JOURNAL OF CARDIOLOGY 2021; 26:4279. [DOI: 10.15829/1560-4071-2021-4279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
The increasing prevalence of obesity, accompanied by an increase in the frequency of metabolic disorders, hypertension, associated conditions and diseases, dictates the need to optimize preventive and therapeutic strategies of the health care system, including pharmacological approaches to correcting obesity and the related risk. The evolution of this area led both to the disappearance of drugs that increase the risks of cardiovascular events, cancer, mental disorders or having other pronounced adverse effects, and to the emergence of unique drugs that not only lead to a decrease in body mass index, but also allow multifactorial effect on various components of adiposopathy or visceral obesity, among which glucagon-like peptide-1 receptor agonist liraglutide is currently registered with the indication for obesity. In this regard, the study continues in this regard and other representatives of this class, as well as drugs from sodium-glucose cotransporter-2 inhibitors group. Many other promising pharmacological agents are currently being studied, a review of which is presented in this article.
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Affiliation(s)
| | | | - G. A. Chumakova
- Altai State Medical University;
Research Institute for Complex Issues of Cardiovascular Diseases
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26
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Icart LP, Souza FG, Lima LMTR. Polymeric microparticle systems for modified release of glucagon-like-peptide-1 receptor agonists. J Microencapsul 2021; 38:249-261. [PMID: 33586588 DOI: 10.1080/02652048.2021.1889059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Type 2 diabetes is a fast-growing worldwide epidemic. Despite the multiple therapies available to treat type 2 diabetes, the disease is not correctly managed in over half of patients, mainly due to non-compliance with prescribed treatment regimes. The development of analogues to the glucagon-like peptide 1 (GLP-1) has resulted in the extension of its half-life and associated benefits. Further benefits in the use of peptide-based GLP-1 receptor agonists have been achieved by the use of controlled-release systems based on polymeric microparticles. In this review, we focus on commercially available formulations and others that remain in development, discussing the preparation methods and the relationship between in vitro and in vivo kinetic release behaviours.
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Affiliation(s)
- Luis Peña Icart
- Pharmaceutical Biotechnology Laboratory (pbiotech), Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,Laboratory of Biopolymers and Sensors (LaBioS), Institute of Macromolecules, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernando Gomes Souza
- Laboratory of Biopolymers and Sensors (LaBioS), Institute of Macromolecules, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luís Maurício T R Lima
- Pharmaceutical Biotechnology Laboratory (pbiotech), Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,Laboratory of Biopolymers and Sensors (LaBioS), Institute of Macromolecules, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,Laboratory for Macromolecules (LAMAC-DIMAV), Brazilian National Institute of Metrology, Quality and Technology, Duque de Caxias, Brazil
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27
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Lin C, Cai X, Yang W, Lv F, Nie L, Ji L. Age, sex, disease severity, and disease duration difference in placebo response: implications from a meta-analysis of diabetes mellitus. BMC Med 2020; 18:322. [PMID: 33190640 PMCID: PMC7667845 DOI: 10.1186/s12916-020-01787-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 09/17/2020] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND The placebo response in patients with diabetes mellitus is very common. A systematic evaluation needs to be updated with the current evidence about the placebo response in diabetes mellitus and the associated factors in clinical trials of anti-diabetic medicine. METHODS Literature research was conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for studies published between the date of inception and June 2019. Randomized placebo-controlled trials conducted in type 1and type 2 diabetes mellitus (T1DM/T2DM) were included. Random-effects model and meta-regression analysis were accordingly used. This meta-analysis was registered in PROSPERO as CRD42014009373. RESULTS Significantly weight elevation (effect size (ES) = 0.33 kg, 95% CI, 0.03 to 0.61 kg) was observed in patients with placebo treatments in T1DM subgroup while significantly HbA1c reduction (ES = - 0.12%, 95% CI, - 0.16 to - 0.07%) and weight reduction (ES = - 0.40 kg, 95% CI, - 0.50 to - 0.29 kg) were observed in patients with placebo treatments in T2DM subgroup. Greater HbA1c reduction was observed in patients with injectable placebo treatments (ES = - 0.22%, 95% CI, - 0.32 to - 0.11%) versus oral types (ES = - 0.09%, 95% CI, - 0.14 to - 0.04%) in T2DM (P = 0.03). Older age (β = - 0.01, 95% CI, - 0.02 to - 0.01, P < 0.01) and longer diabetes duration (β = - 0.02, 95% CI, - 0.03 to - 0.21 × 10-2, P = 0.03) was significantly associated with more HbA1c reduction by placebo in T1DM. However, younger age (β = 0.02, 95% CI, 0.01 to 0.03, P = 0.01), lower male percentage (β = 0.01, 95% CI, 0.22 × 10-2, 0.01, P < 0.01), higher baseline BMI (β = - 0.02, 95% CI, - 0.04 to - 0.26 × 10-2, P = 0.02), and higher baseline HbA1c (β = - 0.09, 95% CI, - 0.16 to - 0.01, P = 0.02) were significantly associated with more HbA1c reduction by placebo in T2DM. Shorter diabetes duration (β = 0.06, 95% CI, 0.06 to 0.10, P < 0.01) was significantly associated with more weight reduction by placebo in T2DM. However, the associations between baseline BMI, baseline HbA1c, and placebo response were insignificant after the adjusted analyses. CONCLUSION The placebo response in diabetes mellitus was systematically outlined. Age, sex, disease severity (indirectly reflected by baseline BMI and baseline HbA1c), and disease duration were associated with placebo response in diabetes mellitus. The association between baseline BMI, baseline HbA1c, and placebo response may be the result of regression to the mean.
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Affiliation(s)
- Chu Lin
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
| | - Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Lin Nie
- Department of Endocrinology and Metabolism, Beijing Airport Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
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28
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Kannt A, Madsen AN, Kammermeier C, Elvert R, Klöckener T, Bossart M, Haack T, Evers A, Lorenz K, Hennerici W, Rocher C, Böcskei Z, Guillemot JC, Mikol V, Pattou F, Staels B, Wagner M. Incretin combination therapy for the treatment of non-alcoholic steatohepatitis. Diabetes Obes Metab 2020; 22:1328-1338. [PMID: 32196896 DOI: 10.1111/dom.14035] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 03/04/2020] [Accepted: 03/16/2020] [Indexed: 12/17/2022]
Abstract
AIMS To test specific mono-agonists to the glucagon-like peptide-1 receptor (GLP-1R), glucagon receptor (GCGR) and glucose-dependent insulinotropic peptide receptor (GIPR), individually and in combination, in a mouse model of diet-induced non-alcoholic steatohepatitis (NASH) and fibrosis in order to decipher the contribution of their activities and potential additive effects to improving systemic and hepatic metabolism. MATERIALS AND METHODS We induced NASH by pre-feeding C57BL/6J mice a diet rich in fat, fructose and cholesterol for 36 weeks. This was followed by 8 weeks of treatment with the receptor-specific agonists 1-GCG (20 μg/kg twice daily), 2-GLP1 (3 μg/kg twice daily) or 3-GIP (30 μg/kg twice daily), or the dual (1 + 2) or triple (1 + 2 + 3) combinations thereof. A dual GLP-1R/GCGR agonistic peptide, 4-dual-GLP1/GCGR (30 μg/kg twice daily), and liraglutide (100 μg/kg twice daily) were included as references. RESULTS Whereas low-dose 1-GCG or 3-GIP alone did not influence body weight, liver lipids and histology, their combination with 2-GLP1 provided additional weight loss, reduction in liver triglycerides and improvement in histological disease activity score. Notably, 4-dual-GLP-1R/GCGR and the triple combination of selective mono-agonists led to a significantly stronger reduction in the histological non-alcoholic fatty liver disease activity score compared to high-dose liraglutide, at the same extent of body weight loss. CONCLUSIONS GCGR and GIPR agonism provide additional, body weight-independent improvements on top of GLP-1R agonism in a murine model of manifest NASH with fibrosis.
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Affiliation(s)
- Aimo Kannt
- Sanofi Research and Development, Frankfurt, Germany
- Experimental Pharmacology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology TMP, Frankfurt, Germany
| | | | | | - Ralf Elvert
- Sanofi Research and Development, Frankfurt, Germany
| | | | | | | | | | | | | | - Corinne Rocher
- Sanofi Research and Development, Chilly-Mazarin Cedex, France
| | - Zsolt Böcskei
- Sanofi Research and Development, Chilly-Mazarin Cedex, France
| | | | - Vincent Mikol
- Sanofi Research and Development, Chilly-Mazarin Cedex, France
| | - Francois Pattou
- Univ Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, Lille, France
| | - Bart Staels
- Univ Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, Lille, France
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Juel CTB, Lund A, Andersen MM, Hansen CP, Storkholm JH, Rehfeld JF, van Hall G, Hartmann B, Wewer Albrechtsen NJ, Holst JJ, Vilsbøll T, Knop FK. The GLP-1 receptor agonist lixisenatide reduces postprandial glucose in patients with diabetes secondary to total pancreatectomy: a randomised, placebo-controlled, double-blinded crossover trial. Diabetologia 2020; 63:1285-1298. [PMID: 32394228 DOI: 10.1007/s00125-020-05158-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 03/11/2020] [Indexed: 12/25/2022]
Abstract
AIMS/HYPOTHESIS Treatment of diabetes secondary to total pancreatectomy remains a challenge and insulin constitutes the only glucose-lowering treatment for these patients. We hypothesised that the glucagon-like peptide 1 (GLP-1) receptor agonist lixisenatide would improve postprandial glucose tolerance in totally pancreatectomised patients. METHODS In a double-blinded, randomised, crossover study, 12 totally pancreatectomised individuals (age: 65.0 ± 9.5 mean±SD years; BMI: 22.9 ± 3.9 kg/m2) and 12 healthy control individuals (age 66.1 ± 7.6 years; BMI: 24.0 ± 2.9 kg/m2) underwent two 3 h liquid mixed-meal tests (with paracetamol for assessment of gastric emptying) after single-dose injection of 20 μg of lixisenatide or placebo. Basal insulin was given the night before each experimental day; no insulin was given during study days. RESULTS Compared with placebo, lixisenatide reduced postprandial plasma glucose excursions in the pancreatectomy group (baseline-subtracted AUC [bsAUC] [mean±SEM]: 548 ± 125 vs 1447 ± 95 mmol/l × min, p < 0.001) and in the control group (-126 ± 12 vs 222 ± 51 mmol/l × min, p < 0.001). In the pancreatectomy group a mean peak glucose concentration of 23.3 ± 1.0 mmol/l was reached at time point 134 ± 11 min with placebo, compared with a mean peak glucose concentration of 18 ± 1.4 mmol/l (p = 0.008) at time point 148 ± 13 min (p = 0.375) with lixisenatide. In the control group a mean peak concentration of 8.2 ± 0.4 mmol/l was reached at time point 70 ± 13 min with placebo, compared with a mean peak concentration of 5.5 ± 0.1 mmol/l (p < 0.001) at time point 8 ± 25 min (p = 0.054) with lixisenatide. Lixisenatide also reduced gastric emptying and postprandial glucagon responses in the pancreatectomy group (66 ± 84 vs 1190 ± 311 pmol/l × min, p = 0.008) and in the control group (141 ± 100 vs 190 ± 100 pmol/l × min, p = 0.034). In the pancreatectomy group, C-peptide was undetectable in plasma. In the control group, postprandial plasma C-peptide responses were reduced with lixisenatide (18 ± 17 vs 189 ± 31 nmol/l × min, p < 0.001). CONCLUSIONS/INTERPRETATION The GLP-1 receptor agonist lixisenatide reduces postprandial plasma glucose excursions in totally pancreatectomised patients. The mode of action seems to involve deceleration of gastric emptying and reduced postprandial responses of gut-derived glucagon. TRIAL REGISTRATION ClinicalTrials.gov NCT02640118. FUNDING This study was funded by an unrestricted investigator-initiated study grant from Sanofi. Support was also received from from the Novo Nordisk Foundation Center for Basic Metabolic Research, the A.P. Møller Foundation for the Advancement of Medical Science and the Faculty of Health and Medical Sciences, University of Copenhagen.
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Affiliation(s)
- Caroline T B Juel
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark
| | - Asger Lund
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark
| | - Maria M Andersen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark
| | - Carsten P Hansen
- Department of Surgery and Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Jan H Storkholm
- Department of Surgery and Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Gerrit van Hall
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Clinical Metabolomics Core Facility, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nicolai J Wewer Albrechtsen
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark.
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Steno Diabetes Center Copenhagen, Gentofte, Denmark.
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Williams DM, Nawaz A, Evans M. Drug Therapy in Obesity: A Review of Current and Emerging Treatments. Diabetes Ther 2020; 11:1199-1216. [PMID: 32297119 PMCID: PMC7261312 DOI: 10.1007/s13300-020-00816-y] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Indexed: 12/25/2022] Open
Abstract
Whilst the prevalence of obesity continues to increase at an alarming rate worldwide, the personal and economic burden of obesity-related complications becomes ever more important. Whilst dietary and lifestyle measures remain the fundamental focus of the patient to counter obesity, more frequently pharmacological and/or surgical interventions are required. Nevertheless, these therapies are often limited by weight loss efficacy, side effects, surgical risks and frequently obesity relapse. Currently, only five drug therapies are approved for the specific treatment of obesity. However, our understanding of the pathophysiology of obesity and of gut hormones has developed precipitously over the last 20-30 years. As a result, there has been a recent movement to create and use analogues that manipulate these gut hormones to support weight loss. In this article we review the efficacy of the currently approved drug therapies and discuss future potential drug mechanisms and early clinical trial results exploring these budding avenues. We discuss the use of glucagon-like peptide-1 (GLP-1) analogues as monotherapy and unimolecular dual or triple agonists that exploit the GLP-1 receptor and/or the gastric inhibitory peptide (GIP) receptor and/or the glucagon receptor. We also explore the use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, amylin mimetics, leptin analogues, ghrelin antagonists and centrally acting agents to suppress appetite [neuropeptide Y (NPY) antagonists, melanocortin-4 receptor (MC4R) agonists and cannabinoid-1 receptor antagonists]. Whilst further evidence is required to support their clinical use, preclinical and early clinical trial results are encouraging.
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Affiliation(s)
- David M Williams
- Department of Diabetes and Endocrinology, University Hospital Llandough, Cardiff, UK.
| | - Asif Nawaz
- Department of Diabetes and Endocrinology, University Hospital Llandough, Cardiff, UK
| | - Marc Evans
- Department of Diabetes and Endocrinology, University Hospital Llandough, Cardiff, UK
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Ghosh-Swaby OR, Goodman SG, Leiter LA, Cheng A, Connelly KA, Fitchett D, Jüni P, Farkouh ME, Udell JA. Glucose-lowering drugs or strategies, atherosclerotic cardiovascular events, and heart failure in people with or at risk of type 2 diabetes: an updated systematic review and meta-analysis of randomised cardiovascular outcome trials. Lancet Diabetes Endocrinol 2020; 8:418-435. [PMID: 32333878 DOI: 10.1016/s2213-8587(20)30038-3] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 01/27/2020] [Accepted: 01/28/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND In our 2015 systematic review and meta-analysis of cardiovascular outcome trials for glucose-lowering drugs or strategies in people with or at risk of type 2 diabetes, we reported a modest reduction in atherosclerotic cardiovascular events and an increased risk of heart failure, but with heterogeneous effects by drug or intervention type. In view of the completion of many large cardiovascular outcome trials since our previous analysis, including trials of novel drugs that have shown beneficial effects on cardiovascular outcomes, we aimed to update our analysis to incorporate these findings. METHODS We did an updated systematic review and meta-analysis of large cardiovascular outcome trials of glucose-lowering drugs or strategies in people with or at risk of type 2 diabetes. We searched Ovid MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials databases for reports of trials published from Nov 15, 2013 to Nov 20, 2019. We included randomised controlled trials with a minimum of 1000 adults (aged ≥19 years) with or at risk of type 2 diabetes, with major adverse cardiovascular events (MACE) as an outcome, and with follow-up of at least 12 months. We excluded trials with patients enrolled with an acute cardiovascular event. The main outcomes of interest were MACE (generally defined as a composite of cardiovascular death, myocardial infarction, or stroke) and heart failure. We calculated pooled risk ratios (RRs) and 95% CIs with inverse-variance random-effects models, did meta-regression to analyse treatment effects per difference in bodyweight achieved, and explored results stratified by baseline subgroups. FINDINGS Our updated search yielded 30 eligible trials (n=225 305). The mean age of participants was 63·0 years (SD 8·4) and mean duration of diabetes was 9·4 years (6·6). After a mean follow-up of 3·8 years (1·8), 23 016 (10·2%) participants had MACE and 8169 (3·6%) had a heart failure event. Glucose-lowering drugs or strategies lowered the risk of MACE compared with standard care or placebo (RR 0·92, 95% CI 0·89-0·95, p<0·0001), with no overall effect on the risk of heart failure (0·98, 0·90-1·08, p=0·71). However, across drug classes or strategies, the magnitude and directionality of RR for heart failure varied (pinteraction<0·0001), with meta-regression showing that a decrease in bodyweight of 1 kg was associated with a 5·9% (3·9-8·0) relative decrease in the risk of heart failure (p<0·0001). Among trials that assessed drug classes or strategies associated with weight loss (intensive lifestyle changes, GLP-1 receptor agonists, or SGLT2 inhibitors), the risk reduction for MACE was consistent among participants with (0·87, 0·83-0·92) and without (0·92, 0·83-1·02) established cardiovascular disease at baseline (pinteraction=0·33). For heart failure, the RR for drug classes or strategies associated with weight loss was consistent among participants with (0·80, 0·73-0·89) and without (0·84, 0·74-0·95) cardiovascular disease at baseline (pinteraction=0·63). INTERPRETATION Glucose-lowering drugs or strategies overall reduced the risk of fatal and non-fatal atherosclerotic events. The effect on heart failure was neutral overall but varied substantially by intervention type, with interventions associated with weight loss showing a beneficial effect. The cardiovascular and heart failure benefits of interventions associated with weight loss might extend to patients without established cardiovascular disease. FUNDING None.
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Affiliation(s)
- Olivia R Ghosh-Swaby
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada; Women's College Research Institute and Cardiovascular Division, Women's College Hospital, Toronto, ON, Canada
| | - Shaun G Goodman
- Department of Medicine, St Michael's Hospital, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada; Canadian VIGOUR Centre, University of Alberta, Edmonton, AB, Canada
| | - Lawrence A Leiter
- Department of Medicine, St Michael's Hospital, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Alice Cheng
- Department of Medicine, St Michael's Hospital, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada; Credit Valley Hospital, Mississauga, ON, Canada
| | - Kim A Connelly
- Department of Medicine, St Michael's Hospital, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada; Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
| | - David Fitchett
- Department of Medicine, St Michael's Hospital, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Peter Jüni
- Department of Medicine, University of Toronto, Toronto, ON, Canada; Applied Health Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
| | - Michael E Farkouh
- Department of Medicine, University of Toronto, Toronto, ON, Canada; Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
| | - Jacob A Udell
- Women's College Research Institute and Cardiovascular Division, Women's College Hospital, Toronto, ON, Canada; Department of Medicine, St Michael's Hospital, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada; Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada.
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William JH, Morales A, Rosas SE. When ESKD complicates the management of diabetes mellitus. Semin Dial 2020; 33:209-222. [PMID: 32274852 DOI: 10.1111/sdi.12873] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Given the increased incidence and prevalence of ESKD (end-stage kidney disease) attributed to diabetes mellitus, it is important to consider the physiological and global sociodemographic factors that give rise to unique challenges in providing excellent care to this population. The individual with diabetes and ESKD faces alterations of glucose homeostasis that require close therapeutic attention, as well as the consideration of safe and effective means of maintaining glycemic control. Implementation of routine monitoring of blood glucose and thoughtful alteration of the individual's hypoglycemic drug regimen must be employed to reduce the risk of neurological, cardiovascular, and diabetes-specific complications that may arise as a result of ESKD. Titration of insulin therapy may become quite challenging, as kidney replacement therapy often significantly impacts insulin requirements. New medications have significantly improved the ability of the clinician to provide effective therapies for the management of diabetes, but have also raised an equal amount of uncertainty with respect to their safety and efficacy in the ESKD population. Additionally, the clinician must consider the challenges related to the delivery of kidney replacement therapy, and how inter-modality differences may impact glycemic control, diabetes, and ESKD-related complications, and issues surrounding dialysis vascular access creation.
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Affiliation(s)
- Jeffrey H William
- Nephrology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Alexander Morales
- Nephrology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Sylvia E Rosas
- Nephrology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.,Kidney and Hypertension Unit, Joslin Diabetes Center, Boston, MA, USA
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Davidson JA, Stager W, Paranjape S, Berria R, Leiter LA. Achieving postprandial glucose control with lixisenatide improves glycemic control in patients with type 2 diabetes on basal insulin: a post-hoc analysis of pooled data. Clin Diabetes Endocrinol 2020; 6:2. [PMID: 31956422 PMCID: PMC6961286 DOI: 10.1186/s40842-019-0088-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 08/12/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND To examine the impact on glycemic control of achieving postprandial glucose (PPG) target with lixisenatide, a once-daily glucagon-like peptide-1 receptor agonist approved in the US, in patients with uncontrolled type 2 diabetes (T2D) on basal insulin, an agent that primarily targets fasting plasma glucose. METHODS A post hoc pooled analysis was conducted using clinical trial data extracted from the intent-to-treat subpopulation of patients with T2D who participated in the 24-week, phase 3, randomized, double-blind, placebo-controlled, 2-arm parallel-group, multicenter GetGoal-L (NCT00715624), GetGoal-Duo 1 (NCT00975286) and GetGoal-L Asia trials (NCT00866658). RESULTS Data from 587 lixisenatide-treated patients and 484 placebo-treated patients were included. Patients on lixisenatide were more likely to achieve a PPG target of < 10 mmol/L (< 180 mg/dL) than placebo-treated patients (P < 0.001), regardless of baseline fasting plasma glucose (FPG) levels. More importantly, those who reached the PPG target experienced a significantly greater reduction in mean HbA1c, were more likely to achieve HbA1c target of < 53 mmol/mol (< 7.0%), and experienced weight loss. Those outcomes were achieved with no significant differences in the risk of symptomatic hypoglycemia compared with placebo. CONCLUSION Compared with placebo, addition of lixisenatide to basal insulin improved HbA1c and reduced PPG, without increasing hypoglycemia risk. These findings highlight the importance of PPG control in the management of T2D, and provide evidence that adding an agent to basal insulin therapy that also impacts PPG has therapeutic value for patients who are not meeting glycemic targets. TRIAL REGISTRATION NCT00715624. Registered 15 July 2008, NCT00975286. Registered 11 September 2009, NCT00866658. Registered 20 March 2009.
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Affiliation(s)
- Jaime A. Davidson
- Department of Internal Medicine, Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, K5.246, Dallas, TX 75390-8549 USA
| | | | | | | | - Lawrence A. Leiter
- Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto, Toronto, ON Canada
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Kamalinia S, Josse RG, Donio PJ, Leduc L, Shah BR, Tobe SW. Risk of any hypoglycaemia with newer antihyperglycaemic agents in patients with type 2 diabetes: A systematic review and meta-analysis. Endocrinol Diabetes Metab 2020; 3:e00100. [PMID: 31922027 PMCID: PMC6947712 DOI: 10.1002/edm2.100] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 10/11/2019] [Accepted: 10/13/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES For patients with type 2 diabetes, newer antihyperglycaemic agents (AHA), including the dipeptidyl peptidase IV inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium glucose co-transporter 2 inhibitors (SGLT2i) offer a lower risk of hypoglycaemia relative to sulfonylurea or insulin. However, it is not clear how AHA compare to placebo on risk of any hypoglycaemia. This study evaluates the risk of any and severe hypoglycaemia with AHA and metformin relative to placebo. DESIGN A systematic review and meta-analysis was conducted of randomized, placebo-controlled trials ≥12 weeks in duration. MEDLINE, Embase and the Cochrane Library were searched up to April 16, 2019. Studies allowing use of other diabetes medications were excluded. Mantel-Haenszel risk ratio with 95% confidence intervals were used to pool estimates based on class of AHA and number of concomitant therapies used. PATIENTS Eligible studies enrolled patients with type 2 diabetes ≥18 years of age. RESULTS 144 studies met our inclusion criteria. Any hypoglycaemia was not increased with AHA when used as monotherapy (DPP4i (RR 1.12; 95% CI 0.81-1.56), GLP1RA (1.77; 0.91-3.46), SGLT2i (1.34; 0.83-2.15)), or as add-on to metformin (DPP4i (0.95; 0.67-1.35), GLP1RA (1.24; 0.80-1.91), SGLT2i (1.29; 0.91-1.83)) or as triple therapy (1.13; 0.67-1.91). However, metformin monotherapy (1.73; 1.02-2.94) and dual therapy initiation (3.56; 1.79-7.10) was associated with an increased risk of any hypoglycaemia. Severe hypoglycaemia was rare not increased for any comparisons. CONCLUSIONS Metformin and the simultaneous initiation of dual therapy, but not AHA used alone or as single add-on combination therapy, was associated with an increased risk of any hypoglycaemia relative to placebo.
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Affiliation(s)
- Sanaz Kamalinia
- Institute of Medical SciencesUniversity of TorontoTorontoONCanada
| | - Robert G. Josse
- St. Michael's HospitalTorontoONCanada
- Department of MedicineUniversity of TorontoTorontoONCanada
| | | | | | - Baiju R. Shah
- Department of MedicineUniversity of TorontoTorontoONCanada
- Sunnybrook Research InstituteTorontoONCanada
| | - Sheldon W. Tobe
- Institute of Medical SciencesUniversity of TorontoTorontoONCanada
- Department of MedicineUniversity of TorontoTorontoONCanada
- Northern Ontario School of MedicineSudburyONCanada
- Sunnybrook Research InstituteTorontoONCanada
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Handelsman Y, Muskiet MHA, Meneilly GS. Combining GLP-1 Receptor Agonists and Basal Insulin in Older Adults with Type 2 Diabetes: Focus on Lixisenatide and Insulin Glargine. Adv Ther 2019; 36:3321-3339. [PMID: 31646466 PMCID: PMC6860469 DOI: 10.1007/s12325-019-01126-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Indexed: 12/14/2022]
Abstract
Estimates suggest that there are currently 122.8 million adults 65-99 years of age living with diabetes, of whom 90-95% are diagnosed with type 2 diabetes (T2D). Over the past two decades, a greater understanding of the complex and multifactorial pathogenesis of T2D has resulted in the development and introduction of new-generation classes of glucose-lowering therapies, which are now extensively endorsed by prevailing guidelines and are increasingly being used worldwide. These newer agents may further assist in the effective pharmacological management of T2D through the provision of patient-centered care that acknowledges multimorbidity and is respectful of and responsive to individual patient preferences and barriers. Given these considerations, the therapeutic approach in older patients with T2D is complex, particularly in those who have functional dependence, frailty, dementia, or who are at end-of-life. It is currently too early to draw conclusions on the long-term use of newer glucose-lowering agents in this population, as their efficacy and safety in older adults remains largely unknown. In this review, we will discuss considerations for the use of glucose-lowering treatments in older adults, with particular focus on the use of basal insulin and glucagon-like peptide-1 receptor agonists, and the rationale for the use of combination therapy comprising these agents. Finally, we will review clinical data from studies of the fixed-ratio combination of insulin glargine and lixisenatide in older patients with T2D. FUNDING: Sanofi US, Inc.
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Affiliation(s)
- Yehuda Handelsman
- Metabolic Institute of America, 18372 Clark St. Suite 212, Tarzana, CA, 91356, USA.
| | - Marcel H A Muskiet
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers (Location VUMC), 1081 HV, Amsterdam, The Netherlands
| | - Graydon S Meneilly
- Department of Medicine, The University of British Columbia, 2775 Laurel Street, Vancouver, BC, V5Z1M9, Canada
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Pratley RE, Kang J, Trautmann ME, Hompesch M, Han O, Stewart J, Sorli CH, Jacob S, Yoon K. Body weight management and safety with efpeglenatide in adults without diabetes: A phase II randomized study. Diabetes Obes Metab 2019; 21:2429-2439. [PMID: 31264757 PMCID: PMC6851541 DOI: 10.1111/dom.13824] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 06/14/2019] [Accepted: 06/26/2019] [Indexed: 12/20/2022]
Abstract
AIM To evaluate the safety of efpeglenatide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), and its effects on body weight management in adults without diabetes. MATERIALS AND METHODS In this phase II, randomized, placebo-controlled, double-blind trial, participants with a body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2 with comorbidity were randomized 1:1:1:1:1 to efpeglenatide (4 mg once weekly, 6 mg once weekly, 6 mg once every 2 wk, or 8 mg once every 2 wk; n = 237) or placebo (n = 60) in combination with a hypocaloric diet. The primary endpoint was body weight change from baseline after 20 wk of treatment, assessed using a mixed-effect model with repeated measures with an unstructured covariance matrix over all post-screening visits; treatment comparisons were based on least squares mean estimates. RESULTS Over 20 wk, all doses of efpeglenatide significantly reduced body weight from baseline versus placebo (P < 0.0001), with placebo-adjusted reductions ranging between -6.3 kg (6 mg once every 2 wk) and -7.2 kg (6 mg once weekly). Greater proportions of efpeglenatide-treated participants had body weight loss of ≥5% or ≥10% versus placebo (P < 0.01, all comparisons). Efpeglenatide led to significant improvements in glycaemic variables (fasting plasma glucose and glycated haemoglobin) and lipid profiles (cholesterol, triglycerides) versus placebo. Rates of study discontinuations as a result of adverse events ranged from 5% to 19% with efpeglenatide. Gastrointestinal effects were the most common treatment-emergent adverse events. CONCLUSIONS Efpeglenatide once weekly and once every 2 wk led to significant body weight reduction and improved glycaemic and lipid variables versus placebo. It was also well tolerated for weight management in adults without diabetes.
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Affiliation(s)
- Richard E. Pratley
- Translational Research Institute for Metabolism and DiabetesAdventHealthOrlandoFlorida
| | - Jahoon Kang
- Clinical Research and DevelopmentHanmi Pharmaceutical Co., LtdSeoulSouth Korea
| | | | | | - OakPil Han
- Department of BiometricsHanmi Pharmaceutical Co., LtdSeoulSouth Korea
| | - John Stewart
- Department of BiostatisticsSanofi CanadaLavalQuebecCanada
| | | | - Stephan Jacob
- Praxis für Prävention und TherapieVillingen‐SchwenningenGermany
| | - Kun‐Ho Yoon
- Endocrinology and MetabolismCatholic University of KoreaSeoulSouth Korea
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Rosenstock J, Sorli CH, Trautmann ME, Morales C, Wendisch U, Dailey G, Hompesch M, Choi IY, Kang J, Stewart J, Yoon KH. Once-Weekly Efpeglenatide Dose-Range Effects on Glycemic Control and Body Weight in Patients With Type 2 Diabetes on Metformin or Drug Naive, Referenced to Liraglutide. Diabetes Care 2019; 42:1733-1741. [PMID: 31320446 DOI: 10.2337/dc18-2648] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 06/23/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To explore the efficacy, safety, and tolerability of once-weekly efpeglenatide, a long-acting glucagon-like peptide 1 receptor agonist (GLP-1 RA), in early type 2 diabetes (T2D) (drug naive or on metformin monotherapy). RESEARCH DESIGN AND METHODS EXCEED 203 was a 12-week, randomized, placebo-controlled, double-blind, parallel-group, dose-ranging study of efpeglenatide once weekly referenced to open-label liraglutide 1.8 mg (exploratory analysis). Participants, ∼90% on metformin monotherapy, were randomized to one of five efpeglenatide doses (0.3, 1, 2, 3, or 4 mg q.w.; n = 181), placebo (n = 37), or liraglutide (≤1.8 mg daily; n = 36). The primary efficacy end point was change in HbA1c from baseline to week 13. RESULTS From a baseline HbA1c of 7.7-8.0% (61.0-63.9 mmol/mol), all efpeglenatide doses ≥1 mg significantly reduced HbA1c versus placebo (placebo-adjusted least squares [LS] mean changes 0.6-1.2%, P < 0.05 for all) to a final HbA1c of 6.3-6.8% (45.4-50.6 mmol/mol); masked efpeglenatide 4 mg was noninferior to open-label liraglutide. Greater proportions treated with efpeglenatide ≥1 mg than placebo achieved HbA1c <7% (61-72% vs. 24%, P < 0.05 for all), and greater reductions in body weight were observed with efpeglenatide 3 and 4 mg versus placebo (placebo-adjusted LS mean differences -1.4 and -2.0 kg, respectively, P < 0.05 for both). Rates of nausea and vomiting were consistent with other GLP-1 RAs and rapidly subsided after the initial 2 weeks. No neutralizing antibodies were detected with efpeglenatide. CONCLUSIONS Efpeglenatide once weekly led to significant reductions in HbA1c and weight, with a safety profile consistent with the GLP-1 RA class in patients with early T2D mostly on metformin monotherapy.
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Affiliation(s)
| | | | | | - Cristóbal Morales
- Day Hospital & Diabetes Research Unit, Clinical Management Unit Endocrinology and Nutrition, Virgen Macarena University Hospital, Seville, Spain
| | - Ulrich Wendisch
- Group Practice in Internal Medicine and Diabetology, Hamburg, Germany
| | - George Dailey
- Scripps Clinic, John R. Anderson V Medical Pavilion, La Jolla, CA
| | | | | | - Jahoon Kang
- Hanmi Pharmaceutical Co., Ltd., Seoul, South Korea
| | | | - Kun-Ho Yoon
- The Catholic University of Korea, Seoul, South Korea
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Chia CW, Egan JM. Incretins in obesity and diabetes. Ann N Y Acad Sci 2019; 1461:104-126. [PMID: 31392745 PMCID: PMC10131087 DOI: 10.1111/nyas.14211] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 07/13/2019] [Accepted: 07/18/2019] [Indexed: 12/11/2022]
Abstract
Incretins are hormones secreted from enteroendocrine cells after nutrient intake that stimulate insulin secretion from β cells in a glucose-dependent manner. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the only two known incretins. Dysregulation of incretin secretion and actions are noted in diseases such as obesity and diabetes. In this review, we first summarize our traditional understanding of the physiology of GIP and GLP-1, and our current knowledge of the relationships between GIP and GLP-1 and obesity and diabetes. Next, we present the results from major randomized controlled trials on the use of GLP-1 receptor agonists for managing type 2 diabetes, and emerging data on treating obesity and prediabetes. We conclude with a glimpse of the future with possible complex interactions between nutrients, gut microbiota, the endocannabinoid system, and enteroendocrine cells.
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Affiliation(s)
- Chee W Chia
- Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
| | - Josephine M Egan
- Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
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39
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Watson LE, Phillips LK, Wu T, Bound MJ, Checklin HL, Grivell J, Jones KL, Clifton PM, Horowitz M, Rayner CK. A whey/guar "preload" improves postprandial glycaemia and glycated haemoglobin levels in type 2 diabetes: A 12-week, single-blind, randomized, placebo-controlled trial. Diabetes Obes Metab 2019; 21:930-938. [PMID: 30520216 DOI: 10.1111/dom.13604] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 11/20/2018] [Accepted: 12/01/2018] [Indexed: 02/05/2023]
Abstract
AIMS To evaluate the effects of 12 weeks of treatment with a whey/guar preload on gastric emptying, postprandial glycaemia and glycated haemoglobin (HbA1c) levels in people with type 2 diabetes (T2DM). MATERIALS AND METHODS A total of 79 people with T2DM, managed on diet or metformin (HbA1c 49 ± 0.7 mmol/mol [6.6 ± 0.1%]), were randomized, in single-blind fashion, to receive 150 mL flavoured preloads, containing either 17 g whey protein plus 5 g guar (n = 37) or flavoured placebo (n = 42), 15 minutes before two meals, each day for 12 weeks. Blood glucose and gastric emptying (breath test) were measured before and after a mashed potato meal at baseline (without preload), and after the preload at the beginning (week 1) and end (week 12) of treatment. HbA1c levels, energy intake, weight and body composition were also evaluated. RESULTS Gastric emptying was slower (P < 0.01) and postprandial blood glucose levels lower (P < 0.05) with the whey/guar preload compared to placebo preload, and the magnitude of reduction in glycaemia was related to the rate of gastric emptying at both week 1 (r = -0.54, P < 0.001) and week 12 (r = -0.54, P < 0.0001). At the end of treatment, there was a 1 mmol/mol [0.1%] reduction in HbA1c in the whey/guar group compared to the placebo group (49 ± 1.0 mmol/mol [6.6 ± 0.05%] vs. 50 ± 0.8 mmol/mol [6.7 ± 0.05%]; P < 0.05). There were no differences in energy intake, body weight, or lean or fat mass between the groups. CONCLUSIONS In patients with well-controlled T2DM, 12 weeks' treatment with a low-dose whey/guar preload, taken twice daily before meals, had sustained effects of slowing gastric emptying and reducing postprandial blood glucose, which were associated with a modest reduction in HbA1c, without causing weight gain.
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Affiliation(s)
- Linda E Watson
- Discipline of Medicine, Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Liza K Phillips
- Discipline of Medicine, Adelaide Medical School, University of Adelaide, Adelaide, Australia
- Departments of Endocrinology and Gastroenterology, Royal Adelaide Hospital, Adelaide, Australia
| | - Tongzhi Wu
- Discipline of Medicine, Adelaide Medical School, University of Adelaide, Adelaide, Australia
- Departments of Endocrinology and Gastroenterology, Royal Adelaide Hospital, Adelaide, Australia
| | - Michelle J Bound
- Discipline of Medicine, Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Helen L Checklin
- Discipline of Medicine, Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Jacqueline Grivell
- Discipline of Medicine, Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Karen L Jones
- Discipline of Medicine, Adelaide Medical School, University of Adelaide, Adelaide, Australia
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
| | - Peter M Clifton
- Departments of Endocrinology and Gastroenterology, Royal Adelaide Hospital, Adelaide, Australia
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
| | - Michael Horowitz
- Discipline of Medicine, Adelaide Medical School, University of Adelaide, Adelaide, Australia
- Departments of Endocrinology and Gastroenterology, Royal Adelaide Hospital, Adelaide, Australia
| | - Christopher K Rayner
- Discipline of Medicine, Adelaide Medical School, University of Adelaide, Adelaide, Australia
- Departments of Endocrinology and Gastroenterology, Royal Adelaide Hospital, Adelaide, Australia
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Whyte MB, Shojaee-Moradie F, Sharaf SE, Jackson NC, Fielding B, Hovorka R, Mendis J, Russell-Jones D, Umpleby AM. Lixisenatide Reduces Chylomicron Triacylglycerol by Increased Clearance. J Clin Endocrinol Metab 2019; 104:359-368. [PMID: 30215735 PMCID: PMC6300412 DOI: 10.1210/jc.2018-01176] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 09/06/2018] [Indexed: 12/17/2022]
Abstract
CONTEXT Glucagon-like peptide-1 (GLP-1) agonists control postprandial glucose and lipid excursion in type 2 diabetes; however, the mechanisms are unclear. OBJECTIVE To determine the mechanisms of postprandial lipid and glucose control with lixisenatide (GLP-1 analog) in type 2 diabetes. DESIGN Randomized, double-blind, cross-over study. SETTING Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom. PATIENTS Eight obese men with type 2 diabetes [age, 57.3 ± 1.9 years; body mass index, 30.3 ± 1.0 kg/m2; glycosylated hemoglobin, 66.5 ± 2.6 mmol/mol (8.2% ± 0.3%)]. INTERVENTIONS Two metabolic studies, 4 weeks after lixisenatide or placebo, with cross-over and repetition of studies. MAIN OUTCOME MEASURES Study one: very-low-density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with an IV bolus of [2H5]glycerol in a 12-hour study, with hourly feeding. Oral [13C]triolein, in a single meal, labeled enterally derived TAG. Study two: glucose kinetics were measured with [U-13C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable IV [6,6-2H2]glucose infusion. RESULTS Study one: CM-TAG (but not VLDL-TAG) pool-size was lower with lixisenatide (P = 0.046). Lixisenatide reduced CM [13C]oleate area under the curve (AUC)60-480min concentration (P = 0.048) and increased CM-TAG clearance, with no effect on CM-TAG production rate. Study two: postprandial glucose and insulin AUC0-240min were reduced with lixisenatide (P = 0.0051; P < 0.05). Total glucose production (P = 0.015), rate of glucose appearance from the meal (P = 0.0098), and acetaminophen AUC0-360min (P = 0.006) were lower with lixisenatide than with placebo. CONCLUSIONS Lixisenatide reduced [13C]oleate concentrations, derived from a single meal in CM-TAG and glucose rate of appearance from the meal through delayed gastric emptying. However, day-long CM production, measured with repeated meal feeding, was not reduced by lixisenatide and decreased CM-TAG concentration resulted from increased CM-TAG clearance.
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Affiliation(s)
- Martin B Whyte
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
- Correspondence and Reprint Requests: Martin B. Whyte, PhD, FRCP, Faculty of Health and Medical Sciences, University of Surrey, Leggett Building, Daphne Jackson Road, Guildford GU2 7WG, United Kingdom. E-mail:
| | | | - Sharaf E Sharaf
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
| | - Nicola C Jackson
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
| | - Barbara Fielding
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
| | - Roman Hovorka
- Diabetes Modelling Group, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Jeewaka Mendis
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
| | - David Russell-Jones
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
| | - A Margot Umpleby
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
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Gentilella R, Pechtner V, Corcos A, Consoli A. Glucagon-like peptide-1 receptor agonists in type 2 diabetes treatment: are they all the same? Diabetes Metab Res Rev 2019; 35:e3070. [PMID: 30156747 DOI: 10.1002/dmrr.3070] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 07/30/2018] [Accepted: 08/18/2018] [Indexed: 02/06/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an important class of drugs with a well-established efficacy and safety profile in patients with type 2 diabetes mellitus. Agents in this class are derived from either exendin-4 (a compound present in Gila monster venom) or modifications of human GLP-1 active fragment. Differences among these drugs in duration of action (ie, short-acting vs long-acting), effects on glycaemic control and weight loss, immunogenicity, tolerability profiles, and administration routes offer physicians several options when selecting the most appropriate agent for individual patients. Patient preference is also an important consideration. The aim of this review is to discuss the differences between and similarities of GLP-1 RAs currently approved for clinical use, focusing particularly on the properties characterising the single short-acting and long-acting GLP-1 RAs rather than on their individual efficacy and safety profiles. The primary pharmacodynamic difference between short-acting (ie, exenatide twice daily and lixisenatide) and long-acting (ie, albiglutide, dulaglutide, exenatide once weekly, liraglutide, and semaglutide) GLP-1 RAs is that short-acting agents primarily delay gastric emptying (lowering postprandial glucose) and long-acting agents affect both fasting glucose (via enhanced glucose-dependent insulin secretion and reduced glucagon secretion in the fasting state) and postprandial glucose (via enhanced postprandial insulin secretion and inhibition of glucagon secretion). Other advantages of long-acting GLP-1 RAs include smaller fluctuations in plasma drug concentrations, improved gastrointestinal tolerability profiles, and simpler, more convenient administration schedules (once daily for liraglutide and once weekly for albiglutide, dulaglutide, the long-acting exenatide formulation, and semaglutide), which might improve treatment adherence and persistence.
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Affiliation(s)
| | - Valeria Pechtner
- Lilly Diabetes, Eli Lilly and Company, Neuilly-sur-Seine, France
| | | | - Agostino Consoli
- Department of Medicine and Ageing Sciences and CeSI-Met, University D'Annunzio, Chieti, Italy
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Wei ZG, Wang MC, Zhang HH, Wang ZY, Wang GN, Wei FX, Zhang YW, Xu XD, Zhang YC. PRISMA-efficacy and safety of lixisenatide for type 2 diabetes mellitus: A meta-analysis of randomized controlled trials. Medicine (Baltimore) 2018; 97:e13710. [PMID: 30572502 PMCID: PMC6320179 DOI: 10.1097/md.0000000000013710] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVE We aimed to systematically evaluate the efficacy and safety of lixisenatide in patients with type 2 diabetes mellitus. METHODS PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, Google, Web of Science and the Chinese Science Citation Database were searched up to March 2018. Randomized controlled trials determining the efficacy and safety of lixisenatide in patients with type 2 diabetes mellitus were eligible for inclusion. Two authors independently extracted the data in a prespecified Microsoft Excel spreadsheet. A meta-analysis was performed using Review Manager 5.3 software. Weighted mean difference (WMD) and relative risk (RR) together with their corresponding 95% confidence intervals (CIs) were estimated, and only the random effects model was used in order to achieve a more conservative estimate of the efficacy and safety. RESULTS Fourteen multicenter randomized controlled trials involving 11,947 patients were eligible for inclusion. Compared to placebo, lixisenatide could more significantly reduce the level of HbA1c (WMD=-0.44; 95% confidence interval [CI] [-0.55,-0.33]), and a higher proportion of lixisenatide-treated patients achieved the HbA1c level of < 7.0% (RR = 1.89, 95% CI [1.75-2.03]) and < 6.5% (RR = 3.03, 95% CI [2.54-3.63]) than the placebo-treated patients. Lixisenatide was also associated with a significant reduction in fasting plasma glucose and 2-hour postprandial plasma glucose levels. The risks for any adverse events, gastrointestinal adverse events, and symptomatic hypoglycemia significantly increased in the lixisenatide-treatedment group compared to those in the placebo group. However, lixisenatideit did not increase the risks of serious adverse events, death, or severe hypoglycemia. CONCLUSIONS Lixisenatide was more effective than placebo in patients with type 2 diabetes mellitus, and the mild-to-moderate adverse events were found to be tolerated during the follow-up.
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Affiliation(s)
- Zhen-gang Wei
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Man-cai Wang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Hui-han Zhang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Zhe-yuan Wang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Gen-nian Wang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Feng-xian Wei
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Ya-wu Zhang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Xiao-dong Xu
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - You-cheng Zhang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
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Sharma D, Verma S, Vaidya S, Kalia K, Tiwari V. Recent updates on GLP-1 agonists: Current advancements & challenges. Biomed Pharmacother 2018; 108:952-962. [PMID: 30372907 DOI: 10.1016/j.biopha.2018.08.088] [Citation(s) in RCA: 188] [Impact Index Per Article: 26.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 08/04/2018] [Accepted: 08/15/2018] [Indexed: 12/16/2022] Open
Abstract
Glucagon-like peptide (GLP)-1 is an incretin hormone exhibiting several pharmacological actions such as neuroprotection, increased cognitive function, cardio-protection, decreased hypertension, suppression of acid secretion, increase in lyposis, and protection from inflammation. The most potent actions are glucose-dependent insulinotropic and glucagonostatic actions, stimulation of β-cell proliferation, enhanced insulin secretion and reduced weight gain in patients with type-2 diabetes pertaining to blood glucose control. Despite all these actions, its short half-life (around 2∼min) and degradation by a dipeptidyl peptidase-4 enzyme (DPP-4) limits the therapeutic utility of GLP1. In this review, we have discussed DPP IV-resistant analogs of GLP-1 currently present in clinical trials such as Exenatide, Liraglutide, Semaglutide, Efpeglenatide, Exenatide ER, Ittca 650 (Intarcia), Dulaglutide, Albiglutide, and Lixisenatide. Moreover, we have also discussed in detail the pharmacology, signaling mechanisms, and pharmacokinetic properties (Cmax, Tmax, T1/2, Vd, and Bioavailability) of DPP IV-resistant analogs of (GLP-1). Interestingly, GLP-1 agonist drugs have shown better potential to treat type-2 diabetes mellitus (T2DM) as compared to currently used drugs in clinics without causing the side effects of hypoglycemia and weight gain.
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Affiliation(s)
- Dilip Sharma
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar 382355, Gujarat, India
| | - Suril Verma
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar 382355, Gujarat, India
| | - Shivani Vaidya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar 382355, Gujarat, India
| | - Kiran Kalia
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar 382355, Gujarat, India.
| | - Vinod Tiwari
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar 382355, Gujarat, India.
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Sfairopoulos D, Liatis S, Tigas S, Liberopoulos E. Clinical pharmacology of glucagon-like peptide-1 receptor agonists. Hormones (Athens) 2018; 17:333-350. [PMID: 29949126 DOI: 10.1007/s42000-018-0038-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 05/14/2018] [Indexed: 02/06/2023]
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are an important asset in the armamentarium for the treatment of type 2 diabetes mellitus (type 2 DM). Incretin failure is a critical etiopathogenetic feature of type 2 DM, which, if reversed, results in improved glycaemic control. GLP-1 RAs are injectable peptides that resemble the structure and function of endogenous incretin GLP-1, but as they are not deactivated by the dipeptidyl peptidase-4 (DPP-4), their half-life is prolonged compared with native GLP-1. Based on their ability to activate GLP-1 receptor, GLP-1 RAs are classified as short-acting (exenatide twice-daily and lixisenatide once-daily), and long-acting (liraglutide once-daily and the once-weekly formulations of exenatide extended-release, dulaglutide, and albiglutide). Semaglutide, another long-acting, once-weekly GLP-1 RA, was recently approved by the FDA and EMA. Although all of these agents potently reduce haemoglobin A1C (HbA1c), there are unique features and fundamental differences among them related to fasting and postprandial hyperglycaemia reduction, weight loss potency, cardiovascular protection efficacy, and adverse events profile. It is imperative that current evidence be integrated and applied in the context of an individualised patient-centred approach. This should include not only glucose management but also targeting as many as possible of the pathophysiologic mechanisms responsible for type 2 DM development and progression.
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Affiliation(s)
- Dimitrios Sfairopoulos
- Department of Internal Medicine, School of Medicine, University of Ioannina, Stavrou Niarchou Str, 45110, Ioannina, Greece
| | - Stavros Liatis
- First Department of Propaedeutic and Internal Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, 10559, Athens, Greece
| | - Stelios Tigas
- Department of Endocrinology, School of Medicine, University of Ioannina, 45110, Ioannina, Greece
| | - Evangelos Liberopoulos
- Department of Internal Medicine, School of Medicine, University of Ioannina, Stavrou Niarchou Str, 45110, Ioannina, Greece.
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45
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Lovshin JA. Glucagon-like Peptide-1 Receptor Agonists: A Class Update for Treating Type 2 Diabetes. Can J Diabetes 2018; 41:524-535. [PMID: 28942790 DOI: 10.1016/j.jcjd.2017.08.242] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 01/24/2017] [Accepted: 02/08/2017] [Indexed: 12/17/2022]
Abstract
Current management options for treating type 2 diabetes are diverse. Many different classes of antidiabetes therapies are used in clinic, and several new candidates are in late-phase clinical trial. This therapeutic abundance is a windfall for patients because it facilitates individualized patient care. Evidence-based positioning of these agents is challenging, however, requiring comprehensive and balanced familiarity with each drug class. In this review, I provide a clinical update of glucagon-like peptide-1 receptor agonists (GLP-1RAs), a class of incretin-based, injectable antidiabetes therapies which improve fasting and postprandial blood glucose control through glucose-dependent pancreatic islet cell hormone secretion without significant risks for hypoglycemia. Chronic use of GLP-1RAs also promotes body weight loss through stimulation of GLP-1 receptors localized in hypothalamic satiety centres that regulate appetite, resulting in reduced caloric intake. Since 2005, when GLP-1RAs first received regulatory approval for type 2 diabetes, this class has expanded to include long-acting, once-weekly GLP-1RAs. Recent cardiovascular outcome trials demonstrate that long-term use of GLP-1RAs (liraglutide and semaglutide) reduce cardiovascular and renal complications of diabetes. Illustrating that GLP-1RAs are favourable in high-risk patients with type 2 diabetes. This review provides a clinical appraisal of the GLP-1RA class, highlighting intraclass similarities and differences, summarizing the clinical development of incretin-based diabetes therapies and focusing on currently approved GLP-1RAs. The review also discusses the implications of structural differences between GLP-1RA molecules and comments on the risks and benefits associated with GLP-1RAs and their positioning in treating type 2 diabetes.
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Affiliation(s)
- Julie A Lovshin
- Toronto General Hospital, Banting and Best Diabetes Centre, Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada.
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Frankel AH, Kazempour-Ardebili S, Bedi R, Chowdhury TA, De P, El-Sherbini N, Game F, Gray S, Hardy D, James J, Kong MF, Ramlan G, Southcott E, Winocour P. Management of adults with diabetes on the haemodialysis unit: summary of guidance from the Joint British Diabetes Societies and the Renal Association. Diabet Med 2018; 35:1018-1026. [PMID: 30152585 DOI: 10.1111/dme.13676] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/12/2018] [Indexed: 12/29/2022]
Abstract
Diabetic nephropathy remains the principal cause of end-stage renal failure in the UK and its prevalence is set to increase. People with diabetes and end-stage renal failure on maintenance haemodialysis are highly vulnerable, with complex comorbidities, and are at high risk of adverse cardiovascular outcomes, the leading cause of mortality in this population. The management of people with diabetes receiving maintenance haemodialysis is shared between diabetes and renal specialist teams and the primary care team, with input from additional healthcare professionals providing foot care, dietary support and other aspects of multidisciplinary care. In this setting, one specialty may assume that key aspects of care are being provided elsewhere, which can lead to important components of care being overlooked. People with diabetes and end-stage renal failure require improved delivery of care to overcome organizational difficulties and barriers to communication between healthcare teams. No comprehensive guidance on the management of this population has previously been produced. These national guidelines, the first in this area, bring together in one document the disparate needs of people with diabetes on maintenance haemodialysis. The guidelines are based on the best available evidence, or on expert opinion where there is no clear evidence to inform practice. We aim to provide clear advice to clinicians caring for this vulnerable population and to encourage and improve education for clinicians and people with diabetes to promote empowerment and self-management.
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Affiliation(s)
- A H Frankel
- Imperial College Healthcare NHS Trust, London, UK
| | - S Kazempour-Ardebili
- Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Iran
| | - R Bedi
- Imperial College Healthcare NHS Trust, London, UK
| | | | - P De
- Birmingham City Hospital (Sandwell and West Birmingham Hospitals NHS Trust), Birmingham, UK
| | | | - F Game
- Derby Teaching Hospitals NHS Foundation Trust and University of Nottingham, UK
| | - S Gray
- East and North Herts NHS Trust, UK
| | - D Hardy
- East and North Herts NHS Trust, UK
| | - J James
- University Hospitals of Leicester NHS Trust, UK
| | - M-F Kong
- University Hospitals of Leicester NHS Trust, UK
| | - G Ramlan
- North Middlesex University Hospital NHS Trust, UK
| | | | - P Winocour
- Queen Elizabeth II Hospital, Welwyn Garden City, UK
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Brandt SJ, Kleinert M, Tschöp MH, Müller TD. Are peptide conjugates the golden therapy against obesity? J Endocrinol 2018; 238:R109-R119. [PMID: 29848610 PMCID: PMC6026923 DOI: 10.1530/joe-18-0264] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 05/30/2018] [Indexed: 12/19/2022]
Abstract
Obesity is a worldwide pandemic, which can be fatal for the most extremely affected individuals. Lifestyle interventions such as diet and exercise are largely ineffective and current anti-obesity medications offer little in the way of significant or sustained weight loss. Bariatric surgery is effective, but largely restricted to only a small subset of extremely obese patients. While the hormonal factors mediating sustained weight loss and remission of diabetes by bariatric surgery remain elusive, a new class of polypharmacological drugs shows potential to shrink the gap in efficacy between a surgery and pharmacology. In essence, this new class of drugs combines the beneficial effects of several independent hormones into a single entity, thereby combining their metabolic efficacy to improve systems metabolism. Such unimolecular drugs include single molecules with agonism at the receptors for glucagon, glucagon-like peptide 1 and the glucose-dependent insulinotropic polypeptide. In preclinical studies, these specially tailored multiagonists outperform both their mono-agonist components and current best in class anti-obesity medications. While clinical trials and vigorous safety analyses are ongoing, these drugs are poised to have a transformative effect in anti-obesity therapy and might hopefully lead the way to a new era in weight-loss pharmacology.
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Affiliation(s)
- S J Brandt
- Institute for Diabetes and ObesityHelmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD)Neuherberg, Germany
| | - M Kleinert
- Institute for Diabetes and ObesityHelmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD)Neuherberg, Germany
| | - M H Tschöp
- Institute for Diabetes and ObesityHelmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD)Neuherberg, Germany
- Division of Metabolic DiseasesTechnische Universität, Munich, Germany
| | - T D Müller
- Institute for Diabetes and ObesityHelmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD)Neuherberg, Germany
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49
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Abstract
In healthy individuals, the incretin hormone glucagon-like peptide 1 (GLP1) potentiates insulin release and suppresses glucagon secretion in response to the ingestion of nutrients. GLP1 also delays gastric emptying and increases satiety. In patients with type 2 diabetes mellitus (T2DM), supraphysiological doses of GLP1 normalize the endogenous insulin response during a hyperglycaemic clamp. Owing to the short plasma half-life of native GLP1, several GLP1 receptor agonists (GLP1RAs) with longer half-lives have been developed for the treatment of T2DM. These compounds vary in chemical structure, pharmacokinetics and size, which results in different clinical effects on hyperglycaemia and body weight loss; these variations might also explain the difference in cardiovascular effect observed in large-scale cardiovascular outcome trials, in which certain GLP1RAs were shown to have a positive effect on cardiovascular outcomes. Owing to their metabolic effects, GLP1RAs are also considered for the treatment of several other lifestyle-induced conditions, such as obesity, prediabetes and liver disease. This Review provides insights into the physiology of GLP1 and its involvement in the pathophysiology of T2DM and an overview of the currently available and emerging GLP1RAs. Furthermore, we review the results from the currently available large-scale cardiovascular outcome trials and the use of GLP1RAs for other indications.
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Affiliation(s)
- Andreas Andersen
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Copenhagen, Denmark
| | - Asger Lund
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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50
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Systematic Review of Efficacy and Safety of Newer Antidiabetic Drugs Approved from 2013 to 2017 in Controlling HbA1c in Diabetes Patients. PHARMACY 2018; 6:pharmacy6030057. [PMID: 29954090 PMCID: PMC6164486 DOI: 10.3390/pharmacy6030057] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 06/01/2018] [Accepted: 06/21/2018] [Indexed: 02/07/2023] Open
Abstract
Type 2 Diabetes Mellitus (T2DM) is the most common form of diabetes mellitus and accounts for about 95% of all diabetes cases. Many newer oral as well as parenteral antidiabetic drugs have been introduced in to the market in recent years to control hyperglycemic conditions in diabetes patients and many of these drugs produce potential side effects in diabetes patients. Hence, this systematic review was aimed to analyze and compare the efficacy and safety of oral antidiabetic agents in controlling HbA1c in T2DM patients, that were approved by the United States-Food and Drug Administration (US-FDA) from 2013 to 2017. All randomized controlled, double-blind trials published in English during the search period involving the newer antidiabetic agents were selected. In the outcome assessment comparison, semaglutide demonstrated the highest efficacy in lowering HbA1c, with a 1.6% reduction (p < 0.0001) when given at a dose of 1.0 mg. The safety profile of all the agents as compared to placebo or control were similar, with no or slight increase in the occurrence of adverse events (AEs) but no fatal reaction was reported. The most common AEs of all the antidiabetic agents were gastrointestinal in nature, with several cases of hypoglycemic events. However, among all these agents, semaglutide seems to be the most efficacious drug to improve glycemic control in terms of HbA1c. Alogliptin has the least overall frequency of AEs compared to other treatment groups.
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