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Aim: To compare the risk of developing kidney outcomes with use of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) versus use of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors among individuals with diabetes. Materials and Methods: In this retrospective observational study, we analysed 12 338 individuals with diabetes who newly initiated SGLT2 inhibitors or GLP‐1RAs using data from the JMDC claims database. The primary outcome was change in the estimated glomerular filtration rate (eGFR), estimated using a linear mixed‐effects model. A 1:4 propensity‐score‐matching algorithm was used to compare the changes in eGFR between GLP‐1RA and SGLT2 inhibitor users. Results: After propensity‐score matching, 2549 individuals (median [range] age 52 [46–58] years, 80.6% men) were analysed (510 GLP‐1RA new users and 2039 SGLT2 inhibitor new users). SGLT2 inhibitor use was associated with a slower eGFR decline when compared with GLP‐1RA use (−1.41 [95% confidence interval −1.63 to −1.19] mL/min/1.73 m2 vs. −2.62 [95% confidence interval −3.15 to −2.10] mL/min/1.73 m2). Conclusions: Our analysis demonstrates the potential advantages of SGLT2 inhibitors over GLP‐1RAs in terms of kidney outcomes in individuals with diabetes. [ABSTRACT FROM AUTHOR]

Aims: To conduct an updated systematic review and meta‐analysis to evaluate the efficacy of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) with regard to cardiac function and structure in people with or without type 2 diabetes mellitus (T2DM). Materials and Methods: We conducted a systematic search using the PubMed, Embase and ClinicalTrials.gov online databases. The primary outcome of interest was changes in mitral inflow E‐velocity to tissue Doppler e' velocity (E/e') ratio. Secondary outcomes included other indicators of cardiac reverse remodelling and functional capacity comprising changes in left ventricular mass (LVM), left ventricular global longitudinal strain, left ventricular end‐diastolic volume, left ventricular end‐systolic volume, left ventricular ejection fraction (LVEF), early to atrial mitral inflow velocity ratio, left atrial volume (LAV), N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) levels and 6‐min walk test (6MWT) results. Results: A total of 15 trials involving 898 patients were included in this analysis. GLP‐1RAs significantly improved E/e' ratio (mean difference [MD] = −0.73; 95% confidence interval [CI] −1.34, −0.13), LVM (MD = −3.86 g; 95% CI −7.60, −0.12), LAV (MD = −8.20 mL; 95% CI −12.37, −4.04), NT‐proBNP level (standardized MD = −0.27; 95% CI −0.47, −0.06), and 6MWT result (MD = +22.31 m; 95% CI 1.64, 42.99). However, GLP‐1RAs had no effect on LVEF (MD = +0.31%; 95% CI −1.02, 1.64). Conclusions: In this systematic review and meta‐analysis, GLP‐1RAs were found to have a positive impact on left ventricle diastolic function, hypertrophy, and exercise capacity, but had no effect on systolic function. [ABSTRACT FROM AUTHOR]

Aim: The cardiovascular benefits provided by glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) extend beyond weight reduction and glycaemic control. One possible mechanism may relate to blood pressure (BP) reduction. We aim to quantify the BP‐lowering effects of GLP1‐RAs. Methods: A comprehensive database search for placebo‐controlled randomized controlled trials on GLP‐1RA treatment was conducted until December 2023. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with a mean difference (MD) in mmHg and 95% confidence intervals (CIs). The primary endpoint was the mean difference in systolic BP (SBP) and diastolic BP. Subgroup analyses and meta‐regressions were done to account for covariates. Results: Compared with placebo, GLP‐1RAs modestly reduced SBP [semaglutide: MD −3.40 (95% CI −4.22 to −2.59, p <.001); liraglutide: MD −2.61 (95% CI −3.48 to −1.74, p <.001); dulaglutide: MD −1.46 (95% CI −2.20 to −0.72, p <.001); and exenatide: MD −3.36 (95% CI −3.63 to −3.10, p <.001)]. This benefit consistently increased with longer treatment durations. Diastolic BP reduction was only significant in the exenatide group [MD −0.94 (95% CI −1.78 to −0.1), p =.03]. Among semaglutide cohorts, mean changes in glycated haemoglobin and mean changes in body mass index were directly associated with SBP reduction. Conclusion: Patients on GLP‐1RA experienced modest SBP lowering compared with placebo. This observed effect was associated with weight/body mass index reduction and better glycaemic control, which suggests that BP‐lowering is an indirect effect of GLP‐1RA and unlikely to be responsible for the benefits. [ABSTRACT FROM AUTHOR]

Despite its considerable and growing burden, there are currently no Food and Drug Administration‐approved treatments for metabolic dysfunction‐associated steatotic liver disease or its progressive form, metabolic dysfunction‐associated steatohepatitis (MASH). Several glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and other agents are in various phases of clinical development for use in MASH; an ideal therapy should reduce liver fat content, improve chronic liver disease, help mitigate metabolic comorbidities and decrease all‐cause mortality. Because of interconnected disease mechanisms, metabolic dysfunction‐associated steatotic liver disease/MASH often coexists with type 2 diabetes (T2D), obesity and cardiovascular disease. Various GLP‐1RAs are Food and Drug Administration‐approved for use in T2D, and two, liraglutide and semaglutide, are approved for overweight and obesity. GLP‐1RAs decrease glucose levels and body weight and improve cardiovascular outcomes in people with T2D who are at high risk of cardiovascular disease. In addition, GLP‐1RAs have been reported to reduce liver fat content and liver enzymes, reduce oxidative stress and improve hepatic de novo lipogenesis and the histopathology of MASH. Weight loss may contribute to these effects; however, the exact mechanisms are unknown. Adverse events that are commonly associated with GLP‐1RAs include vomiting, nausea and diarrhoea. There is a lack of evidence from meta‐analyses regarding the increased risk of acute pancreatitis and various forms of cancer with GLP‐1RAs. Large‐scale, phase 3 trials, which will provide definitive data on GLP‐1RAs and other potential therapies in MASH, are ongoing. Given the spectrum of modalities under investigation, it is hoped that these trials will support the identification of pharmacotherapies that provide clinical benefit for patients with MASH. [ABSTRACT FROM AUTHOR]

Aims: To determine whether a continuous infusion of a glucagon‐like peptide receptor (GLP‐1R)/glucagon receptor (GCGR) co‐agonist, G3215 is safe and well tolerated in adults with overweight or obesity. Methods: A phase 1 randomized, double blind, placebo‐controlled trial of G3215 in overweight or obese participants, with or without type 2 diabetes. Results: Twenty‐six participants were recruited and randomized with 23 completing a 14‐day subcutaneous infusion of G3215 or placebo. The most common adverse events were nausea or vomiting, which were mild in most cases and mitigated by real‐time adjustment of drug infusion. There were no cardiovascular concerns with G3215 infusion. The pharmacokinetic characteristics were in keeping with a continuous infusion over 14 days. A least‐squares mean body weight loss of 2.39 kg was achieved with a 14‐day infusion of G3215, compared with 0.84 kg with placebo infusion (p <.05). A reduction in food consumption was also observed in participants receiving G3215 and there was no deterioration in glycaemia. An improved lipid profile was seen in G3215‐treated participants and consistent with GCGR activation, a broad reduction in circulating amino acids was seen during the infusion period. Conclusion: An adaptive continuous infusion of the GLP‐1/GCGR co‐agonist, G3215, is safe and well tolerated offering a unique strategy to control drug exposure. By allowing rapid, response‐directed titration, this strategy may allow for mitigation of adverse effects and afford significant weight loss within shorter time horizons than is presently possible with weekly GLP‐1R and multi‐agonists. These results support ongoing development of G3215 for the treatment of obesity and metabolic disease. [ABSTRACT FROM AUTHOR]

Aim: To determine the comparative effectiveness regarding major cardiovascular events of glucagon‐like peptide‐1 (GLP‐1) receptor agonists and sodium‐glucose cotransporter‐2 (SGLT‐2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Materials and Methods: We assembled a cohort of commercially insured adult patients with T2DM in the United States (derived from Optum Clinformatics DataMart 2003‐2021) who were new users of GLP‐1 receptor agonists or SGLT‐2 inhibitors. We compared risks of non‐fatal myocardial infarction or stroke in patients with and without CKD, and further categorized by CKD stage: stages G1 or G2 [estimated glomerular filtration rate (eGFR) ≥60 ml/min] and A2 (urine albumin to creatinine ratio 30 to <300 mg/g) or A3 (urine albumin to creatinine ratio ≥300 mg/g), stage G3a (eGFR 45 to <60 ml/min/1.73 m2) and stage G3b (eGFR 30 to <45 ml/min/1.73 m2). We used proportional hazards regression after inverse probability of treatment weighting to compute hazard ratios and 95% confidence intervals. Results: After accounting for the probability of treatment, patients with T2DM and CKD treated with SGLT‐2 inhibitors experienced a 14% lower risk of non‐fatal myocardial infarction or stroke (hazard ratio 0.86, 95% confidence interval 0.78‐0.94) relative to those treated with GLP‐1 receptor agonists. Conclusions: Recognizing the potential for residual confounding, selection bias and immortal time bias, commercially insured patients in the United States with T2DM and CKD treated with SGLT‐2 inhibitors experienced significantly lower risks of non‐fatal myocardial infarction or stroke relative to those treated with GLP‐1 receptor agonists. [ABSTRACT FROM AUTHOR]

Aim: To examine the real‐world efficacy of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) in monogenic obesity in patients with Alström syndrome (ALMS). Methods: We screened 72 UK adult patients with ALMS and offered treatment to 34 patients meeting one of the following criteria: body mass index of 25 kg/m2 or higher, insulin resistance, suboptimal glycaemic control on antihyperglycaemic medications or non‐alcoholic fatty liver disease. Results: In total, 30 patients, with a mean age of 31 ± 11 years and a male to‐female ratio of 2:1, completed 6 months of treatment with GLP‐1 RAs either in the form of semaglutide or exenatide. On average, treatment with GLP‐1 RAs reduced body weight by 5.4 ± 1.7 (95% confidence interval [CI] 3.6‐7) kg and HbA1c by 12 ± 3.3 (95% CI 8.7‐15.3) mmol/mol, equating to 6% weight loss (P <.01) and 1.1% absolute reduction in HbA1c (P <.01). Significant improvements were also observed in serum total cholesterol, triglycerides, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol and alanine aminotransferase. The improvement of metabolic variables in our cohort of monogenic syndromic obesity was comparable with data for polygenic obesity, irrespective of weight loss. Conclusions: Data from our centre highlight the non‐inferiority of GLP‐1 RAs in monogenic syndromic obesity to the available GLP‐1 RA‐use data in polygenic obesity, therefore, these agents can be considered as a treatment option in patients with ALMS, as well as other forms of monogenic obesity. [ABSTRACT FROM AUTHOR]

This article is a comment on a systematic review and meta-analysis conducted by Yang et al. on the impact of tirzepatide (TZP) on heart rate compared to glucagon-like peptide-1 receptor agonists (GLP-1RAs). GLP-1RAs have been shown to increase heart rate, and there is evidence that glucose-dependent insulinotropic polypeptide (GIP) may also increase heart rate. The comment discusses the inclusion of the SURPASS-2 study in the analysis, which was not included by Yang et al. due to missing data. The addition of SURPASS-2 to the analysis showed no significant difference in heart rate change between TZP and GLP-1RAs, except in Japanese individuals. However, more studies are needed to fully understand the impact of TZP on heart rate compared to GLP-1RAs. [Extracted from the article]

Aim: To assess the safety, tolerability, pharmacokinetics (PKs) and pharmacodynamics of HRS‐7535, a novel glucagon‐like peptide‐1 receptor agonist (GLP‐1RA), in healthy participants. Materials and Methods: This phase 1 trial consisted of single‐ascending dose (SAD), food effect (FE) and multiple‐ascending dose (MAD) parts. In the SAD part, participants were randomized (6:2) to receive HRS‐7535 (at doses of 15, 60 and 120 mg; administered orally once daily) or placebo. In the FE part, participants were randomized (8:2) to receive a single dose of 90‐mg HRS‐7535 or placebo, in both fed and fasted states. In the MAD part, participants were randomized (18:6) to receive daily HRS‐7535 (120 mg [30/60/90/120‐mg titration scheme]) or placebo for 28 days. The primary endpoints were safety and tolerability. Results: Nausea and vomiting were the most frequently reported AEs across all three parts. In the SAD part, the median Tmax was 5.98‐5.99 hours and the geometric mean t1/2 was 5.28‐9.08 hours across the HRS‐7535 dosing range. In the MAD part, the median Tmax was 5.98‐10.98 hours and the geometric mean t1/2 was 6.48‐8.42 hours on day 28 in participants on HRS‐7535. PKs were approximately dose‐proportional. On day 29 in the MAD part, the mean (percentage) reduction in body weight from baseline was 4.38 kg (6.63%) for participants who received HRS‐7535, compared with 0.8 kg (1.18%) for those participants who received a placebo. Conclusions: HRS‐7535 exhibited a safety and tolerability profile consistent with other GLP‐1RAs and showed PKs suitable for once‐daily dosing. These findings support further clinical development of HRS‐7535 for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aim: To compare the therapeutic effects of glucose‐dependent insulinotropic polypeptide (GIP)/ glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) or GLP‐1RAs in Japanese patients with type 2 diabetes (T2D). Materials and Methods: We systematically searched PubMed, MEDLINE, EMBASE, and the Cochrane Library up to July 2023. Randomized controlled trials (RCTs) that compared GLP‐1RAs or GIP/GLP‐1RAs in Japanese patients with T2D were selected. A network meta‐analysis was conducted to indirectly compare the treatments, focusing on efficacy in reducing glycated haemoglobin (HbA1c) levels and body weight (BW). Results: A total of 18 RCTs were included in this analysis. Tirzepatide 15 mg showed the most significant reduction in HbA1c levels and BW compared with subcutaneous semaglutide 1.0 mg and oral semaglutide 14 mg (HbA1c: mean difference [95% confidence interval] −0.52 [−0.96; −0.08] and − 1.23 [−1.64; −0.81]; BW: −5.07 [−8.28; −1.86] and −6.84 [−8.97; −4.71], respectively). Subcutaneous semaglutide showed a superior reduction in HbA1c compared with oral semaglutide. Both subcutaneous and oral semaglutide were more effective than conventional GLP‐1RAs, such as dulaglutide, liraglutide and lixisenatide. Conclusions: Among Japanese patients with T2D, tirzepatide showed the greatest effectiveness in reducing HbA1c levels and inducing weight loss. The study provides evidence to guide GLP‐1RA treatment strategies in Japanese patients with T2D. [ABSTRACT FROM AUTHOR]

Aim: We investigated the effect of 52‐week treatment with liraglutide, a glucagon‐like peptide 1 receptor agonist, on glucose tolerance and incretin effect in women with previous gestational diabetes mellitus (pGDM). Materials and Methods: Women with overweight/obesity and pGDM were randomized to once daily subcutaneous liraglutide 1.8 mg or placebo for 52 weeks. Participants underwent oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion at baseline and at 52 weeks, and an additional OGTT after the drug wash‐out. Results: In total, 104 women [age: mean ± SD, 38 ± 5 years; fasting plasma glucose (FPG): 5.5 ± 0.4 mmol/L; glycated haemoglobin (HbA1c): 33 ± 4 mmol/mol, bodyweight: 88.2 ± 14.8 kg, body mass index: 31.1 ± 4.3 kg/m2] were assigned to liraglutide (n = 49) or placebo (n = 55). Estimated treatment difference (ETD) for area under curve during OGTT was −173 (95% confidence interval −250 to −97) mmol/L × min, p <.0001, but after wash‐out the difference disappeared [ETD 58 (−30 to 146) mmol/L × min, p =.536]. Liraglutide reduced FPG [ETD −0.2 (−0.4 to −0.1) mmol/L, p =.018], HbA1c [−2.2 (−3.5 to −0.8) mmol/mol, p =.018] and bodyweight [−3.9 (−6.2 to −1.6) kg, p =.012]. No change in the incretin effect was observed. The number of women with prediabetes was reduced from 64% to 10% with liraglutide vs. 50% with placebo [adjusted odds ratio 0.10 (0.03‐0.32), p =.002]. Conclusions: Treatment with liraglutide for 52 weeks improved glucose tolerance, FPG, HbA1c and bodyweight in women with overweight/obesity and pGDM. Progression to prediabetes while on drug was markedly reduced, but after a 1‐week drug wash‐out, the effect was lost. [ABSTRACT FROM AUTHOR]

Aims: To determine the potential association between the use of either glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) or dipeptidyl peptidase‐4 (DPP‐4) inhibitors, and the risk of thyroid cancer in individuals with type 2 diabetes. Materials and Methods: This population‐based cohort study used claims data from the Korean National Health Insurance Database, 2014‐2020. Two distinct cohorts were established to compare each incretin‐based drug with sodium‐glucose cotransporter‐2 (SGLT2) inhibitors, chosen as active comparators because of their previous non‐association with thyroid cancer, and their common usage as add‐on therapy to metformin along with GLP‐1RAs and DPP‐4 inhibitors. The first cohort included 21 722 new users of GLP‐1RAs and 326 993 new users of SGLT2 inhibitors, whereas the second cohort included 904 300 DPP‐4 inhibitor new users and 112 017 SGLT2 inhibitor new users. The outcome was the time to incident thyroid cancer. Weighted Cox proportional models were used to estimate hazard ratios of thyroid cancer incidence associated with incretin‐based drugs of interest. Results: The use of GLP‐1RAs was not associated with an increased risk of thyroid cancer (weighted hazard ratio 0.98, 95% confidence interval 0.62‐1.53) compared with that of SGLT2 inhibitors. Using DPP‐4 inhibitors was also not associated with an increased risk of thyroid cancer (0.95, 0.79‐1.14) compared with that of SGLT2 inhibitors. No significant effect modifications were observed across subgroup analyses. Sensitivity analyses, including alternative outcome definition analysis of medullary thyroid cancer, were consistent with the primary analysis results. Conclusions: GLP‐1RAs and DPP‐4 inhibitors were not associated with an increased risk of thyroid cancer in individuals with type 2 diabetes. [ABSTRACT FROM AUTHOR]

This document is a clarification letter regarding a study on a novel oral non-peptide glucagon-like peptide-1 receptor agonist called Orforglipron. The authors explain that there are differences between the body weight change values shown in Figure 3 of the main manuscript and the implied weight change values indicated in Table S3. These differences are due to variations in the analysis model used. The authors recommend that readers interpret the treatment effects based on the change from baseline analysis presented in Figure 3. [Extracted from the article]