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Osumili B, Sapin H, Yang Z, Ranta K, Paik JS, Blüher M. Efficacy and Safety of Tirzepatide Compared with GLP-1 RAs in Patients with Type 2 Diabetes Treated with Basal Insulin: A Network Meta-analysis. Diabetes Ther 2025; 16:1279-1311. [PMID: 40214900 DOI: 10.1007/s13300-025-01728-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 03/12/2025] [Indexed: 05/18/2025] Open
Abstract
INTRODUCTION The relative efficacy and safety of tirzepatide was compared with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes mellitus (T2DM) treated with basal insulin using a network meta-analysis (NMA). METHODS A systematic literature review was performed to identify randomized controlled trials of GLP-1 RAs in patients with T2DM treated with insulin and an antihyperglycaemic drug. For the NMA, studies included trials with 100% of patients treated with basal insulin background therapy with a titration scheme comparable to the SURPASS-5 trial. The following data were extracted for efficacy and safety assessment at the primary endpoint of each study: changes from baseline in glycated haemoglobin (HbA1c) and body weight and the incidence of nausea, vomiting or diarrhoea, hypoglycaemia, and patients discontinuing treatment because of adverse events. In this study, a comparative analysis of tirzepatide was performed with the GLP-1 RAs dulaglutide, exenatide, and lixisenatide in addition to placebo. RESULTS A total of six studies were included across the analyses. Tirzepatide 5, 10, and 15 mg showed statistically significant, greater reductions in HbA1c and body weight at the primary endpoint versus all GLP-1 RA comparators and placebo. Tirzepatide 5, 10, and 15 mg showed a statistically significant, higher likelihood of experiencing nausea compared with those who received placebo or exenatide 2 mg; no statistically significant differences were observed when compared with all other GLP-1 RA comparators. No statistically significant differences were observed in the proportions of patients who discontinued treatment because of adverse events when tirzepatide 5, 10, and 15 mg were compared with GLP-1 RA comparators, apart from tirzepatide 10 and 15 mg versus placebo. CONCLUSION Tirzepatide demonstrated statistically significantly greater reductions in HbA1c and body weight when compared with selected GLP-1 RAs and placebo in patients with T2DM treated with basal insulin. Overall, the safety profile of tirzepatide was similar to that of GLP-1RAs.
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Affiliation(s)
- Beatrice Osumili
- Health Economics and Outcomes Research, Eli Lilly and Company Limited, Bracknell, UK
| | - Hélène Sapin
- Research and Development Statistics, Lilly France SAS, Neuilly-Sur-Seine, France
| | | | - Kari Ranta
- Medical Affairs, Eli Lilly Finland, Helsinki, Finland.
| | - Jim S Paik
- Medical Affairs, Eli Lilly and Company, Indianapolis, IN, USA
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München, University of Leipzig and University Hospital Leipzig, Leipzig, Germany
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Zhou ZD, Yi L, Popławska-Domaszewicz K, Chaudhuri KR, Jankovic J, Tan EK. Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges. Pharmacol Res 2025; 216:107770. [PMID: 40344943 DOI: 10.1016/j.phrs.2025.107770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 04/10/2025] [Accepted: 05/07/2025] [Indexed: 05/11/2025]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists (GRA) belong to a class of compounds that reduce blood glucose and energy intake by simulating actions of endogenous incretin hormone GLP-1 after it is released by the gut following food consumption. They are used to treat type 2 diabetes mellitus (T2DM) and obesity and have systemic effects on various organs, including the brain, liver, pancreas, heart, and the gut. Patients with T2DM have a higher risk of developing neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), accompanied by more severe motor deficits and faster disease progression, suggesting dysregulation of insulin signaling in these diseases. Experimental studies have shown that GRA have protective effects to modulate neuroinflammation, oxidative stress, mitochondrial and autophagic functions, and protein misfolding. Hence the compounds have generated enormous interest as novel therapeutic agents against NDs. To date, clinical trials have shown that three GRA, exenatide, liraglutide and lixisenatide can improve motor deficits as an add-on therapy in PD patients and liraglutide can improve cognitive function in AD patients. The neuroprotective effects of these and other GRA, such as PT320 (a sustained-released exenatide) and semaglutide, are still under investigation. The dual GLP-1/gastric inhibitory polypeptide (GIP) receptor agonists have been demonstrated to have beneficial effects in AD and PD mice models. Overall, GRA are highly promising novel drugs, but future clinical studies should identify which subsets of patients should be targeted as potential candidates for their symptomatic and/or neuroprotective benefits, investigate whether combinations with other classes of drugs can further augment their efficacy, and evaluate their long-term disease-modifying and adverse effects.
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Affiliation(s)
- Zhi Dong Zhou
- National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, 308433, Singapore; Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, 169857, Singapore.
| | - Lingxiao Yi
- National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, 308433, Singapore.
| | - Karolina Popławska-Domaszewicz
- Department of Neurology, Poznan University of Medical Sciences, Poznan 60-355, Poland; Parkinson's Foundation Centre of Excellence, King's College Hospital, Denmark Hill, London SE5 9RS, UK.
| | - Kallol Ray Chaudhuri
- Department of Basic and Clinical Neuroscience, The Maurice Wohl Clinical Neuroscience Institute, King's College London, Cutcombe Road, London SE5 9RT, UK.
| | - Joseph Jankovic
- Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
| | - Eng King Tan
- National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, 308433, Singapore; Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, 169857, Singapore.
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Liu Y, He L, Han S, Ping F, Li W, Xu L, Zhang H, Li Y. Glucagon-Like Peptide-1 Receptor Agonists and Risk of Venous Thromboembolism: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc 2025; 14:e039446. [PMID: 40314346 DOI: 10.1161/jaha.124.039446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 03/13/2025] [Indexed: 05/03/2025]
Abstract
BACKGROUND Limited data exist on the association of glucagon-like peptide 1 receptor agonists (GLP-1RAs) with the risk of venous thromboembolism. This meta-analysis aimed to investigate the association between GLP-1RAs and the risk of venous thromboembolism including deep vein thrombosis (DVT) and pulmonary embolism. METHODS AND RESULTS A systematic search of PubMed, Web of Science, EMBASE, and Cochrane library was conducted from inception until July 3, 2024, to identify randomized controlled trials comparing GLP-1RAs with placebo or other anti-iabetic drugs, with reported data on DVT and pulmonary embolism. The primary outcome was venous thromboembolism, and secondary outcomes included DVT and pulmonary embolism. Pooled odds ratios (ORs) were calculated using fixed-effects models with Mantel-Haenszel method and treatment arm continuity correction for zero-event trials. A total of 39 randomized controlled trials involving 70 499 participants were included. A nonsignificant upward trend in the risk of venous thromboembolism was observed among participants using GLP-1RAs (OR, 1.19 [95% CI, 0.94-1.50]). GLP-1RAs were significantly associated with an increased risk of DVT (OR, 1.64 [95% CI, 1.14-2.36]); risk difference 25 (5-52) more events per 10 000 person-years). Subgroup analyses revealed that increased risk of DVT was particularly prominent in randomized controlled trials with treatment duration >1.5 years (OR, 2.32 [95% CI, 1.49-3.60]) and in cardiovascular outcome trials (OR, 2.18 [95% CI, 1.36-3.49]). No significant association was observed between GLP-1RAs and risk of pulmonary embolism. CONCLUSIONS GLP-1RAs might increase the risk of DVT, especially for long-term use of GLP-1RAs. Clinicians should be aware of this potential risk when prescribing GLP-1RAs.
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Affiliation(s)
- Yiwen Liu
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
| | - Liyun He
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
| | - Shumeng Han
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
| | - Fan Ping
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
| | - Wei Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
| | - Lingling Xu
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
| | - Huabing Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
| | - Yuxiu Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China
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Natale P, Green SC, Tunnicliffe DJ, Pellegrino G, Toyama T, Strippoli GF. Glucagon-like peptide 1 (GLP-1) receptor agonists for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev 2025; 2:CD015849. [PMID: 39963952 PMCID: PMC11834151 DOI: 10.1002/14651858.cd015849.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
BACKGROUND Approximately 40% of people with diabetes develop kidney failure and experience an accelerated risk of cardiovascular complications. Glucagon-like peptide 1 (GLP-1) receptor agonists are glucose-lowering agents that manage glucose and weight control. OBJECTIVES We assessed the benefits and harms of GLP-1 receptor agonists in people with chronic kidney disease (CKD) and diabetes. SEARCH METHODS The Cochrane Kidney and Transplant Register of Studies was searched to 10 September 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA Randomised controlled studies were eligible if participants with diabetes and CKD were randomly allocated to a GLP-1 receptor agonist, placebo, standard care or a second glucose-lowering agent. CKD included all stages (from 1 to 5). DATA COLLECTION AND ANALYSIS Three authors independently extracted data and assessed the risk of bias using the risk of bias assessment tool 2. Pooled analyses using summary estimates of effects were obtained using a random-effects model, and results were expressed as risk ratios (RR) and/or hazard ratio (HR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. The primary outcomes included death (all-cause and cardiovascular), 3- and 4-point major adverse cardiovascular events (MACE), kidney failure, composite kidney outcome, and severe hypoglycaemia. The secondary outcomes included non-fatal or fatal myocardial infarction (MI) or stroke, non-fatal peripheral arterial events, heart failure, hospitalisation due to heart failure, estimated glomerular filtration rate or creatinine clearance, doubling of serum creatinine, urine albumin-to-creatinine ratio, albuminuria progression, vascular access outcomes, body weight, body mass index, fatigue, life participation, peritoneal dialysis infection, peritoneal dialysis failure, adverse events, serious adverse events, withdrawal due to adverse events, HbA1c, sudden death, acute MI, ischaemic stroke, and coronary revascularisation. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS Forty-two studies involving 48,148 participants were included. All studies were conducted on people with type 2 diabetes, and no studies were carried out on children. The median study age was 66 years. The median study follow-up was 26 weeks. Six studies were conducted in people with CKD stages 1-2, 11 studies in people with CKD stages 3-5, one study in people on dialysis, and the remaining studies included people with both CKD stages 1-2 and 3-5. Risks of bias in the included studies for all the primary outcomes in studies that compared GLP-1 receptor agonists to placebo were low in most methodological domains, except one study that was assessed at high risk of bias due to missing outcome data for death (all-cause and cardiovascular). The overall risk of bias for all-cause and cardiovascular death in studies that reported the treatment effects of GLP-1 receptor agonists compared to standard care, dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter 2 (SGLT2) inhibitors were assessed as unclear or at high risk of bias due to deviations from intended interventions or missing data. For GLP-1 receptor agonists compared to insulin or another GLP-1 receptor agonist, the risk of bias for all-cause and cardiovascular death was low or unclear. Compared to placebo, GLP-1 receptor agonists probably reduced the risk of all-cause death (RR 0.85, 95% CI 0.74 to 0.98; I2 = 23%; 8 studies, 17,861 participants; moderate-certainty evidence), but may have little or no effect on cardiovascular death (RR 0.84, 95% CI 0.68 to 1.05; I2 = 42%; 7 studies, 17,801 participants; low-certainty evidence). Compared to placebo, GLP-1 receptor agonists probably decreased 3-point MACE (RR 0.84, 95% CI 0.73 to 0.98; I² = 65%; 4 studies, 19,825 participants; moderate-certainty evidence), and 4-point MACE compared to placebo (RR 0.77, 95% CI 0.67 to 0.89; 1 study, 2,158 participants; moderate-certainty evidence). Based on absolute risks of clinical outcomes, it is likely that GLP-1 receptor agonists prevent all-cause death in 52 people with CKD stages 1-2 and 116 in CKD stages 3-5, cardiovascular death in 34 people with CKD stages 1-2 and 71 in CKD stages 3-5, while 95 CKD stages 1-2 and 153 in CKD stages 3-5 might experience a major cardiovascular event for every 1000 people treated over 1 year. Compared to placebo, GLP-1 receptor agonists probably had little or no effect on kidney failure, defined as starting dialysis or kidney transplant (RR 0.86, 95% CI 0.66 to 1.13; I2 = 0%; 3 studies, 4,134 participants; moderate-certainty evidence), or on composite kidney outcomes (RR 0.89, 95% CI 0.78 to 1.02; I2 = 0%; 2 studies, 16,849 participants; moderate-certainty evidence). Compared to placebo, GLP-1 receptor agonists may have little or no effect on the risk of severe hypoglycaemia (RR 0.82, 95% CI 0.54 to 1.25; I2 = 44%; 4 studies, 6,292 participants; low-certainty evidence). The effects of GLP-1 receptor agonists compared to standard care or other hypoglycaemic agents were uncertain. No studies evaluated treatment on risks of fatigue, life participation, amputation or fracture. AUTHORS' CONCLUSIONS GLP-1 receptor agonists probably reduced all-cause death but may have little or no effect on cardiovascular death in people with CKD and diabetes. GLP-1 receptor agonists probably lower major cardiovascular events, probably have little or no effect on kidney failure and composite kidney outcomes, and may have little or no effect on the risk of severe hypoglycaemia in people with CKD and diabetes.
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Affiliation(s)
- Patrizia Natale
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari Aldo Moro, Bari, Italy
| | - Suetonia C Green
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
| | | | - Giovanni Pellegrino
- Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari Aldo Moro, Bari, Italy
| | - Tadashi Toyama
- Department of Nephrology, Kanazawa University, Kanazawa, Japan
- Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan
| | - Giovanni Fm Strippoli
- Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari Aldo Moro, Bari, Italy
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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Candido R, Nicolucci A, Larosa M, Rossi MC, Napoli R. Treatment intensification following glucagon-like peptide-1 receptor agonist treatment in type 2 diabetes: The RESTORE-G real-world study. Nutr Metab Cardiovasc Dis 2023; 33:2294-2305. [PMID: 37679243 DOI: 10.1016/j.numecd.2023.07.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 07/10/2023] [Accepted: 07/14/2023] [Indexed: 09/09/2023]
Abstract
BACKGROUND AND AIMS To assess intensification approaches with basal insulin (BI) following glucagon-like peptide-1 receptor agonist (GLP-1 RA) treatment in type 2 diabetes (T2D). METHODS AND RESULTS Real-world data were collected in electronic medical records by 32 Italian diabetes clinics between 2011 and 2021. Primary endpoint was the proportion of insulin-naïve T2D patients treated with GLP-1 RA who initiated (add-on or switch) BI. Secondary endpoints were: treatment approaches, mean time to BI start, effectiveness and safety. Among 7,962 eligible patients, BI was prescribed to 3,164 (39.7%; 95%CI 38.7; 40.8): 67.6% switched to BI (22.1% also starting 1-3 injections of short-acting insulin), 22.7% added BI while maintaining GLP-1 RA, and 9.7% switched to a fixed-ratio combination of GLP-1 RA and BI (FRC). Median time since the first GLP-1 RA to BI/FRC prescription was 27.4 (IQ range 11.8-53.5) months. In this study 60.3% of patients did not start BI/FRC, among whom 15.2% intensified GLP-1 RA therapy with other oral agents. Effectiveness and safety were documented in all intensification approaches with BI/FRC, but HbA1c level at intensification time of ≥9.0% and suboptimal BI titration suggested clinical inertia. Use of second generation BI and add-on to GLP-1 RA schemes increased over time and effectiveness improved. CONCLUSION Clinical inertia should be overcome using innovative insulin options. Timely combination therapy of BI and GLP-1 RA is a valuable choice.
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Affiliation(s)
- Riccardo Candido
- Diabetes Centre District 4, Azienda Sanitaria Universitaria Integrata, Trieste, Italy
| | - Antonio Nicolucci
- CORESEARCH, Center for Outcomes Research and Clinical Epidemiology, Pescara, Italy.
| | | | - Maria Chiara Rossi
- CORESEARCH, Center for Outcomes Research and Clinical Epidemiology, Pescara, Italy
| | - Raffaele Napoli
- Department of Translational Medical Sciences, Unit of Internal Medicine and Diabetes, Federico II University School of Medicine and Institute of Experimental Endocrinology and Oncology, National Research Council, Napoli, Italy
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Zhang Z, Zhang Q, Tan Y, Chen Y, Zhou X, Liu S, Yu J. GLP-1RAs caused gastrointestinal adverse reactions of drug withdrawal: a system review and network meta-analysis. Front Endocrinol (Lausanne) 2023; 14:1149328. [PMID: 37484944 PMCID: PMC10359616 DOI: 10.3389/fendo.2023.1149328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 06/14/2023] [Indexed: 07/25/2023] Open
Abstract
Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) significantly reduce postprandial blood glucose, inhibit appetite, and delay gastrointestinal emptying. However, it is controversial that some patients are intolerant to GLP-1RAs. Methods PubMed, Embase, Web of Science, and Cochrane Library were searched for randomized controlled trials (RCTs) using GLP-1RAs with documented withdrawal due to gastrointestinal adverse reactions (GI AEs) from their inception to September 28, 2022. After extracting the information incorporated into the studies, a random-effects network meta-analysis was performed within a frequentist framework. Results 64 RCTs were finally enrolled, which included six major categories of the GLP-1RA. The sample size of the GLP-1RAs treatment group was 16,783 cases. The risk of intolerable gastrointestinal adverse reactions of Liraglutide and Semaglutide was higher than that of Dulaglutide. Meanwhile, the higher the dose of the same GLP-1RA preparation, the more likely to cause these adverse reactions. These intolerable GI AEs were not significantly related to drug homology or formulations and may be related to the degree of suppression of the appetite center. Conclusion Dulaglutide caused the lowest intolerable GI AEs, while Liraglutide and Semaglutide were the highest. For Semaglutide, the higher the dose, the more likely it is to drive GI AEs. Meanwhile, the risk of these GI AEs is independent of the different formulations of the drug. All these findings can effectively guide individualized treatment. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022359346, identifier CRD42022359346.
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Affiliation(s)
- Ziqi Zhang
- Department of Endocrinology, Jiangsu Provincial Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu, China
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Qiling Zhang
- Department of Endocrinology, Jiangsu Provincial Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu, China
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Ying Tan
- Department of Endocrinology, Jiangsu Provincial Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu, China
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yu Chen
- Department of Endocrinology, Jiangsu Provincial Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu, China
- The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiqiao Zhou
- Department of Endocrinology, Jiangsu Provincial Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu, China
| | - Su Liu
- Department of Endocrinology, Jiangsu Provincial Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu, China
| | - Jiangyi Yu
- Department of Endocrinology, Jiangsu Provincial Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu, China
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Popoviciu MS, Păduraru L, Yahya G, Metwally K, Cavalu S. Emerging Role of GLP-1 Agonists in Obesity: A Comprehensive Review of Randomised Controlled Trials. Int J Mol Sci 2023; 24:10449. [PMID: 37445623 DOI: 10.3390/ijms241310449] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 06/13/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Obesity is a chronic disease with high prevalence and associated comorbidities, making it a growing global concern. These comorbidities include type 2 diabetes, hypertension, ventilatory dysfunction, arthrosis, venous and lymphatic circulation diseases, depression, and others, which have a negative impact on health and increase morbidity and mortality. GLP-1 agonists, used to treat type 2 diabetes, have been shown to be effective in promoting weight loss in preclinical and clinical studies. This review summarizes numerous studies conducted on the main drugs in the GLP-1 agonists class, outlining the maximum achievable weight loss. Our aim is to emphasize the active role and main outcomes of GLP-1 agonists in promoting weight loss, as well as in improving hyperglycemia, insulin sensitivity, blood pressure, cardio-metabolic, and renal protection. We highlight the pleiotropic effects of these medications, along with their indications, contraindications, and precautions for both diabetic and non-diabetic patients, based on long-term follow-up studies.
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Affiliation(s)
- Mihaela-Simona Popoviciu
- Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410073 Oradea, Romania
| | - Lorena Păduraru
- Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410073 Oradea, Romania
| | - Galal Yahya
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Al Sharqia 44519, Egypt
- Department of Molecular Genetics, Faculty of Biology, Technical University of Kaiserslautern, Paul-Ehrlich Str. 24, 67663 Kaiserslautern, Germany
| | - Kamel Metwally
- Department of Medicinal Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia
- Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | - Simona Cavalu
- Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410073 Oradea, Romania
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Haddad F, Dokmak G, Bader M, Karaman R. A Comprehensive Review on Weight Loss Associated with Anti-Diabetic Medications. Life (Basel) 2023; 13:1012. [PMID: 37109541 PMCID: PMC10144237 DOI: 10.3390/life13041012] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/11/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
Obesity is a complex metabolic condition that can have a negative impact on one's health and even result in mortality. The management of obesity has been addressed in a number of ways, including lifestyle changes, medication using appetite suppressants and thermogenics, and bariatric surgery for individuals who are severely obese. Liraglutide and semaglutide are two of the five Food and Drug Administration (FDA)-approved anti-obesity drugs that are FDA-approved agents for the treatment of type 2 diabetes mellitus (T2DM) patients. In order to highlight the positive effects of these drugs as anti-obesity treatments, we analyzed the weight loss effects of T2DM agents that have demonstrated weight loss effects in this study by evaluating clinical studies that were published for each agent. Many clinical studies have revealed that some antihyperglycemic medications can help people lose weight, while others either cause weight gain or neutral results. Acarbose has mild weight loss effects and metformin and sodium-dependent glucose cotransporter proteins-2 (SGLT-2) inhibitors have modest weight loss effects; however, some glucagon-like peptide-1 (GLP-1) receptor agonists had the greatest impact on weight loss. Dipeptidyl peptidase 4 (DPP-4) inhibitors showed a neutral or mild weight loss effect. To sum up, some of the GLP-1 agonist drugs show promise as weight-loss treatments.
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Affiliation(s)
- Fatma Haddad
- Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem 9103401, Palestine; (F.H.); (G.D.); (M.B.)
- Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK
| | - Ghadeer Dokmak
- Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem 9103401, Palestine; (F.H.); (G.D.); (M.B.)
| | - Maryam Bader
- Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem 9103401, Palestine; (F.H.); (G.D.); (M.B.)
| | - Rafik Karaman
- Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem 9103401, Palestine; (F.H.); (G.D.); (M.B.)
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy
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Yao J, Zhang M, Zhang X, Zhang J. Impact of Type 2 Diabetes Duration on the Efficacy and Safety of Add-on Lixisenatide in Asian Individuals Receiving Basal Insulin: A Pooled Analysis. Diabetes Ther 2023; 14:653-669. [PMID: 36809495 PMCID: PMC10064411 DOI: 10.1007/s13300-023-01369-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 01/11/2023] [Indexed: 02/23/2023] Open
Abstract
INTRODUCTION This analysis investigated the efficacy and safety of add-on lixisenatide by disease duration in Asian people with type 2 diabetes inadequately controlled with basal insulin ± oral antidiabetic drugs. METHODS Data for Asian participants in the GetGoal-Duo 1, GetGoal-L, and GetGoal-L-C studies were pooled and categorized by diabetes duration: < 10 years (group 1), 10 to < 15 years (group 2), and ≥ 15 years (group 3). Efficacy and safety of lixisenatide versus placebo were evaluated by subgroup. The potential influence of diabetes duration on efficacy was examined using multivariable regression analyses. RESULTS A total of 555 participants were included (mean age 53.9 years, 52.4% male). No significant differences in treatment effect between the duration subgroups were observed for the changes from baseline to 24 weeks in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial glucose (PPG), PPG excursion, body weight or body mass index, or the proportion of participants with HbA1c < 7% at 24 weeks (all P values for interaction > 0.1). Change in insulin dosage (U/day) was significantly different between subgroups (P = 0.038). Multivariable regression analysis showed participants in group 1 had a smaller change in body weight and basal insulin dose over the 24-week treatment period than participants in group 3 (P = 0.014 and 0.030, respectively) and were less likely to achieve an HbA1c < 7% than participants in group 2 (P = 0.047). No severe hypoglycemia was reported. A higher proportion of participants in group 3 versus the other groups had symptomatic hypoglycemia, for both lixisenatide and placebo, and T2D duration had a significant effect on hypoglycemia risk (P = 0.001). CONCLUSIONS Lixisenatide improved glycemic control in Asian individuals regardless of diabetes duration, without increasing the risk of hypoglycemia. Individuals with longer disease duration had a greater risk of symptomatic hypoglycemia than individuals with shorter disease duration regardless of treatment. No additional safety concerns were observed. CLINICAL TRIAL REGISTRATION GetGoal-Duo 1, ClinicalTrials.gov record NCT00975286; GetGoal-L, ClinicalTrials.gov record NCT00715624; GetGoal-L-C, ClinicalTrials.gov record NCT01632163.
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Affiliation(s)
- Jun Yao
- Department of Endocrinology, Peking University First Hospital, Nov. 8 Xishiku Street, West City District, Beijing, 100034, China
| | | | | | - Junqing Zhang
- Department of Endocrinology, Peking University First Hospital, Nov. 8 Xishiku Street, West City District, Beijing, 100034, China.
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Kaneto H, Baxter M, Takahashi Y, Terauchi Y. Simultaneous Versus Sequential Initiation of Lixisenatide and Basal Insulin for Type 2 Diabetes: Subgroup Analysis of a Japanese Post-Marketing Surveillance Study of Lixisenatide (PRANDIAL). Adv Ther 2022; 39:5453-5473. [PMID: 36207508 PMCID: PMC9618543 DOI: 10.1007/s12325-022-02311-1] [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] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/25/2022] [Indexed: 01/30/2023]
Abstract
INTRODUCTION We aimed to assess the efficacy and safety of lixisenatide and basal insulin (BI) according to timing of treatment initiation, treatment compliance, and number of concomitant daily injections in Japanese individuals with type 2 diabetes (T2D). METHODS Each substudy analyzed subgroup data from the 3-year post-marketing surveillance PRANDIAL study. Endpoints included glycated hemoglobin (HbA1c), postprandial glucose, treatment response (HbA1c < 7.0% at week 24 and 156), and safety. Changes in HbA1c levels were analyzed using paired t tests; between-group comparisons were made using analysis of variance (ANOVA). RESULTS Of 2679 participants, 46.5% initiated BI before lixisenatide, 12.0% the same day, 2.7% between 1 and 90 days, and 2.8% at 91 or more days after lixisenatide; 36.0% did not receive BI. Overall, 85.4% of patients were compliant with lixisenatide treatment. The majority of patients (52.4%) received two injections/day (one was lixisenatide). Compared with other subgroups taking BI and lixisenatide, the subgroup starting them simultaneously had a mean change in HbA1c of - 0.69% [8 mmol/mol] (vs + 0.07% [0.8 mmol/mol] to - 0.79% [9 mmol/mol]) and numerically higher treatment response (21.0% vs 8.3-18.7%), but more hypoglycemia (8.1% vs 2.3-2.8%). CONCLUSIONS Japanese people with T2D achieved better glycemic control by simultaneous as opposed to sequential initiation of lixisenatide and BI.
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Affiliation(s)
| | - Mike Baxter
- Medical Affairs, Sanofi, Reading, UK
- Swansea University, Swansea, Wales, UK
| | - Yoko Takahashi
- Sanofi K.K. General Medicine Medical Department, Tokyo, Japan.
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Yokohama City University, Yokohama, Japan
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Barrientos‐Pérez M, Hsia DS, Sloan L, Nell H, Mungur O, Hovsepian L, Schmider W, Spranger R, Yang N, Niemoeller E. A study on pharmacokinetics, pharmacodynamics and safety of lixisenatide in children and adolescents with type 2 diabetes. Pediatr Diabetes 2022; 23:641-648. [PMID: 35411611 PMCID: PMC9790255 DOI: 10.1111/pedi.13343] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 02/28/2022] [Accepted: 03/30/2022] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVE The aim of this study was to investigate the pharmacokinetic, pharmacodynamic and safety profile of the glucagon-like peptide-1 receptor agonist, lixisenatide, for the treatment of type 2 diabetes (T2D) in pediatric individuals. MATERIALS AND METHODS In this Phase 1, multicenter, randomized, double-blind, placebo-controlled, parallel-group, ascending repeated dose study (NCT02803918), participants aged ≥10 and < 18 years were randomized 3:1 to receive once-daily lixisenatide in 2-week increments of 5, 10, and 20 μg (n = 18) or placebo (n = 5) for 6 weeks. RESULTS Mean lixisenatide concentrations generally increased with increasing doses irrespective of anti-drug antibody (ADA) status; however, mean lixisenatide concentrations and inter-subject variability were higher for participants with positive ADA status. Improvements in fasting plasma glucose, post-prandial glucose, AUC0-4.5 , HbA1c , and body weight were observed with lixisenatide. Overall, the safety profile was consistent with the known profile in adults, with no unexpected side effects and no treatment-emergent adverse events resulting in death or discontinuation. The most common events in the lixisenatide group were vomiting (11.1%) and nausea (11.1%). No symptomatic hypoglycemia was reported in either group. No clinically significant hematologic, biochemical or vital sign abnormalities were observed. CONCLUSIONS Mean lixisenatide concentrations generally increased with increasing dose, irrespective of ADA status. Lixisenatide was associated with improved glycemic control and a trend in body weight reduction compared with placebo. The safety and tolerability profile of repeated lixisenatide doses of up to 20 μg per day in children and adolescents with T2D was reflective of the established safety profile of lixisenatide in adults.
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Affiliation(s)
| | - Daniel S. Hsia
- Pennington Biomedical Research CenterBaton RougeLouisianaUSA
| | - Lance Sloan
- Texas Institute for Kidney and Endocrine DisordersLufkinTexasUSA,Department of Internal MedicineUniversity of Texas Medical BranchGalvestonTexasUSA
| | - Haylene Nell
- Tiervlei Trial CentreKarl Bremer HospitalCape TownSouth Africa
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12
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Nurcahyanti ADR, Cokro F, Wulanjati MP, Mahmoud MF, Wink M, Sobeh M. Curcuminoids for Metabolic Syndrome: Meta-Analysis Evidences Toward Personalized Prevention and Treatment Management. Front Nutr 2022; 9:891339. [PMID: 35757255 PMCID: PMC9218575 DOI: 10.3389/fnut.2022.891339] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 04/21/2022] [Indexed: 12/22/2022] Open
Abstract
The metabolic syndrome (MS) is a multifactorial syndrome associated with a significant economic burden and healthcare costs. MS management often requires multiple treatments (polydrug) to ameliorate conditions such as diabetes mellitus, insulin resistance, obesity, cardiovascular diseases, hypertension, and non-alcoholic fatty liver disease (NAFLD). However, various therapeutics and possible drug-drug interactions may also increase the risk of MS by altering lipid and glucose metabolism and promoting weight gain. In addition, the medications cause side effects such as nausea, flatulence, bloating, insomnia, restlessness, asthenia, palpitations, cardiac arrhythmias, dizziness, and blurred vision. Therefore, is important to identify and develop new safe and effective agents based on a multi-target approach to treat and manage MS. Natural products, such as curcumin, have multi-modalities to simultaneously target several factors involved in the development of MS. This review discusses the recent preclinical and clinical findings, and up-to-date meta-analysis from Randomized Controlled Trials regarding the effects of curcumin on MS, as well as the metabonomics and a pharma-metabolomics outlook considering curcumin metabolites, the gut microbiome, and environment for a complementary personalized prevention and treatment for MS management.
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Affiliation(s)
- Agustina Dwi Retno Nurcahyanti
- Department of Pharmacy, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia
| | - Fonny Cokro
- Department of Pharmacy, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia
| | - Martha P Wulanjati
- Research Division for Natural Products Technology (BPTBA), National Research and Innovation Agency (BRIN), Yogyakarta, Indonesia
| | - Mona F Mahmoud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Michael Wink
- Institute of Pharmacy and Molecular Biotechnology (IPMB), Heidelberg University, Heidelberg, Germany
| | - Mansour Sobeh
- AgroBioSciences Department, Mohammed VI Polytechnic University, Ben-Guerir, Morocco
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13
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Terauchi Y, Usami M, Inoue T. The Durable Safety and Effectiveness of Lixisenatide in Japanese People with Type 2 Diabetes: The Post-Marketing Surveillance PRANDIAL Study. Adv Ther 2022; 39:2873-2888. [PMID: 35449321 PMCID: PMC9122860 DOI: 10.1007/s12325-022-02121-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 03/09/2022] [Indexed: 11/30/2022]
Abstract
Introduction Real-world evidence on lixisenatide in Japanese people with type 2 diabetes (T2D) is lacking. Therefore, the 3-year post-marketing PRANDIAL study was conducted to evaluate the safety (primary objective) and effectiveness (secondary objective) of lixisenatide in Japanese people with T2D during routine clinical practice. Methods This prospective, observational, multicenter, open-label study was conducted in Japanese individuals with T2D who initiated lixisenatide treatment between March 2014 and June 2017. Using electronic case report forms, investigators collected baseline demographic and clinical information and data on medications, safety and effectiveness up to 3 years after initiation of lixisenatide. Results Overall, 3046 participants were analyzed; their mean ± standard deviation (SD) age was 58.9 ± 13.1 years, and 53.7% were male. Mean ± SD duration of T2D was 12.8 ± 8.6 years, and baseline glycated hemoglobin (HbA1c) was 8.7% ± 1.7%. Most participants (93.9%) were receiving concomitant antidiabetic medications when they initiated lixisenatide. Median (range) lixisenatide treatment duration was 382 (1–1096) days. Adverse drug reactions (ADRs) were reported in 604 participants (19.8%) and serious ADRs in 22 (0.7%). The most common ADR was nausea (9.0%). Of ADRs of special interest, hypoglycemia occurred in 2.9% of participants, injection site reactions in 0.9%, and hypoglycemic unconsciousness in 0.03%. Baseline characteristics associated with an increased risk of ADRs (p < 0.05) were history of treatment for cardiovascular disease, hepatic dysfunction, and other complications. Effectiveness was analyzed in 2675 participants; HbA1c, fasting plasma glucose, postprandial glucose, and body weight all decreased significantly at last observation (all p < 0.0001 vs. baseline). Conclusions Lixisenatide was well tolerated, with no unexpected ADRs or new safety signals identified, and showed effective glycemic control and weight reduction up to 3 years, supporting the use of lixisenatide as a safe and effective treatment option for T2D in routine clinical practice in Japan. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-022-02121-5. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are antidiabetic drugs that lower blood glucose levels by stimulating the release of insulin and suppressing glucagon, the key hormones involved in controlling blood glucose levels in the body. The selective GLP-1RA lixisenatide was approved for the management of adults with type 2 diabetes (T2D) in Japan based on data from randomized clinical trials. However, these studies may not be representative of the safety and effectiveness of the drug when used in routine clinical practice. Therefore, we conducted the 3-year post-marketing PRANDIAL study to assess the safety and effectiveness of lixisenatide in 3046 Japanese individuals with T2D who started the drug between March 2014 and June 2017. Adverse drug reactions (adverse events for which lixisenatide causality could not be excluded) occurred in 19.8% of participants, with the most common adverse drug reaction being nausea. Hypoglycemia (abnormally low blood glucose levels) was reported in 2.9%. Individuals with a history of treatment for cardiovascular disease, hepatic dysfunction, and other complications had an increased risk of adverse drug reactions. Lixisenatide provided significant improvements in blood glucose control, with significant decreases in glycated hemoglobin (a marker of blood glucose control), fasting plasma glucose, and postprandial glucose levels from baseline, as well as significant reductions in body weight. In this real-world post-marketing surveillance study, lixisenatide was well tolerated, raising no new safety concerns, and provided durable effective blood glucose control and weight reduction. These results support the use of lixisenatide in Japanese individuals with T2D in routine clinical practice.
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Affiliation(s)
- Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Makiko Usami
- Post-Authorization Regulatory Studies, Sanofi K.K., Opera City Tower, 3-20-2 Nishi-Shinjuku, Shinjuku-ku, Tokyo, 163-1488, Japan.
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Wolters J, Wollenhaupt D, El Aziz MA, Nauck MA. Impact of the Fasting Plasma Glucose Titration Target on the Success of Basal Insulin Titration in Insulin-Naïve Patients with Type 2 Diabetes: A Systematic Analysis. J Diabetes Res 2022; 2022:4758042. [PMID: 35942330 PMCID: PMC9356801 DOI: 10.1155/2022/4758042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 07/01/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND/AIM We aimed to examine beneficial and adverse outcomes of basal insulin titration performed with different fasting plasma glucose (FPG) titration targets (TT). METHODS A PubMed literature search retrieved 43 reported prospective clinical trials introducing basal insulin in 17643 insulin-naïve patients with type 2 diabetes reporting fasting plasma glucose (FPG), HbA1c, target achievement, hypoglycemic events, and insulin doses. 61 individual study arms were grouped by fasting plasma glucose titration target (TT; 1: ≤5.0 mmol/l/90 mg/dl; 2: 5.01-5.6 mmol/l/90-100 mg/dl; and 3: ≥5.61 mmol/l/101 mg/dl). Weighted means and their standard deviations were calculated for baseline and end-of-treatment FPG (primary endpoint), HbA1c, target achievement, hypoglycemic events, insulin doses, and body weight gain and compared over a duration of 31 ± 10 weeks. RESULTS Achieved FPG and HbA1c at the end of the study were significantly lower (by up to 0.8 mmol/l or 0.23%, respectively) with more ambitious TTs (p < 0.0001), leading to better HbA1c target achievement with more ambitious TTs (by up to 14.6% for HbA1c ≤ 6.5%), without increasing the risk for hypoglycemic episodes. CONCLUSIONS Aiming for a lower FPG TT improves glycemic control without increasing the risk for hypoglycemia.
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Affiliation(s)
- Jannik Wolters
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Dominik Wollenhaupt
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Mirna Abd El Aziz
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Michael A. Nauck
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
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Lisco G, De Tullio A, Disoteo O, De Geronimo V, Piazzolla G, De Pergola G, Giagulli VA, Jirillo E, Guastamacchia E, Sabbà C, Triggiani V. Basal insulin intensification with GLP-1RA and dual GIP and GLP-1RA in patients with uncontrolled type 2 diabetes mellitus: A rapid review of randomized controlled trials and meta-analysis. Front Endocrinol (Lausanne) 2022; 13:920541. [PMID: 36157450 PMCID: PMC9494570 DOI: 10.3389/fendo.2022.920541] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 08/19/2022] [Indexed: 11/13/2022] Open
Abstract
Tirzepatide, a dual agonist of Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide 1 (GLP-1) receptors, improved glucose control and reduced body weight in different therapeutic approaches. Herein, we overviewed the role of GIP and GLP-1 in the pathophysiology of type 2 diabetes and systematically reviewed the efficacy and safety of injectable incretin-based therapy added to basal insulin in light of the results of the SURPASS-5 trial. We identified eleven randomized clinical trials. GLP-1 receptor agonists (GLP-1RAs) or Tirzepatide added to basal insulin than rigorously titrated basal insulin significantly ameliorates glucose control (Δ HbA1c = -1%, 95% CI -1.25; -0.74, I2 94%; Δ FPG = -14.6 mg/dL, 95% CI -21.6-; -7.6, I2 90%; chance to achieve HbA1c <7% = RR 2.62, 95% CI 2.10; 3.26, I2 89%), reduces body weight (Δ = -3.95 kg, 95% CI -5.1, -2.79, I2 96%) without increasing the risk of hypoglycemia (RR = 1.01, 95% CI 0.86; 1.18, I2 7.7%). Tirzepatide provides an impressive weight loss exceeding that observed with GLP-1RAs. Injectable incretin-based therapy plus basal insulin remains a potent and safe therapeutic approach in uncontrolled type 2 diabetes patients previously treated with basal insulin alone. Tirzepatide is expected to ameliorate the management of "diabesity" in this usually difficult-to-treat cluster of patients.
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Affiliation(s)
- Giuseppe Lisco
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari “Aldo Moro”, School of Medicine, Policlinico, Bari, Italy
| | - Anna De Tullio
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari “Aldo Moro”, School of Medicine, Policlinico, Bari, Italy
| | - Olga Disoteo
- Diabetology Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | | | - Giuseppina Piazzolla
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari “Aldo Moro”, School of Medicine, Policlinico, Bari, Italy
| | - Giovanni De Pergola
- National Institute of Gastroenterology, Saverio de Bellis, Research Hospital, Bari, Italy
| | - Vito Angelo Giagulli
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari “Aldo Moro”, School of Medicine, Policlinico, Bari, Italy
| | - Emilio Jirillo
- Department of Basic Medical Sciences, Neuroscience and Sensory Organs, School of Medicine, University of Bari, Bari, Italy
| | - Edoardo Guastamacchia
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari “Aldo Moro”, School of Medicine, Policlinico, Bari, Italy
| | - Carlo Sabbà
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari “Aldo Moro”, School of Medicine, Policlinico, Bari, Italy
| | - Vincenzo Triggiani
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari “Aldo Moro”, School of Medicine, Policlinico, Bari, Italy
- *Correspondence: Vincenzo Triggiani,
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Abstract
With the concept of patient-centered care in mind, this article outlines the current diabetes medications available for glucose lowering and the characteristics of each of these medications that need to be considered in shared decision-making for durable and effective therapy. Important patient characteristics such as weight, risk for hypoglycemia, cost, social determinants of health, and medical literacy need to be considered. The evidence-base informing the use of antihyperglycemic agents has changed dramatically due to 2008 FDA guidance for cardiovascular safety and cardiorenal protection with antihyperglycemic agents. New evidence supports an approach to diabetes management that addresses pre-existing cardiorenal disease.
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Affiliation(s)
- Layla A Abushamat
- Division of Endocrinology, Metabolism, and Diabetes, University of Colorado School of Medicine, MS 8106, 12801 East 17th Avenue, Room 7103, Aurora, CO 80045, USA.
| | - Jane E B Reusch
- Division of Endocrinology, Metabolism, and Diabetes, University of Colorado School of Medicine, MS 8106, 12801 East 17th Avenue, Room 7103, Aurora, CO 80045, USA; Ludeman Family Center for Women's Health Research, 12348 East Montview Boulevard, Mail Stop C-263, Aurora, CO 80045 USA; Rocky Mountain Regional Veteran Affairs Medical Center, 1700 North Wheeling Street, Aurora, CO 80045, USA
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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] [Scholar 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.
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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
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Feng W, Wang W, Meng R, Wu G, Zhang M, Zhang X, Yin H, Zhu D. Lixisenatide is effective and safe as add-on treatment to basal insulin in Asian individuals with type 2 diabetes and different body mass indices: a pooled analysis of data from the GetGoal Studies. BMJ Open Diabetes Res Care 2021; 9:e002290. [PMID: 34452904 PMCID: PMC8404431 DOI: 10.1136/bmjdrc-2021-002290] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 07/17/2021] [Indexed: 11/10/2022] Open
Abstract
INTRODUCTION This analysis aims to investigate the efficacy and safety of once-daily lixisenatide add-on treatment to basal insulin in Asian individuals with type 2 diabetes, by baseline body mass index (BMI). RESEARCH DESIGN AND METHODS Data from all Asian participants in the placebo-controlled GetGoal-Duo 1, GetGoal-L, and GetGoal-L-C Studies were pooled and categorized according to the following BMI subgroups:<25 kg/m2, 25-<30 kg/m2 and ≥30 kg/m2. Efficacy and safety of lixisenatide versus placebo were evaluated among BMI subgroups. Multivariable regression analyses were also conducted to explore the potential influence of BMI on efficacy outcomes after adjusting for baseline characteristics. RESULTS 555 participants were included (mean age 53.9 years, 52.4% men). No significant differences in treatment effect between the BMI subgroups were observed for the changes from baseline to 24 weeks in glycated hemoglobin (HbA1c), fasting plasma glucose, postprandial glucose (PPG), PPG excursion, body weight, BMI, and basal insulin dose with lixisenatide, as well as the change in basal insulin dose at study endpoint and the proportion of participants achieving an HbA1c <7% at 24 weeks (all p values for interaction >0.15). In the multivariable regression analysis, participants in the lowest BMI group had a smaller reduction in body weight over the 24-week treatment period relative to the highest BMI group (p=0.023). CONCLUSIONS This post hoc analysis indicates that lixisenatide improved glycemic control regardless of baseline BMI and was well tolerated in Asian individuals unable to achieve their HbA1c target on basal insulin±oral antidiabetic drugs.
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Affiliation(s)
- Wenhuan Feng
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Weimin Wang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Ran Meng
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Guangyu Wu
- Department of Medical Affair, Sanofi, Shanghai, China
| | - Minlu Zhang
- Department of Medical Affair, Sanofi, Shanghai, China
| | - Xia Zhang
- Department of Medical Affair, Sanofi, Shanghai, China
| | - Huiqiu Yin
- Department of Medical Affair, Sanofi, Shanghai, China
| | - Dalong Zhu
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
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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: 145] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar 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.
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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
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20
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Chubb B, Gupta P, Gupta J, Nuhoho S, Kallenbach K, Orme M. Once-Daily Oral Semaglutide Versus Injectable GLP-1 RAs in People with Type 2 Diabetes Inadequately Controlled on Basal Insulin: Systematic Review and Network Meta-analysis. Diabetes Ther 2021; 12:1325-1339. [PMID: 33723769 PMCID: PMC8099977 DOI: 10.1007/s13300-021-01034-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 02/13/2021] [Indexed: 01/15/2023] Open
Abstract
INTRODUCTION The relative efficacy and safety of once-daily oral semaglutide vs. injectable glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in subjects with type 2 diabetes (T2D) inadequately controlled on basal insulin were assessed using network meta-analysis (NMA). METHODS A systematic literature review (SLR) was performed to identify randomised controlled trials of GLP-1 RAs in this population. Data at 26 ± 4 weeks were extracted for efficacy and safety outcomes feasible for the NMA: change from baseline in glycated haemoglobin (HbA1c), weight and blood pressure; HbA1c target levels (< 7.0% and ≤ 6.5%); composite endpoint; incidence of nausea, vomiting or diarrhoea. Comparators of interest were all licensed doses of dulaglutide, exenatide, liraglutide, lixisenatide and once-weekly injectable semaglutide. RESULTS The NMA included seven trials. Once-daily oral semaglutide 14 mg was associated with significantly greater HbA1c reductions vs. most comparators (treatment differences: - 0.42 to - 1.32%); differences vs. once-weekly injectable semaglutide (0.5 mg and 1 mg doses) were not statistically significant. Once-daily oral semaglutide 14 mg was associated with significantly greater weight reductions vs. exenatide 2 mg and lixisenatide 20 μg (- 2.21 and - 2.39 kg respectively); non-statistically significant weight reductions in favour of once-daily oral semaglutide 14 mg were observed vs. all other comparators except once-weekly injectable semaglutide 1 mg. Similar trends were observed for the proportion of subjects achieving HbA1c < 7.0% and ≤ 6.5% and the composite endpoint. Once-daily oral semaglutide 14 mg was associated with similar odds of experiencing nausea, vomiting or diarrhoea vs. all comparators. CONCLUSION Once-daily oral semaglutide 14 mg, as an add-on to basal insulin, is an efficacious treatment for reducing HbA1c and weight and meeting glycaemic targets at 26 ± 4 weeks. Once-daily oral semaglutide 14 mg also offers the option of an oral treatment with similar or better efficacy and similar tolerability vs. most injectable GLP-1 RAs.
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Affiliation(s)
| | - Palvi Gupta
- DRG Abacus Part of Clarivate, Bangalore, India
| | - Jatin Gupta
- DRG Abacus Part of Clarivate, Gurgaon, India
| | | | | | - Michelle Orme
- ICERA Consulting, UK on behalf of DRG Abacus Part of Clarivate, Swindon, UK
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Skolnik N, Del Prato S, Blonde L, Galstyan G, Rosenstock J. Translating iGlarLixi Evidence for the Management of Frequent Clinical Scenarios in Type 2 Diabetes. Adv Ther 2021; 38:1715-1731. [PMID: 33620694 PMCID: PMC8004501 DOI: 10.1007/s12325-020-01614-5] [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] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 12/19/2020] [Indexed: 12/15/2022]
Abstract
Treatment of type 2 diabetes (T2D) requires progressive therapy intensification to reach and maintain individualized glycemic targets. iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL (iGlar) and lixisenatide (Lixi), has been shown to provide robust HbA1c reductions allowing more people to reach HbA1c targets compared with separate administration of iGlar or Lixi. The purpose of this review is to help clinicians understand treatment intensification using iGlarLixi by presenting typical clinical scenarios supported by research evidence. These cases will focus on individuals with T2D inadequately controlled by oral antihyperglycemic drugs, basal insulin, or glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and take into consideration T2D duration, body mass index, incidence of adverse events, and regimen simplicity. Clinical evidence on the efficacy, effectiveness, and safety of iGlarLixi from randomized controlled trials and real-world studies will be discussed in the context of these cases.
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Affiliation(s)
- Neil Skolnik
- Sidney Kimmel Medical College, Thomas Jefferson University, Abington Jefferson Health, Abington, PA, USA.
- Abington Hospital-Jefferson Health, Abington, PA, USA.
| | - Stefano Del Prato
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Lawrence Blonde
- Department of Endocrinology, Ochsner Medical Center, Frank Riddick Diabetes Institute, New Orleans, LA, USA
| | - Gagik Galstyan
- Diabetic Foot Department, Endocrinology Research Center, Moscow, Russia
| | - Julio Rosenstock
- Dallas Diabetes Research Center at Medical City, Dallas, TX, USA
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Gautier T, Umpierrez G, Renard E, Kovatchev B. The Differential and Combined Action of Insulin Glargine and Lixisenatide on the Fasting and Postprandial Components of Glucose Control. J Diabetes Sci Technol 2021; 15:371-376. [PMID: 31810389 PMCID: PMC8256059 DOI: 10.1177/1932296819891170] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND iGlarLixi is an injectable combination of long acting insulin glargine (iGlar) and glucagon-like peptide 1 receptor agonist lixisenatide in a fixed ratio, which was proven safe and effective for the treatment of type 2 diabetes. Lixisenatide and iGlar act differently on fasting and postprandial plasma glucose (fasting plasma glucose [FPG] and postprandial glucose [PPG]). Here, we deconstruct quantitatively their respective FPG and PPG effects. METHOD This post hoc study analyzes data from the Lixilan-O trial, where 1170 subjects with type 2 diabetes were randomly assigned to 30 weeks of once daily injections of lixisenatide, iGlar, and iGlarLixi (1:2:2). The FPG and PPG components of glucose control were assessed in terms of mean glucose (fasting mean plasma glucose [FMPG] and prandial mean plasma glucose [PMPG], respectively). The MPGP was computed across all meals as a delta between post- and premeal glucose; glucose variability was measured by the high blood glucose index (HBGI) (fasting HBGI and prandial HBGI [PHBGI], respectively), and glycemic exposure measured by area under the curve (AUC) computed overall. All metrics were derived from seven-point self-monitoring glucose profiles. RESULTS Insulin glargine lowered significantly FMPG by 15.3 mg/dL (P < .01) without any significant change in PMPG. Lixisenatide, when added to iGlar, reduced PMPG by 9.7 mg/dL (P < .01), AUC by 96.3 mg∙h/dL (P < .01), and PHBGI by 2.4 (P < .01), primarily due to attenuation of PPG and without significant change in mean FPG. CONCLUSION Insulin glargine and lixisenatide act selectively on FPG and PPG. Their combination iGlarLixi offers more effective glucose control than its components due to the cumulative effect on FPG and PPG, which is evidenced by reduced average glycemia, glycemic exposure, and glucose variability.
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Affiliation(s)
- Thibault Gautier
- Center for Diabetes Technology,
University of Virginia, Charlottesville, VA, USA
| | - Guillermo Umpierrez
- Emory University School of Medicine,
Division of Endocrinology, Metabolism, Atlanta, GA, USA
| | - Eric Renard
- Department of Endocrinology, Diabetes,
Nutrition, Montpellier University Hospital, France
- Institute of Functional Genomics, CNRS,
INSERM, University of Montpellier, France
| | - Boris Kovatchev
- Center for Diabetes Technology,
University of Virginia, Charlottesville, VA, USA
- Boris Kovatchev, Center for Diabetes
Technology, University of Virginia, 560 Ray C Hunt Dr, Charlottesville, VA
22903, USA.
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Giorgino F, Caruso I, Napoli R. Titratable fixed-ratio combination of insulin glargine plus lixisenatide: A simplified approach to glycemic control in type 2 diabetes mellitus. Diabetes Res Clin Pract 2020; 170:108478. [PMID: 33002548 DOI: 10.1016/j.diabres.2020.108478] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 09/11/2020] [Accepted: 09/20/2020] [Indexed: 12/17/2022]
Abstract
Approximately 50% of patients with type 2 diabetes mellitus (T2DM) do not achieve glycemic targets and require treatment intensification. A fixed-ratio combination of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with basal insulin, such as lixisenatide with insulin glargine (iGlarLixi), exploits the complementary mechanisms of action of each component to address hyperglycemia while mitigating potential adverse events (AEs). The iGlarLixi dose is titrated considering the effect of basal insulin on fasting plasma glucose, and the fixed-ratio combination ensures that the lixisenatide dose never exceeds 20 μg/day. We describe the characteristics of iGlarLixi therapy, based on the LixiLan clinical program, and provide guidance on the characteristics of patients likely to benefit from such treatment in routine clinical practice. In the phase III LixiLan trials, iGlarLixi resulted in significantly greater reductions in glycated hemoglobin (HbA1c), better achievement of HbA1c targets, less glycemic variability versus insulin glargine, lixisenatide or GLP-1 RA alone, and was associated with weight control, less hypoglycemia versus insulin glargine, and fewer GI AEs versus lixisenatide. Findings were consistent regardless of age, diabetes duration, and baseline HbA1c. The efficacy, safety, and convenient once-daily administration schedule of iGlarLixi make it a valuable treatment option for patients with T2DM requiring treatment intensification.
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Affiliation(s)
- Francesco Giorgino
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Piazza Umberto I, 1, 70121 Bari BA, Italy.
| | - Irene Caruso
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Piazza Umberto I, 1, 70121 Bari BA, Italy
| | - Raffaele Napoli
- Department of Translational Medical Sciences, Federico II University School of Medicine, Via Sergio Pansini, 5, 80131 Napoli NA, Italy.
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Lin C, Cai X, Yang W, Lv F, Nie L, Ji L. Age, sex, disease severity, and disease duration difference in placebo response: implications from a meta-analysis of diabetes mellitus. BMC Med 2020; 18:322. [PMID: 33190640 PMCID: PMC7667845 DOI: 10.1186/s12916-020-01787-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 09/17/2020] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND The placebo response in patients with diabetes mellitus is very common. A systematic evaluation needs to be updated with the current evidence about the placebo response in diabetes mellitus and the associated factors in clinical trials of anti-diabetic medicine. METHODS Literature research was conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for studies published between the date of inception and June 2019. Randomized placebo-controlled trials conducted in type 1and type 2 diabetes mellitus (T1DM/T2DM) were included. Random-effects model and meta-regression analysis were accordingly used. This meta-analysis was registered in PROSPERO as CRD42014009373. RESULTS Significantly weight elevation (effect size (ES) = 0.33 kg, 95% CI, 0.03 to 0.61 kg) was observed in patients with placebo treatments in T1DM subgroup while significantly HbA1c reduction (ES = - 0.12%, 95% CI, - 0.16 to - 0.07%) and weight reduction (ES = - 0.40 kg, 95% CI, - 0.50 to - 0.29 kg) were observed in patients with placebo treatments in T2DM subgroup. Greater HbA1c reduction was observed in patients with injectable placebo treatments (ES = - 0.22%, 95% CI, - 0.32 to - 0.11%) versus oral types (ES = - 0.09%, 95% CI, - 0.14 to - 0.04%) in T2DM (P = 0.03). Older age (β = - 0.01, 95% CI, - 0.02 to - 0.01, P < 0.01) and longer diabetes duration (β = - 0.02, 95% CI, - 0.03 to - 0.21 × 10-2, P = 0.03) was significantly associated with more HbA1c reduction by placebo in T1DM. However, younger age (β = 0.02, 95% CI, 0.01 to 0.03, P = 0.01), lower male percentage (β = 0.01, 95% CI, 0.22 × 10-2, 0.01, P < 0.01), higher baseline BMI (β = - 0.02, 95% CI, - 0.04 to - 0.26 × 10-2, P = 0.02), and higher baseline HbA1c (β = - 0.09, 95% CI, - 0.16 to - 0.01, P = 0.02) were significantly associated with more HbA1c reduction by placebo in T2DM. Shorter diabetes duration (β = 0.06, 95% CI, 0.06 to 0.10, P < 0.01) was significantly associated with more weight reduction by placebo in T2DM. However, the associations between baseline BMI, baseline HbA1c, and placebo response were insignificant after the adjusted analyses. CONCLUSION The placebo response in diabetes mellitus was systematically outlined. Age, sex, disease severity (indirectly reflected by baseline BMI and baseline HbA1c), and disease duration were associated with placebo response in diabetes mellitus. The association between baseline BMI, baseline HbA1c, and placebo response may be the result of regression to the mean.
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Affiliation(s)
- Chu Lin
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
| | - Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Lin Nie
- Department of Endocrinology and Metabolism, Beijing Airport Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
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25
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Huthmacher JA, Meier JJ, Nauck MA. Efficacy and Safety of Short- and Long-Acting Glucagon-Like Peptide 1 Receptor Agonists on a Background of Basal Insulin in Type 2 Diabetes: A Meta-analysis. Diabetes Care 2020; 43:2303-2312. [PMID: 32910778 DOI: 10.2337/dc20-0498] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 05/03/2020] [Indexed: 02/03/2023]
Abstract
PURPOSE To compare the efficacy and safety of short- and long-acting glucagon-like peptide 1 receptor agonists (GLP-1 RAs), both used in combination with basal insulin, in patients with type 2 diabetes. DATA SOURCES AND STUDY SELECTION Randomized controlled trials comparing the coadministration of short- or long-acting GLP-1 RAs and basal insulin with basal insulin ± placebo were identified (PubMed search). Of 974 identified publications, 14 clinical trials were included. Eight trials examined short-acting and six long-acting GLP-1 RAs. DATA EXTRACTION AND DATA SYNTHESIS Differences in HbA1c, fasting plasma glucose, body weight, and adverse events were compared between studies using short- or long-acting GLP-1 RAs by random-effects meta-analysis. LIMITATIONS There were relatively small numbers of available publications, some heterogeneity regarding protocols, and differences in the GLP-1 RA compound used. CONCLUSIONS Long-acting GLP-1 RAs more effectively reduced HbA1c (∆ -6 mmol/mol [95% CI -10; -2], P = 0.007), fasting plasma glucose (∆ -0.7 mmol/L [-1.2; -0.3], P = 0.007), and body weight (∆ -1.4 kg [-2.2; -0.6], P = 0.002) and raised the proportion of patients achieving an HbA1c target <7.0% (<53 mmol/mol) (P = 0.03) more than the short-acting ones. Patients reporting symptomatic (P = 0.048) but not severe (P = 0.96) hypoglycemia were fewer with long- versus short-acting GLP-1 RAs added to insulin. A lower proportion of patients reported nausea (-52%, P < 0.0001) or vomiting (-36%, P = 0.0002) with long-acting GLP-1 RAs. Overall, GLP-1 RAs improved HbA1c, fasting plasma glucose, and body weight when added to basal insulin. However, long-acting GLP-1 RAs were significantly more effective for glycemic and body weight control and displayed better gastrointestinal tolerability.
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Affiliation(s)
- Jessica A Huthmacher
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Juris J Meier
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Michael A Nauck
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
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26
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Deerochanawong C, Leelawattana R, Kosachunhanun N, Tantiwong P. Basal Insulin Dose Titration for Glycemic Control in Patients With Type 2 Diabetes Mellitus in Thailand: Results of the REWARDS Real-World Study. CLINICAL MEDICINE INSIGHTS-ENDOCRINOLOGY AND DIABETES 2020; 13:1179551420935930. [PMID: 32774082 PMCID: PMC7391425 DOI: 10.1177/1179551420935930] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 05/22/2020] [Indexed: 12/20/2022]
Abstract
This multicenter, longitudinal, descriptive, observational study of T2DM adults in Thailand aimed to assess real-world outcomes of basal insulin (BI) dose titration on glycemic control. Three-hundred and twenty-four patients were recruited and followed up over 24 weeks. Basal insulin titration was physician-driven in 58.2% of patients and patient-driven in the rest. During the 24-week study period, the total daily BI dose moved from 20.9 to 25.6 in the physician-driven group, while in the patient-driven group, it increased from 25.3 to 29.7. Thirty-five patients (11.2%) achieved their individualized HbA1c targets, with 18 patients (5.8%) achieving HbA1c ⩽ 7% without documented hypoglycemia. In summary, this study highlights that BI titration is suboptimal in the real world, and patients are unable to achieve their glycemic targets.
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Affiliation(s)
- Chaicharn Deerochanawong
- Diabetes and Endocrinology Unit, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Krung Thep Maha Nakhon, Thailand
| | - Rattana Leelawattana
- Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Prince of Songkla University Hospital, Hat Yai, Thailand
| | - Natapong Kosachunhanun
- Division of Endocrinology, Department of Medicine, Maharaj Nakorn Chiang Mai Hospital, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Puntip Tantiwong
- Department of Medicine, Maharat Nakhon Ratchasima Hospital, Nakhon Ratchasima, Thailand
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Muzurović E, Dragnić S, Medenica S, Smolović B, Bulajić P, Mikhailidis DP. Weight-centric pharmacological management of type 2 diabetes mellitus - An essential component of cardiovascular disease prevention. J Diabetes Complications 2020; 34:107619. [PMID: 32499116 DOI: 10.1016/j.jdiacomp.2020.107619] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 04/26/2020] [Accepted: 05/06/2020] [Indexed: 12/19/2022]
Abstract
Obesity and overweight are contributing factors for diseases such as type 2 diabetes mellitus (T2DM), hypertension, hyperlipidemia, and ultimately, cardiovascular (CV) disease. Obesity is imposing an increasing health burden in rich and poor nations, with almost 30% of people globally now either obese or overweight - a staggering 2.1 billion. The link between obesity and T2DM is widely held to involve two adverse effects: obesity-induced insulin resistance and β-cell failure. This "unified field theory" raises questions about whether defects favoring progressive weight gain and metabolic impairment also contribute to β-cell decompensation. The concept of weight-centric management of T2DM is considered justified because of the strong negative impact of obesity on the effects of treatment of diabetes. Two pharmacotherapy options are considered: drugs developed primarily for blood glucose control that also exert a favorable effect on body weight and drugs developed primarily to induce weight loss that also have a favorable effect on glycemia. Treating hunger counter-regulatory mechanisms will have an additional effect on glucose control in T2DM. This narrative review addresses advances in pharmacotherapy for the management of obesity and obesity-related co-morbidities, with a focus on T2DM. It is also important to identify the correct balance between weight-centric and glucose-centric management of T2DM.
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Affiliation(s)
- Emir Muzurović
- Department of Internal Medicine, Endocrinology Section, Clinical Center of Montenegro, Ljubljanska bb, 81000 Podgorica, Montenegro; Faculty of Medicine, University of Montenegro, Kruševac bb, 81000, Podgorica, Montenegro.
| | - Siniša Dragnić
- Faculty of Medicine, University of Montenegro, Kruševac bb, 81000, Podgorica, Montenegro
| | - Sanja Medenica
- Department of Internal Medicine, Endocrinology Section, Clinical Center of Montenegro, Ljubljanska bb, 81000 Podgorica, Montenegro; Faculty of Medicine, University of Montenegro, Kruševac bb, 81000, Podgorica, Montenegro
| | - Brigita Smolović
- Faculty of Medicine, University of Montenegro, Kruševac bb, 81000, Podgorica, Montenegro
| | - Predrag Bulajić
- Department of Internal Medicine, Endocrinology Section, Clinical Center of Montenegro, Ljubljanska bb, 81000 Podgorica, Montenegro
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), Pond Street, London NW3 2QG, UK
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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] [Scholar 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.
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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
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Egede LE, Bogdanov A, Fischer L, Da Rocha Fernandes JD, Kallenbach L. Glycemic Control Among Patients Newly Prescribed IDegLira Across Prior Therapy Group in US Real-World Practice. Diabetes Ther 2020; 11:1579-1589. [PMID: 32506223 PMCID: PMC7324461 DOI: 10.1007/s13300-020-00850-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Indexed: 01/22/2023] Open
Abstract
INTRODUCTION IDegLira is a fixed-ratio combination of insulin degludec and liraglutide indicated for the treatment of type 2 diabetes (T2D). We report the first real-world study describing change in glycated hemoglobin (HbA1c) among US patients who initiated IDegLira. The aim of the study was to observe and describe changes in glycemic control and weight in patients initiating IDegLira in real-world clinical practice. METHODS Patients in the Practice Fusion electronic medical record database who initiated treatment with IDegLira between March 2017 and June 2018 were identified (n = 1384). To be included in the analyses, the study population needed to meet age, time in database pre- and post-initiation, and availability of HbA1c data at baseline and follow-up requirements. Data were analyzed according to baseline therapy subgroups and whether patients were intensifying (primary analysis group) or simplifying (secondary analysis group) their diabetes treatment. Changes in clinical outcomes from baseline were evaluated by paired t tests and linear regression. RESULTS The overall study population comprised 296 patients, of whom 206 were included in the primary analysis group and 90 were included in the secondary analysis group. In the adjusted analyses, there was a reduction in HbA1c of - 1.1% in the primary analysis group, with the HbA1c reduction in all prior therapy groups ranging from - 0.8% for those previously on basal insulin to - 1.0% for those previously on non-injectable therapy (p < 0.0001 for all). In a similar adjusted analysis, there was a statistically significant but small (1.0 lb/0.45 kg) change in weight in the primary analysis group. In the secondary analysis, patients previously on more than one injection daily switched to a more simplified therapy without compromising on glycemic control (HbA1c change of - 0.16%). CONCLUSION Consistent with previous real-world studies, IDegLira lowered HbA1c across different background prior glucose-lowering therapies, with minimal impact on weight.
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Meier JJ, Menge BA, Schenker N, Erdmann S, Kahle-Stephan M, Schliess F, Kapitza C, Nauck MA. Effects of sequential treatment with lixisenatide, insulin glargine, or their combination on meal-related glycaemic excursions, insulin and glucagon secretion, and gastric emptying in patients with type 2 diabetes. Diabetes Obes Metab 2020; 22:599-611. [PMID: 31793165 DOI: 10.1111/dom.13935] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/19/2019] [Accepted: 11/27/2019] [Indexed: 12/13/2022]
Abstract
AIM To examine the glucose-lowering mechanisms of the glucagon-like peptide-1 receptor agonist lixisenatide after two subsequent meals and in combination with basal insulin. MATERIALS AND METHODS Twenty-eight metformin-treated patients with type 2 diabetes were randomly assigned to treatment sequences with either lixisenatide or insulin glargine alone for 4 weeks, and a combination of both treatments for 4 weeks. Metabolic examinations were performed before and after each treatment period following breakfast and a late lunch 8 hours later. RESULTS Lixisenatide mainly reduced postprandial glycaemia, while insulin glargine mainly reduced fasting glucose after breakfast (P < 0.05). This was partially preserved after a late lunch (P < 0.05). After breakfast, lixisenatide reduced insulin secretion and glucagon levels significantly. These effects were lost after a late lunch. Insulin glargine did not significantly reduce glucagon or insulin secretion. Gastric emptying was slowed by lixisenatide, but not by insulin glargine after breakfast. After the late lunch, lixisenatide slightly accelerated gastric emptying. CONCLUSIONS Lixisenatide decelerates gastric emptying after breakfast, thereby reducing glycaemic excursions, insulin secretion and glucagon levels. The glycaemic reduction persists until after a late lunch, despite accelerated gastric emptying. The combination with insulin glargine enhances the glucose-lowering effect because of complementary modes of action.
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Affiliation(s)
- Juris J Meier
- Diabetes Center Bochum-Hattingen, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Björn A Menge
- Diabetes Center Bochum-Hattingen, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Nina Schenker
- Diabetes Center Bochum-Hattingen, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Silke Erdmann
- Diabetes Center Bochum-Hattingen, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Melanie Kahle-Stephan
- Diabetes Center Bochum-Hattingen, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | | | | | - Michael A Nauck
- Diabetes Center Bochum-Hattingen, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
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Davidson JA, Stager W, Paranjape S, Berria R, Leiter LA. Achieving postprandial glucose control with lixisenatide improves glycemic control in patients with type 2 diabetes on basal insulin: a post-hoc analysis of pooled data. Clin Diabetes Endocrinol 2020; 6:2. [PMID: 31956422 PMCID: PMC6961286 DOI: 10.1186/s40842-019-0088-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 08/12/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND To examine the impact on glycemic control of achieving postprandial glucose (PPG) target with lixisenatide, a once-daily glucagon-like peptide-1 receptor agonist approved in the US, in patients with uncontrolled type 2 diabetes (T2D) on basal insulin, an agent that primarily targets fasting plasma glucose. METHODS A post hoc pooled analysis was conducted using clinical trial data extracted from the intent-to-treat subpopulation of patients with T2D who participated in the 24-week, phase 3, randomized, double-blind, placebo-controlled, 2-arm parallel-group, multicenter GetGoal-L (NCT00715624), GetGoal-Duo 1 (NCT00975286) and GetGoal-L Asia trials (NCT00866658). RESULTS Data from 587 lixisenatide-treated patients and 484 placebo-treated patients were included. Patients on lixisenatide were more likely to achieve a PPG target of < 10 mmol/L (< 180 mg/dL) than placebo-treated patients (P < 0.001), regardless of baseline fasting plasma glucose (FPG) levels. More importantly, those who reached the PPG target experienced a significantly greater reduction in mean HbA1c, were more likely to achieve HbA1c target of < 53 mmol/mol (< 7.0%), and experienced weight loss. Those outcomes were achieved with no significant differences in the risk of symptomatic hypoglycemia compared with placebo. CONCLUSION Compared with placebo, addition of lixisenatide to basal insulin improved HbA1c and reduced PPG, without increasing hypoglycemia risk. These findings highlight the importance of PPG control in the management of T2D, and provide evidence that adding an agent to basal insulin therapy that also impacts PPG has therapeutic value for patients who are not meeting glycemic targets. TRIAL REGISTRATION NCT00715624. Registered 15 July 2008, NCT00975286. Registered 11 September 2009, NCT00866658. Registered 20 March 2009.
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Affiliation(s)
- Jaime A. Davidson
- Department of Internal Medicine, Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, K5.246, Dallas, TX 75390-8549 USA
| | | | | | | | - Lawrence A. Leiter
- Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto, Toronto, ON Canada
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Handelsman Y, Muskiet MHA, Meneilly GS. Combining GLP-1 Receptor Agonists and Basal Insulin in Older Adults with Type 2 Diabetes: Focus on Lixisenatide and Insulin Glargine. Adv Ther 2019; 36:3321-3339. [PMID: 31646466 PMCID: PMC6860469 DOI: 10.1007/s12325-019-01126-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Indexed: 12/14/2022]
Abstract
Estimates suggest that there are currently 122.8 million adults 65-99 years of age living with diabetes, of whom 90-95% are diagnosed with type 2 diabetes (T2D). Over the past two decades, a greater understanding of the complex and multifactorial pathogenesis of T2D has resulted in the development and introduction of new-generation classes of glucose-lowering therapies, which are now extensively endorsed by prevailing guidelines and are increasingly being used worldwide. These newer agents may further assist in the effective pharmacological management of T2D through the provision of patient-centered care that acknowledges multimorbidity and is respectful of and responsive to individual patient preferences and barriers. Given these considerations, the therapeutic approach in older patients with T2D is complex, particularly in those who have functional dependence, frailty, dementia, or who are at end-of-life. It is currently too early to draw conclusions on the long-term use of newer glucose-lowering agents in this population, as their efficacy and safety in older adults remains largely unknown. In this review, we will discuss considerations for the use of glucose-lowering treatments in older adults, with particular focus on the use of basal insulin and glucagon-like peptide-1 receptor agonists, and the rationale for the use of combination therapy comprising these agents. Finally, we will review clinical data from studies of the fixed-ratio combination of insulin glargine and lixisenatide in older patients with T2D. FUNDING: Sanofi US, Inc.
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Affiliation(s)
- Yehuda Handelsman
- Metabolic Institute of America, 18372 Clark St. Suite 212, Tarzana, CA, 91356, USA.
| | - Marcel H A Muskiet
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers (Location VUMC), 1081 HV, Amsterdam, The Netherlands
| | - Graydon S Meneilly
- Department of Medicine, The University of British Columbia, 2775 Laurel Street, Vancouver, BC, V5Z1M9, Canada
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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: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [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.
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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
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Maiorino MI, Chiodini P, Bellastella G, Scappaticcio L, Longo M, Giugliano D, Esposito K. The good companions: insulin and glucagon-like peptide-1 receptor agonist in type 2 diabetes. A systematic review and meta-analysis of randomized controlled trials. Diabetes Res Clin Pract 2019; 154:101-115. [PMID: 31238059 DOI: 10.1016/j.diabres.2019.06.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 06/13/2019] [Accepted: 06/17/2019] [Indexed: 12/12/2022]
Abstract
We provided an updated systematic review with meta-analysis of randomized controlled trials (RCTs) assessing the metabolic effects of combination therapy of insulin and GLP-1RA (combo) in comparison with other injectable therapy. We searched PubMed, Cochrane Register of Controlled Trials, Scholar, and ClinicalTrials.gov for RCTs evaluating changes in HbA1c (primary outcome), proportion of patients at HbA1c target <7%, hypoglycaemia, and weight change (secondary end-points). We included 36 RCTs involving 14,636 patients. Compared with comparator therapies (overall analysis), the combo led to a significant HbA1c reduction (=-0.49%, 95% CI -0.61 to -0.38%, P < 0.001), more patients at HbA1c target [relative risk, (RR) = 1.77, 95% CI, 1.56, 2.01, P < 0.001], similar hypoglycaemic events (RR = 1.03, 95% CI, 0.88, 1.19, P = 0.728), and reduction in body weight (-2.5 Kg, 95% CI -3.1 to -1.8 kg, P < 0.001), with high heterogeneity in each analysis. The quality of the evidence was low for three of the considered outcomes. Compared with intensified insulin regimens (basal-plus/basal-bolus) the combo produced similar glycemic control with reduction of both hypoglycaemia, and body weight. Combination therapy of GLP-1RA and insulin could represent a valuable treatment strategy to improve glycemic control in the management of type 2 diabetes.
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Affiliation(s)
- Maria Ida Maiorino
- Unit of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples 80138, Italy.
| | - Paolo Chiodini
- Medical Statistics Unit, University of Campania "Luigi Vanvitelli", Naples 80138, Italy.
| | - Giuseppe Bellastella
- Unit of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples 80138, Italy.
| | - Lorenzo Scappaticcio
- Unit of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples 80138, Italy.
| | - Miriam Longo
- Unit of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples 80138, Italy.
| | - Dario Giugliano
- Unit of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples 80138, Italy.
| | - Katherine Esposito
- Diabetes Unit, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples 80138, Italy.
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Hershon KS, Hirsch BR, Odugbesan O. Importance of Postprandial Glucose in Relation to A1C and Cardiovascular Disease. Clin Diabetes 2019; 37:250-259. [PMID: 31371856 PMCID: PMC6640888 DOI: 10.2337/cd18-0040] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
IN BRIEF This article reviews the evidence regarding the impact of postprandial glucose (PPG) on overall A1C and its relation to cardiovascular disease (CVD). To date, four randomized, controlled trials have evaluated the impact of PPG reduction on CVD; however, only one of these successfully demonstrated a positive effect. Despite this, epidemiological evidence does indicate a cardiovascular benefit of PPG reduction, and agents that can be used to manage PPG in people with type 2 diabetes are also discussed.
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Affiliation(s)
| | | | - Ola Odugbesan
- North Atlanta Endocrinology and Diabetes, Lawrenceville, GA
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Brath H, Abrahamian H, Karuza T, Mihaljevic R, Pfohl M. Austrian Experience with Lixisenatide Under Real-Life Conditions: A Prospective Observational Study. Diabetes Ther 2019; 10:451-462. [PMID: 30656523 PMCID: PMC6437236 DOI: 10.1007/s13300-018-0558-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Lixisenatide has been studied extensively in randomized clinical trials; however, data on its use in the real-life practice are scarce. METHODS This study was a prospective, 26-week, multicenter, observational study conducted in Austrian diabetes centers and office-based practices to evaluate efficacy and safety of lixisenatide under real-life conditions in patients with type 2 diabetes. RESULTS Out of 144 patients (mean BMI 36.4 kg/m2, disease duration 12.4 years), 113 completed the documentation at 6 months and 42% received basal insulin with or without oral antidiabetic drugs. The HbA1c declined from 8.7% (72 mmol/mol) to 7.9% (63 mmol/mol) and at study end 24.8% of the patients reached an HbA1c level below 7%. Fasting and postprandial glucose after lixisenatide administration were reduced by 27 ± 58 mg/dl and 45 ± 67 mg/dl, respectively. At study end body weight (- 4.5 ± 5.4 kg), triglycerides (- 10.8 ± 105 mg/dl), systolic blood pressure (- 4.8 ± 17.1 mmHg), and LDL cholesterol (- 3.7 ± 25 mg/dl) were reduced. The most commonly reported adverse events were gastrointestinal disorders (18.8%). Forty-three patients (30%) discontinued prematurely, mostly caused by lack of efficacy, occurrence of gastrointestinal disorders, and missing reimbursement. The average dose of insulin decreased slightly by 1.5 units (from 29.4 to 27.9). CONCLUSION Lixisenatide demonstrated a similar efficacy and safety profile under real-life conditions as previously shown in randomized clinical trials. FUNDING sanofi-aventis GmbH Austria.
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Affiliation(s)
- Helmut Brath
- Diabetes Outpatient Clinic, Health Centre South, 1100, Vienna, Austria.
| | - Heidemarie Abrahamian
- Sozialmedizinisches Zentrum Baumgartner Höhe Otto-Wagner-Spital, 1140, Vienna, Austria
| | | | | | - Martin Pfohl
- Ev. Krankenhaus Bethesda, 47053, Duisburg, Germany
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Pablo Frias J, Lorenz M, Roberts M, Dex T, Schmider W, Hurst W, Skolnik N. Impact of lixisenatide dose range on clinical outcomes with fixed-ratio combination iGlarLixi in patients with type 2 diabetes. Curr Med Res Opin 2019; 35:689-695. [PMID: 30360647 DOI: 10.1080/03007995.2018.1541316] [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] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To evaluate the lixisenatide dose range delivered by the iGlarLixi SoloSTAR pen (5-20 µg), alone or in fixed-ratio combination with insulin glargine (iGlar; iGlarLixi). METHODS Data from three clinical studies were analyzed to assess lixisenatide efficacy and safety: a phase 2a trial assessing gastric emptying effects (ACT6011); a phase 2b dose-ranging trial (DRI6012); and a randomized controlled phase 3 trial comparing iGlarLixi with its components of iGlar and lixisenatide (LixiLan-O). Efficacy metrics included glycated hemoglobin A1c (A1C), post-prandial glucose (PPG) values following a standardized breakfast, fasting plasma glucose (FPG), and weight change. Occurrence of gastrointestinal adverse events was also assessed. RESULTS ACT6011: lixisenatide doses from 5-20 μg once daily (QD) suppressed PPG; maximal reductions in mean PPG area under the curve were achieved with doses ≥12.5 µg QD, but doses as low as 5 μg achieved 44% of maximal reduction. DRI6012: lixisenatide doses 5-20 μg QD resulted in significant, dose-dependent decreases in A1C, percentage of patients achieving A1C <7.0%, and 2-h PPG levels; doses of 20 μg achieved complete suppression of PPG. LixiLan-O: iGlarLixi decreased 2-h PPG across the entire dose range. Lixisenatide dose was unrelated to reductions in FPG with iGlarLixi. Similar reductions in A1C were seen with iGlarLixi across all lixisenatide doses. CONCLUSIONS This analysis demonstrates the clinical benefit of lixisenatide alone or in the formulation of iGlarLixi over the entire dose range of lixisenatide contained in iGlarLixi (5-20 µg), supporting the selection of the lixisenatide dose range delivered by the iGlarLixi SoloSTAR pen.
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Affiliation(s)
| | | | | | - Terry Dex
- c Sanofi US, Inc. , Bridgewater , NJ , USA
| | | | | | - Neil Skolnik
- d Abington Family Medicine , Jenkintown , PA , USA
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Handelsman Y, Chovanes C, Dex T, Giorgino F, Skolnik N, Souhami E, Stager W, Niemoeller E, Frias JP. Efficacy and safety of insulin glargine/lixisenatide (iGlarLixi) fixed-ratio combination in older adults with type 2 diabetes. J Diabetes Complications 2019; 33:236-242. [PMID: 30600136 DOI: 10.1016/j.jdiacomp.2018.11.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 11/02/2018] [Accepted: 11/23/2018] [Indexed: 12/11/2022]
Abstract
AIMS This study assessed the efficacy and safety of iGlarLixi (a titratable, fixed-ratio combination of insulin glargine [iGlar] plus lixisenatide) in older patients with type 2 diabetes. METHODS This post hoc analysis used patient-level data from patients aged ≥65 years from the phase III LixiLan-O and LixiLan-L studies, which compared iGlarLixi with iGlar and lixisenatide (LixiLan-O only). Efficacy endpoints were changes in glycated hemoglobin A1C, fasting plasma glucose, postprandial glucose, weight, and achievement of A1C <7.0% (53 mmol/mol). Safety measures included incidence of documented symptomatic hypoglycemia (defined as typical symptoms of hypoglycemia plus self-measured plasma glucose ≤70 mg/dL [3.9 mmol/L]), severe hypoglycemia (requiring assistance of another person), and incidence of gastrointestinal adverse events. Results were compared with those from patients aged <65 years. RESULTS In both trials, older patients treated with iGlarLixi achieved significantly greater reductions in A1C at Week 30 than comparators. Treatment with iGlarLixi mitigated insulin-associated weight gain and lixisenatide-associated gastrointestinal events. Results were largely comparable between patients aged ≥65 versus <65 years. CONCLUSIONS iGlarLixi provides significant improvements in glycemic control in patients aged ≥65 years without increasing hypoglycemia risk. As a once-daily injection, it simplifies treatment regimens and may contribute to improved adherence in this patient population.
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Affiliation(s)
- Yehuda Handelsman
- Metabolic Institute of America, 18372 Clark St. Suite 212, Tarzana, CA 91356, USA.
| | - Christina Chovanes
- Abington Memorial Hospital, 500 York Rd Suite 108, Jenkintown, PA 19046, USA.
| | - Terry Dex
- Sanofi US, Inc., 55 Corporate Drive, Bridgewater, NJ 08807, USA.
| | - Francesco Giorgino
- University of Bari Aldo Moro, Piazza Giulio Cesare 11, Bari 70124, Italy.
| | - Neil Skolnik
- Abington Memorial Hospital, 500 York Rd Suite 108, Jenkintown, PA 19046, USA.
| | | | - William Stager
- Sanofi US, Inc., 55 Corporate Drive, Bridgewater, NJ 08807, USA.
| | | | - Juan Pablo Frias
- National Research Institute, 2010 Wilshire Blvd #302, Los Angeles, 90057, CA, USA.
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Frias JP, Dex T, Roberts M, Kaplan A. A Review of the Safety and Adverse Event Profile of the Fixed-Ratio Combination of Insulin Glargine and Lixisenatide. Diabetes Ther 2019; 10:21-33. [PMID: 30539523 PMCID: PMC6349286 DOI: 10.1007/s13300-018-0547-5] [Citation(s) in RCA: 6] [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] [Scholar Register] [Received: 09/28/2018] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION iGlarLixi is a titratable, fixed-ratio combination of insulin glargine (100 units/mL) and lixisenatide (33 μg/mL). This review evaluates the overall safety and adverse event (AE) profile of iGlarLixi in patients with type 2 diabetes. METHODS We collated patient-level data from the phase 2 LixiLan proof-of-concept trial and the phase 3 LixiLan-L (insulin-experienced patients) and LixiLan-O (insulin-naïve patients) trials to evaluate AEs associated with iGlarLixi. We also describe data from the ELIXA study to examine pancreatitis and pancreatic cancer, and the ELIXA and ORIGIN studies for cardiovascular safety data. RESULTS Patients treated with iGlarLixi had improved glycemic control with a similar incidence of documented symptomatic hypoglycemia (plasma glucose ≤ 70 mg/dL) compared with iGlar. Incidence of severe hypoglycemia (an event requiring third-party assistance) was low in all treatment arms in both LixiLan-L and LixiLan-O. Rates of gastrointestinal AEs in patients treated with iGlarLixi tended to be lower compared with lixisenatide alone, but higher than those treated with iGlar alone. Gastrointestinal AEs were generally mild to moderate in intensity and transient. Antibodies formed in response to iGlarLixi did not have any significant clinical impact, with similar safety observed for antibody-positive and antibody-negative populations. Rates of allergic reactions, malignancy, renal impairment, and cardiovascular events were low and comparable between treatment groups. Older age (≥ 65 years) and gender did not affect efficacy or safety. CONCLUSION iGlarLixi has a safety profile that is consistent with that of its two active components insulin glargine and lixisenatide, with no signals for pancreatitis or thyroid C cell tumors, and no black-box warning for iGlarLixi. There were no unexpected safety findings; iGlarLixi had beneficial effects on glycemic control, with no increased risk of hypoglycemia, despite a greater glycated hemoglobin A1c reduction. In addition, there were also fewer gastrointestinal AEs associated with iGlarLixi compared with lixisenatide alone. FUNDING Sanofi US Inc.
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Affiliation(s)
- Juan P Frias
- National Research Institute, Los Angeles, CA, USA.
| | | | | | - Allen Kaplan
- Medical University of South Carolina, Charleston, SC, USA
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Gentilella R, Pechtner V, Corcos A, Consoli A. Glucagon-like peptide-1 receptor agonists in type 2 diabetes treatment: are they all the same? Diabetes Metab Res Rev 2019; 35:e3070. [PMID: 30156747 DOI: 10.1002/dmrr.3070] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 07/30/2018] [Accepted: 08/18/2018] [Indexed: 02/06/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an important class of drugs with a well-established efficacy and safety profile in patients with type 2 diabetes mellitus. Agents in this class are derived from either exendin-4 (a compound present in Gila monster venom) or modifications of human GLP-1 active fragment. Differences among these drugs in duration of action (ie, short-acting vs long-acting), effects on glycaemic control and weight loss, immunogenicity, tolerability profiles, and administration routes offer physicians several options when selecting the most appropriate agent for individual patients. Patient preference is also an important consideration. The aim of this review is to discuss the differences between and similarities of GLP-1 RAs currently approved for clinical use, focusing particularly on the properties characterising the single short-acting and long-acting GLP-1 RAs rather than on their individual efficacy and safety profiles. The primary pharmacodynamic difference between short-acting (ie, exenatide twice daily and lixisenatide) and long-acting (ie, albiglutide, dulaglutide, exenatide once weekly, liraglutide, and semaglutide) GLP-1 RAs is that short-acting agents primarily delay gastric emptying (lowering postprandial glucose) and long-acting agents affect both fasting glucose (via enhanced glucose-dependent insulin secretion and reduced glucagon secretion in the fasting state) and postprandial glucose (via enhanced postprandial insulin secretion and inhibition of glucagon secretion). Other advantages of long-acting GLP-1 RAs include smaller fluctuations in plasma drug concentrations, improved gastrointestinal tolerability profiles, and simpler, more convenient administration schedules (once daily for liraglutide and once weekly for albiglutide, dulaglutide, the long-acting exenatide formulation, and semaglutide), which might improve treatment adherence and persistence.
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Affiliation(s)
| | - Valeria Pechtner
- Lilly Diabetes, Eli Lilly and Company, Neuilly-sur-Seine, France
| | | | - Agostino Consoli
- Department of Medicine and Ageing Sciences and CeSI-Met, University D'Annunzio, Chieti, Italy
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Wei ZG, Wang MC, Zhang HH, Wang ZY, Wang GN, Wei FX, Zhang YW, Xu XD, Zhang YC. PRISMA-efficacy and safety of lixisenatide for type 2 diabetes mellitus: A meta-analysis of randomized controlled trials. Medicine (Baltimore) 2018; 97:e13710. [PMID: 30572502 PMCID: PMC6320179 DOI: 10.1097/md.0000000000013710] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVE We aimed to systematically evaluate the efficacy and safety of lixisenatide in patients with type 2 diabetes mellitus. METHODS PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, Google, Web of Science and the Chinese Science Citation Database were searched up to March 2018. Randomized controlled trials determining the efficacy and safety of lixisenatide in patients with type 2 diabetes mellitus were eligible for inclusion. Two authors independently extracted the data in a prespecified Microsoft Excel spreadsheet. A meta-analysis was performed using Review Manager 5.3 software. Weighted mean difference (WMD) and relative risk (RR) together with their corresponding 95% confidence intervals (CIs) were estimated, and only the random effects model was used in order to achieve a more conservative estimate of the efficacy and safety. RESULTS Fourteen multicenter randomized controlled trials involving 11,947 patients were eligible for inclusion. Compared to placebo, lixisenatide could more significantly reduce the level of HbA1c (WMD=-0.44; 95% confidence interval [CI] [-0.55,-0.33]), and a higher proportion of lixisenatide-treated patients achieved the HbA1c level of < 7.0% (RR = 1.89, 95% CI [1.75-2.03]) and < 6.5% (RR = 3.03, 95% CI [2.54-3.63]) than the placebo-treated patients. Lixisenatide was also associated with a significant reduction in fasting plasma glucose and 2-hour postprandial plasma glucose levels. The risks for any adverse events, gastrointestinal adverse events, and symptomatic hypoglycemia significantly increased in the lixisenatide-treatedment group compared to those in the placebo group. However, lixisenatideit did not increase the risks of serious adverse events, death, or severe hypoglycemia. CONCLUSIONS Lixisenatide was more effective than placebo in patients with type 2 diabetes mellitus, and the mild-to-moderate adverse events were found to be tolerated during the follow-up.
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Affiliation(s)
- Zhen-gang Wei
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Man-cai Wang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Hui-han Zhang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Zhe-yuan Wang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Gen-nian Wang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Feng-xian Wei
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Ya-wu Zhang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - Xiao-dong Xu
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
| | - You-cheng Zhang
- Department of General Surgery, Lanzhou University Second Hospital
- Hepatobiliary and pancreatic surgery laboratory, Lanzhou University Second Hospital
- Gansu Provincial-level Key Laboratory of Digestive System Tumors, Lanzhou 730030, China
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Rosenstock J, Handelsman Y, Vidal J, Ampudia Blasco FJ, Giorgino F, Liu M, Perfetti R, Meier JJ. Propensity-score-matched comparative analyses of simultaneously administered fixed-ratio insulin glargine 100 U and lixisenatide (iGlarLixi) vs sequential administration of insulin glargine and lixisenatide in uncontrolled type 2 diabetes. Diabetes Obes Metab 2018; 20:2821-2829. [PMID: 29974618 PMCID: PMC6282993 DOI: 10.1111/dom.13462] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 06/29/2018] [Accepted: 06/29/2018] [Indexed: 01/02/2023]
Abstract
AIM To conduct two exploratory analyses to compare indirectly the efficacy and safety of simultaneous administration of insulin glargine 100 U (iGlar) and the glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide (Lixi) as a single-pen, titratable, fixed-ratio combination (iGlarLixi [LixiLan trials]) vs sequential administration of iGlar + Lixi (GetGoal Duo trials) in people with type 2 diabetes (T2D). MATERIALS AND METHODS Propensity-score matching based on baseline covariates was used to compare simultaneous iGlarLixi vs sequential combination of iGlar + Lixi with the addition of Lixi in patients who did not reach the glycated haemoglobin (HbA1c) goal of <53 mmol/mol (<7%) after short-term use of iGlar alone (LixiLan-O vs GetGoal Duo-1 comparison) and vs sequential addition of Lixi in uncontrolled patients after long-term use of iGlar alone (LixiLan-L vs GetGoal Duo-2 comparison). RESULTS In both analyses, compared with sequential iGlar + Lixi, iGlarLixi led to significantly greater HbA1c reductions with associated weight loss and significantly more patients reaching target HbA1c <53 mmol/mol despite lower insulin doses. Symptomatic hypoglycaemia rates were similar, despite greater HbA1c reductions with iGlarLixi. Lower rates of gastrointestinal adverse events were observed with iGlarLixi, probably as a result of the more gradual titration of Lixi with iGlarLixi. CONCLUSIONS Indirect propensity-score-matched exploratory comparisons suggest that early treatment with a simultaneous, titratable, fixed-ratio combination of basal insulin and a GLP-1RA (iGlarLixi) may be more effective and possess better gastrointestinal tolerability than a sequential approach of adding a GLP-1RA in patients with uncontrolled T2D initiating or intensifying basal insulin therapy.
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Affiliation(s)
| | | | - Josep Vidal
- Hospital Clinic of BarcelonaBarcelonaSpain
- Centro Investigación Biomédica en Red en Diabetes y Enfermeades Metabólicas (CIBERDEM)MadridSpain
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Trujillo JM, Roberts M, Dex T, Chao J, White J, LaSalle J. Low incidence of gastrointestinal adverse events over time with a fixed-ratio combination of insulin glargine and lixisenatide versus lixisenatide alone. Diabetes Obes Metab 2018; 20:2690-2694. [PMID: 29923298 PMCID: PMC6221077 DOI: 10.1111/dom.13444] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 06/08/2018] [Accepted: 06/16/2018] [Indexed: 12/14/2022]
Abstract
This post hoc analysis of gastrointestinal (GI) adverse events (AEs) from the phase 3 LixiLan-L (NCT02058160) and LixiLan-O (NCT02058147) trials aimed to determine the frequency and timing of nausea, vomiting, and diarrhoea for iGlarLixi, a titratable, fixed-ratio combination of insulin glargine 100 units/mL (iGlar) and lixisenatide, versus iGlar alone or iGlar and lixisenatide alone, in patients with type 2 diabetes uncontrolled with oral antidiabetes drugs (OADs) or basal insulin ± OADs. In iGlarLixi-treated patients, the rate of GI AEs during the initial weeks of treatment was lower versus patients treated with lixisenatide alone (9.6% and 11.7% of iGlarLixi-treated patients in LixiLan-L and LixiLan-O, respectively, vs. 27.5% of lixisenatide-treated patients in LixiLan-O). Beyond day 60, these rates were generally low and similar to those of lixisenatide. These lower rates are likely due to the gradual titration of lixisenatide in iGlarLixi. Median durations of intermittent GI AEs in the iGlarLixi arms were 6.0, 2.0 and 2.5 days (LixiLan-L), and 5.0, 1.0 and 3.5 days (LixiLan-O), respectively. iGlarLixi-associated GI AEs were transient, mostly mild or moderate in severity, and occurred mainly during initial titration.
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Affiliation(s)
- Jennifer M. Trujillo
- Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical SciencesUniversity of ColoradoAuroraColorado
| | | | - Terry Dex
- Sanofi US, Inc.BridgewaterNew Jersey
| | | | - John White
- Department of PharmacyWashington State UniversitySpokaneWashington
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Bellido D, Abellán P, Ruiz Palomar JM, Álvarez Sintes R, Nubiolae A, Bellido V, Romero G. Intensification of Basal Insulin Therapy with Lixisenatide in Patients with Type 2 Diabetes in a Real-World Setting: The BASAL-LIXI Study. Curr Ther Res Clin Exp 2018; 89:37-42. [PMID: 30455779 PMCID: PMC6218842 DOI: 10.1016/j.curtheres.2018.09.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 09/27/2018] [Accepted: 09/28/2018] [Indexed: 01/02/2023] Open
Abstract
Adding lixisenatide to basal insulin was effective for uncontrolled type 2 diabetes. Glycemic control improved and body weight lowered during 24 weeks of treatment. These benefits were achieved with a low risk of hypoglycemia in clinical practice. These findings in the clinical practice setting support those of clinical trials. Background Basal insulin reduces fasting blood glucose levels, but postprandial blood glucose levels may remain higher. Traditional strategies with rapid insulin intensification can cause hypoglycemic episodes and weight gain. Glucagon-like peptide-1 receptor agonists, such as the short-acting lixisenatide, are able to control postprandial excursions, without weight gain, and with a low risk of hypoglycemic events. Objective Due to the limited data on the combination of lixisenatide with basal insulin (with or without oral antidiabetes drugs) in clinical practice, this study evaluated changes in parameters associated with glycemic control and anthropometric data after 24 weeks of this therapy intensification. Methods This was a multicenter, retrospective observational study of 129 patients with type 2 diabetes that was uncontrolled by basal insulin. Their treatment was intensified by the addition of lixisenatide at least 24 weeks before being included in the study. Data were retrospectively collected to determine changes in glycated hemoglobin (HbA1c) levels, blood glucose levels, weight, and body mass index. Adverse reactions and hypoglycemic events were also recorded. Results After 24 weeks of therapy intensification with lixisenatide, a significant reduction in HbA1c levels was observed (–1.1%; P < 0.001). An HbA1c <7% was achieved in 30.2% of patients, and 17.1% reached an HbA1c <6.5%. There was a reduction in fasting blood glucose (31.8 [60.3] mg/dL; P < 0.001) and postprandial blood glucose (55.0 [49] mg/dL; P < 0.001) levels, as well as body weight (4.0 [5.4] kg; P < 0.001) and body mass index (1.5 [1.9]; P < 0.001). The most commonly observed adverse reactions were nausea (n = 9), in line with previous studies. Hypoglycemia events were rare; only reported in 2 patients. Conclusions Intensification strategy based on lixisenatide added to basal insulin (with or without oral antidiabetes drugs) can be an effective treatment option in patients with uncontrolled type 2 diabetes. In this small, selected population, glycemic control was significantly improved in terms of HbA1, fasting blood glucose levels, and postprandial glucose levels, with a reduction of body weight and low risk of hypoglycemic events. (Curr Ther Res Clin Exp. 2018; 79:XXX–XXX)
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Affiliation(s)
- Diego Bellido
- Department of Endocrinology and Nutrition, Ferrol Universitary Hospital Complex (CHUF), Ferrol, Spain
| | - Pablo Abellán
- Department of Endocrinology and Nutrition, Castellón General Universitary Hospital, Castellón de la Plana, Spain; Department of Medicine, Universidad Cardenal Herrera-CEU University, CEU Universities, Castellón, Spain.,Department of Endocrinology and Nutrition, Elda Hospital, Elda, Spain
| | - José Manuel Ruiz Palomar
- Department of Endocrinology and Nutrition, Quirón Health, Miguel Domínguez Hospitals Group, Pontevedra, Spain
| | | | - Andreu Nubiolae
- Department of Endocrinology and Nutrition, Cruces Universitary Hospital, Barakaldo, Spain
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Goldenberg RM, Assimakopoulos P, Gilbert JD, Gottesman IS, Yale JF. A practical approach and algorithm for intensifying beyond basal insulin in type 2 diabetes. Diabetes Obes Metab 2018; 20:2064-2074. [PMID: 29707875 DOI: 10.1111/dom.13337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 04/09/2018] [Accepted: 04/24/2018] [Indexed: 11/29/2022]
Abstract
Despite the availability of long-term data demonstrating the benefits of timely and aggressive intensification of antihyperglycaemic regimens among individuals with type 2 diabetes, intensification beyond basal insulin continues to be suboptimal and a global challenge. This review summarizes the evidence surrounding the various options of advancing glucose-lowering management beyond basal insulin and provides a practical algorithm to assist in optimizing patient care and enhancing glycaemic target achievements.
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Affiliation(s)
| | - Peter Assimakopoulos
- Division of Endocrinology and Metabolism, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
| | - Jeremy D Gilbert
- Division of Endocrinology and Metabolism, Sunnybrook Health Sciences Centre, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Irving S Gottesman
- Trillium Health Partners, Credit Valley Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Jean-François Yale
- Division of Endocrinology and Metabolism, McGill University Health Centre, McGill University and LMC Diabetes and Endocrinology, Montreal, Quebec, Canada
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Lovshin JA. Glucagon-like Peptide-1 Receptor Agonists: A Class Update for Treating Type 2 Diabetes. Can J Diabetes 2018; 41:524-535. [PMID: 28942790 DOI: 10.1016/j.jcjd.2017.08.242] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 01/24/2017] [Accepted: 02/08/2017] [Indexed: 12/17/2022]
Abstract
Current management options for treating type 2 diabetes are diverse. Many different classes of antidiabetes therapies are used in clinic, and several new candidates are in late-phase clinical trial. This therapeutic abundance is a windfall for patients because it facilitates individualized patient care. Evidence-based positioning of these agents is challenging, however, requiring comprehensive and balanced familiarity with each drug class. In this review, I provide a clinical update of glucagon-like peptide-1 receptor agonists (GLP-1RAs), a class of incretin-based, injectable antidiabetes therapies which improve fasting and postprandial blood glucose control through glucose-dependent pancreatic islet cell hormone secretion without significant risks for hypoglycemia. Chronic use of GLP-1RAs also promotes body weight loss through stimulation of GLP-1 receptors localized in hypothalamic satiety centres that regulate appetite, resulting in reduced caloric intake. Since 2005, when GLP-1RAs first received regulatory approval for type 2 diabetes, this class has expanded to include long-acting, once-weekly GLP-1RAs. Recent cardiovascular outcome trials demonstrate that long-term use of GLP-1RAs (liraglutide and semaglutide) reduce cardiovascular and renal complications of diabetes. Illustrating that GLP-1RAs are favourable in high-risk patients with type 2 diabetes. This review provides a clinical appraisal of the GLP-1RA class, highlighting intraclass similarities and differences, summarizing the clinical development of incretin-based diabetes therapies and focusing on currently approved GLP-1RAs. The review also discusses the implications of structural differences between GLP-1RA molecules and comments on the risks and benefits associated with GLP-1RAs and their positioning in treating type 2 diabetes.
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Affiliation(s)
- Julie A Lovshin
- Toronto General Hospital, Banting and Best Diabetes Centre, Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada.
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Guja C, Frías JP, Somogyi A, Jabbour S, Wang H, Hardy E, Rosenstock J. Effect of exenatide QW or placebo, both added to titrated insulin glargine, in uncontrolled type 2 diabetes: The DURATION-7 randomized study. Diabetes Obes Metab 2018; 20:1602-1614. [PMID: 29473704 PMCID: PMC6032936 DOI: 10.1111/dom.13266] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 02/12/2018] [Accepted: 02/19/2018] [Indexed: 02/07/2023]
Abstract
AIMS To compare the efficacy and safety of adding the glucagon-like peptide-1 receptor agonist exenatide once weekly (QW) 2 mg or placebo among patients with type 2 diabetes who were inadequately controlled despite titrated insulin glargine (IG) ± metformin. METHODS This multicentre, double-blind study (ClinicalTrials.gov identifier: NCT02229383) randomized (1:1) patients with persistent hyperglycaemia after an 8-week titration phase (glycated haemoglobin [HbA1c] 7.0%-10.5% [53-91 mmol/mol]) to exenatide QW or placebo. The primary endpoint was HbA1c change from baseline to week 28. Secondary endpoints included body weight, 2-hour postprandial glucose, and mean daily IG dose. RESULTS Of 464 randomized patients (mean: age, 58 years; HbA1c, 8.5% [69 mmol/mol]; diabetes duration, 11.3 years), 91% completed 28 weeks. Exenatide QW + IG vs placebo + IG significantly reduced HbA1c (least-squares mean difference, -0.73% [-8.0 mmol/mol]; 95% confidence interval, -0.93%, -0.53% [-10.2, -5.8 mmol/mol]; P < .001; final HbA1c, 7.55% [59 mmol/mol] and 8.24% [67 mmol/mol], respectively); body weight (-1.50 kg; -2.17, -0.84; P < .001); and 2-hour postprandial glucose (-1.52 mmol/L [-27.5 mg/dL]; -2.15, -0.90 [-38.7, -16.2]; P < .001). Significantly more exenatide QW + IG-treated patients vs placebo + IG-treated patients reached HbA1c <7.0% (<53 mmol/mol) (32.5% vs 7.4%; P < .001); daily IG dose increased by 2 and 4 units, respectively. Gastrointestinal and injection-site adverse events were more frequent with exenatide QW + IG (15.1% and 7.8%, respectively) than with placebo + IG (10.8% and 3.0%, respectively); hypoglycaemia incidence was similar between the exenatide QW + IG (29.7%) and placebo + IG (29.0%) groups, with no major hypoglycaemic events. CONCLUSIONS Among patients with inadequate glycaemic control, exenatide QW significantly improved glucose control and decreased body weight, without increased hypoglycaemia or unexpected safety findings.
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Affiliation(s)
- Cristian Guja
- Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and PharmacyBucharestRomania
- National Institute of Diabetes, Nutrition and Metabolic Diseases, “NC Paulescu”BucharestRomania
| | | | - Aniko Somogyi
- 2nd Department of Internal Medicine, Semmelweis UniversityBudapestHungary
| | - Serge Jabbour
- Division of Endocrinology, Diabetes & Metabolic Diseases, Sidney Kimmel Medical College of Thomas Jefferson UniversityPhiladelphiaPennsylvania
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Yang W, Cai X, Gao X, Chen Y, Chen L, Ji L. Addition of dipeptidyl peptidase-4 inhibitors to insulin treatment in type 2 diabetes patients: A meta-analysis. J Diabetes Investig 2018; 9:813-821. [PMID: 29047219 PMCID: PMC6031492 DOI: 10.1111/jdi.12764] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 09/25/2017] [Accepted: 10/09/2017] [Indexed: 12/30/2022] Open
Abstract
AIMS/INTRODUCTION To evaluate the efficacy and safety of combining insulin therapy with dipeptidyl peptidase-4 (DPP-4) inhibitors compared with combining insulin therapy with a placebo or other antihyperglycemic agents. MATERIALS AND METHODS A literature search was carried out via electronic databases. The inclusion criteria were randomized controlled trials comparing the addition of DPP-4 inhibitors to insulin with the addition of a placebo or other active hypoglycemic agents to insulin therapy, study duration of no less than 12 weeks carried out in type 2 diabetes patients and the availability of outcome data to evaluate a change in the glycated hemoglobin. RESULTS The glycated hemoglobin-lowering efficacy was significantly greater with DPP-4 inhibitor/insulin (DPP-4i/INS) than with placebo/insulin (weighted mean difference -0.53%, 95% confidence interval -0.63, -0.43, P < 0.01). The postprandial plasma glucose-lowering efficacies was also significantly greater with DPP-4i/INS than with placebo/insulin (weighted mean difference -1.65 mmol/L, 95% CI: -2.34, -0.96, P < 0.05). The risk of hypoglycemia or severe hypoglycemia was similar for DPP4i/INS and placebo/insulin treatments. There was no significant difference in the glycemia-lowering efficacy between DPP-4i/INS and alpha-glucosidase inhibitors/insulin, thiazolidinedione/insulin and glucagon-like peptide-1 receptor agonist/insulin. Sodium-glucose cotransporter 2 inhibitor/insulin treatment achieved better placebo-corrected efficacy in lowering postprandial plasma glucose, with less weight gain and no higher risk of hypoglycemia. CONCLUSIONS Treatment with DPP-4 inhibitors combined with insulin improved glycemic control without an increased risk of hypoglycemia or weight gain compared with insulin treatment alone.
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Affiliation(s)
- Wenjia Yang
- Endocrinology and Metabolism DepartmentPeking University People's HospitalBeijingChina
| | - Xiaoling Cai
- Endocrinology and Metabolism DepartmentPeking University People's HospitalBeijingChina
| | - Xueying Gao
- Endocrinology and Metabolism DepartmentPeking University People's HospitalBeijingChina
| | - Yifei Chen
- Endocrinology and Metabolism DepartmentPeking University People's HospitalBeijingChina
| | - Ling Chen
- Endocrinology and Metabolism DepartmentPeking University People's HospitalBeijingChina
| | - Linong Ji
- Endocrinology and Metabolism DepartmentPeking University People's HospitalBeijingChina
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Systematic Review of Efficacy and Safety of Newer Antidiabetic Drugs Approved from 2013 to 2017 in Controlling HbA1c in Diabetes Patients. PHARMACY 2018; 6:pharmacy6030057. [PMID: 29954090 PMCID: PMC6164486 DOI: 10.3390/pharmacy6030057] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 06/01/2018] [Accepted: 06/21/2018] [Indexed: 02/07/2023] Open
Abstract
Type 2 Diabetes Mellitus (T2DM) is the most common form of diabetes mellitus and accounts for about 95% of all diabetes cases. Many newer oral as well as parenteral antidiabetic drugs have been introduced in to the market in recent years to control hyperglycemic conditions in diabetes patients and many of these drugs produce potential side effects in diabetes patients. Hence, this systematic review was aimed to analyze and compare the efficacy and safety of oral antidiabetic agents in controlling HbA1c in T2DM patients, that were approved by the United States-Food and Drug Administration (US-FDA) from 2013 to 2017. All randomized controlled, double-blind trials published in English during the search period involving the newer antidiabetic agents were selected. In the outcome assessment comparison, semaglutide demonstrated the highest efficacy in lowering HbA1c, with a 1.6% reduction (p < 0.0001) when given at a dose of 1.0 mg. The safety profile of all the agents as compared to placebo or control were similar, with no or slight increase in the occurrence of adverse events (AEs) but no fatal reaction was reported. The most common AEs of all the antidiabetic agents were gastrointestinal in nature, with several cases of hypoglycemic events. However, among all these agents, semaglutide seems to be the most efficacious drug to improve glycemic control in terms of HbA1c. Alogliptin has the least overall frequency of AEs compared to other treatment groups.
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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] [Scholar 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.
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Affiliation(s)
| | - J. Vora
- Diabetes and EndocrinologyRoyal Liverpool University HospitalLiverpoolUK
- AstraZenecaCambridgeUK
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