1
|
Di Loreto C, Celleno R, Pezzuto D, Ambrosi F, Bellavita S, Biagini M, Passeri M, Del Sindaco P. Effectiveness, Simplification and Persistence of IDegLira in Poorly Controlled People with Type 2 Diabetes: A 4-Year Follow-Up Real-World Study. Diabetes Ther 2024; 15:1313-1331. [PMID: 38605275 PMCID: PMC11096145 DOI: 10.1007/s13300-024-01564-z] [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] [Academic Contribution Register] [Received: 02/09/2024] [Accepted: 03/11/2024] [Indexed: 04/13/2024] Open
Abstract
INTRODUCTION Efficacy and safety of the fixed ratio combination of insulin degludec and liraglutide (IDegLira) has been largely documented. However, long-term data are limited. This study aimed at describing persistence in therapy and the effectiveness at 48 months of IDegLira. METHODS We conducted an observational study based on retrospective chart review. All patients treated with IDegLira during 2018-2022 were included. Data on treatment approaches and clinical outcomes were collected at the first prescription of IDegLira (T0) and after 6, 12, 24, 36, and 48 months. RESULTS Overall, 156 patients (mean age 68 years, 64.1% men) started IDegLira, of whom 88 (56.4%) were previously treated with basal-oral therapy (BOT) and 68 (43.6%) with basal-bolus schemes (BB). Before starting IDegLira, 23.8% were treated with ≥ 2 oral antihyperglycemic agents in association with insulin; at T0, the proportion decreased to 3.2%. Short-acting insulin was discontinued after the first week. After 48 months, levels of HbA1c were significantly reduced by 1.34% in the BOT group and 1.07% in the BB group (p < 0.0001 in both groups). In the BOT group, FBG levels decreased by about 50 mg/dl and body weight was unchanged. In the BB group, FBG levels decreased by about 40 mg/dl and body weight was significantly reduced by an average of 7.7 kg. Five patients (3.2%) interrupted therapy with IDegLira during 48 months, and no severe hypoglycemia occurred. CONCLUSIONS Our study emphasizes the important role of IDegLira in maintaining a good metabolic control while minimizing the risk of major hypoglycemia and weight gain in the long term. The substantial simplification of treatment schemes can increase adherence.
Collapse
Affiliation(s)
- Chiara Di Loreto
- U.O.S. Diabetologia, Distretto del Perugino, USL Umbria 1, "Poliambulatorio Europa", Perugia, Italy.
| | - Roberta Celleno
- U.O.S. Diabetologia, Distretto del Perugino, USL Umbria 1, "Poliambulatorio Europa", Perugia, Italy
| | - Debora Pezzuto
- U.O.S. Diabetologia, Distretto del Perugino, USL Umbria 1, "Poliambulatorio Europa", Perugia, Italy
| | - Franca Ambrosi
- U.O.S. Diabetologia, Distretto del Perugino, USL Umbria 1, "Poliambulatorio Europa", Perugia, Italy
| | - Silvia Bellavita
- U.O.S. Diabetologia, Distretto del Perugino, USL Umbria 1, "Poliambulatorio Europa", Perugia, Italy
| | - Marinella Biagini
- U.O.S. Diabetologia, Distretto del Perugino, USL Umbria 1, "Poliambulatorio Europa", Perugia, Italy
| | - Monica Passeri
- U.O.S. Diabetologia, Distretto del Perugino, USL Umbria 1, "Poliambulatorio Europa", Perugia, Italy
| | - Paola Del Sindaco
- U.O.S. Diabetologia, Distretto del Perugino, USL Umbria 1, "Poliambulatorio Europa", Perugia, Italy
| |
Collapse
|
2
|
Fadini GP, Buzzetti R, Pitocco D, Tortato E, Scatena A, Lamacchia O, Lastoria G, Simoni L, Consoli A. IDegLira for the real-world treatment of type 2 diabetes in Italy. Final results from the REX observational study. Diabetes Obes Metab 2024; 26:1746-1756. [PMID: 38327240 DOI: 10.1111/dom.15486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 11/30/2023] [Revised: 01/15/2024] [Accepted: 01/21/2024] [Indexed: 02/09/2024]
Abstract
AIM The study was designed to generate real-world evidence on IDegLira in the Italian clinical practice in two groups of patients with type 2 diabetes (T2D), switching to IDegLira either from a basal only (basal group) or basal-bolus insulin regimen (BB group). MATERIALS AND METHODS This was a non-interventional, multicentre, single-cohort, prospective study assessing the long-term glycaemic control in patients with T2D, who switched to IDegLira from a basal insulin ± glucose-lowering medication regimen with or without a bolus insulin component for approximately 18 months, conducted in 28 Italian diabetes centres. The primary endpoint was the change in glycated haemoglobin (HbA1c) levels from baseline to 6 months after IDegLira initiation. RESULTS The study included 358 patients with a mean age 67.2 years and diabetes duration of 15.7 years. HbA1c significantly decreased from IDegLira start to all study time points in the overall population (basal group -1.19%; BB group -0.60% at the end of observation). Patients achieving HbA1c <7% levels increased from 12.9% (n = 43) to 40.3% (n = 110) at 18 months. Fasting blood glucose and body weight also significantly decreased in both groups, although more in the BB group. Overall, 14.3% of completed patients had an intensification of treatment (mainly in the basal group) and 48.6% had a simplification of treatment (mainly in the BB group). CONCLUSIONS Switching to IDegLira in a real-world clinical setting is a valid therapeutic option for patients with T2D with inadequate glycaemic control on basal or BB insulin regimen and/or need to simplify their insulin therapy, with specific reasons and therapeutic goals according to different T2D management trajectories.
Collapse
Affiliation(s)
- Gian Paolo Fadini
- Department of Medicine, University of Padova, Padua, Italy
- Division of Metabolic Diseases, Padova Hospital, Padua, Italy
| | - Raffaella Buzzetti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Dario Pitocco
- Diabetology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Elena Tortato
- Metabolic Diseases and Diabetology Department, IRCCS INRCA, Ancona, Italy
| | | | - Olga Lamacchia
- Endocrinology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Giusi Lastoria
- Clinical Medical & Regulatory Department, Novo Nordisk SpA, Rome, Italy
| | - Lucia Simoni
- Medineos Observational Research, an IQVIA Company, Modena, Italy
| | - Agostino Consoli
- Department of Medicine and Aging Sciences (DMSI) and Center for Advanced Studies and Technology (CAST), University G. D'Annunzio, Chieti, Italy
| |
Collapse
|
3
|
Wang R, Luo S, Xiao Z, Zhou Z. Efficacy and safety of fixed-ratio combination insulin degludec/liraglutide in type 2 diabetes: A systematic review and meta-analysis of randomised controlled trials. Diabetes Metab Res Rev 2024; 40:e3752. [PMID: 38013215 DOI: 10.1002/dmrr.3752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/02/2023] [Revised: 09/30/2023] [Accepted: 11/05/2023] [Indexed: 11/29/2023]
Abstract
BACKGROUND The efficacy and safety of fixed-ratio combination insulin degludec/liraglutide (IDegLira) for type 2 diabetes (T2DM) were extensively investigated by the global DUAL trials. However, the evidence on its efficacy and safety in T2DM has not been systematically reviewed. METHODS Randomized controlled trials published in English that compared IDegLira with placebo or GLP-1 agonists or insulin in patients with T2DM were selected up to December 2022. Data on the study characteristics, efficacy and safety outcomes were extracted. We compared the efficacy and safety between "IDegLira versus Insulin," "IDegLira versus GLP-1RA," and "IDegLira versus Placebo". The risk of potential bias was assessed. RESULTS In terms of glycaemic efficacy, IDegLira reduced levels of glycated haemoglobin (HbA1c; weighted mean differences (WMDs) 0.52%, 95% CI 0.33%-0.71%); fasting blood glucose (0.32 mg/dL, 0.14-0.50 mg/dL), and the nine-point self-measured plasma glucose (0.25 mmol/L, 0.25-0.36 mmol/L). Furthermore, IDegLira was generally better in the attainment of HbA1c < 7.0% or ≤6.5%, HbA1c < 7.0% or ≤6.5% without weight gain and/or without severe or blood glucose-confirmed hypoglycaemic episodes. In non-glycaemic efficacy aspects, IDegLira decreased systolic blood pressure but elevated heart rate. In terms of safety outcomes, IDegLira did not appear to be associated with a risk of hypoglycaemia (RR 1.23, 0.85-1.78) and nocturnal hypoglycaemia (0.89, 0.52-1.52) occurring when compared with other hypoglycaemic agents or placebo. CONCLUSIONS IDegLira improves better glycaemic and non-glycaemic outcomes without weight gain and/or without severe or blood glucose-confirmed hypoglycaemic episodes in T2DM. Side effects of IDegLira are mild.
Collapse
Affiliation(s)
- Rui Wang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Shuoming Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zilin Xiao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| |
Collapse
|
4
|
Nreu B, Dicembrini I, Tinti F, Mannucci E, Monami M. Pancreatitis and pancreatic cancer in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonists: an updated meta-analysis of randomized controlled trials. Minerva Endocrinol (Torino) 2023; 48:206-213. [PMID: 32720500 DOI: 10.23736/s2724-6507.20.03219-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 05/16/2023]
Abstract
INTRODUCTION An association between glucagon-like peptide-1 receptor agonists (GLP1-RA) and risk of pancreatitis and pancreatic cancer has been suggested. Since its first description, several new trials (including three cardiovascular outcome trials) have been published, substantially increasing the available data set. This suggests the need for an update of the previous meta-analysis. EVIDENCE ACQUISITION A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials, with duration ≥52 weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. The endpoints were pancreatitis, pancreatic cancer reported as serious adverse events. Mantel-Haenszel Odds Ratio (MH-OR) with 95% confidence interval (95% CI) was calculated for all outcomes defined above, on an intention-to-treat basis. EVIDENCE SYNTHESIS A total of 43 trials fulfilling inclusion criteria (all reporting data on pancreatitis and pancreatic cancer) was identified. GLP-1 RA showed no association with pancreatitis (MH-OR 1.24 [0.94, 1.64]; P=0.13) and pancreatic cancer (MH-OR 1.28 [0.87, 1.89]; P=0.20). CONCLUSIONS No clear evidence of risk for pancreatitis was observed, whereas data on pancreatic cancer are too scarce to draw any conclusion.
Collapse
Affiliation(s)
- Besmir Nreu
- Department of Diabetology, Careggi University Hospital, Florence, Italy
| | - Ilaria Dicembrini
- Department of Diabetology, Careggi University Hospital, Florence, Italy
| | - Federico Tinti
- Department of Diabetology, Careggi University Hospital, Florence, Italy
| | - Edoardo Mannucci
- Department of Diabetology, Careggi University Hospital, Florence, Italy
| | - Matteo Monami
- Department of Diabetology, Careggi University Hospital, Florence, Italy -
| |
Collapse
|
5
|
Bai S, Lin C, Jiao R, Cai X, Hu S, Lv F, Yang W, Zhu X, Ji L. Is the steady-state concentration, duration of action, or molecular weight of GLP-1RA associated with cardiovascular and renal outcomes in type 2 diabetes? Eur J Intern Med 2023; 109:79-88. [PMID: 36628824 DOI: 10.1016/j.ejim.2023.01.008] [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] [Academic Contribution Register] [Received: 10/26/2022] [Revised: 01/02/2023] [Accepted: 01/05/2023] [Indexed: 01/09/2023]
Abstract
IMPORTANCE Disparities were found in the cardiovascular and renal outcomes among different glucagon-like peptide 1 receptor agonist (GLP-1RA) subtypes. However, whether the characteristics of GLP-1RA itself are associated with these disparities remains unclear. OBJECTIVE To assess the association between the steady-state concentration, duration of action, or molecular weight of GLP-1RA and the risks of cardiovascular and renal outcomes in patients with type 2 diabetes (T2D). DATA SOURCES PubMed, MEDLINE, EMBASE, Cochrane and Clinicaltrial.gov from inception to April 2022. STUDY SELECTION Randomized controlled trials (RCTs) investigating GLP-1RAs in patients with T2D were included. DATA EXTRACTION AND SYNTHESIS Literature screening and data extraction were performed independently by 2 researchers. The outcomes were computed as odds ratio (OR) and its 95% confidence interval (CI). Subgroup analyses were conducted according to steady-state concentration, duration of action and molecular weight of GLP-1RAs. MAIN OUTCOMES AND MEASURES Primary outcomes were major adverse cardiovascular events (MACE), composite renal outcome and all-cause mortality. RESULTS In all, 61 RCTs were included. When compared with non-GLP-1RA agents, GLP-1RAs with high steady-state concentration were associated with greater risk reduction in MACE (p for subgroup difference = 0.01) and the composite renal outcome (p for subgroup difference = 0.008) in patients with T2D. Greater risk reductions in MACE between GLP-1RA users versus non-GLP-RA users were observed in long acting stratum when compared with short acting stratum (p for subgroup difference = 0.04) in patients with T2D. The molecular weight of GLP-1RAs was not associated with the risk of cardiovascular and renal outcomes. CONCLUSIONS AND RELEVANCE GLP-1RAs with high steady-state concentrations might be associated with greater risk reductions in cardiovascular and renal outcomes in patients with T2D. Long acting GLP-1RAs might outperform short acting ones in reducing the risk of cardiovascular outcomes. These findings provided new insights for guiding the clinical applications of GLP-1RAs in patients with T2D.
Collapse
Affiliation(s)
- Shuzhen Bai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Chu Lin
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Ruoyang Jiao
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
| | - Suiyuan Hu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xingyun Zhu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
| |
Collapse
|
6
|
Zhou F, Jiang L, Guo J, Fan Y, Pan Q, Li T, Sun X, Li P. Degree of obesity and gastrointestinal adverse reactions influence the weight loss effect of liraglutide in overweight or obese patients with type 2 diabetes. Ther Adv Chronic Dis 2023; 14:20406223231161516. [PMID: 36950020 PMCID: PMC10026133 DOI: 10.1177/20406223231161516] [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] [Subscribe] [Academic Contribution Register] [Received: 03/25/2022] [Accepted: 02/17/2023] [Indexed: 03/24/2023] Open
Abstract
Background Liraglutide can effectively reduce the weight of patients with type 2 diabetes. Nonetheless, its weight loss effect was highly heterogeneous in different patients in the clinical practice. Objective To identify the factors most associated with the weight loss effect of liraglutide in obese or overweight patients with type 2 diabetes with poorly controlled oral medication in northeast China. Design A prospective study. Methods A prospective study was performed in subjects with type 2 diabetes who were taking oral medication and had a body mass index (BMI) of ⩾24 kg/m2. Liraglutide was administered for at least 12 weeks, while the original hypoglycemic regimen was kept unchanged (Phase I). Later, liraglutide treatment was continued or stopped as necessary or as subjects thought fit in the 13-52 weeks that followed (Phase II), and the potential factors affecting the effect of weight loss of liraglutide were analyzed. Results Of the 127 recruited subjects, 90 had comprehensive follow-up data at week 12. In Phase I, the subjects' blood sugar levels and weight decreased significantly(P < 0.001). Among all the significant factors, the gastrointestinal adverse reactions score (GARS) was more correlated with BMI change (ΔBMI; r = 0.43) and waist circumference change (ΔWC; r = 0.32) than the baseline BMI (BMI0) and WC (WC0). At week 12, linear regression showed that BMI0 independently affected ΔBMI and ΔWC, whereas WC0 only affected ΔWC. The GARS was significantly associated with ΔBMI and ΔWC, and this association continued until week 52, even after most subjects had discontinued liraglutide treatment. Conclusion The degree of obesity and gastrointestinal adverse reactions were the most promising predictors of weight loss in liraglutide treatment.
Collapse
Affiliation(s)
- Fang Zhou
- Department of Endocrinology, Shengjing Hospital
of China Medical University, Shenyang, China
| | - Lu Jiang
- Department of Cardiovascular Medicine,
Northeast International Hospital, Shenyang, China
| | - Jiamei Guo
- Department of Endocrinology, Shengjing Hospital
of China Medical University, Shenyang, China
| | - Yuting Fan
- Department of General Medicine, Shanxi
Provincial People’s Hospital, Taiyuan, China
| | - Qin Pan
- Department of Endocrinology, Shengjing Hospital
of China Medical University, Shenyang, China
| | - Tianlian Li
- Department of Endocrinology, Shengjing Hospital
of China Medical University, Shenyang, China
| | - Xiaoshi Sun
- Department of Endocrinology, Shengjing Hospital
of China Medical University, Shenyang, China
| | | |
Collapse
|
7
|
Szépkúti S, Bandur S, Kovács G, Ferenci T, Svébis MM, Turbucz P, Tabák ÁG. Real-world effectiveness of IDegLira compared with intensified conventional insulin therapy in adults with type 2 diabetes: a retrospective cohort study. BMC Endocr Disord 2022; 22:229. [PMID: 36104712 PMCID: PMC9476268 DOI: 10.1186/s12902-022-01139-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 05/30/2022] [Accepted: 08/26/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND IDegLira is a fixed-ratio combination of insulin degludec and liraglutide with proven efficacy against simpler regimens and non-inferiority against basal-bolus insulin therapy. However, the evaluation of its real-world effectiveness is hindered by technical issues and requires further exploration. Thus we aimed to compare effectiveness of insulin degludec/liraglutide (IDegLira) versus intensified conventional insulin therapy (ICT) for type 2 diabetes in a real-world setting. METHODS This retrospective cohort study from an outpatient clinic in Hungary included people who initiated IDegLira due to inadequate glycaemic control (HbA1c > 7.0% [53.0 mmol/mol]) with oral and/or injectable antidiabetic drugs. Data were compared with a historical cohort who initiated ICT. Outcomes included HbA1c, body weight, and hypoglycaemia differences over 18 months of follow-up. RESULTS Data were included from 227 and 72 people who initiated IDegLira and ICT, respectively. Estimated mean difference (MD) in HbA1c at 18 months favoured IDegLira versus ICT (MD 0.60, 95% CI 0.88-0.32 [MD 6.6 mmol/mol, 95% CI 9.6-3.5]). More people reached target HbA1c ≤7.0% (53.0 mmol/mol) with IDegLira than ICT (odds ratio 3.36, 95% CI 1.52-7.42). IDegLira treatment was associated with weight loss compared with gain for ICT (MD 6.7 kg, 95% CI 5.0-8.5). The hazard ratio for hypoglycaemia comparing IDegLira with ICT was 0.18 (95% CI 0.08-0.49). CONCLUSIONS Treatment with IDegLira over 18 months resulted in greater HbA1c reductions, weight loss versus gain, and a lower rate of hypoglycaemia versus ICT in people with type 2 diabetes.
Collapse
Affiliation(s)
- Sándor Szépkúti
- Diabetology, Pest County Flór Ferenc Hospital, Kistarcsa, Hungary
| | - Szilvia Bandur
- Diabetology, Pest County Flór Ferenc Hospital, Kistarcsa, Hungary
| | - Gábor Kovács
- Diabetology, Pest County Flór Ferenc Hospital, Kistarcsa, Hungary
| | - Tamás Ferenci
- Physiological Controls Research Center, Óbuda University, Budapest, Hungary
- Department of Statistics, Corvinus University of Budapest, Budapest, Hungary
| | - Márk M. Svébis
- Department of Internal Medicine and Oncology, Semmelweis University Faculty of Medicine, Üllői út 26, Budapest, H1085 Hungary
| | - Piroska Turbucz
- Diabetology, Pest County Flór Ferenc Hospital, Kistarcsa, Hungary
| | - Ádám G. Tabák
- Department of Internal Medicine and Oncology, Semmelweis University Faculty of Medicine, Üllői út 26, Budapest, H1085 Hungary
- Department of Public Health, Semmelweis University Faculty of Medicine, Üllői út 26, Budapest, H1085 Hungary
- Department of Epidemiology and Public Health, University College London, London, UK
| |
Collapse
|
8
|
Madsbad S, Holst JJ. Cardiovascular effects of incretins - focus on GLP-1 receptor agonists. Cardiovasc Res 2022; 119:886-904. [PMID: 35925683 DOI: 10.1093/cvr/cvac112] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 01/03/2022] [Revised: 03/29/2022] [Accepted: 04/04/2022] [Indexed: 11/13/2022] Open
Abstract
GLP-1 receptor agonists (GLP-1 RAs) have been used to treat patients with type 2 diabetes since 2005 and have become popular because of the efficacy and durability in relation to glycaemic control in combination with weight loss in most patients. Today in 2022, seven GLP-1 RAs, including oral semaglutide are available for treatment of type 2 diabetes. Since the efficacy in relation to reduction of HbA1c and body weight as well as tolerability and dosing frequency vary between agents, the GLP-1 RAs cannot be considered equal. The short acting lixisenatide showed no cardiovascular benefits, while once daily liraglutide and the weekly agonists, subcutaneous semaglutide, dulaglutide, and efpeglenatide, all lowered the incidence of cardiovascular events. Liraglutide, oral semaglutide and exenatide once weekly also reduced mortality. GLP-1 RAs reduce the progression of diabetic kidney disease. In the 2019 consensus report from EASD/ADA, GLP-1 RAs with demonstrated cardio-renal benefits (liraglutide, semaglutide and dulaglutide) are recommended after metformin to patients with established cardiovascular diseases or multiple cardiovascular risk factors. European Society of Cardiology (ESC) suggests starting with a SGLT-2 inhibitor or a GLP-1 RA in drug naïve patients with type 2 diabetes and atherosclerotic CVD or high CV Risk. However, the results from cardiovascular outcome trials (CVOT) are very heterogeneous suggesting that some GLP-1RA are more suitable to prevent CVD than others. The CVOTs provide a basis upon which individual treatment decisions for patients with T2D and CVD can be made.
Collapse
Affiliation(s)
- Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Denmark
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
9
|
Mannucci E, Targher G, Nreu B, Pintaudi B, Candido R, Giaccari A, Gallo M, Monami M. Effects of insulin on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis 2022; 32:1353-1360. [PMID: 35422359 DOI: 10.1016/j.numecd.2022.03.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 10/27/2021] [Revised: 01/31/2022] [Accepted: 03/04/2022] [Indexed: 10/18/2022]
Abstract
AIM In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin with this respect. DATA SYNTHESIS A MEDLINE database search was performed to identify all RCTs, up to June 1st, 2021, with duration≥52 weeks, in which insulin was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Six RCTs (enrolling 8091 patients and 10,139 in the insulin and control group, respectively) were included in the analysis for MACEs and HF, and 18 in that for all-cause mortality (9760 and 11,694 patients in the insulin and control group, respectively). Treatment with insulin neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 1.09, 95% CI 0.97-1.23; 0.99, 95% CI 0.91, 1.08; and 0.90, 95% CI 0.78, 1.04, respectively). CONCLUSIONS This meta-analysis showed no significant effects of insulin on incident MACE, all-cause mortality, and HHF.
Collapse
Affiliation(s)
| | - Giovanni Targher
- Endocrinology, Diabetes and Metabolism, University of Verona, Italy
| | - Besmir Nreu
- Diabetology, Careggi Hospital and University of Florence, Italy
| | | | - Riccardo Candido
- Diabetes Centre District 3, Azienda Sanitaria Universitaria Integrata di Trieste, Via Puccini 48/50, 34100, Trieste, Italy
| | - Andrea Giaccari
- Centro per le Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica Del Sacro Cuore, Rome, Italy
| | - Marco Gallo
- Endocrinology and Metabolic Diseases Unit, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - Matteo Monami
- Diabetology, Careggi Hospital and University of Florence, Italy.
| |
Collapse
|
10
|
Liu H, Luo B, Chen X, Ingwersen SH, Jia T, Vestergård Jacobsen L, Hu P. Preserved pharmacokinetics and pharmacodynamics of insulin degludec and liraglutide when administered as insulin degludec/liraglutide in a Chinese population. J Diabetes Investig 2022; 13:652-656. [PMID: 34797962 PMCID: PMC9017614 DOI: 10.1111/jdi.13716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/11/2021] [Revised: 11/10/2021] [Accepted: 11/17/2021] [Indexed: 11/30/2022] Open
Abstract
We report the findings of a single-dose, randomized, three-period cross-over, clinical trial in healthy Chinese individuals (n = 24) comparing the pharmacokinetics of insulin degludec/liraglutide (IDegLira) with its individual components. Furthermore, we report a population pharmacokinetic analysis of a 26-week, phase III, treat-to-target, randomized trial of 720 Chinese individuals with type 2 diabetes. Participants were randomized to IDegLira, degludec or liraglutide, all once daily with metformin. The pharmacokinetic profiles of IDegLira were similar to its individual components. Dose proportionality was indicated for both IDegLira components. Although there were no relevant covariate effects on degludec exposure, liraglutide exposure was inversely correlated with bodyweight. In conclusion, for the Chinese population, the pharmacokinetics of the fixed-ratio combination IDegLira is similar to that of its individual components.
Collapse
Affiliation(s)
- Hongzhong Liu
- Clinical Pharmacology Research CenterChinese Academy of Medical Sciences & Peking Union Medical CollegePeking Union Medical College HospitalBeijingChina
- Beijing Key Laboratory of Clinical Pharmacokinetics & Pharmacodynamics Investigation for Innovative DrugsPeking Union Medical College HospitalBeijingChina
| | - Bin Luo
- Novo Nordisk China Pharmaceuticals Co. LtdBeijingChina
| | - Xia Chen
- Clinical Pharmacology Research CenterChinese Academy of Medical Sciences & Peking Union Medical CollegePeking Union Medical College HospitalBeijingChina
- National Clinical Research Center for Neurological DiseasesClinical Trial CenterBeijing Tiantan HospitalBeijingChina
| | | | | | | | - Pei Hu
- Clinical Pharmacology Research CenterChinese Academy of Medical Sciences & Peking Union Medical CollegePeking Union Medical College HospitalBeijingChina
- Beijing Key Laboratory of Clinical Pharmacokinetics & Pharmacodynamics Investigation for Innovative DrugsPeking Union Medical College HospitalBeijingChina
| |
Collapse
|
11
|
Cowart K, Gonzalez R, Carris NW. Cardiovascular and microvascular outcomes with iGlarLixi versus iDegLira: A real-world, population-based cohort study. Diabetes Obes Metab 2022; 24:348-353. [PMID: 34676657 DOI: 10.1111/dom.14579] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/24/2021] [Revised: 10/12/2021] [Accepted: 10/17/2021] [Indexed: 01/09/2023]
Affiliation(s)
- Kevin Cowart
- Taneja College of Pharmacy, Morsani College of Medicine & College of Public Health, University of South Florida, Tampa, Florida, USA
| | - Rachel Gonzalez
- Taneja College of Pharmacy, University of South Florida, Tampa, Florida, USA
| | - Nicholas W Carris
- Taneja College of Pharmacy & Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| |
Collapse
|
12
|
McCrimmon RJ, Falla E, Sha JZ, Alsaleh AJO, Lew E, Hudson R, Baxter M, Palmer K. Cost-Effectiveness of iGlarLixi in People with Type 2 Diabetes Mellitus Suboptimally Controlled on Basal Insulin Plus Metformin in the UK. Diabetes Ther 2021; 12:3217-3230. [PMID: 34714523 PMCID: PMC8586275 DOI: 10.1007/s13300-021-01159-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/04/2021] [Accepted: 09/18/2021] [Indexed: 01/28/2023] Open
Abstract
INTRODUCTION A cost-effectiveness analysis was conducted comparing a fixed-ratio combination (FRC) of insulin glargine 100 units/mL plus lixisenatide (iGlarLixi) versus the FRC of insulin degludec plus liraglutide (iDegLira) and the free-combination comparators insulin glargine plus dulaglutide (iGlar plus Dula) and basal insulin plus liraglutide (BI plus Lira). METHODS The IQVIA Core Diabetes Model was used to estimate lifetime costs and outcomes for a cohort of patients with type 2 diabetes mellitus (T2DM) from the UK healthcare perspective. Initial clinical data for iGlarLixi were based on the randomized, controlled LixiLan-L trial and the relative treatment effects for comparators were based on an indirect treatment comparison using data from the AWARD-9 (iGlar plus Dula), LIRA ADD2 BASAL (BI plus Lira), and DUAL V (iDegLira) trials. Costs were derived from publicly available sources. Lifetime costs (in British Pound Sterling [£]) and quality-adjusted life-years (QALYs) were predicted; net monetary benefit (NMB) for iGlarLixi versus comparators was derived using a willingness-to-pay threshold of £20,000. Extensive scenario and sensitivity analyses were conducted. RESULTS Estimated costs were lowest with iGlarLixi (£31,295) compared with iGlar plus Dula (£38,790), iDegLira (£40,179), and BI plus Lira (£42,467). Total QALYs gained were identical with iGlarLixi and iDegLira (8.438), and comparable with iGlar plus Dula (8.439) and BI plus Lira (8.466). NMB for iGlarLixi was positive versus all comparators (£10,603.86 vs. BI plus Lira; £7,466.24 vs. iGlar plus Dula; £8.874.11 vs. iDegLira). CONCLUSION In patients with T2DM with suboptimal glycemic control on basal insulin, iGlarLixi provides very similar outcomes and substantial cost savings, compared with other fixed and free combinations of insulins plus glucagon-like peptide-1 receptor agonists.
Collapse
|
13
|
Novodvorský P, Haluzík M. An update on the safety of insulin-GLP-1 receptor agonist combinations in type 2 diabetes mellitus. Expert Opin Drug Saf 2021; 21:349-361. [PMID: 34641742 DOI: 10.1080/14740338.2021.1978974] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/14/2023]
Abstract
INTRODUCTION Recent development of novel antidiabetic drugs with proven cardiovascular (CV) and renal benefit and positive effect on body weight enable to take a more complex approach toward the management of type 2 diabetes mellitus (T2DM). Fixed-ratio combinations of insulin-GLP-1 receptor agonist (FRC) utilize complementary mechanisms of action of their individual components and address multiple pathologies linked with T2DM at the same time. AREAS COVERED There are currently three FRCs on the market: iGlarLixi (glargine and lixisenatide in 2 different formulations) and IDegLira (degludec and liraglutide). We provide an up-to-date review on the rationale for the use of FRCs and their current position in the management of T2DM. We discuss the available evidence from randomized controlled trials, post hoc analyses, indirect comparative studies and real-world data on their effect on glycemic control, risk of hypoglycemia, body weight, CV safety, and their safety profile. EXPERT OPINION FRCs represent an efficacious option for treatment intensification from basal insulin or even the first insulin-based therapy in T2DM. Their excellent glucose-lowering efficacy is complemented with lower risk of hypoglycemia in comparison to basal insulin, neutral effect on body weight and the lower risk of gastrointestinal adverse effects in comparison to GLP-1 receptor agonists.
Collapse
Affiliation(s)
- Peter Novodvorský
- Diabetes Centre, Institute for Clinical and Experimental Medicine (Ikem), Prague, Czech Republic.,Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK.,MUDr. Korecová Metabolické Centrum, Trenčín, Slovakia
| | - Martin Haluzík
- Diabetes Centre, Institute for Clinical and Experimental Medicine (Ikem), Prague, Czech Republic.,First Faculty of Medicine, Charles University, Prague, Czech Republic
| |
Collapse
|
14
|
Shah N, Abdalla MA, Deshmukh H, Sathyapalan T. Therapeutics for type-2 diabetes mellitus: a glance at the recent inclusions and novel agents under development for use in clinical practice. Ther Adv Endocrinol Metab 2021; 12:20420188211042145. [PMID: 34589201 PMCID: PMC8474306 DOI: 10.1177/20420188211042145] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/25/2021] [Accepted: 08/06/2021] [Indexed: 12/18/2022] Open
Abstract
Diabetes mellitus (DM) is a chronic, progressive, and multifaceted illness resulting in significant physical and psychological detriment to patients. As of 2019, 463 million people are estimated to be living with DM worldwide, out of which 90% have type-2 diabetes mellitus (T2DM). Over the years, significant progress has been made in identifying the risk factors for developing T2DM, understanding its pathophysiology and uncovering various metabolic pathways implicated in the disease process. This has culminated in the implementation of robust prevention programmes and the development of effective pharmacological agents, which have had a favourable impact on the management of T2DM in recent times. Despite these advances, the incidence and prevalence of T2DM continue to rise. Continuing research in improving efficacy, potency, delivery and reducing the adverse effect profile of currently available formulations is required to keep pace with this growing health challenge. Moreover, new metabolic pathways need to be targeted to produce novel pharmacotherapy to restore glucose homeostasis and address metabolic sequelae in patients with T2DM. We searched PubMed, MEDLINE, and Google Scholar databases for recently included agents and novel medication under development for treatment of T2DM. We discuss the pathophysiology of T2DM and review how the emerging anti-diabetic agents target the metabolic pathways involved. We also look at some of the limiting factors to developing new medication and the introduction of unique methods, including facilitating drug delivery to bypass some of these obstacles. However, despite the advances in the therapeutic options for the treatment of T2DM in recent years, the industry still lacks a curative agent.
Collapse
Affiliation(s)
- Najeeb Shah
- Hull University Teaching Hospitals NHS Trust,
Hull, UK
- Department of Academic Diabetes, Endocrinology
& Metabolism, Hull York Medical School, University of Hull, Brocklehurst
Building, 220-236 Anlaby Road, Hull, HU3 2RW, UK
| | - Mohammed Altigani Abdalla
- Department of Academic Diabetes, Endocrinology
& Metabolism, Hull York Medical School, University of Hull, Hull,
UK
| | - Harshal Deshmukh
- University Teaching Hospitals NHS Trust and
Department of Academic Diabetes, Endocrinology & Metabolism, Hull York
Medical School, University of Hull, Hull, UK
| | - Thozhukat Sathyapalan
- University Teaching Hospitals NHS Trust and
Department of Academic Diabetes, Endocrinology & Metabolism, Hull York
Medical School, University of Hull, Hull, UK
| |
Collapse
|
15
|
Komatsu M, Watada H, Kaneko S, Ross Agner BF, Nishida T, Kaku K. Efficacy and safety of the fixed-ratio combination of insulin degludec and liraglutide by baseline glycated hemoglobin, body mass index and age in Japanese individuals with type 2 diabetes: A subgroup analysis of two phase III trials. J Diabetes Investig 2021; 12:1610-1618. [PMID: 33595901 PMCID: PMC8409843 DOI: 10.1111/jdi.13525] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 10/26/2020] [Revised: 01/21/2021] [Accepted: 02/14/2021] [Indexed: 11/28/2022] Open
Abstract
AIMS/INTRODUCTION To assess efficacy and safety of insulin degludec/liraglutide (IDegLira) in Japanese participants with type 2 diabetes across different baseline characteristics. MATERIALS AND METHODS Data from two randomized controlled trials were used: DUAL I Japan (n = 819 insulin-naïve participants) and DUAL II Japan (n = 210 insulin-experienced participants). Outcomes were assessed according to baseline glycated hemoglobin ( HbA1c ; <8.0%, ≥8.0-<9.0%, ≥9.0%), body mass index (<25, ≥25-<30, ≥30 kg/m2 ) and age (<65, ≥65 years). RESULTS In DUAL I Japan, reductions in HbA1c with IDegLira versus degludec and liraglutide were observed across all subgroups (treatment differences: -0.48% to -0.72% vs degludec, -0.29% to -0.73% vs liraglutide). Results were similar with IDegLira versus degludec in DUAL II Japan (treatment differences: -0.82% to -1.61%). Treatment-by-subgroup interactions were significant for IDegLira versus liraglutide for baseline HbA1c and age in DUAL I Japan, and for IDegLira versus degludec for baseline HbA1c in DUAL II Japan. In DUAL I Japan, IDegLira was associated with less weight gain than degludec in most subgroups. In DUAL II Japan, IDegLira was associated with a small mean weight loss (except for baseline HbA1c ≥9.0%) versus a small gain for degludec (except for age ≥65 years subgroup); treatment-by-subgroup interactions were not significant. Total daily insulin dose was lower with IDegLira versus degludec across all categories, except for age >65 years in DUAL II Japan. CONCLUSIONS IDegLira reduced HbA1c in Japanese participants with type 2 diabetes across baseline HbA1c , body mass index and age categories, without unexpected safety issues.
Collapse
Affiliation(s)
- Mitsuhisa Komatsu
- Division of Diabetes, Endocrinology and MetabolismDepartment of Internal MedicineShinshu University School of MedicineNaganoJapan
| | - Hirotaka Watada
- Department of Metabolism and EndocrinologyJuntendo UniversityTokyoJapan
| | | | | | | | - Kohei Kaku
- Department of Internal MedicineKawasaki Medical SchoolKurashikiJapan
| |
Collapse
|
16
|
Hur KY, Moon MK, Park JS, Kim SK, Lee SH, Yun JS, Baek JH, Noh J, Lee BW, Oh TJ, Chon S, Yang YS, Son JW, Choi JH, Song KH, Kim NH, Kim SY, Kim JW, Rhee SY, Lee YB, Jin SM, Kim JH, Kim CH, Kim DJ, Chun S, Rhee EJ, Kim HM, Kim HJ, Jee D, Kim JH, Choi WS, Lee EY, Yoon KH, Ko SH. 2021 Clinical Practice Guidelines for Diabetes Mellitus of the Korean Diabetes Association. Diabetes Metab J 2021; 45:461-481. [PMID: 34352984 PMCID: PMC8369224 DOI: 10.4093/dmj.2021.0156] [Citation(s) in RCA: 132] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/11/2021] [Accepted: 07/21/2021] [Indexed: 12/15/2022] Open
Abstract
The Committee of Clinical Practice Guidelines of the Korean Diabetes Association (KDA) updated the previous clinical practice guidelines for Korean adults with diabetes and prediabetes and published the seventh edition in May 2021. We performed a comprehensive systematic review of recent clinical trials and evidence that could be applicable in real-world practice and suitable for the Korean population. The guideline is provided for all healthcare providers including physicians, diabetes experts, and certified diabetes educators across the country who manage patients with diabetes or the individuals at the risk of developing diabetes mellitus. The recommendations for screening diabetes and glucose-lowering agents have been revised and updated. New sections for continuous glucose monitoring, insulin pump use, and non-alcoholic fatty liver disease in patients with diabetes mellitus have been added. The KDA recommends active vaccination for coronavirus disease 2019 in patients with diabetes during the pandemic. An abridgement that contains practical information for patient education and systematic management in the clinic was published separately.
Collapse
Affiliation(s)
- Kyu Yeon Hur
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min Kyong Moon
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Jong Suk Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Soo-Kyung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Seung-Hwan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae-Seung Yun
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jong Ha Baek
- Division of Endocrinology & Metabolism, Department of Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Changwon, Korea
| | - Junghyun Noh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Byung-Wan Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Tae Jung Oh
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Suk Chon
- Department of Endocrinology and Metabolism, Kyung Hee University College of Medicine, Kyung Hee University Hospital, Seoul, Korea
| | - Ye Seul Yang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jang Won Son
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jong Han Choi
- Division of Endocrinology and Metabolism, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Kee Ho Song
- Division of Endocrinology and Metabolism, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Nam Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sang Yong Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chosun University College of Medicine, Gwangju, Korea
| | - Jin Wha Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chosun University College of Medicine, Gwangju, Korea
| | - Sang Youl Rhee
- Department of Endocrinology and Metabolism, Kyung Hee University College of Medicine, Kyung Hee University Hospital, Seoul, Korea
| | - You-Bin Lee
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang-Man Jin
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Hyeon Kim
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Chong Hwa Kim
- Division of Endocrinology & Metabolism, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea
| | - Dae Jung Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Korea
| | - SungWan Chun
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Eun-Jung Rhee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyun Min Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Hyun Jung Kim
- Institute for Evidence-based Medicine, Cochrane Korea, Department of Preventive Medicine, Korea University College of Medicine, Seoul, Korea
| | - Donghyun Jee
- Division of Vitreous and Retina, Department of Ophthalmology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Jae Hyun Kim
- Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Won Seok Choi
- Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Korea University Ansan Hospital, Ansan, Korea
| | - Eun-Young Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kun-Ho Yoon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Hyun Ko
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Committee of Clinical Practice Guidelines, Korean Diabetes Association
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Endocrinology & Metabolism, Department of Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Changwon, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
- Department of Endocrinology and Metabolism, Kyung Hee University College of Medicine, Kyung Hee University Hospital, Seoul, Korea
- Division of Endocrinology and Metabolism, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chosun University College of Medicine, Gwangju, Korea
- Division of Endocrinology & Metabolism, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Korea
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
- Institute for Evidence-based Medicine, Cochrane Korea, Department of Preventive Medicine, Korea University College of Medicine, Seoul, Korea
- Division of Vitreous and Retina, Department of Ophthalmology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
- Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
- Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Korea University Ansan Hospital, Ansan, Korea
| |
Collapse
|
17
|
Naidoo P, Bouharati C, Rambiritch V, Karamchand S, Tafuto BA, Leisegang RF. Glycated haemoglobin reduction and fixed ratio combinations of analogue basal insulin and glucagon-like peptide-1 receptor agonists: A systematic review. World J Meta-Anal 2021; 9:297-308. [DOI: 10.13105/wjma.v9.i3.297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/27/2021] [Revised: 06/05/2021] [Accepted: 07/02/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Fixed ratio combinations (FRCs) of analogue basal insulin and glucagon-like peptide-1 receptor agonists are a newer addition to the therapeutic armamentarium for the management of type 2 diabetes mellitus. They reduce treatment complexity by combining two injectables in a single daily injectable, thus potentially improving adherence and persistence. Clinicians wanting to use FRCs would need to choose between members of the class.
AIM To describe and contrast the glycated haemoglobin reduction of two FRCs of analogue basal insulin and glucagon like peptide-1 receptor agonist in adults with type 2 diabetes mellitus.
METHODS The following Population, Intervention, Comparison, Outcome question was used for the primary analysis: Among adult patients with type 2 diabetes mellitus [P], what is the effect of iGlarLixi [I] compared to IDegLira [C] for bringing about glycaemic control (as measured by reduction in glycosylated haemoglobin) [O]? The Prisma Statement was used as a guideline for framing this systematic review. We searched PubMed, EMBASE and Cochrane library databases and Clinicaltrials.gov using various keywords and medical search headings related to type 2 diabetes mellitus, iGlarlixi, IDegLira and glycated haemoglobin A1c.
RESULTS All 14 studies identified by the systematic search met the primary efficacy endpoint of reduction in glycated haemoglobin. There were no head-to-head studies between the FRCs of iGlarlixi and IDegLira, and we therefore did an indirect comparison based on a common comparator of insulin glargine U100. Both iGlarLixi and IDegLira effectively reduce glycated haemoglobin when compared to insulin glargine U100. However, using indirect comparisons, IDegLira had a greater haemoglobin A1c reducing ability (0.6% vs 0.3%). The indirect comparison is limited by the differences between the studies; the fasting blood glucose targets were slightly higher for iGlarLixi studies when compared to the IDegLira studies (4.0-5.0 mmol/L and 4.4-5.6 mmol/L), and the IDegLira study used a greater average dose of insulin glargine when compared to the iGlarLixi studies (66 U/d vs 40 U/d).
CONCLUSION Both iGlarLixi and IDegLira effectively reduce glycated haemoglobin. Indirect comparisons, using insulin glargine as the common comparator, suggest that IDegLira reduces glycated haemoglobin to a greater extent than iGlarLixi. However, given the limitations of indirect comparisons, robust head to head studies and real-world data would better inform clinician choice and clinical practice guidelines.
Collapse
Affiliation(s)
- Poobalan Naidoo
- Department of Nephrology, Inkosi Albert Luthuli Central Hospital, Durban 4092, KwaZulu-Natal, South Africa
| | - Celia Bouharati
- Department of Medical Research, Independent Researcher, Paris 75000, France
| | - Virendra Rambiritch
- Department of Pharmacology, University of KwaZulu-Natal, Durban 3629, KwaZulu-Natal, South Africa
| | - Sumanth Karamchand
- Department of Internal Medicine, Stellenbosch University and Tygerberg Hospital, Cape Town 7600, South Africa
| | - Barbara A Tafuto
- Department of Health Informatics, Rutgers University, Piscataway, NJ 08854, United States
| | - Rory F Leisegang
- Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 75236, Sweden
| |
Collapse
|
18
|
Piccoli GF, Mesquita LA, Stein C, Aziz M, Zoldan M, Degobi NAH, Spiazzi BF, Lopes Junior GL, Colpani V, Gerchman F. Do GLP-1 Receptor Agonists Increase the Risk of Breast Cancer? A Systematic Review and Meta-analysis. J Clin Endocrinol Metab 2021; 106:912-921. [PMID: 33248445 DOI: 10.1210/clinem/dgaa891] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/13/2020] [Indexed: 12/20/2022]
Abstract
CONTEXT Risk of cancer is a major concern in the development of drugs for the treatment of obesity and diabetes. In randomized controlled trials (RCTs) of the Liraglutide Clinical Development Program, subjects treated with a glucagon-like peptide-1 receptor agonist (GLP-1RA) had a higher absolute number of breast cancer events. OBJECTIVE To assess whether patients treated with GLP-1RAs had a higher risk of breast neoplasms. DATA SOURCES We searched MEDLINE, Embase, Web of Science, and CENTRAL from July 31, 2019 to February 8, 2020. STUDY SELECTION Reviewers assessed abstracts and full-text articles for RCTs of GLP-1RAs in adults with excessive weight and/or diabetes and a minimum follow-up of 24 weeks. DATA EXTRACTION Researchers extracted study-level data and assessed within-study risk of bias with the RoB 2.0 tool and quality of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). DATA SYNTHESIS We included 52 trials, of which 50 reported breast cancer events and 11 reported benign breast neoplasms. Overall methodological quality was high. Among 48 267 subjects treated with GLP-1RAs, 130 developed breast cancer compared with 107 of 40 755 controls (relative risk [RR], 0.98; 95% confidence interval [CI], 0.76-1.26). Subset analyses according to follow-up, participant/investigator blinding, and type of GLP-1RA did not reveal any differences. The risk of benign breast neoplasms also did not differ between groups (RR, 0.99; 95% CI, 0.48-2.01). Trial sequential analysis provided evidence that the sample size was sufficient to avoid missing alternative results. CONCLUSIONS Treatment with GLP-1RAs for obesity and diabetes does not increase the risk of breast neoplasms.
Collapse
Affiliation(s)
- Giovana F Piccoli
- Endocrine and Metabolism Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Leonardo A Mesquita
- Graduate Program in Medical Sciences (Endocrinology), Department of Internal Medicine, Faculty of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Cinara Stein
- Research Projects Office, Hospital Moinhos de Vento, Porto Alegre, Brazil
| | - Marina Aziz
- Research Projects Office, Hospital Moinhos de Vento, Porto Alegre, Brazil
| | - Maira Zoldan
- Endocrine and Metabolism Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Nathália A H Degobi
- Endocrine and Metabolism Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Bernardo F Spiazzi
- Faculty of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | | | - Verônica Colpani
- Endocrine and Metabolism Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Fernando Gerchman
- Endocrine and Metabolism Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Graduate Program in Medical Sciences (Endocrinology), Department of Internal Medicine, Faculty of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| |
Collapse
|
19
|
Fadini GP, Disoteo O, Candido R, Di Bartolo P, Laviola L, Consoli A. Delphi-Based Consensus on Treatment Intensification in Type 2 Diabetes Subjects Failing Basal Insulin Supported Oral Treatment: Focus on Basal Insulin + GLP-1 Receptor Agonist Combination Therapies. Diabetes Ther 2021; 12:781-800. [PMID: 33550569 PMCID: PMC7947045 DOI: 10.1007/s13300-021-01012-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 12/18/2020] [Accepted: 01/23/2021] [Indexed: 01/27/2023] Open
Abstract
INTRODUCTION The aim of this study was to elaborate a consensus on treatment intensification strategies in patients with type 2 diabetes failing basal insulin supported oral therapy (BOT). The panel focused on glucagon-like peptide-1 receptor agonists (GLP-1RA) and basal insulin (BI) combinations. METHODS The authors developed a Delphi questionnaire organized into ten statements and 77 items that focused on: the definition of BOT and BOT failure, intensification strategies, fixed-dose combinations in general and the BI/GLP-1RA fixed combination. The survey was administered in two rounds to a panel of 80 Italian diabetes specialists, who rated their level of agreement with each item on a 5-point Likert scale. Consensus was predefined as > 66% of the panel agreeing/disagreeing on any given item. RESULTS Consensus was achieved for 71 of the 77 items. The panel agreed that the use of sulfonylureas in the BOT regimen is inappropriate. BOT failure was defined as individualized targets not being met for glycated hemoglobin, fasting plasma glucose and/or postprandial plasma glucose. There was agreement that postprandial hyperglycaemia and/or presence of nocturnal hypoglycaemia or weight gain define BOT failure. Addition of a GLP-1RA to BI therapy was considered to be the best option for BOT intensification. There was consensus for the use of BI/GLP-1RA fixed combinations as valuable options to increase compliance and safely improve glycaemic control. The panel agreed in considering the fixed-ratio combination insulin degludec/liraglutide (IDegLira) to be preferable to the fixed-ratio combination insulin glargine/lixisenatide (iGlarLixi) in the control of glycaemia, body weight and cardiovascular risk. CONCLUSION According to this Delphi consensus, the addition of a GLP-1RA may be the best option to intensify BOT. The BI/GLP-1RA fixed combinations may increase compliance and optimize the advantages of each of these molecules.
Collapse
Affiliation(s)
- Gian Paolo Fadini
- Division of Metabolic Diseases, Department of Medicine, University of Padova, Padua, Italy.
| | - Olga Disoteo
- Diabetes Unit, SSD Diabetologia, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Riccardo Candido
- Diabetes Center District 3, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy
| | - Paolo Di Bartolo
- Ravenna Diabetes Clinic, Romagna Local Health Authority, Ravenna, Italy
| | - Luigi Laviola
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Emergency and Transplants, University of Bari Aldo Moro, Bari, Italy
| | - Agostino Consoli
- Department of Medicine and Aging Sciences (DMSI) and Center for Research on Ageing and Translational Medicine (CeSI-Met), University of Chieti, Chieti, Italy
| |
Collapse
|
20
|
Rayner CK, Wu T, Aroda VR, Whittington C, Kanters S, Guyot P, Shaunik A, Horowitz M. Gastrointestinal adverse events with insulin glargine/lixisenatide fixed-ratio combination versus glucagon-like peptide-1 receptor agonists in people with type 2 diabetes mellitus: A network meta-analysis. Diabetes Obes Metab 2021; 23:136-146. [PMID: 32991041 PMCID: PMC7756611 DOI: 10.1111/dom.14202] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/16/2020] [Revised: 09/08/2020] [Accepted: 09/23/2020] [Indexed: 02/05/2023]
Abstract
AIMS Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the recommended first injectable therapy in type 2 diabetes. However, long-term persistence is suboptimal and partly attributable to gastrointestinal tolerability, particularly during initiation/escalation. Gradual titration of fixed-ratio combination GLP-1 RA/insulin therapies may improve GLP-1 RA gastrointestinal tolerability. We compared gastrointestinal adverse event (AE) rates for iGlarLixi versus GLP-1 RAs during the first 12 weeks of therapy, including a sensitivity analysis with IDegLira. MATERIALS AND METHODS The PICO framework was used to identify studies from MEDLINE, EMBASE and CENTRAL searches using a proprietary, web-based, standardized tool with single data extraction. Gastrointestinal AEs were modelled using a Bayesian network meta-analysis (NMA), using fixed and random effects for each recommended dose (treatment-specific NMA) and class (drug-class NMA). RESULTS Treatment-specific NMA included 17 trials (n = 9030; 3665 event-weeks). Nausea rates were significantly lower with iGlarLixi versus exenatide 10 μg twice daily (rate ratio: 0.32; 95% credible interval: 0.15, 0.66), once-daily lixisenatide 20 μg (0.35; 0.24, 0.50) and liraglutide 1.8 mg once daily (0.48; 0.23, 0.98). Rates were numerically, but not statistically, lower versus once-weekly semaglutide 1 mg (0.60; 0.30, 1.23) and dulaglutide 1.5 mg (0.60; 0.29, 1.26), and numerically, but not statistically, higher versus once-weekly exenatide (1.91; 0.91, 4.03). Sensitivity analysis results were similar. In a naïve, pooled analysis, vomiting was lower with iGlarLixi versus other GLP-1 RAs. CONCLUSIONS During the first 12 weeks of treatment, iGlarLixi was generally associated with less nausea and vomiting than single-agent GLP-1 RAs. Enhanced gastrointestinal tolerability with fixed-ratio combinations may favour treatment persistence.
Collapse
Affiliation(s)
- Christopher K. Rayner
- Centre of Research Excellence in Translating Nutritional Science to Good HealthUniversity of AdelaideAdelaideSouth AustraliaAustralia
| | - Tongzhi Wu
- Centre of Research Excellence in Translating Nutritional Science to Good HealthUniversity of AdelaideAdelaideSouth AustraliaAustralia
| | - Vanita R. Aroda
- Brigham and Women's HospitalHarvard Medical SchoolBostonMassachusettsUSA
| | | | | | | | | | - Michael Horowitz
- Centre of Research Excellence in Translating Nutritional Science to Good HealthUniversity of AdelaideAdelaideSouth AustraliaAustralia
| |
Collapse
|
21
|
IRWIS (IDegLira Real world Indian Study): A Real-World Observational Study For Use of IDegLira In Indian Patients. ENDOCRINE AND METABOLIC SCIENCE 2020. [DOI: 10.1016/j.endmts.2020.100057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/22/2022] Open
|
22
|
Tibaldi J, Mercado ME, Strong J. How Effective Is the Fixed-Ratio Combination of Insulin Degludec and Liraglutide (IDegLira) in Different Patient Populations, and When Should It Be Used in Clinical Practice? Clin Diabetes 2020; 38:339-347. [PMID: 33132503 PMCID: PMC7566936 DOI: 10.2337/cd20-0014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 11/13/2022]
Abstract
The efficacy and safety of the fixed-ratio combination of insulin degludec (degludec) and liraglutide (IDegLira) were confirmed in the DUAL clinical trial program, in which IDegLira demonstrated superior or noninferior glycemic control over comparators in addition to its low risks of hypoglycemia and weight gain. This article identifies the patient types for whom IDegLira is most appropriate by reviewing the DUAL results and subsequent post hoc analyses and presenting real-world cases in which IDegLira has been used effectively in U.S. clinical practice. In the clinic, IDegLira has been used effectively when patients wanted to avoid more complex injectable regimens, particularly those with renal insufficiency for whom treatment options are limited.
Collapse
Affiliation(s)
- Joseph Tibaldi
- Department of Medicine, New York Presbyterian Queens, New York, NY
| | | | - Jodi Strong
- Ascension St. Michael’s Hospital, Stevens Point, WI
| |
Collapse
|
23
|
Harris S, Abrahamson MJ, Ceriello A, Charpentier G, Evans M, Lehmann R, Liebl A, Linjawi S, Holt RIG, Hosszúfalusi N, Rutten G, Vilsbøll T. Clinical Considerations When Initiating and Titrating Insulin Degludec/Liraglutide (IDegLira) in People with Type 2 Diabetes. Drugs 2020; 80:147-165. [PMID: 31960258 PMCID: PMC7007423 DOI: 10.1007/s40265-019-01245-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/14/2022]
Abstract
Therapeutic inertia is a substantial obstacle to the initiation of insulin therapy in people with uncontrolled type 2 diabetes (T2D). This effect has in part been perpetuated by concerns over the impact of a burdensome regimen and the increased risk of hypoglycemia and body weight gain often associated with insulin use. An effective, yet simple, less burdensome regimen with a lower risk of body weight gain and hypoglycemia compared with an insulin-only regimen, may help to address these concerns more effectively. We review the available clinical and real-world data on IDegLira, a once-daily, injectable, fixed-ratio combination of insulin degludec (degludec) and the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide, in people with T2D. Evidence from the comprehensive DUAL clinical trial program suggests an advantage of IDegLira over traditional insulin therapies in a number of clinical outcomes, including maintenance of glycemic control, achievement of glycemic targets, reducing the risk of hypoglycemia, and body weight loss. These findings were demonstrated in participants with T2D irrespective of prior GLP-1RA and insulin use. Furthermore, the individual components of IDegLira have confirmed safety (degludec) or significant benefit in terms of improvement of cardiovascular risk (liraglutide). As an injectable therapy that is simple to titrate, IDegLira has the potential to optimize the ability to achieve relevant glycemic targets, and offers a suitable treatment option for people with T2D requiring insulin therapy who are at risk of hypoglycemia or weight gain.
Collapse
Affiliation(s)
- Stewart Harris
- Centre for Studies in Family Medicine, Schulich School of Medicine and Dentistry, Western University, WCPHFM, 1151 Richmond St, London, ON, N6K 3K7, Canada.
| | - Martin J Abrahamson
- Division of Endocrinology, Harvard Medical School, Beth Israel Deaconess Medical Center, 110 Francis Street, Lowry 6A, Boston, MA, 02215, USA
| | - Antonio Ceriello
- IRCCS MultiMedica, Via Milanese 300, 20099, Sesto San Giovanni, MI, Italy
| | - Guillaume Charpentier
- CERITD (Centre d'Etude et de Recherche pour l'Intensification du Traitement du Diabete), Centre Hospitalier Sud Francilien, 1 Rue Pierre Fontaine, 9100, Corbeil-Essonnes, Evry, France
| | - Marc Evans
- Diabetes Resource Centre, University Hospital Llandough, Penlan Road, Llandough, Cardiff, CF64 2XX, UK
| | - Roger Lehmann
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital of Zürich, Rämistrasse 100 (Arrival), 8091, Zürich, Switzerland
| | - Andreas Liebl
- Center for Diabetes and Metabolism, m&i-Fachklinik, Woernerweg 30, 83670, Bad Heilbrunn, Germany
| | - Sultan Linjawi
- Coffs Diabetes Centre, 9 Murdock Street, Coffs Harbour, NSW, 2450, Australia
| | - Richard I G Holt
- Human Development and Health, University of Southampton Faculty of Medicine, Southampton, UK
| | - Nóra Hosszúfalusi
- 3rd Department of Medicine, Semmelweis University, Kútvölgyi út 4, Budapest, 1125, Hungary
| | - Guy Rutten
- Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands
| | - Tina Vilsbøll
- Steno Diabetes Center Copenhagen, Gentofte Hospital, University of Copenhagen, Kildegaards Vej 28, 2900, Hellerup, Denmark
| |
Collapse
|
24
|
John M, Gopinath D, Oommen T. Co-Formulations as the First Injectable in Type 2 Diabetes: A Review of Efficacy, Safety, and Implications in Clinical Practice. DUBAI DIABETES AND ENDOCRINOLOGY JOURNAL 2020. [DOI: 10.1159/000509045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/20/2022] Open
Abstract
<b><i>Background:</i></b> Progression of type 2 diabetes will necessitate the use of injectable therapies in a significant number of people. Co-formulations of degludec with liraglutide (IDegLira) and glargine with lixisenatide (IGlarLixi) are currently recommended for intensification in people with type 2 diabetes on basal insulin or glucagon-like peptide receptor agonist (GLP-1RA) alone or in people with type 2 diabetes who are naïve to insulin with very high glycated haemoglobin. Co-formulation of aspart with degludec (IDegAsp) is recommended as a substitute for premixed insulin. The aim of this article is to review the evidence in the use of co-formulations as the first injectable in type 2 diabetes and its clinical implications. <b><i>Summary:</i></b> In people with type 2 diabetes who are naïve to insulin or GLP-1RA, IDegLira and IGlarLixi achieved stable and durable glycaemic control over a wide range of baseline glycated haemoglobin (HbA1c) levels. People on IDegLira and IGlarLixi had lesser risk of hypoglycaemia and weight gain in studies compared to basal insulin and lesser gastrointestinal adverse effects in comparison to GLP-1RA. IDegAsp achieved similar glycaemic control to basal and premixed insulin with lesser risk of nocturnal hypoglycaemia. <b><i>Key Messages:</i></b> IDegLira, IGlarLixi, and IDegAsp can be used as the first injectable in people with type 2 diabetes with very high glycated haemoglobin on oral antidiabetic drugs. These co-formulations combine efficacy and durability with lesser injection burden. The components of these agents have proven cardiovascular and renal safety. Their limitations in flexibility of dosing, renal and cardiovascular considerations, and adverse effects are discussed.
Collapse
|
25
|
Lisco G, De Tullio A, Guastamacchia E, Triggiani V. Fixed-Ratio Combinations of Basal Insulin and GLP-1RA in the Management of Type 2 Diabetes Mellitus: Highlights from the Literature. Endocr Metab Immune Disord Drug Targets 2020; 21:626-646. [PMID: 32628602 DOI: 10.2174/1871530320666200705211224] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 01/15/2020] [Revised: 03/20/2020] [Accepted: 05/20/2020] [Indexed: 11/22/2022]
Abstract
New pieces of evidence suggest that combining basal insulin with glucagone-like peptide 1 receptor agonists (GLP-1RA) in patients with type 2 diabetes could promptly ameliorate glucose control and prevent both hypoglycemic events and unnecessary weight gain compared to more intensive insulin regimens. To review the efficacy/effectiveness and safety of fixed-ratio combinations of basal insulin and GLP- 1RA (FRCs). Authors searched PubMed/MEDLINE, ClinicalTrials.gov, Cochrane Library, and Google Scholar for freely available original articles, randomized clinical trials (RCTs), clinical reviews, and meta-analysis written in English until January 2020. FRCs provide significative reductions in HbA1c levels in both insulin-naïve (-1.4% to -2%) and insulin- experienced (-1.5% to -2%) type 2 diabetic patients with moderate glucose impairment. More patients achieved the recommended glycemic targets on FRCs compared to those on mono-therapy with basal insulin or GLP-1RAs. The intensification with FRCs results in better glycemic control compared to basal insulin at fasting as well as during the postprandial state. The frequency of hypoglycemia is similar or lower in patients treated with FRCs than in those on basal insulin alone at a similar dose. Weight trend can be variable, ranging from -2.7 to +2 Kg for iDegLira and -0.7 to -1.3 Kg for iGlar- Lixi. However, a lower weight gain is obtained with iDegLira compared to iDeg (-2.2 to -2.5 Kg), iGlar (-1.7 to -3.2 Kg), and basal-bolus (-3.6 Kg) as well as with iGlarLixi compared to iGlar (-1.4 Kg). FRCs should be considered to safely improve the metabolic control in type 2 diabetic patients with moderate glycemic impairment while on oral medications, basal oral regimen or GLP-1RAs. However, a few but significative pieces of evidence suggest that FRCs could be a safe and effective treatment instead of a low dose basal-bolus intensification for patients with mild or moderate glucose impairment in order to reduce the risk of hypoglycemia and unnecessary weight gain, and for simplifying treatment regimen as well.
Collapse
Affiliation(s)
- Giuseppe Lisco
- Unit of Endocrinology, Metabolic Disease & Clinical Nutrition, Hospital "A. Perrino", Brindisi, Italy
| | - Anna De Tullio
- Section of Endocrinology, Local Health District of Bari, Bari, Italy
| | - Edoardo Guastamacchia
- Interdisciplinary Department of Medicine - Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases. University of Bari "Aldo Moro", Bari, Italy
| | - Vincenzo Triggiani
- Interdisciplinary Department of Medicine - Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases. University of Bari "Aldo Moro", Bari, Italy
| |
Collapse
|
26
|
Nreu B, Dicembrini I, Tinti F, Sesti G, Mannucci E, Monami M. Major cardiovascular events, heart failure, and atrial fibrillation in patients treated with glucagon-like peptide-1 receptor agonists: An updated meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis 2020; 30:1106-1114. [PMID: 32448716 DOI: 10.1016/j.numecd.2020.03.013] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 01/21/2020] [Revised: 03/13/2020] [Accepted: 03/14/2020] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIMS Glucagon-like Peptide 1 Receptor Agonists (GLP1-RA) has been associated with a reduction of major cardiovascular events (MACE) and mortality on the basis of the results of cardiovascular outcome trials (CVOT). Several meta-analyses on this issue have been recently published; however, they were all restricted to CVOT, with the exclusion of all studies designed for other endpoints; moreover, other cardiovascular endpoints, such as atrial fibrillation and heart failure have not been fully explored. METHODS AND RESULTS A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials with a duration ≥52 weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. We included 43 trials, enrolling 63,134 patients. A significant reduction of MACE (MH-OR 0.87 [0.83, 0.92]), all-cause mortality (MH-OR 0.89 [0.83, 0.96]), and a nonstatistical trend toward reduction of heart failure (MH-OR 0.93 [0.85, 1.01]) was observed - GLP1-RA did not increase the risk of atrial fibrillation (MH-OR 0.94 [0.84, 1.04]). CONCLUSION The present meta-analysis confirms the favorable effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events, cardiovascular and all-cause mortality, stroke, and possibly myocardial infarction. Conversely, the effects on heart failure remain uncertain. Available data on atrial fibrillation seems to exclude any major safety issues in this respect. REGISTRATION NUMBER (PROSPERO) CRD42018115577.
Collapse
Affiliation(s)
- Besmir Nreu
- Diabetology, Careggi Hospital and University of Florence, Italy
| | | | - Federico Tinti
- Diabetology, Careggi Hospital and University of Florence, Italy
| | - Giorgio Sesti
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology of the Sapienza University of Rome, Rome, Italy
| | | | - Matteo Monami
- Diabetology, Careggi Hospital and University of Florence, Italy.
| |
Collapse
|
27
|
Insulin degludec/liraglutide in type 2 diabetes: a profile of its use. DRUGS & THERAPY PERSPECTIVES 2020. [DOI: 10.1007/s40267-020-00731-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 10/24/2022]
|
28
|
Sesti G, Bardtrum L, Dagdelen S, Halladin N, Haluzík M, Őrsy P, Rodríguez M, Aroda VR. A greater proportion of participants with type 2 diabetes achieve treatment targets with insulin degludec/liraglutide versus insulin glargine 100 units/mL at 26 weeks: DUAL VIII, a randomized trial designed to resemble clinical practice. Diabetes Obes Metab 2020; 22:873-878. [PMID: 31903724 PMCID: PMC7187233 DOI: 10.1111/dom.13957] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/25/2019] [Revised: 12/23/2019] [Accepted: 12/28/2019] [Indexed: 01/10/2023]
Abstract
This report presents the efficacy and safety of insulin degludec/liraglutide (IDegLira) versus insulin glargine 100 units/mL (IGlar U100) as initial injectable therapy at 26 weeks in the 104-week DUAL VIII durability trial (NCT02501161). Participants (N = 1012) with type 2 diabetes (T2D) uncontrolled on oral antidiabetic drugs (OADs) were randomized 1:1 to open-label IDegLira or IGlar U100. Visits were scheduled at weeks 1, 2, 4 and 12, and every 3 months thereafter. After 26 weeks, glycated haemoglobin (HbA1c) reductions were greater with IDegLira versus IGlar U100 (-21.5 vs. -16.4 mmol/mol [-2.0 vs. -1.5%]), as was the percentage of participants achieving HbA1c <53 mmol/mol (78.7% vs. 55.7%) and HbA1c targets without weight gain and/or hypoglycaemia. Estimated treatment differences for insulin dose (-13.01 U) and body weight change (-1.57 kg) significantly favoured IDegLira. The hypoglycaemia rate was 44% lower with IDegLira versus IGlar U100. Safety results were similar. In a trial resembling clinical practice, more participants receiving IDegLira than IGlar U100 met treatment targets, supporting use of IDegLira as an initial injectable therapy for people with T2D uncontrolled on OADs and eligible for insulin initiation.
Collapse
Affiliation(s)
- Giorgio Sesti
- Department of Clinical and Molecular MedicineSapienza University of RomeRomeItaly
| | | | - Selcuk Dagdelen
- Department of Endocrinology and MetabolismHacettepe University School of MedicineAnkaraTurkey
| | | | - Martin Haluzík
- Institute for Clinical and Experimental Medicine and Institute of EndocrinologyPragueCzech Republic
| | | | - Martin Rodríguez
- Area of Endocrinology, Metabolism and Nutrition, Faculty of Medical SciencesNational University of CuyoMendozaArgentina
| | - Vanita R. Aroda
- Brigham and Women's HospitalBostonMassachusettsUnited States
- MedStar Health Research InstituteHyattsvilleMarylandUnited States
| |
Collapse
|
29
|
Watada H, Ross Agner BF, Doshi A, Bardtrum L, Ranthe MF, Billings LK. IDegLira Improves Glycemic Control in Japanese Patients with Uncontrolled Type 2 Diabetes on Premixed Insulin Therapy. Diabetes Ther 2020; 11:331-339. [PMID: 31760599 PMCID: PMC6965526 DOI: 10.1007/s13300-019-00730-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/12/2019] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION DUAL II Japan (NCT02911948) was a 26-week, phase 3a randomized, treat-to-target trial which compared the efficacy and safety of IDegLira with degludec in 210 Japanese patients with type 2 diabetes (T2D) uncontrolled on premixed or basal insulin therapy. The DUAL II Japan trial presented the opportunity for a post hoc analysis to examine the safety and efficacy of switching patients from a premixed regimen (containing both basal and bolus insulin components) to IDegLira. METHODS Patients from DUAL II Japan were stratified according to prior insulin regimen (premixed or basal insulin). The following endpoints were assessed in this post hoc analysis by pre-trial insulin regimen: change in HbA1c, body weight, daily total insulin dose, nine-point self-measured blood glucose, and severe or blood glucose-confirmed hypoglycemia (defined as severe or plasma glucose less than 56 mg/dL). RESULTS This post hoc analysis included 39 patients who switched from premixed insulin to IDegLira. The treatment effect in this population was independent of insulin type at baseline (premixed or basal; interaction test, P = 0.2535). In patients switching from premixed insulin to IDegLira, mean [standard deviation (SD)] HbA1c was 8.26% (0.73) at baseline and 6.68% (0.93) at week 26. Mean (SD) body weight was reduced by 1.5 (2.9) kg. At week 26, daily insulin dose was 34.2 dose steps. After 26 weeks, the mean prandial increment was smaller at all meals with IDegLira irrespective of pre-trial insulin regimen. Rate of hypoglycemic events was 2.59 events/patient-year of exposure over the 26 weeks. CONCLUSION This post hoc study is the first to evaluate the switch from premixed insulin to IDegLira in patients with uncontrolled T2D. IDegLira initiation resulted in improved HbA1c and weight loss. This study offers insight into the effectiveness and safety of switching patients from premixed insulin therapy to IDegLira, and provides support for further investigation. TRIAL REGISTRATION NCT02911948.
Collapse
Affiliation(s)
- Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University, Tokyo, Japan.
| | | | | | | | | | - Liana K Billings
- NorthShore University HealthSystem, Skokie, IL, USA
- University of Chicago Pritzker School of Medicine, Skokie, IL, USA
| |
Collapse
|
30
|
David J, Fonseca V. When should fixed ratio basal insulin/glucagon-like peptide-1 receptor agonists combination products be considered? J Diabetes Complications 2019; 33:107473. [PMID: 31668591 DOI: 10.1016/j.jdiacomp.2019.107473] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 10/10/2019] [Accepted: 10/10/2019] [Indexed: 10/25/2022]
Abstract
Diabetes management with achievement and maintenance of good glycemic control is very challenging in patients requiring multiple daily injections. This article is focusing on broader use of recently approved fixed ratio combination therapies, basal insulin and glucagon-like peptide-1 receptor agonists (GLP1 RA). These combination therapy improve patient compliance and adherence with the therapy, decrease burden of multiple injection, target multiple abnormalities in the pathophysiology of diabetes, decrease postprandial hypoglycemia, assist in weight loss and decrease weight related comorbidities. These combinations were recently approved for use as first injectables after failure of oral agents. Review of combination treatment with existing fixed doses of basal insulin with GLP1 RA opens door for further clinical trials for other dose combinations that can be used, particularly for patients who need higher doses of insulin.
Collapse
Affiliation(s)
- Julia David
- Section of Endocrinology, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
| | - Vivian Fonseca
- Section of Endocrinology, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
| |
Collapse
|
31
|
McCarty D, Olenik A, McCarty BP. Efficacy and Safety of Basal Insulin/GLP-1 Receptor Agonist Used in Combination for Type 2 Diabetes Management. J Pharm Pract 2019; 32:671-678. [PMID: 29566586 DOI: 10.1177/0897190018764984] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/15/2022]
Abstract
PURPOSE The purpose of this article is to review the efficacy, safety, and place in therapy of insulin degludec/liraglutide (IDegLira) and insulin glargine/lixisenatide (IGlarLixi) in the treatment of type 2 diabetes mellitus. SUMMARY Type 2 diabetes is a condition affecting nearly 30 million American adults. Management of type 2 diabetes is complex and multifactorial. Using medications targeted at a variety of the physiologic defects known to contribute to the development of type 2 diabetes allows for a patient-specific approach to care. Utilizing combination products is a way to target several areas of the disease while decreasing the complexity and burden to the patient. Basal insulin/glucagon-like peptide-1 (GLP-1) agonist combination products have the benefit of being highly efficacious while having favorable effects on weight, reduced gastrointestinal adverse effects, and low hypoglycemic risks compared to the individual agents used alone. CONCLUSION This article will review 2 basal insulin/GLP-1 agonist combination products, IDegLira and IGlarLixi, which were approved in November 2016.
Collapse
Affiliation(s)
- Delilah McCarty
- Field Medical Affairs, Diabetes & Obesity, Novo Nordisk Inc, Plainsboro, NJ, USA
| | - Alaina Olenik
- Ambulatory Care Management, Carolinas HealthCare System, Mint Hill, NC, USA
| | | |
Collapse
|
32
|
Kaku K, Araki E, Tanizawa Y, Ross Agner B, Nishida T, Ranthe M, Inagaki N. Superior efficacy with a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with insulin degludec and liraglutide in insulin-naïve Japanese patients with type 2 diabetes in a phase 3, open-label, randomized trial. Diabetes Obes Metab 2019; 21:2674-2683. [PMID: 31407845 PMCID: PMC6899795 DOI: 10.1111/dom.13856] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/29/2019] [Revised: 08/05/2019] [Accepted: 08/06/2019] [Indexed: 01/09/2023]
Abstract
AIMS To investigate the efficacy and safety of insulin degludec/liraglutide (IDegLira) compared with its individual components in Japanese people with type 2 diabetes (T2D) uncontrolled on an oral antidiabetic drug (OAD). MATERIALS AND METHODS This 52-week, open-label, multicentre, treat-to-target trial randomized participants (n = 819) 1:1:1 to IDegLira, liraglutide 1.8 mg or degludec, as add-on to their pre-trial OAD. The maximum IDegLira dose was 50 dose steps (50 U degludec/1.8 mg liraglutide), there was no maximum dose for degludec, and both were titrated based on individual blood glucose measurements. RESULTS After 52 weeks, glycated haemoglobin (HbA1c) decreased by 26 mmol/mol with IDegLira vs 20 mmol/mol with degludec and liraglutide: estimated treatment differences were -6.91 mmol/mol (95% confidence interval [CI] -8.18; -5.64) and -5.30 mmol/mol (95% CI -6.58; -4.03), confirming non-inferiority of IDegLira to degludec and superiority of IDegLira to liraglutide (P < .0001 for both [primary endpoint]). Mean body weight changes were 2.9 kg, 4.1 kg and -1.0 kg with IDegLira, degludec and liraglutide, respectively, showing superiority of IDegLira versus degludec (P = .0001), but a significant difference in favour of liraglutide (P < .0001). Rates of severe or blood glucose-confirmed hypoglycaemia for IDegLira were lower versus degludec (rate ratio 0.48 [95% CI 0.35; 0.68]; P < .0001), but higher versus liraglutide (rate ratio 37.58 [95% CI 19.80; 71.31]; P < .0001). Mean daily total insulin dose was lower with IDegLira (27.7 U) versus degludec (34.8 U; P < .0001). Overall adverse event (AE) rates were similar. In total, 34.9%, 22.9% and 41.8% of IDegLira-, degludec- and liraglutide-treated participants experienced gastrointestinal AEs. CONCLUSION IDegLira was superior to degludec and liraglutide in terms of HbA1c reduction and superior to degludec in terms of body weight change and rates of hypoglycaemia in Japanese people with T2D.
Collapse
Affiliation(s)
- Kohei Kaku
- Department of Internal MedicineKawasaki Medical SchoolKurashikiJapan
| | - Eiichi Araki
- Department of Metabolic MedicineKumamoto UniversityKumamotoJapan
| | | | | | | | | | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and NutritionKyoto University Graduate School of MedicineKyotoJapan
| |
Collapse
|
33
|
Watada H, Kaneko S, Komatsu M, Agner BR, Nishida T, Ranthe M, Nakamura J. Superior HbA1c control with the fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with a maximum dose of 50 units of insulin degludec in Japanese individuals with type 2 diabetes in a phase 3, double-blind, randomized trial. Diabetes Obes Metab 2019; 21:2694-2703. [PMID: 31423685 PMCID: PMC6900157 DOI: 10.1111/dom.13859] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/29/2019] [Revised: 07/25/2019] [Accepted: 08/11/2019] [Indexed: 12/24/2022]
Abstract
AIMS To investigate the efficacy and safety of insulin degludec/liraglutide (IDegLira) compared with 50 U insulin degludec (degludec) or less in Japanese individuals with type 2 diabetes (T2D). MATERIALS AND METHODS In this 26-week, double-blind, multicentre, treat-to-target trial, Japanese individuals with T2D that was uncontrolled with basal or pre-mix insulin (20-50 units) were randomized (1:1) to receive IDegLira or degludec, both with metformin. The maximum dose was 50 dose steps (IDegLira) or 50 units (degludec). The primary endpoint was change from baseline in HbA1c with IDegLira vs degludec after 26 weeks of treatment. RESULTS In total, 210 Japanese individuals were randomized to IDegLira or degludec and completion rates were 100% and 93%, respectively. IDegLira was superior to degludec with respect to change from baseline in HbA1c: estimated treatment difference (ETD) (95% confidence interval), -13.98 mmol/Mol (-16.41; -11.55); P < 0.0001. The change in mean HbA1c was from 70.6 by -21.3 mmol/Mol with IDegLira and from 70.1 by -7.1 mmol/Mol with degludec. Mean change in body weight was -0.7 kg with IDegLira and 0.7 kg with degludec: ETD (95% CI) -1.41 kg (-2.26; -0.56); P = 0.0012. Mean daily total insulin dose was significantly lower with IDegLira (37.6 U) as compared to that with degludec (41.2 U) at Week 26. Overall rates of severe or blood glucose-confirmed hypoglycaemia and adverse events were comparable between treatment groups. CONCLUSIONS IDegLira provided superior reductions in HbA1c compared with ≤50 U degludec, with weight loss and similar hypoglycaemia rates and no unexpected safety or tolerability issues. These results suggest that this treatment could be an attractive intensification option for Japanese subjects with T2D that was uncontrolled with basal or pre-mixed insulin.
Collapse
Affiliation(s)
- Hirotaka Watada
- Department of Metabolism and EndocrinologyJuntendo University Graduate School of MedicineTokyoJapan
| | - Shizuka Kaneko
- Division of Diabetes/Endocrinology/Lifestyle‐related DiseaseTakatsuki Red Cross HospitalTakatsukiJapan
| | - Mitsuhisa Komatsu
- Department of Diabetes, Endocrinology and Metabolism, Division of Internal MedicineShinshu University School of MedicineMatsumotoJapan
| | | | | | | | - Jiro Nakamura
- Division of Diabetes, Department of Internal MedicineAichi Medical University School of MedicineNagakuteJapan
| |
Collapse
|
34
|
Cao C, Yang S, Zhou Z. GLP-1 receptor agonists and risk of cancer in type 2 diabetes: an updated meta-analysis of randomized controlled trials. Endocrine 2019; 66:157-165. [PMID: 31420784 DOI: 10.1007/s12020-019-02055-z] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/05/2019] [Accepted: 08/06/2019] [Indexed: 02/08/2023]
Abstract
PURPOSE Some preliminary studies reported a link between GLP-1 receptor agonists (GLP-1RAs) and thyroid/pancreatic neoplasms, while its human relevance remained undetermined. The present meta-analysis was performed to collect information on cancers associated with GLP-1RAs in patients with type 2 diabetes mellitus (T2DM). METHODS Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and ClinicalTrials.gov were extensively searched to identify randomized controlled trials that reported cancer events in T2DM patients treated with GLP-1RAs for at least 52 weeks, up to March 18, 2019. Odds ratio (OR) with 95% Confidence Interval (CI) was calculated for overall cancer (primary outcome), thyroid and pancreatic cancer. RESULTS A total of 37 eligible trials were identified. The OR for overall cancer associated with GLP-1RAs was 1.03 (95% CI 0.95-1.12; p = 0.41) compared with comparators. Subgroup analyses showed that treatment with albiglutide was associated with a lower risk of overall cancer (OR 0.76 [95% CI 0.60-0.97]; p = 0.03), and no elevated risk of overall cancer was identified for other GLP-1RAs. No significant differences in the risks of thyroid nor pancreatic cancer were disclosed between GLP-1RAs and comparators. CONCLUSIONS This meta-analysis did not suggest any increased risk of cancers associated with GLP-1RAs use in T2DM. The reduction in the risk of overall cancer associated with albiglutide needs to be examined further.
Collapse
Affiliation(s)
- Chuqing Cao
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Shuting Yang
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Zhiguang Zhou
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, China.
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China.
| |
Collapse
|
35
|
Taybani Z, Bótyik B, Katkó M, Gyimesi A, Várkonyi T. Simplifying Complex Insulin Regimens While Preserving Good Glycemic Control in Type 2 Diabetes. Diabetes Ther 2019; 10:1869-1878. [PMID: 31347100 PMCID: PMC6778557 DOI: 10.1007/s13300-019-0673-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/17/2019] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Type 2 diabetic patients suffering from severe hyperglycemia are often assigned a regimen involving multiple daily injections (MDI) of insulin. If the glucose toxicity resolves, the regimen can potentially be simplified, but there are no guidelines for this, and many patients are left on the MDI regimen. We aimed to prospectively examine the safety and efficacy of switching from MDI to once-daily IDegLira, a fixed-ratio combination of insulin degludec and liraglutide, in relatively well controlled (HbA1c ≤ 7.5%) subjects with type 2 diabetes on a low total daily insulin dose (TDD). METHODS 62 adults with type 2 diabetes (baseline age 64.06 ± 10.24 years, HbA1c 6.42 ± 0.68%, BMI 33.53 ± 6.90 kg/m2, body weight 93.81 ± 19.26 kg, TDD 43.31 ± 10.99 IU/day, insulin requirement 0.47 ± 0.13 IU/kg, duration of diabetes 10.84 ± 7.50 years, mean ± SD) treated with MDI ± metformin were enrolled in our study. Previous insulins were stopped and once-daily IDegLira was started. IDegLira was titrated by the patients to achieve a self-measured pre-breakfast blood glucose concentration of < 6 mmol/L. RESULTS After a mean follow-up period of 99.2 days, mean HbA1c had decreased by 0.30% to 6.12 ± 0.65% (p < 0.0001), body weight had decreased by 3.11 kg to 90.70 ± 19.12 kg (p < 0.0001), and BMI had reduced to 32.39 ± 6.71 kg/m2 (p < 0.0001). After 3 months of treatment, the mean dose of IDegLira was 20.76 ± 6.60 units and the mean insulin requirement had decreased to 0.23 ± 0.08 IU/kg. IDegLira ± metformin combination therapy was found to be safe and generally well tolerated. During the month before the baseline visit, 28 patients (45%) had at least one episode of documented or symptomatic hypoglycemia, while only 6 (9.67%) patients reported a total of 13 documented episodes during the follow-up. CONCLUSION In everyday clinical practice, switching from low-dose MDI to IDegLira in patients with well-controlled type 2 diabetes is safe, may result in weight loss and similar or better glycemic control, and substantially reduces the insulin requirement. Simplifying complex treatment regimens decreases treatment burden and may improve adherence to therapy. CLINICAL TRIAL NUMBER NCT04020445.
Collapse
Affiliation(s)
- Zoltán Taybani
- 1st Department of Endocrinology, Dr. Réthy Pál Member Hospital, Békés County Central Hospital, Gyulai street 18, Békéscsaba, 5600, Hungary.
| | - Balázs Bótyik
- 1st Department of Endocrinology, Dr. Réthy Pál Member Hospital, Békés County Central Hospital, Gyulai street 18, Békéscsaba, 5600, Hungary
| | - Mónika Katkó
- Division of Endocrinology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, Debrecen, 4032, Hungary
| | - András Gyimesi
- 1st Department of Endocrinology, Dr. Réthy Pál Member Hospital, Békés County Central Hospital, Gyulai street 18, Békéscsaba, 5600, Hungary
| | - Tamás Várkonyi
- 1st Department of Internal Medicine, University of Szeged, Korányi fasor 8, Szeged, 6720, Hungary
| |
Collapse
|
36
|
Alexopoulos AS, Buse JB. Initial injectable therapy in type 2 diabetes: Key considerations when choosing between glucagon-like peptide 1 receptor agonists and insulin. Metabolism 2019; 98:104-111. [PMID: 31255662 PMCID: PMC6690751 DOI: 10.1016/j.metabol.2019.06.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 04/14/2019] [Revised: 06/17/2019] [Accepted: 06/24/2019] [Indexed: 12/24/2022]
Abstract
Managing type 2 diabetes is complex and necessitates careful consideration of patient factors such as engagement in self-care, comorbidities and costs. Since type 2 diabetes is a progressive disease, many patients will require injectable agents, usually insulin. Recent ADA-EASD guidelines recommend glucagon-like peptide 1 receptor agonists (GLP-1 RAs) as first injectable therapy in most cases. The basis for this recommendation is the similar glycemic efficacy of GLP-1 RAs and insulin, but with GLP-1 RAs promoting weight loss instead of weight gain, at lower hypoglycemia risk, and with cardiovascular benefits in patients with pre-existing cardiovascular disease. GLP-1 RAs also reduce burden of glucose self-monitoring. However, tolerability and costs are important considerations, and notably, rates of drug discontinuation are often higher for GLP-1 RAs than basal insulin. To minimize risk of gastrointestinal symptoms patients should be started on lowest doses of GLP-1 RAs and up-titrated slowly. Overall healthcare costs may be lower with GLP-1 RAs compared to insulin. Though patient-level costs may still be prohibitive, GLP-1 RAs can replace 50-80 units of insulin daily and reduce costs associated with glucose self-monitoring. Decisions regarding initiating injectable therapy should be individualized. This review provides a framework to guide decision-making in the real-world setting.
Collapse
Affiliation(s)
| | - John B Buse
- University of North Carolina, Chapel Hill, NC, United States
| |
Collapse
|
37
|
Aroda VR, González-Galvez G, Grøn R, Halladin N, Haluzík M, Jermendy G, Kok A, Őrsy P, Sabbah M, Sesti G, Silver R. Durability of insulin degludec plus liraglutide versus insulin glargine U100 as initial injectable therapy in type 2 diabetes (DUAL VIII): a multicentre, open-label, phase 3b, randomised controlled trial. Lancet Diabetes Endocrinol 2019; 7:596-605. [PMID: 31189519 DOI: 10.1016/s2213-8587(19)30184-6] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 04/15/2019] [Revised: 05/07/2019] [Accepted: 05/15/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND Durability of glycaemic control might reduce disease burden and improve long-term outcomes. DUAL VIII investigated the durability of insulin degludec plus liraglutide (IDegLira) versus insulin glargine 100 units/mL (IGlar U100) in patients with type 2 diabetes with the use of a visit schedule that mirrored routine clinical practice. METHODS In this 104-week international, multicentre, open-label, phase 3b randomised controlled trial, insulin-naive patients aged 18 years and older, with HbA1c between 7·0-11·0% (53-97 mmol/mol), BMI of 20 kg/m2 or higher, on stable doses of oral antidiabetic drugs, were recruited from outpatient clinics. Patients were randomly assigned 1:1, with a simple sequential allocation randomisation schedule (block size of four), to IDegLira or IGlar U100, each treatment being an add-on to existing therapy. The internal safety committee, the independent external committee, and the personnel involved in defining the analysis sets were masked until the database was released for statistical analysis. Patients and all other investigators were not masked. In the IDegLira group, patients were given degludec 100 units/mL plus liraglutide 3·6 mg/mL in a 3 mL prefilled PDS290 pen for subcutaneous injection; in the IGlar U100 group, patients were given IGlar U100 solution, in a 3 mL prefilled Solostar pen for subcutaneous injection. Both treatments were given once daily at any time of day and it was recommended that the time of day remained the same throughout the trial. The primary endpoint was time from randomisation to need for treatment intensification (HbA1c ≥7·0% [53 mmol/mol] at two consecutive visits, including week 26). Once patients met this criterion, the trial product was permanently discontinued and patients were not withdrawn from trial but rather remained on follow-up for the entire treatment and follow-up period. The primary analysis was in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT02501161. FINDINGS From Jan 8, 2016, to Oct 3, 2018, 1345 patients were screened, of which 1012 (75·2%) were eligible and randomly assigned to either IDegLira (n=506) or IGlar U100 (n=506). 484 (96%) of 506 in the IDegLira group and 481 (95%) of 506 in the IGlar U100 group completed the trial. Baseline characteristics were similar and representative of patients eligible for basal insulin intensification (overall mean diabetes duration 10 years; HbA1c 8·5% [69 mmol/mol]; fasting plasma glucose 10 mmol/L). Patients in the IDegLira group had significantly longer time until intensification was needed than those in the IGlar U100 group (median >2 years vs about 1 year). Fewer patients in the IDegLira group needed treatment intensification over 104 weeks than those in the IGlar U100 group (189 [37%] of 506 vs 335 [66%] of 506). The preplanned sensitivity analyses of the primary endpoint were in agreement with the primary analysis (hazard ratio 0·45 [95% CI 0·38-0·54]) in the proportional hazards regression model and the generalised log-rank test was also in favour of IDegLira (p<0·0001). No new or unexpected safety and tolerability issues were identified and there were no treatment-related deaths. INTERPRETATION In patients with uncontrolled type 2 diabetes on oral antidiabetic drugs, initial injectable therapy with IDegLira resulted in fewer patients reaching the treatment intensification criterion during 104 weeks versus IGlar U100, with longer durability of the treatment effect with IDegLira. FUNDING Novo Nordisk.
Collapse
Affiliation(s)
- Vanita R Aroda
- Brigham and Women's Hospital, Boston, MA, USA; MedStar Health Research Institute, Hyattsville, MD, USA.
| | | | | | | | - Martin Haluzík
- Institute for Clinical and Experimental Medicine and Institute of Endocrinology, Prague, Czech Republic
| | | | - Adri Kok
- Union and Clinton Hospitals in Alberton, Gauteng, South Africa
| | | | | | - Giorgio Sesti
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Robert Silver
- Southern New Hampshire Diabetes and Endocrinology, Nashua, NH, USA
| |
Collapse
|
38
|
Schlosser R. Fixed-Dose and Fixed-Ratio Combination Therapies in Type 2 Diabetes. Can J Diabetes 2019; 43:440-444. [PMID: 31375179 DOI: 10.1016/j.jcjd.2019.05.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 11/12/2018] [Revised: 04/12/2019] [Accepted: 05/14/2019] [Indexed: 11/18/2022]
Abstract
The progressive natural history underlying type 2 diabetes often necessitates the use of multiple anti-hyperglycemic medications to achieve therapeutic goals and targets. The associated complexity of these regimens presents significant challenges to both physicians and patients. Fixed-dose oral and fixed-ratio injectable combination agents offer significant potential to simplify and consolidate therapy and lessen barriers to adherence.
Collapse
Affiliation(s)
- Robert Schlosser
- LMC Diabetes & Endocrinology-Vaughan, Thornhill, Ontario, Canada.
| |
Collapse
|
39
|
Madsbad S. Liraglutide for the prevention of major adverse cardiovascular events in diabetic patients. Expert Rev Cardiovasc Ther 2019; 17:377-387. [DOI: 10.1080/14779072.2019.1615444] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 02/06/2023]
Affiliation(s)
- Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
| |
Collapse
|
40
|
Blonde L, Anderson JE, Chava P, Dendy JA. Rationale for a titratable fixed-ratio co-formulation of a basal insulin analog and a glucagon-like peptide 1 receptor agonist in patients with type 2 diabetes. Curr Med Res Opin 2019; 35:793-804. [PMID: 30370783 DOI: 10.1080/03007995.2018.1541790] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 01/05/2023]
Abstract
OBJECTIVE Achieving and maintaining recommended glycemic targets, including those for glycated hemoglobin A1c (A1C), is key to improving outcomes in patients with type 2 diabetes (T2D). As fasting plasma glucose and postprandial glucose contribute to overall A1C, targeting both is essential for sustaining glycemic control. METHODS This review examines the complementary mechanisms of action of glucagon-like peptide 1 (GLP-1) receptor agonists and basal insulin; they both enhance glucose-stimulated insulin release and suppress glucagon secretion. GLP-1 receptor agonists also slow gastric emptying and increase satiety. RESULTS Adding a GLP-1 receptor agonist to therapy with a basal insulin analog has been associated with improved overall glycemic control, with comparable risk of hypoglycemia and no weight gain. Titratable fixed-ratio co-formulations of basal insulin and a GLP-1 receptor agonist have been shown to improve glycemic control, with less complex dosing schedules, possibly increasing treatment adherence. The slow titration of fixed-ratio co-formulations has been shown to reduce the occurrence and severity of gastrointestinal adverse events associated with the use of a separate GLP-1 receptor agonist. Titratable fixed-ratio co-formulations also mitigate insulin-associated weight gain, and show a comparable risk of hypoglycemia to basal insulin use alone. CONCLUSIONS The efficacy and safety of titratable fixed-ratio co-formulations have been demonstrated for insulin degludec/liraglutide and insulin glargine/lixisenatide in the DUAL and LixiLan trials, respectively, in both insulin-naive and -experienced patients. Titratable fixed-ratio co-formulations represent an attractive treatment option for many patients with T2D.
Collapse
Affiliation(s)
- Lawrence Blonde
- a Ochsner Diabetes Clinical Research Unit, Frank Riddick Diabetes Institute, Department of Endocrinology , Ochsner Medical Center , New Orleans , LA , USA
| | | | - Pavan Chava
- c Ochsner Medical Center , Department of Endocrinology , New Orleans , LA , USA
| | - Jared A Dendy
- c Ochsner Medical Center , Department of Endocrinology , New Orleans , LA , USA
| |
Collapse
|
41
|
Abstract
The progressive nature of type 2 diabetes (T2D) means that many patients will require basal insulin therapy at some point in the course of the disease due to β-cell failure. As basal insulin primarily targets fasting plasma glucose, patients may still experience considerable postprandial glucose excursions and therefore require an additional agent to achieve good glycemic control. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) provide an alternative to prandial insulin, with the benefits of fewer daily injections, and a lower risk of hypoglycemia and weight gain. Two fixed-ratio combinations (FRCs) of basal insulin and a GLP-1 RA are now available in the USA and the EU: insulin glargine + lixisenatide (iGlarLixi) and insulin degludec + liraglutide (IDegLira). Titratable FRCs are suitable for most patients with T2D and can help to simplify treatment regimens into one daily injection, potentially aiding in patient adherence. The complementary modes of action of the two components target seven of the many known pathophysiologic defects in T2D. FRCs have demonstrated enhanced glycemic control compared with their constituent components alone, comparable risk of hypoglycemia compared with basal insulin alone, and better tolerability compared with the GLP-1RA component alone due to the slower titration. In this article, we discuss the advantages of FRCs over multiple daily injections, present case studies of typical patients who could benefit from FRC therapy, and outline practical considerations for the initiation of FRC therapy in clinical practice.Funding Sanofi.
Collapse
Affiliation(s)
- Leigh Perreault
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
| | | | | | - Eric Johnson
- Department of Family and Community Medicine, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
| |
Collapse
|
42
|
Santos Cavaiola T, Kiriakov Y, Reid T. Primary Care Management of Patients With Type 2 Diabetes: Overcoming Inertia and Advancing Therapy With the Use of Injectables. Clin Ther 2019; 41:352-367. [PMID: 30655008 DOI: 10.1016/j.clinthera.2018.11.015] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/01/2018] [Revised: 11/07/2018] [Accepted: 11/26/2018] [Indexed: 12/31/2022]
Abstract
Type 2 diabetes (T2D) is a progressive disease caused by insulin resistance and associated progressive β-cell functional decline, as well as multiple other related metabolic and pathophysiologic changes. Left unchecked, T2D increases the risk of long-term microvascular and cardiovascular complications and is associated with excess morbidity and mortality. Despite multiple effective options for reducing hyperglycemia, patients are not optimally managed, largely due to delays in appropriate and timely advancement of therapy. Glucagon-like peptide-1 receptor agonists and basal insulin are recommended by treatment guidelines as effective options for advancing therapy to achieve glycemic control. However, injected therapies often face resistance from patients and clinicians. Glucagon-like peptide-1 receptor agonists are associated with weight loss, low risk of hypoglycemia, and potential beneficial cardiovascular effects. The class is recommended for patients across the spectrum of disease severity and represents an attractive option to add to basal insulin therapy when additional control is needed. Newer second-generation basal insulin analogues offer advantages over first-generation basal insulins in terms of lower hypoglycemia rates and greater flexibility in dosing. Incorporating injectable therapy into patient care in a timely manner has the potential to improve outcomes and must not be overlooked. Primary care clinicians play a significant role in managing patients with T2D, and they must be able to address and overcome patient resistance and their own barriers to advancing therapy if optimal treatment outcomes are to be achieved. The purpose of this expert opinion article was to provide a commentary on the key principle of advancing therapy with injectables to control hyperglycemia.
Collapse
Affiliation(s)
| | - Yan Kiriakov
- Abington-Jefferson Urgent Care, Willow Grove, PA, United States
| | - Timothy Reid
- Mercy Diabetes Center, Janesville, WI, United States
| |
Collapse
|
43
|
Avgerinos I, Karagiannis T, Malandris K, Liakos A, Mainou M, Bekiari E, Matthews DR, Tsapas A. Glucagon-like peptide-1 receptor agonists and microvascular outcomes in type 2 diabetes: A systematic review and meta-analysis. Diabetes Obes Metab 2019; 21:188-193. [PMID: 30058208 DOI: 10.1111/dom.13484] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 04/23/2018] [Revised: 07/19/2018] [Accepted: 07/24/2018] [Indexed: 12/29/2022]
Abstract
We conducted a systematic review and meta-analysis of randomized controlled trials to assess the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on microvascular endpoints in adult patients with type 2 diabetes. We included 60 studies with 60 077 patients. GLP-1 RAs marginally reduced urinary albumin-to-creatinine ratio compared with placebo or other antidiabetic agents (weighted mean difference - 2.55 mg/g; 95% confidence interval [CI] -4.37 to -0.73 and -5.52; -10.89 to -0.16, respectively) and had no clinically relevant effect on change in estimated glomerular filtration rate. Treatment with GLP-1 RAs did not increase incidence of diabetic retinopathy, macular oedema, retinal detachment and retinal haemorrhage, irrespective of comparator. Nevertheless, incidence of vitreous haemorrhage was higher in subjects treated with GLP-1 RAs compared with placebo (odds ratios 1.93; 95% CI 1.09 to 3.42). In conclusion, GLP-1 RAs are safe regarding nephropathy- and retinopathy-related outcomes. Caution may be warranted for incidence of vitreous haemorrhage. The low overall quality of evidence highlights the need for consistent assessment and reporting of microvascular endpoints in future trials.
Collapse
Affiliation(s)
- Ioannis Avgerinos
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Thomas Karagiannis
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Konstantinos Malandris
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Aris Liakos
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Maria Mainou
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eleni Bekiari
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - David R Matthews
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
- Harris Manchester College, University of Oxford, Oxford, UK
| | - Apostolos Tsapas
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Harris Manchester College, University of Oxford, Oxford, UK
| |
Collapse
|
44
|
Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler DJ, Buse JB. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018; 61:2461-2498. [PMID: 30288571 DOI: 10.1007/s00125-018-4729-5] [Citation(s) in RCA: 768] [Impact Index Per Article: 109.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 02/07/2023]
Abstract
The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the prior position statements, published in 2012 and 2015, on the management of type 2 diabetes in adults. A systematic evaluation of the literature since 2014 informed new recommendations. These include additional focus on lifestyle management and diabetes self-management education and support. For those with obesity, efforts targeting weight loss, including lifestyle, medication and surgical interventions, are recommended. With regards to medication management, for patients with clinical cardiovascular disease, a sodium-glucose cotransporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) receptor agonist with proven cardiovascular benefit is recommended. For patients with chronic kidney disease or clinical heart failure and atherosclerotic cardiovascular disease, an SGLT2 inhibitor with proven benefit is recommended. GLP-1 receptor agonists are generally recommended as the first injectable medication.
Collapse
Affiliation(s)
- Melanie J Davies
- Diabetes Research Centre, University of Leicester, Leicester, UK.
- Leicester Diabetes Centre, Leicester General Hospital, Leicester,, LE5 4PW, UK.
| | - David A D'Alessio
- Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Judith Fradkin
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Walter N Kernan
- Department of Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Chantal Mathieu
- Clinical and Experimental Endocrinology, UZ Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Geltrude Mingrone
- Department of Internal Medicine, Catholic University, Rome, Italy
- Diabetes and Nutritional Sciences, King's College London, London, UK
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- University of Copenhagen, Copenhagen, Denmark
| | - Apostolos Tsapas
- Second Medical Department, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Deborah J Wexler
- Department of Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - John B Buse
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| |
Collapse
|
45
|
Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler DJ, Buse JB. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018; 41:2669-2701. [PMID: 30291106 PMCID: PMC6245208 DOI: 10.2337/dci18-0033] [Citation(s) in RCA: 1761] [Impact Index Per Article: 251.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 02/07/2023]
Abstract
The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the prior position statements, published in 2012 and 2015, on the management of type 2 diabetes in adults. A systematic evaluation of the literature since 2014 informed new recommendations. These include additional focus on lifestyle management and diabetes self-management education and support. For those with obesity, efforts targeting weight loss, including lifestyle, medication, and surgical interventions, are recommended. With regards to medication management, for patients with clinical cardiovascular disease, a sodium-glucose cotransporter 2 (SGLT2) inhibitor or a glucagon-like peptide 1 (GLP-1) receptor agonist with proven cardiovascular benefit is recommended. For patients with chronic kidney disease or clinical heart failure and atherosclerotic cardiovascular disease, an SGLT2 inhibitor with proven benefit is recommended. GLP-1 receptor agonists are generally recommended as the first injectable medication.
Collapse
Affiliation(s)
- Melanie J Davies
- Diabetes Research Centre, University of Leicester, Leicester, U.K.,Leicester Diabetes Centre, Leicester General Hospital, Leicester, U.K
| | - David A D'Alessio
- Department of Medicine, Duke University School of Medicine, Durham, NC
| | - Judith Fradkin
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Walter N Kernan
- Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Chantal Mathieu
- Clinical and Experimental Endocrinology, UZ Gasthuisberg, KU Leuven, Leuven, Belgium
| | - Geltrude Mingrone
- Department of Internal Medicine, Catholic University, Rome, Italy.,Diabetes and Nutritional Sciences, King's College London, London, U.K
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, Gentofte, Denmark.,University of Copenhagen, Copenhagen, Denmark
| | - Apostolos Tsapas
- Second Medical Department, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Deborah J Wexler
- Department of Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA.,Harvard Medical School, Boston, MA
| | - John B Buse
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC
| |
Collapse
|
46
|
Usui R, Sakuramachi Y, Seino Y, Murotani K, Kuwata H, Tatsuoka H, Hamamoto Y, Kurose T, Seino Y, Yabe D. Retrospective analysis of liraglutide and basal insulin combination therapy in Japanese type 2 diabetes patients: The association between remaining β-cell function and the achievement of the glycated hemoglobin target 1 year after initiation. J Diabetes Investig 2018; 9:822-830. [PMID: 29106046 PMCID: PMC6031501 DOI: 10.1111/jdi.12773] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/05/2017] [Revised: 09/28/2017] [Accepted: 10/27/2017] [Indexed: 02/06/2023] Open
Abstract
AIMS/INTRODUCTION The glucose-lowering effects of the glucagon-like peptide-1 receptor agonist, liraglutide, have been shown to rely on remaining β-cell function. However, the possible associations of remaining β-cell function with the glucose-lowering effects of liraglutide in combination with basal insulin remain unknown and warrant investigation. MATERIALS AND METHODS This was a single-center, retrospective, observational study carried out in a private hospital in Osaka, Japan. Type 2 diabetes patients who received a prescription change from insulin therapy, both multiple-dose insulin and basal insulin-supported oral therapy, to liraglutide and basal insulin combination and continued the therapy for 54 weeks without additional oral antidiabetic drugs or bolus insulin were retrospectively analyzed. RESULTS Among the 72 participants who received a prescription change from multiple-dose insulin and basal insulin-supported oral therapy to liraglutide and basal insulin combination, 57 continued the therapy for 54 weeks. Of those who continued the therapy without receiving additional oral antidiabetic drugs or bolus insulin, seven participants achieved glycated hemoglobin < 7.0% at 54 weeks, but 30 participants did not. The participants who achieved glycated hemoglobin < 7.0% at 54 weeks had a significantly higher C-peptide immunoreactivity index, a β-cell function-related index frequently used in Japanese clinical settings. The receiver operating curve analysis showed that the C-peptide immunoreactivity index cut-off value for the achievement of glycated hemoglobin <7.0% at 54 weeks is 1.103. CONCLUSIONS The current findings show that the glucose-lowering effects of liraglutide rely on remaining β-cell function, even when used with basal insulin; and suggest that liraglutide and basal insulin combination might require additional bolus insulin to fully compensate insulin insufficiency in individuals with reduced β-cell function.
Collapse
Affiliation(s)
- Ryota Usui
- Center for Diabetes, Endocrinology and MetabolismKansai Electric Power HospitalOsakaJapan
- Present address:
Department of Diabetes, Endocrinology and NutritionGraduate School of MedicineKyoto UniversitySakyo‐kuKyoto 606‐8507Japan
| | - Yui Sakuramachi
- Center for Diabetes, Endocrinology and MetabolismKansai Electric Power HospitalOsakaJapan
- Present address:
Department of EndocrinologyTenri HospitalTenriNara 632‐8552Japan
| | - Yusuke Seino
- Departments of Endocrinology and Diabetes Metabolic MedicineNagoya University Graduate School of MedicineNagoyaJapan
| | - Kenta Murotani
- Division of BiostatisticsClinical Research CenterAichi Medical University HospitalNagakuteJapan
| | - Hitoshi Kuwata
- Center for Diabetes, Endocrinology and MetabolismKansai Electric Power HospitalOsakaJapan
- Yutaka Seino Distinguished Center for Diabetes ResearchKansai Electric Power Medical Research InstituteKobeJapan
| | - Hisato Tatsuoka
- Center for Diabetes, Endocrinology and MetabolismKansai Electric Power HospitalOsakaJapan
- Yutaka Seino Distinguished Center for Diabetes ResearchKansai Electric Power Medical Research InstituteKobeJapan
| | - Yoshiyuki Hamamoto
- Center for Diabetes, Endocrinology and MetabolismKansai Electric Power HospitalOsakaJapan
- Yutaka Seino Distinguished Center for Diabetes ResearchKansai Electric Power Medical Research InstituteKobeJapan
- Center for Metabolism and Clinical NutritionKansai Electric Power HospitalOsakaJapan
| | - Takeshi Kurose
- Center for Diabetes, Endocrinology and MetabolismKansai Electric Power HospitalOsakaJapan
- Yutaka Seino Distinguished Center for Diabetes ResearchKansai Electric Power Medical Research InstituteKobeJapan
| | - Yutaka Seino
- Center for Diabetes, Endocrinology and MetabolismKansai Electric Power HospitalOsakaJapan
- Yutaka Seino Distinguished Center for Diabetes ResearchKansai Electric Power Medical Research InstituteKobeJapan
| | - Daisuke Yabe
- Center for Diabetes, Endocrinology and MetabolismKansai Electric Power HospitalOsakaJapan
- Yutaka Seino Distinguished Center for Diabetes ResearchKansai Electric Power Medical Research InstituteKobeJapan
- Division of Molecular and Metabolic MedicineDepartment of Physiology and Cell BiologyKobe University Graduate School of MedicineKobeJapan
- Department of DiabetesEndocrinology and NutritionKyoto University Graduate School of MedicineKyotoJapan
| |
Collapse
|
47
|
Abstract
GLP-1 receptor agonists (GLP-1 RAs), introduced for clinical use in 2005, have excellent potency in reducing HbA1c and mean glucose, improving fasting plasma glucose, inducing weight loss or protecting against the weight gain associated with insulin therapy, reducing appetite, and delaying gastric emptying. Two of these medications, liraglutide and semaglutide, appear to have cardioprotective effects as reflected in cardiovascular outcomes studies. The GLP-1 RAs are associated with gastrointestinal side effects that tend to diminish over time. They have very low risk of hypoglycemia unless used in conjunction with insulin or insulin secretagogues. Two coformulations of GLP-1 RAs together with long-acting basal insulin are available for daily use. The original GLP-1 RA, exenatide, requires twice-daily injections; two short-acting analogs are given once daily. Three currently available long-acting GLP-1 RAs are injected once weekly, providing greater convenience and potentially improving patient adherence. Semaglutide appears to be the most effective in terms of HbA1c reduction and weight loss. GLP-1 RAs can be combined with all classes of antihyperglycemic agents except DPP-4 inhibitors. Current studies are exploring the use of an implantable osmotic pump for long-term administration of a rapid acting analog (exenatide), an oral preparation of semaglutide, benefits for management of obesity and nonalcoholic steatohepatitis, and mechanisms of cardioprotective effects.
Collapse
|
48
|
Trautmann ME, Vora J. Use of glucagon-like peptide-1 receptor agonists among individuals on basal insulin requiring treatment intensification. Diabet Med 2018; 35:694-706. [PMID: 29478255 PMCID: PMC5969085 DOI: 10.1111/dme.13610] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Accepted: 02/21/2018] [Indexed: 12/14/2022]
Abstract
As Type 2 diabetes progresses, treatment is intensified with additional therapies in an effort to manage hyperglycaemia effectively and therefore avoid complications. When greater efficacy is required, options for injectable treatments include glucagon-like peptide-1 receptor agonists and insulin, which may be added on to oral glucose-lowering treatments. Among individuals receiving long-acting basal insulin as their first injectable treatment, ~40-60% are unable to achieve or maintain their target HbA1c goals. For these people, treatment intensification options are relatively limited and include the addition of short-acting prandial insulin or a glucagon-like peptide-1 receptor agonist. Glucagon-like peptide-1 receptor agonists vary in their effects, with short- and long-acting agents having a greater impact on postprandial and fasting hyperglycaemia, respectively. Studies comparing treatment intensification options have found both glucagon-like peptide-1 receptor agonists and prandial insulin to be effective in reducing HbA1c concentrations; however, recipients of glucagon-like peptide-1 receptor agonists lost weight and had a greater frequency of gastrointestinal adverse events, whereas those receiving prandial insulin gained weight and had a greater incidence of hypoglycaemia. In addition to the separate administration of a glucagon-like peptide-1 receptor agonist and basal insulin, fixed-ratio combinations of a glucagon-like peptide-1 receptor agonist and basal insulin offer a single administration for both treatments but have less flexibility in dose titration than treatment with their individual components. For individuals who require treatment intensification beyond basal insulin, use of these various options allows physicians to target the individual needs of their patients for the achievement of optimal long-term glycaemic control.
Collapse
Affiliation(s)
| | - J. Vora
- Diabetes and EndocrinologyRoyal Liverpool University HospitalLiverpoolUK
- AstraZenecaCambridgeUK
| |
Collapse
|
49
|
Abstract
UNLABELLED As the number of people living with type 2 diabetes (T2D) continues to rise, managing their complex needs presents an increasing challenge to physicians. While treatment guidelines provide evidence-based guidance, they are not prescriptive-rather they emphasize individualization of management based on a patient's clinical needs and preferences. Physicians, therefore, need to be fully aware of the advantages and disadvantages of the multiple and increasing treatment options available to them at each stage of the disease. The progressive nature of T2D means that treatment with basal insulin will become inevitable for many patients, while for some patients basal insulin alone will eventually be insufficient for maintaining glycemic targets. Recent guidelines recommend two basic approaches for intensifying basal insulin: the use of rapid-acting insulin, either as additional prandial injections or as part of premix (biphasic) insulin; and the addition of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to the insulin therapy, which can be administered via subcutaneous injection once or twice daily, or weekly depending on formulation. More recently, two fixed-ratio combinations of basal insulin and a GLP-1 RA that allow for once-daily dosing have been approved. Each of these approaches has potential benefits and drawbacks, particularly in terms of risk for hypoglycemia, weight change, convenience, and side effects. Understanding these differences is central to guiding patient and physician choice. This article discusses the rationale, advantages, disadvantages, and implementation of currently available strategies for basal insulin treatment intensification in patients with T2D. FUNDING Sanofi US, Inc.
Collapse
Affiliation(s)
- Jerry Meece
- Clinical Services, Plaza Pharmacy and Wellness Center, Gainesville, TX, USA.
| |
Collapse
|
50
|
Abstract
INTRODUCTION OR BACKGROUND Type 2 diabetes, which accounts for ~90% of all diabetes, is a heterogeneous and progressive disease with a variety of causative and potentiating factors. The hyperglycaemia of type 2 diabetes is often inadequately controlled, hence the need for a wider selection of glucose-lowering treatments. SOURCES OF DATA Medline, PubMed, Web of Science and Google Scholar. AREAS OF AGREEMENT Early, effective and sustained control of blood glucose defers the onset and reduces the severity of microvascular and neuropathic complications of type 2 diabetes and helps to reduce the risk of cardiovascular (CV) complications. AREAS OF CONTROVERSY Newer glucose-lowering agents require extensive long-term studies to confirm CV safety. The positioning of newer agents within therapeutic algorithms varies. GROWING POINTS In addition to their glucose-lowering efficacy, some new glucose-lowering agents may act independently to reduce CV and renal complications. AREAS TIMELY FOR DEVELOPING RESEARCH Studies of potential new glucose-lowering agents offer the opportunity to safely improve glycaemic control with prolonged efficacy and greater opportunity for therapeutic individualisation.
Collapse
Affiliation(s)
- Clifford J Bailey
- Department of Biomedical Sciences, School of Life and Health Sciences, Aston University, Birmingham, UK
| | - Caroline Day
- Department of Biomedical Sciences, School of Life and Health Sciences, Aston University, Birmingham, UK
| |
Collapse
|