GLP-1 Receptor Agonists: Advances in Mechanism, Therapeutic Applications, and Future Perspectives

Benefit-risk assessment of incretin and other anti-diabetic agents in type 2 diabetes using a stochastic multicriteria acceptability analysis model.

T2DM (type 2 diabetes mellitus) is a chronic and progressive illness with high morbidity and death rates. Oral semaglutide (Rybelsus®) is a combination of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), and sodium N- (8- [2-hydroxybenzoyl] amino) caprylate (SNAC), an absorption enhancer that facilitates semaglutide absorption across the gastric epithelium in a concentration-dependent manner. This family of drugs apart from glucose lowering effects causes significant weight loss with lower risk of hypoglycemia, and some of them have been linked to a significant reduced major adverse cardiovascular events. GLP-1 RAs may assist persons with T2DM and chronic kidney disease (CKD), a major microvascular consequence of T2DM, in ways other than lowering blood sugar. Several large clinical studies, the bulk of which are cardiovascular outcome trials, show that GLP-1 RA treatment is safe and tolerated for persons with T2DM and impaired renal function and that it may potentially have renoprotective characteristics. This article focuses on the advances of oral GLP1-RA and describes the key milestones and predicted advantages.

New Glucose-Lowering Agents for Diabetic Kidney Disease.

PDB52 - A Comparison of Patient Characteristics Between Glp-1 Ra and Insulin Initiators in China

Comparison of Characteristics Between Chinese Patients Taking Glucagon-like Peptide 1 Receptor Agonists and Insulin: A Cross-sectional Database Analysis

Background: Type 2 diabetes mellitus (T2DM) combined with heart failure (HF) markedly raises cardiovascular risk, underscoring the need for integrated therapeutic strategies. Sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have shown promise in managing glycemic control and enhancing cardiovascular outcomes. While both therapies independently offer cardioprotective effects, combining SGLT2 inhibitors and GLP-1 receptor agonists may provide superior efficacy in reducing mortality and hospitalizations in this vulnerable population. Objective: To assess the cardioprotective efficacy of combined SGLT2 inhibitors and GLP-1 receptor agonists versus monotherapy on cardiovascular outcomes, specifically mortality and hospitalization rates, in patients with T2DM and HF. Methods: A systematic literature search was conducted in PubMed, Scopus, and Google Scholar following PRISMA guidelines. Studies included were randomized controlled trials (RCTs) and observational studies that evaluated the impact of SGLT2 inhibitors, GLP-1 receptor agonists, or their combination on cardiovascular outcomes, specifically mortality and hospitalization rates, in patients with T2DM and HF. A random-effects model was applied to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs), adjusting for heterogeneity. Results: Analysis included 10 studies encompassing T2DM and HF patients, with combined therapy showing superior efficacy. The pooled RR indicated a significant reduction in mortality (RR: 0.78; 95% CI: 0.70–0.88; p < 0.001) and hospitalizations (RR: 0.85; 95% CI: 0.77–0.93; p = 0.002) with combination therapy compared to monotherapy. However, a slight increase in gastrointestinal side effects was observed (RR: 1.10; 95% CI: 1.02–1.20; p < 0.05). Conclusion: Combined therapy with SGLT2 inhibitors and GLP-1 receptor agonists is potentially more effective than monotherapy for cardiovascular risk reduction in T2DM patients with HF, despite a marginal increase in gastrointestinal side effects. This supports the clinical consideration of combination therapy to optimize cardiovascular outcomes in this high-risk group.

IntroductionInternational guidelines recommend treatment with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist for treatment intensification in type 2 diabetes mellitus (T2DM) patients with progression on metformin. In the randomised, controlled, Peptide Innovation for Early Diabetes Treatment (PIONEER) 2 trial, the SGLT-2 inhibitor empagliflozin was compared with the GLP-1 receptor agonist oral semaglutide, in addition to metformin. The aim of the current study was to assess the long-term cost-effectiveness of empagliflozin 25 mg versus oral semaglutide 14 mg, in addition to metformin, for T2DM patients in the UK.MethodsAnalyses were conducted from the UK healthcare payer perspective, using the IQVIA Core Diabetes model, with a time horizon of 50 years. Patients received either empagliflozin or oral semaglutide, in addition to metformin, until Hba1c threshold of 7.5% (58 mmol/mol) was exceeded, following which treatment intensification with insulin glargine in addition to empagliflozin or oral semaglutide plus metformin was assumed. Baseline cohort characteristics and 52-week treatment effects were derived from the PIONEER 2 trial. Treatment effects of empagliflozin and GLP-1 receptor agonists on hospitalisation for heart failure (hHF) were based on the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) real-world study. Utilities, treatment costs and costs of diabetes-related complications were obtained from published sources.ResultsDirect costs for empagliflozin plus metformin were considerably lower than those for oral semaglutide plus metformin (by more than GBP 6000). Compared with oral semaglutide plus metformin, empagliflozin plus metformin was a cost-effective treatment for T2DM patients in all scenarios tested. Probabilistic sensitivity analysis showed cost-effectiveness in > 95% of the iterations using a threshold of 20,000 GBP/QALY.ConclusionEmpagliflozin 25 mg is a cost-effective treatment option versus oral semaglutide 14 mg, when used in addition to metformin, for the treatment of T2DM patients in the UK.Electronic supplementary materialThe online version of this article (10.1007/s13300-020-00883-1) contains supplementary material, which is available to authorized users.

Preoperative considerations of new long-acting glucagon-like peptide-1 receptor agonists in diabetes mellitus

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are incretin-mimetic agents that are effective adjuncts in the treatment of diabetes. This class of medications is also associated with promoting weight loss and a low risk of hypoglycemia, and some have been shown to be associated with a significant reduction of major cardiovascular events. Mounting evidence suggests that GLP-1 RAs have benefits beyond reducing blood glucose that include improving kidney function in people living with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), a common microvascular complication of T2DM. Several large clinical studies, the majority of which are cardiovascular outcome trials, indicate that GLP-1 RA therapy is safe and tolerable for people living with T2DM and compromised renal function, and also suggest that GLP-1 RAs may have renoprotective properties. Although evidence from clinical trials has shown GLP-1 RAs to be safe and efficacious in people living with T2DM and renal impairment, their use is uncommon in this patient population. With continuing developments in the field of GLP-1 RA therapy, it is important for physicians to understand the benefits and practical use of GLP-1 RAs, as well as the clinical evidence, in order to achieve positive patient outcomes. Here, we review evidence on GLP-1 RA use in people living with T2DM and CKD and summarize renal outcomes from clinical studies. We provide practical considerations for GLP-1 RA use to provide an added benefit to guide treatment in this high-risk patient population.Graphical

Time to Follow the Evidence: Glycemic Control and Cardiovascular Benefits of New Diabetes Medications

New Medications for the Treatment of Diabetes

The twin epidemic of diabesity is a major concern in current practice. Treatment strategies that benefit weight and glycemia are the need of the hour. Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 inhibitors are known to have a beneficial effect on weight reduction. Further, patients are often noncompliant with injectable medications despite the medications being effective. GLP-1 receptor agonist is one of the high glycemic efficacy therapies that can potentially reduce the risk of cardio-renal diseases. Until recently, GLP-1 receptor agonists were available in an injectable formulation. Semaglutide is the first in this class of drugs available as an oral formulation. Direct and indirect evidence has confirmed the safety and efficacy of semaglutide, including oral formulation. There are no trial data on oral semaglutide in Indian subjects with type 2 diabetes and obesity. We present a series of case reports where semaglutide was added to achieve adequate glycemic control with the added benefit of weight loss. Oral semaglutide was associated with a 1.5% reduction in glycosylated haemoglobin and 3–14 kg weight reduction after 3 months. Large clinical trials must confirm the findings from isolated cases, though the Indian population also responded as reported cases.

According to current guidelines, glucagon-like peptide-1 (GLP-1) receptor agonists are the antidiabetic agent of choice in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease (CVD) and are also the preferable antidiabetic agent in patients with T2DM without CVD but with indicators of high cardiovascular risk. A limitation in the use of GLP-1 receptor agonists is that they are delivered by subcutaneous injections. In this context, the development of an orally administered formulation of semaglutide offers an additional option in the management of patients with T2DM. In the present review, we discuss the findings of the main trials that evaluated the safety and efficacy of oral semaglutide. Oral semaglutide appears to be more effective in reducing HbA1c levels and body weight than other antidiabetic agents and similarly effective to other GLP-1 receptor agonists. The safety profile of oral semaglutide is also comparable with other members of its class. Even though oral semaglutide did not reduce the incidence of the composite primary endpoint in a randomized controlled trial, a reduction in cardiovascular and all-cause mortality was observed. Therefore, oral semaglutide appears to represent a useful tool in the management of patients with TD2M, particularly those with established CVD or high cardiovascular risk and unwilling to receive injectable GLP-1 receptor agonists.

BackgroundWe performed a systematic overview of the cost-effectiveness analyses (CEAs) comparing Non-insulin antidiabetic drugs (NIADs) with other NIADs for the treatment of type 2 diabetes mellitus (T2DM), using decision-analytical modelling (DAM), focusing on both the economic results and the underlying methodological choices.MethodsEligible studies were CEAs using DAM to compare NIADs within the glucagon-like peptide-1 (GLP1) receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, or dipeptidyl peptidase-4 (DPP4) inhibitor classes with other NIADs within those classes for the treatment of T2DM. The PubMed, Embase and Econlit databases were searched from 1 January 2018 to 15 November 2022. Two reviewers screened the studies for relevance by titles and abstracts and then for eligibility via full-text screening, extracted the data from the full texts and appendices, and then stored the data in a spreadsheet.ResultsThe search yielded 890 records and 50 studies were eligible for inclusion. The studies were mainly based on a European setting (60%). Industry sponsorship was found in 82% of studies. The CORE diabetes model was used in 48% of the studies. GLP1 and SGLT2 products were the main comparators in 31 and 16 studies, respectively, while one study had DPP4 and two had no easily discernible main comparator. Direct comparison between SGLT2 and GLP1 occurred in 19 studies. At a class level, SGLT2 dominated GLP1 in six studies and was cost effective against GLP1 once as part of a treatment pathway. GLP1 was cost effective in nine studies and not cost effective against SGLT2 in three studies. At a product level, oral and injectable semaglutide, and empagliflozin, were cost effective against other within-class products. Injectable and oral semaglutide were more frequently found cost effective in these comparisons, with some conflicting results. Most of the modelled cohorts and treatment effects were sourced from randomised controlled trials. The following model assumptions varied depending on the class of the main comparator: choice of and reasoning behind risk equations, the time until the treatment switch, and how often the comparators were discontinued. Diabetes-related complications were emphasised on par with quality-adjusted life-years as model outputs. The main quality issues were regarding the description of alternatives, the perspective of analysis, the measurement of costs and consequences, and patient subgroups.ConclusionThe included CEAs using DAMs have limitations that hinder their ability to inform decision makers on the cost-effective choice: lack of updated reasoning behind the choice of key model assumptions, over-reliance on risk equations based on older treatment practices, and sponsorship bias. The question of which NIAD is cost effective for the treatment of which T2DM patient is a pressing one and the answer remains unclear.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40273-023-01268-5.

Background:Sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been demonstrated to be able to improve the cardiovascular and renal prognosis in patients with type 2 diabetes (T2D). However, the relative efficacy of various SGLT2 inhibitors and GLP-1 RAs on cardiorenal outcomes is unestablished.Methods:We searched PubMed and Embase for relevant cardiovascular or renal outcome trials (CVOTs). Endpoints of interest were major adverse cardiovascular events (MACE), stroke, myocardial infarction (MI), cardiovascular death (CVD), all-cause death (ACD), kidney function progression (KFP), and hospitalization for heart failure (HHF). Bayesian network meta-analysis was conducted to produce pooled hazard ratio (HR) and 95% confidence interval (CI). We calculated the probability values of surface under the cumulative ranking curve to rank active and placebo interventions.Results:Fourteen COVTs were included in analysis. Sotagliflozin (HR 0.76, 95% CI 0.61–0.94), subcutaneous semaglutide, and albiglutide lowered MACE versus lixisenatide among others. Sotagliflozin (HR 0.59, 95% CI 0.40–0.89), canagliflozin, and empagliflozin lowered HHF versus subcutaneous semaglutide among others. Dapagliflozin and empagliflozin lowered KFP versus exenatide among others. Empagliflozin and oral semaglutide lowered CVD versus dapagliflozin among others. Sotagliflozin (HR 0.65, 95% CI 0.47–0.91) and albiglutide lowered MI versus ertugliflozin among others. Sotagliflozin (HR 0.56, 95% CI 0.37–0.85) and subcutaneous semaglutide lowered stroke versus empagliflozin among others. Oral semaglutide and empagliflozin lowered ACD versus subcutaneous semaglutide among others. The maximum surface under the cumulative ranking curve values followed sotagliflozin, subcutaneous semaglutide, and albiglutide in lowering MACE; sotagliflozin, canagliflozin, and empagliflozin in lowering HHF; dapagliflozin and empagliflozin in lowering KFP; empagliflozin and oral semaglutide in lowering CVD; sotagliflozin and albiglutide in lowering MI; sotagliflozin and subcutaneous semaglutide in lowering stroke; and oral semaglutide and empagliflozin in lowering ACD.Conclusions:This updated network meta-analysis reproduced the findings in the first network meta-analysis, and moreover revealed that sotagliflozin was one of the most effective drugs as for lowering MI, stroke, MACE, and HHF, whereas ertugliflozin was not. These findings will provide the according evidence regarding the usage of specific SGLT2 inhibitors and GLP-1 RAs in T2D patients for prevention of specific cardiorenal endpoints.