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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]

Aim: To compare the clinical usefulness of once‐weekly glucagon‐like peptide‐1 receptor agonists dulaglutide and semaglutide at the doses approved for use in Japanese patients with type 2 diabetes. Methods: In total, 120 patients with glycated haemoglobin (HbA1c) ≥7% were randomly assigned to dulaglutide (n = 59) or semaglutide group (n = 61), and 107 participants (dulaglutide/semaglutide = 53/54) completed the 24‐week trial. The primary endpoint was the difference of HbA1c level between the two groups at 24 weeks. Results: HbA1c level at 24 weeks was significantly lower in the semaglutide group (7.9 ± 0.5%‐6.7 ± 0.5%) compared with the dulaglutide group (8.1 ± 0.6%‐7.4 ± 0.8%) (p <.0001). Reduction in body mass index and visceral fat area were also more significant in the semaglutide group (p <.05, respectively). The achievement rate of HbA1c <7% was higher in the semaglutide group (p <.0001). The parameters such as low‐density lipoprotein cholesterol, alanine aminotransferase and γ‐glutamyl transpeptidase were decreased in the semaglutide group. Surprisingly, only semaglutide group significantly improved the apolipoprotein B/A1 ratio, which is considered a useful myocardial infarction risk index. Using computed tomography, the liver to spleen ratio was significantly elevated only in the semaglutide group. In contrast, gastrointestinal symptoms were observed in 13.2% of dulaglutide and 46.3% of semaglutide group (p <.01). The Diabetes Treatment‐Related Quality of Life scores related to pain and gastrointestinal symptoms were also superior in the dulaglutide group. Conclusions: This prospective trial showed that semaglutide has more pronounced glucose‐ and body mass index‐lowering effects and reduces liver fat percentage and visceral fat area and that dulaglutide has less gastrointestinal symptoms and superior Diabetes Treatment‐Related Quality of Life scores related to pain and gastrointestinal symptoms. [ABSTRACT FROM AUTHOR]

Aims: Whether to recommend specifically the glucose‐lowering therapies with cardiovascular benefit only in secondary prevention, or also in patients with multiple risk factors (MRF) but without established atherosclerotic cardiovascular disease (ASCVD), is controversial across the guidelines for diabetes. Materials and Methods: We performed a meta‐analysis of clinical trials with major adverse cardiovascular events (MACE) as an outcome. Results: The definitions of ASCVD and MRF were heterogeneous across trials; nevertheless, the incidence of MACE was 2.8‐fold higher in people with ASCVD in trials with sodium‐glucose cotransporter 2 inhibitors (SGLT2is), and 3.9‐fold in trials with glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA). Both SGLT2i and GLP‐1 RA were associated with a significant reduction in the incidence of MACE in people with previous ASCVD [inverse variance‐odds ratio 0.91, 95% confidence interval (0.86: 0.97) for SGLT2i, Mantel‐Haenszel odds ratio 0.85, 95% confidence interval (0.81: 0.90) for GLP‐1 RA], whereas no significant reduction was detected in those without; on the other hand, no significant difference in effect was found between the two groups as well. The sample of patients without ASCVD enrolled in clinical trials is insufficient to draw reliable conclusions in this population; however, even assuming the same benefit detected in people with ASCVD also in those with MRF, the number needed to treat would differ (35 for secondary, 99 for primary prevention of a MACE with a SGLT2i; 21 for secondary, 82 for primary prevention with a GLP‐1 RA, respectively), given the difference in absolute cardiovascular risk at baseline. Conclusion: The distinction between patients with ASCVD and those without ASCVD and MRF appears therefore justified by available evidence. [ABSTRACT FROM AUTHOR]

Aim: To develop and investigate an imbalanced dual gastric inhibitory polypeptide receptor (GIPR)/glucagon‐like peptide‐1 receptor (GLP‐1 R) agonist with Fc fusion protein structure. Methods: We designed and constructed an Fc fusion protein that is a dual agonist (HEC‐CG115) with an empirically optimized potency ratio for GLP‐1R and GIPR. The long‐term effects of HEC‐CG115 on body weight and glycaemic control were evaluated in diet‐induced obese mice and diabetic db/db mice. Repeat dose toxicity assays were performed to investigate the safety profile of HEC‐CG115 in Sprague‐Dawley rats. Results: HEC‐CG115 displayed high potency for GIPR and relatively low potency for GLP‐1R, and we labelled it 'imbalanced'. In animal models, HEC‐CG115 (3 nmol/kg) led to more weight loss than semaglutide at a higher dose (10 nmol/kg) in diet‐induced obese model mice. HEC‐CG115 (one dose every 3 days) reduced fasting blood glucose and glycated haemoglobin levels similar to those after semaglutide (once daily) at the same dose. In a 4‐week subcutaneous toxicity study conducted to assess the biosafety of HEC‐CG115, the no observed adverse effect level was determined to be 3 mg/kg. Conclusion: HEC‐CG115 is a novel Fc fusion protein with imbalanced dual agonism that shows superior weight loss, glycaemic control and metabolic improvement in animal models, and has an optimal safety profile according to a repeat‐dose toxicity study. Therefore, the use of HEC‐CG115 appears to be safe and effective for the treatment of obesity and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aim: To investigate the potential mechanism of once‐weekly glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) in the treatment of type 2 diabetes mellitus (T2DM) complicated with coronary artery disease (CAD). Methods: We searched both Chinese and English databases for randomized controlled trials related to once‐weekly GLP‐1 RA for T2DM complicated with CAD to verify the safety and efficacy of GLP‐1 RA. The underlying mechanism was analysed by network pharmacology. Results: In total, 13 studies with 35 563 participants were included in the analysis. The pooled analysis found that dulaglutide, exenatide and semaglutide outperformed placebo in cardiovascular outcomes in patients with T2DM, with a significant reduction in the incidence of non‐fatal stroke (p <.00). Levels of cardiovascular risk factors were significantly reduced in the once‐weekly GLP‐1 RA group compared with the conventional treatment group (glycated haemoglobin: p <.00; fasting blood glucose: p <.00; weight: p <.00; systolic blood pressure: p <.00; total cholesterol: p <.00; low‐density lipoprotein cholesterol: p <.00). Network pharmacology results were enriched to the renin‐angiotensin system, and matrix metalloproteinase 2 and renin (REN) may be the key targets. In addition, four key targets of dulaglutide, five key targets of exenatide and two key targets of semaglutide were enriched. Conclusions: Our study suggests that once‐weekly GLP‐1 RA may have a potential protective effect on cardiovascular events in patients with T2DM combined with CAD, possibly through the renin‐angiotensin system. However, further research is needed to confirm these findings and determine cause and effect. [ABSTRACT FROM AUTHOR]

Tirzepatide is a unimolecular co‐agonist of the glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor‐activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP‐1 and GIP, their receptors, and previous results of co‐targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP‐1 and GIP receptor activation, tirzepatide does not seem to have a classical co‐activating mode of action in humans. Rather, in vitro studies of the human GLP‐1 and GIP receptors reveal a biased GLP‐1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the tolerability, safety and pharmacodynamics of different dose‐escalation schemes of the oral small‐molecule glucagon‐like peptide‐1 receptor (GLP‐1R) agonist danuglipron. Materials and Methods: This Phase 2a, double‐blind, placebo‐controlled, parallel‐group study randomly assigned adults with type 2 diabetes (T2D) treated with metformin to placebo or danuglipron (low [5‐mg] or high [10‐mg] starting dose, with 1‐ or 2‐week dose‐escalation steps, to target doses of 80, 120 or 200 mg twice daily [BID]) and adults with obesity without diabetes to placebo or danuglipron 200 mg BID. Results: Participants with T2D (n = 123, mean glycated haemoglobin [HbA1c] 8.19%) or obesity without diabetes (n = 28, mean body mass index 37.3 kg/m2) were randomly assigned and treated. Discontinuation from study medication occurred in 27.3% to 72.7% of participants across danuglipron groups versus 16.7% to 18.8% for placebo, most often due to adverse events. Nausea (20.0%‐47.6% of participants across danuglipron groups vs. 12.5% for placebo) and vomiting (18.2%‐40.9% danuglipron vs. 12.5% placebo, respectively) were most commonly reported in participants with T2D. Gastrointestinal adverse events were generally related to danuglipron target dose and were not substantially affected by starting dose. In participants with T2D, least squares mean changes from baseline in HbA1c (−1.04% to −1.57% across danuglipron groups vs. −0.32% for placebo), fasting plasma glucose (−23.34 mg/dL to −53.94 mg/dL danuglipron vs. −13.09 mg/dL placebo) and body weight (−1.93 to −5.38 kg danuglipron vs. −0.42 kg placebo) at Week 12 were generally statistically significant for danuglipron compared with placebo (P < 0.05). Conclusions: Danuglipron resulted in statistically significant reductions in HbA1c, FPG and body weight over 12 weeks, in the setting of higher discontinuation rates and incidence of gastrointestinal adverse events with higher target doses. Clinicaltrials.gov identifier: NCT04617275. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) in healthy participants. Materials and Methods: This was a double‐blind, placebo‐controlled, Phase 1 study. Overtly healthy adults aged 18 to 65 years with body mass index of 20 to 40 kg/m2 and glycated haemoglobin concentration of 47.5 mmol/mol (<6.5%) were eligible. In Part A, participants received single‐dose orforglipron, with four cohorts receiving escalating doses (0.3‐6 mg). In Part B, participants received 4 weeks of daily repeated oral orforglipron with doses escalating weekly to four different final target doses (2‐24 mg). Results: Ninety‐two participants enrolled and received at least one study drug dose (32 in Part A [mean age 43.4 years] and 60 in Part B [mean age 42.5 years]). The most common adverse events were gastrointestinal tract‐related. Pharmacokinetics were approximately dose proportional, and the mean t1/2 was 24.6 to 35.3 hours after a single dose (0.3‐6 mg). On Day 28, the mean t1/2 was 48.1 to 67.5 hours across the dose range (2‐24 mg). Substantial reductions in body weight of up to 5.4 kg were observed after 4 weeks in orforglipron‐treated participants, compared to a reduction of 2.4 kg with placebo (P < 0.05). Orforglipron decreased fasting glucose levels across Days 1 to 28, and gastric emptying was delayed on Day 28. Conclusions: Orforglipron's long half‐life (25‐68 hours) allows once‐daily oral dosing, without water and food restrictions. Orforglipron had a pharmacodynamic and safety profile similar to that of injectable GLP‐1RAs, which supports continued clinical development. [ABSTRACT FROM AUTHOR]

Aim: To report the results of a Phase 1b trial evaluating the safety, pharmacokinetics and pharmacodynamics of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA), in patients with type 2 diabetes (T2D). Materials and Methods: This was a double‐blind, placebo‐controlled Phase 1 study evaluating five different dosing regimens. The first group established that weekly dose escalation of the daily doses of orforglipron was generally well tolerated. This enabled a parallel‐arm design for the four groups following. Participants were randomized 3:1 to daily doses of orforglipron or placebo for 12 weeks. Eligible participants with T2D were aged 18 to 70 years and had glycated haemoglobin (HbA1c) levels ≥53.0 mmol/mol (7.0%) and ≤91.3 mmol/mol (10.5%). Results: A total of 51 participants received orforglipron and 17 received placebo. In the placebo and orforglipron groups, respectively, baseline HbA1c was 8.1% and 8.0%, and baseline body weight was 90.3 and 88.4 kg. The most common adverse events were gastrointestinal‐related, and occurred early in treatment, similar to findings with other GLP‐1RAs. At Week 12, mean t1/2 ranged from 29 to 49 hours. Mean HbA1c change ranged from −1.5% to −1.8% across orforglipron doses, versus −0.4% with placebo, and body weight change was −0.24 to −5.8 kg across orforglipron doses, versus 0.5 kg with placebo. Conclusions: Orforglipron treatment resulted in meaningful reductions in HbA1c and body weight, with an adverse event profile consistent with that of other GLP‐1RAs. Orforglipron may provide a safe and effective once‐daily oral treatment alternative to injectable GLP‐1RAs or peptide oral formulations without water and food restrictions. [ABSTRACT FROM AUTHOR]

Aim: To investigate the changes of circulating levels of all proglucagon‐derived peptides (PGDPs) in individuals with overweight or obesity receiving liraglutide (3 mg) or naltrexone/bupropion (32/360 mg), and to explore the association between induced changes in postprandial PGDP levels and body composition, as well as metabolic variables, after 3 and 6 months on treatment. Materials and Methods: Seventeen patients with obesity or with overweight and co‐morbidities, but without diabetes, were assigned to receive once‐daily oral naltrexone/bupropion 32/360 mg (n = 8) or once‐daily subcutaneous liraglutide 3 mg (n = 9). Participants were assessed before treatment initiation and after 3 and 6 months on treatment. At the baseline and 3‐month visits, participants underwent a 3‐hour mixed meal tolerance test to measure fasting and postprandial levels of PGDPs, C‐peptide, hunger and satiety. Clinical and biochemical indices of metabolic function, magnetic resonance‐assessed liver steatosis and ultrasound‐assessed liver stiffness were measured at each visit. Results: Both medications improved body weight and composition, carbohydrate and lipid metabolism, and liver fat and function. Naltrexone/bupropion produced a weight‐independent increase in the levels of proglucagon (P <.001) and decreases in glucagon‐like peptide‐2 (GLP‐2), glucagon and the major proglucagon fragment (P ≤.01), whereas liraglutide markedly upregulated total glucagon‐like peptide‐1 (GLP‐1) levels in a weight‐independent manner (P =.04), and similarly downregulated the major proglucagon fragment, GLP‐2 and glucagon (P <.01). PGDP levels at the 3‐month visit were positively and independently correlated with improvements in fat mass, glycaemia, lipaemia and liver function, and negatively with reductions in fat‐free mass, at both the 3‐ and 6‐month visits. Conclusions: PGDP levels in response to liraglutide and naltrexone/bupropion are associated with improvements in metabolism. Our study provides support for the administration of the downregulated members of the PGDP family as replacement therapy (e.g. glucagon), in addition to the medications currently in use that induced their downregulation (e.g. GLP‐1), and future studies should explore whether the addition of other PGDPs (e.g. GLP‐2) could offer additional benefits. [ABSTRACT FROM AUTHOR]

Aim: To determine the kinase activity profiles of human pancreatic beta cells downstream of glucagon‐like peptide‐1 receptor (GLP‐1R) balanced versus biased agonist stimulations. Materials and Methods: This study analysed the kinomic profiles of human EndoC‐βh1 cells following vehicle and GLP‐1R stimulation with the pharmacological agonist exendin‐4, as well as exendin‐4–based biased derivatives exendin‐phe1 and exendin‐asp3 for acute (10‐minute) versus sustained (120‐minute) responses, using PamChip protein tyrosine kinase and serine/threonine kinase assays. The raw data were filtered and normalized using BioNavigator. The kinase analyses were conducted with R, mainly including kinase‐substrate mapping and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Results: The present analysis reveals that kinomic responses are distinct for acute versus sustained GLP‐1R agonist exposure, with individual responses associated with agonists presenting specific bias profiles. According to pathway analysis, several kinases, including JNKs, PKCs, INSR and LKB1, are important GLP‐1R signalling mediators, constituting potential targets for further research on biased GLP‐1R downstream signalling. Conclusion: The results from this study suggest that differentially biased exendin‐phe1 and exendin‐asp3 can modulate distinct kinase interaction networks. Further understanding of these mechanisms will have important implications for the selection of appropriate anti‐type 2 diabetes therapies with optimized downstream kinomic profiles. [ABSTRACT FROM AUTHOR]

Aims: To describe clinical characteristics, treatment patterns and glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) persistence in individuals with type 2 diabetes (T2D) initiating their first GLP‐1 RA. Materials and Methods: A real‐world analysis of adults with T2D initiating GLP‐1 RA therapy between 2007 and June 2020 from the multicentre Diabetes Prospective Follow‐Up (DPV) Registry, stratified by antidiabetes therapy at the time of GLP‐1 RA initiation: oral antidiabetic drugs (OAD), insulin ± OAD or lifestyle modification (LM). GLP‐1 RA treatment persistence in individuals with ≥12 months follow‐up was determined by Kaplan‐Meier analysis. Results: Overall, 15 111 individuals with T2D initiating GLP‐1 RA therapy (55% men) were identified; median [interquartile range (IQR)] age [58.7 (50.6‐66.7) years], diabetes duration [8.5 (3.6‐14.7) years], glycated haemoglobin [HbA1c; 8.2 (7.1‐9.8)%]. Median (95% confidence interval) GLP‐1 RA persistence in eligible individuals (n = 5189) was 11 (10‐12) months; OAD 12 (11‐14) months (n = 2453); insulin ± OAD 11 (9‐12) months (n = 2204); and LM 7 (5‐9) months (n = 532). Median treatment persistence tended to increase from 2007‐2012 to 2017‐2020. Median (IQR) HbA1c decreased from baseline [8.2 (7.1‐9.8)%] to discontinuation [7.5 (6.6‐8.7)%], with a greater decrease observed in individuals with persistence >12 months versus ≤12 months. Individuals who discontinued GLP‐1 RA therapy predominantly switched to insulin (if not already using) or dipeptidyl peptidase‐4 inhibitors. Conclusion: Real‐world registry data revealed improved outcomes with longer median GLP‐1 RA persistence; ~50% of patients overall achieved HbA1c <7% at 12 months. Persistence was highest with baseline OAD and/or insulin, and tended to increase over the period 2007‐2020. [ABSTRACT FROM AUTHOR]

Aim: To investigate the impact of treatment with once‐weekly subcutaneous semaglutide, a glucagon‐like peptide‐1 receptor agonist (GLP‐1RA), for up to 2 years in people with type 2 diabetes (T2D) managed in routine clinical practice. Materials and methods: The study was based on data from national registries. People who redeemed at least one prescription of semaglutide and had 2 years of follow‐up were included. Data were collected at baseline and after 180, 360, 540 and 720 days of treatment (all timepoints ± 90 days). Results: In total, 9284 people redeemed at least one semaglutide prescription (intention‐to‐treat) and 4132 people redeemed semaglutide continuously (on‐treatment). For the on‐treatment cohort, the median (interquartile range) age was 62.0 (16.0) years, diabetes duration was 10.8 (8.7) years, and glycated haemoglobin (HbA1c) level was 62.0 (18.0) mmol/mol at baseline. A subset of the on‐treatment cohort, comprising 2676 people, had HbA1c measurements at baseline and at least once during 720 days. The mean (95% confidence interval) changes in HbA1c after 720 days were –12.6 (–13.6; –11.6) mmol/mol (P < 0.001) for GLP‐1RA‐naïve people, and –5.6 (–6.2; –5.0) mmol/mol (P < 0.001) for GLP‐1RA‐experienced people. Similarly, 55% of GLP‐1RA‐naïve people and 43% of GLP‐1RA‐experienced people reached a HbA1c target of ≤53 mmol/mol after 2 years. Conclusions: People treated with semaglutide in routine clinical practice experienced clinically relevant and sustained improvements in glycaemic control after 180, 360, 540 and 720 days, irrespective of former GLP‐1RA exposure, effects which were comparable with those observed in clinical studies. These results support the use of semaglutide in routine clinical practice for the long‐term management of T2D. [ABSTRACT FROM AUTHOR]

Aim: Glucagon‐like peptide 1 receptor agonists (GLP1‐RA) reduce atherosclerotic events in patients with type 2 diabetes (T2D) and a high cardiovascular risk. The effect of GLP1‐RA to reduce heart failure (HF) has been inconsistent across T2D trials, and individual trials were underpowered to assess the effect of GLP1‐RA according to HF history. In this meta‐analysis we aim to assess the effect of GLP1‐RA in patients with and without HF history in stable ambulatory patients with T2D. Methods: Random‐effects meta‐analysis of placebo‐controlled trials. The hazard ratio (HR) and 95% confidence intervals (95% CI) were extracted from the treatment effect estimates of HF subgroup analyses reported in each individual study. The primary outcome was a composite of HF hospitalization or cardiovascular death. Results: In total, 54 092 patients with T2D from seven randomized controlled trials were included, of whom 8460 (16%) had HF history. Compared with placebo, GLP1‐RA did not reduce the composite of HF hospitalization or cardiovascular death in patients with HF history: HR 0.96, 95% CI: 0.84‐1.08, but reduced this outcome in patients without HF history: HR 0.84, 95% CI: 0.76‐0.92. GLP1‐RA did not reduce all‐cause death in patients with HF history: HR 0.98, 95% CI: 0.86‐1.11, but reduced mortality in patients without HF history: HR 0.85, 95% CI: 0.79‐0.92. GLP1‐RA reduced atherosclerotic events regardless of HF history: HR 0.85, 95% CI: 0.75‐0.97 with HF, and HR 0.88, 95% CI: 0.83‐0.93 without HF. Conclusions: Treatment with GLP1‐RA did not reduce HF hospitalizations and mortality in patients with concomitant T2D and HF, but may prevent new‐onset HF and mortality in patients with T2D without HF. The reduction of atherosclerotic events with GLP1‐RA was not influenced by HF history status. [ABSTRACT FROM AUTHOR]

Objective: To assess comparative efficacy, safety and tolerability of injectable incretin‐based glucose‐lowering medications (IBGLMs) versus basal insulin treatment in patients with type 2 diabetes. Research Design and Methods: We performed an updated meta‐analysis of randomized clinical trials of head‐to‐head comparisons of IBGLMs (short‐ and long‐acting glucagon‐like peptide‐1 [GLP‐1] receptor agonists [GLP‐1RAs] and glucose‐dependent insulinotropic polypeptide [GIP]/GLP‐1 receptor co‐agonist tirzepatide) versus basal insulin using a PubMed database search (April 2022). The primary endpoint was difference in reduction of glycated haemoglobin (HbA1c) versus baseline between pooled IBGLMs (fixed‐effects meta‐analysis) and their subgroups (random‐effects meta‐analysis) versus basal insulin treatment (mean differences). Secondary endpoints were fasting plasma glucose, body weight, HbA1c target achievement, hypoglycaemia, blood pressure and lipids. Risk of bias assessment was performed using Jadad scores and the Risk of Bias tool 2.0. Results: In all, 20 studies, representing 47 study arms and 11 843 patients, were eligible. Compared with basal insulin, IGBLMs lowered HbA1c by 0.48 (0.45‐0.52)% more than did basal insulin treatment. This effect was driven by pooled long‐acting GLP‐1RAs (ΔHbA1c −0.25 [−0.38; −0.11]%) and the only GIP/GLP‐1 receptor co‐agonist, tirzepatide (pooled doses; ΔHbA1c −0.90 [−1.06; −0.75]%), while short‐acting GLP‐1RAs were equally effective compared with basal insulin (P = 0.90). All IBGLM subgroups achieved significantly lower body weight versus insulin treatment (−4.6 [−4.7; −4.4] kg), in particular tirzepatide (−12.0 [−13.8; −10.1] kg). IBGLMs significantly reduced hypoglycaemia and blood pressure and improved lipid variables. Risk of bias was low. IBGLM treatment was associated with more nausea, vomiting and diarrhoea and study medication discontinuation. Conclusions: Recently introduced, highly effective IBGLMs were superior to basal insulin treatment, reinforcing the recommendation that IBGLMs should be considered as the first injectable treatment for most patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims: To determine the extent of therapeutic inertia related to the weekly injectable glucagon‐like peptide‐1 receptor agonists dulaglutide and semaglutide in patients with type 2 diabetes (T2D) in the United Kingdom. Materials and methods: Adults with T2D who received their first primary care prescription of dulaglutide or semaglutide between January and July 2019 were identified from the UK Clinical Practice Research Datalink GOLD primary care database. Doses prescribed, glycated haemoglobin (HbA1c), body mass index (BMI) and concomitant T2D medications were assessed at first prescription and at 3, 6 and 9 months. Results: Of the patients prescribed dulaglutide (N = 748; mean [SD] age 59.0 [11.2] years) and semaglutide (N = 437; mean [SD] age 58.4 [10.6] years), 93.0% and 89.0%, respectively, had an HbA1c level ≥7.5% (≥58.46 mmol/mol), and 56.4% and 54.9%, respectively, had an HbA1c level ≥9.0% (≥74.86 mmol/mol), at first prescription. At 6 to 9 months, 75.0% of those on dulaglutide 0.75 mg and 57.6% of those on semaglutide 0.25 mg or 0.5 mg had an HbA1c level ≥7.5% (≥58.46 mmol/mol). At 9 months, 21.9% of the dulaglutide cohort were on the suboptimal dose of 0.75 mg, and 46.1% of the semaglutide cohort were on the suboptimal doses of 0.25 mg or 0.5 mg. Conclusions: Multiple examples of therapeutic inertia were identified, including first prescription at HbA1c levels considerably above target and failure to escalate to optimal doses even with evidence of suboptimal metabolic control. A substantial proportion of patients therefore did not achieve optimal HbA1c targets. [ABSTRACT FROM AUTHOR]

Early and intensive management of type 2 diabetes has been shown to delay disease progression, reduce the risk of cardiorenal complications and prolong time to treatment failure. Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are being increasingly recognized for their potential in early disease management, with recent guideline updates recommending second‐line use of this injectable drug class alongside oral glucose‐lowering drugs. GLP‐1RAs target at least six of the eight core defects implicated in the pathogenesis of type 2 diabetes and offer significant glycaemic and weight‐related improvements over other second‐line agents in head‐to‐head trials. In addition, placebo‐controlled clinical trials have shown cardiovascular protection with GLP‐1RA use. Even so, this therapeutic class is underused in primary care, largely owing to clinical inertia and patient‐related barriers to early intensification with GLP‐1RAs. Fortunately, clinicians can overcome barriers to treatment acceptance through patient education and training, and management of treatment expectations. In this review we comment on global and Australian guideline updates and evidence in support of early intensification with this therapeutic class, and provide clinicians with practical advice for GLP‐1RA use in primary care. [ABSTRACT FROM AUTHOR]

Aim: To investigate changes in the pattern of drugs used to treat type 2 diabetes in Denmark from 2005 to 2021. Materials and Methods: A nationwide, population‐based drug utilization study based on medical databases covering the Danish population was conducted. We assessed incident and prevalent use patterns among all 441 205 individuals initiating at least one non‐insulin, glucose‐lowering drug. Results: The rate of new users of non‐insulin, glucose‐lowering drugs increased from 2005, peaked in 2011, decreased to stable levels during 2013 to 2019, then increased dramatically during 2020‐2021. The prevalence of use increased from 2.1% (in 2005) to 5.0% (in 2021) of the entire adult population. In 2021, metformin comprised 39% of all glucose‐lowering drug consumption, followed by insulin (17%), sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2is) (17%), glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) (16%) and dipeptidyl peptidase‐4 inhibitors (7.5%). Overall, 56% of users were on monotherapy, 28% used dual therapy, while 13% and 2.8% used three and four drug classes, respectively. Both the intensity and diversity of therapies increased substantially over time, with 15 different treatment regimens each covering more than 1% of users in 2021. General practitioners prescribed 88% of all glucose‐lowering drugs. Marked shifts towards GLP‐1RA initiation by general practitioners and SGLT‐2i initiation by specialists were observed, and changing user profiles suggested increasing use for non‐diabetes indications. Conclusions: The rate of new users of non‐insulin, glucose‐lowering drugs has increased in recent years and the prevalence of glucose‐lowering drug use increases steadily. Glucose‐lowering drugs are mainly prescribed by general practitioners, and the intensity, diversity and indications of glucose‐lowering treatment are increasing. [ABSTRACT FROM AUTHOR]

Aim: To assess composite endpoints combining glycaemic control (HbA1c < 7.0%, ≤ 6.5% or < 5.7%) with weight loss (≥ 5%, ≥ 10% or ≥ 15%) and without hypoglycaemia with tirzepatide in type 2 diabetes (T2D). Materials and Methods: Data from the phase 3 SURPASS programme were evaluated post hoc by trial. Participants with T2D were randomized to tirzepatide (5, 10 and 15 mg), placebo (SURPASS‐1,5), semaglutide 1 mg (SURPASS‐2) or titrated basal insulin (SURPASS‐3,4). The proportions of participants achieving the composite endpoints were compared between tirzepatide and the respective comparator groups at week 40/52. Results: The proportions of participants achieving an HbA1c value of less than 7.0% with 5% or more weight loss and without hypoglycaemia ranged from 43% to 82% with tirzepatide across the SURPASS‐1 to ‐5 trials versus 4%‐5% with placebo, 51% with semaglutide 1 mg and 5% with basal insulin (P <.001 vs. all comparators). The proportions of participants achieving an HbA1c value of less than 7.0% with 10% or more, or 15% or more weight loss and without hypoglycaemia were significantly higher with all tirzepatide doses versus comparators across trials (P <.001 or P <.05). Similar results were observed for all other combinations of endpoints with an HbA1c value of 6.5% or less, or less than 5.7%, with more tirzepatide‐treated participants achieving these endpoints versus those in the comparator groups, including semaglutide. Conclusions: Across the SURPASS‐1 to ‐5 clinical trials, more tirzepatide‐treated participants with T2D achieved clinically meaningful composite endpoints, which included reaching glycaemic targets with various degrees of weight loss and without hypoglycaemia, than those in the comparator groups. [ABSTRACT FROM AUTHOR]

Aims: This study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF‐06882961), which is a novel, oral small‐molecule glucagon‐like peptide‐1 receptor agonist, in Japanese participants with type 2 diabetes mellitus (T2DM). Materials and Methods: This phase 1, randomized, double‐blind, placebo‐controlled, parallel‐group study enrolled adult Japanese participants with T2DM inadequately controlled on diet and exercise. Participants received twice‐daily oral doses of placebo or multiple ascending doses of danuglipron titrated to 40, 80 or 120 mg twice daily over 8 weeks. The primary outcome was the safety and tolerability of danuglipron. Secondary and exploratory outcomes included plasma pharmacokinetics, glycaemic parameters and body weight. Results: In the 37 participants randomized, the most common treatment‐emergent adverse events were nausea, vomiting, abdominal discomfort, diarrhoea and headache. Most treatment‐emergent adverse events were of mild or moderate intensity. Dose‐proportional increases in danuglipron exposure parameters were observed at steady state (Day 56). Significant reductions from baseline were observed with danuglipron on Day 56 for mean daily glucose [least squares mean (90% confidence interval) placebo‐adjusted difference of up to −67.89 (−88.98, −46.79) mg/dl] and on Day 57 for fasting plasma glucose [up to −40.87 (−53.77, −27.98) mg/dl], glycated haemoglobin [up to −1.41% (−2.01%, −0.82%)] and body weight [up to −1.87 (−3.58, −0.17) kg]. Conclusions: In Japanese adults with T2DM, danuglipron exhibited dose‐proportional increases in plasma exposure at steady state and robustly reduced glycaemic parameters and body weight after 8 weeks of dosing, with a safety profile consistent with the mechanism of action. [ABSTRACT FROM AUTHOR]

Aims: To investigate the effects of glucose‐lowering agents on all‐cause mortality, and cardiovascular and renal outcomes in adults with type 2 diabetes. Methods: A MEDLINE and EMBASE search was performed to identify randomized controlled trials, published up to 28 February 2022, with a follow‐up ≥52 weeks, in which glucose‐lowering drugs were compared with either placebo or active comparators. We included only trials reporting formal external adjudication of events. All‐cause mortality, 3‐point MACE (major cardiovascular events), and hospitalization for heart failure (HHF) were considered as principal outcomes. Doubling of serum creatinine, worsening albuminuria, and renal death were considered as secondary endpoints. Results: We included randomized controlled trials performed on metformin (n = 17), pioglitazone (n = 20), alpha‐glucosidase inhibitors (n = 9), insulin secretagogues (n = 42), dipeptidyl‐peptidase‐4 inhibitors (n = 67), glucagon‐like peptide‐1 receptor agonists (n = 45) or sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2i; n = 42) and insulin (n = 18). Glucagon‐like peptide‐1 receptor agonist and SGLT‐2i were associated with a significant reduction in all‐cause mortality [Mantel‐Haenszel odds ratio (MH‐OR), 95% confidence interval: 0.88 (0.83; 0.95) and 0.85 (0.79; 0.91), respectively] and MACE [MH‐OR, 95% confidence interval: 0.89 (0.84; 0.94) and 0.90 (0.84; 0.96), respectively]. SGLT‐2i was associated with a reduced risk of HHF [MH‐OR 0.68 (0.62; 0.75)], worsening albuminuria [MH‐OR 0.67 (0.55; 0.80)] and doubling of serum creatinine [MH‐OR 0.58 (0.44; 0.79)]. Metformin and pioglitazone were associated with a significantly lower risk of MACE [MH‐OR 0.60 (0.47; 0.80) and 0.85 (0.74; 0.97), respectively] and pioglitazone with a higher risk of HHF [MH‐OR 1.30 (1.04; 1.62)]. Insulin secretagogues were associated with increased risk of all‐cause mortality [MH‐OR 1.12 (1.01; 1.24)] and MACE [MH‐OR 1.19 (1.02; 1.39)]. Conclusions: The results of this updated meta‐analysis need to be considered in the choice of drug treatment for type 2 diabetes mellitus, which cannot be merely based on the effect of glucose‐lowering drugs on long‐term glycaemic control. [ABSTRACT FROM AUTHOR]

Aims: To explore the modifying effect of glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) use on outcomes with finerenone across a wide spectrum of patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the pooled analysis of FIDELIO‐DKD and FIGARO‐DKD. Materials and methods: Patients with T2D and CKD treated with optimized renin‐angiotensin system blockade were randomized to finerenone or placebo. Effects of finerenone on a cardiovascular composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and a kidney composite outcome (kidney failure, sustained ≥57% estimated glomerular filtration rate [eGFR] decline, or renal death), change in urine albumin‐to‐creatinine ratio (UACR), and safety were analysed by GLP‐1RA use. Results: Of 13 026 patients, 944 (7.2%) used GLP‐1RAs at baseline. Finerenone reduced the risk of the cardiovascular composite outcome (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.52–1.11 with GLP‐1RA; HR 0.87, 95% CI 0.79–0.96 without GLP‐1RA; P‐interaction = 0.63) and the kidney composite outcome (HR 0.82, 95% CI 0.45–1.48 with GLP‐1RA; HR 0.77, 95% CI 0.67–0.89 without GLP‐1RA; P‐interaction = 0.79) irrespective of baseline GLP‐1RA use. Reduction in UACR with finerenone at Month 4 was –38% in patients with baseline GLP‐1RA use compared with –31% in those without GLP‐1RA use (P‐interaction = 0.03). Overall safety and incidence of hyperkalaemia were similar, irrespective of GLP‐1RA use. Conclusions: The cardiorenal benefits of finerenone on composite cardiovascular and kidney outcomes and UACR reduction in patients with CKD and T2D appear to be maintained, regardless of GLP‐1RA use. Subsequent studies are needed to investigate any potential benefit of this combination. [ABSTRACT FROM AUTHOR]

Aims: The primary objective of the TROPHIES observational study is to estimate the duration of treatment on dulaglutide or liraglutide without a significant treatment change by 24 months in patients with type 2 diabetes (T2D) initiating their first injectable treatment with these glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs). This manuscript presents 12‐month interim data. Materials and Methods: TROPHIES is a prospective, non‐comparative, observational study of patients with T2D in Europe, naïve to injectable antihyperglycaemic treatments and initiating dulaglutide or liraglutide. Data on clinical characteristics, GLP‐1 RA persistence and treatment patterns of glucose‐lowering medication were collected at initiation of first injectable therapy and by 12 months. Results: By 12 months, 1014 dulaglutide and 991 liraglutide patients were eligible across France, Germany and Italy. Both cohorts presented a high probability [95% confidence interval (CI)] of GLP‐1 RA persistence [dulaglutide, 0.88 (0.86 to 0.90); liraglutide, 0.83 (0.80 to 0.85)] and reduction in mean glycated haemoglobin percentage (95% CI) from baseline [dulaglutide, −1.18 (−1.27 to −1.08); liraglutide, −1.15 (−1.26 to −1.05)] with 48.2% of dulaglutide and 41.2% of liraglutide patients reaching their individualized glycated haemoglobin percentage target set by the physician at baseline. Mean weight (95% CI) change from baseline was −3.2 kg (−3.6 to −2.8) for dulaglutide and −3.4 kg (−3.9 to −3.0) for liraglutide. Slight changes in concomitant medications were observed compared with baseline. Conclusions: In the real‐world setting, dulaglutide and liraglutide cohorts achieved good persistence with similarly improved glycaemic control that was accompanied by weight loss at 12 months, consistent with previous clinical trial results. [ABSTRACT FROM AUTHOR]

Aim: To examine whether sequential administration of (d‐Arg35)‐sea lamprey peptide tyrosine tyrosine (1–36) (SL‐PYY) and the glucagon‐like peptide‐1 (GLP‐1) mimetic, liraglutide, has beneficial effects in diabetes. Methods: SL‐PYY is an enzymatically stable neuropeptide Y1 receptor (NPY1R) agonist known to induce pancreatic beta‐cell rest and improve overall beta‐cell health. We employed SL‐PYY and liraglutide to induce appropriate recurrent periods of beta‐cell rest and stimulation, to assess therapeutic benefits in high fat fed (HFF) mice with streptozotocin (STZ)‐induced insulin deficiency, namely HFF‐STZ mice. Results: Previous studies confirm that, at a dose of 0.25 nmol/kg, liraglutide exerts bioactivity over an 8‐12 hour period in mice. Initial pharmacokinetic analysis revealed that 75 nmol/kg SL‐PYY yielded a similar plasma drug time profile. When SL‐PYY (75 nmol/kg) and liraglutide (0.25 nmol/kg) were administered sequentially at 08:00 AM and 08:00 PM, respectively, to HFF‐STZ mice for 28 days, reductions in energy intake, body weight, circulating glucose, insulin and glucagon were noted. Similarly positive, but slightly less striking, effects were also apparent with twice‐daily liraglutide‐only therapy. The sequential SL‐PYY and liraglutide treatment also improved insulin sensitivity and glucose‐induced insulin secretory responses, which was not apparent with liraglutide treatment, although benefits on glucose tolerance were mild. Interestingly, combined therapy also elevated pancreatic insulin, decreased pancreatic glucagon and enhanced the plasma insulin/glucagon ratio compared with liraglutide alone. This was not associated with an enhancement of beneficial changes in islet cell areas, proliferation or apoptosis compared with liraglutide alone, but the numbers of centrally stained glucagon‐positive islet cells were reduced by sequential combination therapy. Conclusion: These data show that NPY1R‐induced intervals of beta‐cell rest, combined with GLP‐1R–stimulated periods of beta‐cell stimulation, should be further evaluated as an effective treatment option for obesity‐driven forms of diabetes. [ABSTRACT FROM AUTHOR]

Aim: To clarify the importance of HbA1c reduction and antidiabetic drug use in preventing major adverse cardiovascular events (MACE) for patients with type 2 diabetes (T2D). Materials and Methods: We conducted an updated systematic review of contemporary large randomized controlled trials assessing the relative efficacy and safety of antidiabetic drugs with less hypoglycaemia risk in adult T2D patients. Mixed‐effects meta‐regression was performed to examine the associations of HbA1c reduction with subsequent risk of macrovascular and microvascular events. We evaluated the potential mediating role of HbA1c reduction in the relationship between antidiabetic drugs and MACE. Results: Eighteen placebo‐controlled trials comprising 155 610 participants were included. The effects of treatment differed among antidiabetic drug classes for most adverse outcomes with high heterogeneity (I2: 63.7%‐95.8%). Mean HbA1c reduction was lowest with dipeptidyl peptidase‐4 inhibitors (0.30%), followed by sodium‐glucose co‐transporter‐2 inhibitors (0.46%), and was highest with glucagon‐like peptide‐1 receptor agonists (0.58%) and thiazolidinediones (0.60%). Lower relative risks of MACE were significantly associated with larger reductions in achieved HbA1c (β −0.3182; 95% CI: −0.5366 to −0.0998; P =.0043), even after adjusting for drug classes. When considering HbA1c lowering as a mediator to be controlled, beneficial effects owing to specific antidiabetic treatment for MACE were not observed (χ2 = 1.4494; P =.6940). The proportion mediated by HbA1c reduction was 50.0%‐63.5% for these antidiabetic agents. Conclusions: The main benefits of antidiabetic agents might result from the reduction in blood sugar levels and are generally independent of drugs used. Risk reduction in MACE was proportional to the magnitude of HbA1c decrease conferred by antidiabetic agents with less hypoglycaemic hazard. [ABSTRACT FROM AUTHOR]

Aims: To describe the in vitro characteristics and antidiabetic in vivo efficacy of the novel glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) GL0034. Materials and Methods: Glucagon‐like peptide‐1 receptor (GLP‐1R) kinetic binding parameters, cyclic adenosine monophosphate (cAMP) signalling, endocytosis and recycling were measured using HEK293 and INS‐1832/3 cells expressing human GLP‐1R. Insulin secretion was measured in vitro using INS‐1832/3 cells, mouse islets and human islets. Chronic administration studies to evaluate weight loss and glycaemic effects were performed in db/db and diet‐induced obese mice. Results: Compared to the leading GLP‐1RA semaglutide, GL0034 showed increased binding affinity and potency‐driven bias in favour of cAMP over GLP‐1R endocytosis and β‐arrestin‐2 recruitment. Insulin secretory responses were similar for both ligands. GL0034 (6 nmol/kg) led to at least as much weight loss and lowering of blood glucose as did semaglutide at a higher dose (14 nmol/kg). Conclusions: GL0034 is a G protein‐biased agonist that shows powerful antidiabetic effects in mice, and may serve as a promising new GLP‐1RA for obese patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims: To determine the effect of glucagon‐like peptide 1 receptor agonists (GLP‐1RAs) on albuminuria in adult patients with type 2 diabetes mellitus (T2DM). Methods: Medline Ovid, Scopus, Web of Science, EMCARE and CINAHL databases from database inception until 27 January 2022. Studies were eligible for inclusion if they were randomized controlled trials that involved treatment with a GLP‐1RA in adult patients with T2DM and assessed the effect on albuminuria in each treatment arm. Data extraction was conducted independently by three individual reviewers. The PRISMA guidelines were followed regarding data extraction and quality assessment. Data were pooled using a random effects inverse variance model and all analysis was carried out with RevMan 5.4 software. The Jadad scoring tool was employed to assess the quality of evidence and risk of bias in the randomized controlled trials. Results: The initial search revealed 2419 articles, of which 19 were included in this study. An additional three articles were identified from hand‐searching references of included reviews. Therefore, in total, 22 articles comprising 39 714 patients were included. Meta‐analysis suggested that use of GLP1‐RAs was associated with a reduction in albuminuria in patients with T2DM (weighted mean difference −16.14%, 95% CI −18.42 to −13.86%; p <.0001) compared with controls. Conclusions: This meta‐analysis indicates that GLP‐1RAs are associated with a significant reduction in albuminuria in adult patients with T2DM when compared with placebo. [ABSTRACT FROM AUTHOR]

Triglyceride content of the SAT biopsy and plasma lipids SAT triglyceride content was unchanged during infusion of GLP-1 + GIP(3-30)NH SB 2 sb compared with GLP-1 + placebo (Figure 1L). Keywords: GIP; GIP receptor antagonist; GLP-1; incretin hormones; incretins; obesity; type 2 diabetes EN GIP GIP receptor antagonist GLP-1 incretin hormones incretins obesity type 2 diabetes 1882 1887 6 08/04/22 20220901 NES 220901 BACKGROUND In type 2 diabetes (as well as other forms of diabetes), the insulinotropic effect of exogenous glucose-dependent insulinotropic polypeptide (GIP) is markedly reduced or even lost, in contrast to that of exogenous glucagon-like peptide-1 (GLP-1), which retains its insulinotropic effect to a greater degree.1,2 Optimized glycaemic control improves the insulinotropic effect of exogenous GIP in patients with type 2 diabetes, suggesting that diabetic GIP resistance is a reversible phenomenon.3,4 Furthermore, we recently showed that endogenous GIP has insulinotropic properties in type 2 diabetes.5 Several GLP-1 receptor (GLP-1R) agonists (GLP-1RAs) are now approved for the treatment of type 2 diabetes and obesity.6 Previously, GIP was described as an obesity hormone.7,8 In recent years, paradoxically, both GIP receptor (GIPR) agonism and GIPR antagonism have shown anti-obesity effects when combined with GLP-1RAs in preclinical models.9-13 Potentially, the beneficial effects of GIPR agonists arise from functional GIPR antagonism elicited by GIPR internalization.14,15 Several new treatment modalities for type 2 diabetes and obesity combining GLP-1RA with GIPR agonism or GIPR antagonism are emerging.16 However, no human data are currently available describing the combined effects of GLP-1RAs and GIPR antagonism. Peptide infusions Plasma concentrations of total GLP-1 reached a steady state of 55.1 ± 6.0 pmol/L during GLP-1 + GIP(3-30)NH SB 2 sb and 57.0 ± 6.5 pmol/L during GLP-1 + placebo (Figure 1A). [Extracted from the article]

Aims: To evaluate the time‐varying cardio‐protective effect of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) using pooled data from eight contemporary cardiovascular outcome trials using the difference in the restricted mean survival time (ΔRMST) as the effect estimate. Material and Methods: Data from eight multinational cardiovascular outcome randomized controlled trials of GLP‐1RAs for type 2 diabetes mellitus were pooled. Flexible parametric survival models were fit from published Kaplan‐Meier plots. The differences between arms in RMST (ΔRMST) were calculated at 12, 24, 36 and 48 months. ΔRMST values were pooled using an inverse variance‐weighted random‐effects model; heterogeneity was tested with Cochran's Q statistic. The endpoints studied were: three‐point major adverse cardiovascular events (MACE), all‐cause mortality, stroke, cardiovascular mortality and myocardial infarction. Results: We included eight large (3183‐14 752 participants, total = 60 080; median follow‐up range: 1.5 to 5.4 years) GLP‐1RA trials. Among GLP‐1RA recipients, we observed an average delay in three‐point MACE of 0.03, 0.15, 0.37 and 0.63 months at 12, 24, 36 and 48 months, respectively. At 48 months, while cardiovascular mortality was comparable in both arms (pooled ΔRMST 0.163 [−0.112, 0.437]; P = 0.24), overall survival was higher (ΔRMST = 0.261 [0.08‐0.43] months) and stroke was delayed (ΔRMST 0.22 [0.15‐0.33]) in patients receiving GLP‐1RAs. Conclusions: Glucagon‐like peptide‐1 receptor agonists may delay the occurrence of MACE by an average of 0.6 months at 48 months, with meaningfully larger gains in patients with cardiovascular disease. This metric may be easier for clinicians and patients to interpret than hazard ratios, which assume a knowledge of absolute risk in the absence of treatment. [ABSTRACT FROM AUTHOR]

Aims: To examine the comparative effectiveness of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium‐glucose cotransporter‐2 (SGLT2) inhibitors for select cardiovascular outcomes and to examine whether the relative risks varied across different patient subgroups in patients with type 2 diabetes. Materials and Methods: We conducted a nationwide cohort study of patients with type 2 diabetes who initiated GLP‐1RAs or SGLT2 inhibitors between 2012 and 2018 in Taiwan. The study outcomes included myocardial infarction and total stroke, further classified into ischaemic or haemorrhagic stroke. We estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) for each outcome, comparing GLP‐1RAs with SGLT2 inhibitors using Cox proportional hazards models after 1:1 propensity‐score (PS) matching. We also examined if there was effect modification by age, underlying chronic kidney disease, or coexisting cardiovascular disease in prespecified subgroup analyses. Results: Among 26 032 PS‐matched patients, GLP‐1RA initiators and SGLT2 inhibitor initiators showed similar risks of myocardial infarction (HR 0.99, 95% CI 0.65‐1.52), total stroke (HR 0.90, 95% CI 0.69‐1.17), ischaemic stroke (HR 0.86, 95% CI 0.65‐1.14) and haemorrhagic stroke (HR 0.88, 95% CI 0.63‐1.25). However, GLP‐1RA treatment was associated with an increased risk of total stroke (HR 1.76, 95% CI 1.06‐2.94) and ischaemic stroke (HR 1.88, 95% CI 1.09‐3.23) among patients with chronic kidney disease, but not among patients without chronic kidney disease. GLP‐1RA therapy seemed to have a lower risk of haemorrhagic stroke among patients with cardiovascular disease (HR 0.64, 95% CI 0.43‐0.97), but not in patients without cardiovascular disease. Conclusions: Glucagon‐like peptide‐1 receptor agonists and SGLT2 inhibitors appeared to have comparable effectiveness with regard to several cardiovascular outcomes overall, but their comparative effectiveness may vary in certain patient subgroups. [ABSTRACT FROM AUTHOR]

Aims: To provide real‐world data on the addition of basal insulin (BI) in people with type 2 diabetes mellitus (PWD2) suboptimally controlled with glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) therapy. However, real‐world data on the addition of BI to GLP‐1RA therapy are limited. Materials and Methods: We used a US electronic medical record data source (IBM® Explorys®) that includes approximately 4 million PWD2 to assess the real‐world impact of adding the second‐generation BI analogue insulin glargine 300 U/mL (Gla‐300) to GLP‐1RA therapy. Insulin‐naïve PWD2 receiving GLP‐1RAs who also received Gla‐300 between March 1, 2015 and September 30, 2019 were identified; participants were required to have data for ≥12 months before, and ≥6 months after, addition of Gla‐300. Results: The mean (standard deviation [SD]) age of participants (N = 271) was 57.9 (10.8) years. Baseline glycated haemoglobin (HbA1c) was 9.16% and was significantly reduced (−0.97 [SD 1.60]%; P < 0.0001) after addition of Gla‐300; a significant increase in the proportion of PWD2 achieving HbA1c control was observed after addition of Gla‐300 (HbA1c <7.0%: 4.80% vs. 22.14%, P < 0.0001; HbA1c <8.0%: 19.56% vs. 51.29%, P < 0.0001). The incidence of overall (8.49% vs. 9.59%; P = 0.513) and inpatient/emergency department (ED)‐associated hypoglycaemia (0.37% vs. 0.74%; P = 1.000), as well as overall (0.33 vs. 0.46 per person per year [PPPY]; P = 0.170) and inpatient/ED‐associated hypoglycaemia events (0.01 vs. 0.04 PPPY; P = 0.466) were similar before and after addition of Gla‐300. Conclusions: In US real‐world clinical practice, adding Gla‐300 to GLP‐1RA significantly improved glycaemic control without significantly increasing hypoglycaemia in PWD2. Further research into the effect of adding Gla‐300 to GLP‐1RA therapy is warranted. [ABSTRACT FROM AUTHOR]

Aims: Most trials leading to the approval of glucagon‐like peptide receptor agonists (GLP‐1RAs) and sodium‐glucose co‐transporter‐2 inhibitors (SGLT2is) were primarily designed to confirm their non‐inferiority to placebo (commonly using an upper 95% confidence limit threshold of 1.3) and, if confirmed, superiority (threshold 1): this asymmetry of margins (1 vs. 1.3) favours the active intervention. We aimed to quantify the probability of clinical superiority of the active treatment by applying the same threshold used to claim non‐inferiority. Materials and Methods: We searched PubMed and Cochrane CENTRAL for cardiorenal outcome trials in subjects with type 2 diabetes published before 5 December 2021, to reconstruct from Kaplan‐Meier plots individual‐level data for the primary outcome or all‐cause mortality. We calculated Bayesian posterior densities to obtain the probability for a treatment effect (hazard ratio) <0.769, which is symmetric to the 1.3 threshold (i.e. its reciprocal 1/1.3), emulating a scenario where the active treatment is placebo and placebo is the active treatment. Results: We extracted data from 27 Kaplan‐Meier plots (18 for the primary outcome, nine for mortality). Probabilities of clinical superiority to placebo varied significantly: for GLP‐1RAs, from a minimum of 0% to a maximum of 69% for the primary outcome and from 0% to 8% for mortality; corresponding estimates for SGLT2is were 0% to 96% and 0% to 93%. Probabilities were on average greater for SGLT2is, particularly in trials investigating kidney or heart failure outcomes. Conclusions: The probability of clinical superiority to placebo varies widely across trials previously reported as showing superiority of GLP‐1RAs or SGLT2is compared with placebo. These results showed within‐ and between‐class differences, highlight the drawbacks of a binary interpretation of the results, particularly in the context of the current designs of non‐inferiority trials, and have implications for decision makers and future clinical recommendations. [ABSTRACT FROM AUTHOR]

Aim: Multiple studies support the efficacy of combining a glucagon‐like peptide 1 receptor agonist (GLP‐1RA) with basal insulin in people with type 2 diabetes inadequately controlled on dual/triple oral therapy. Fixed‐ratio combinations of basal insulin + GLP‐1RA represent a further advance to facilitate management. We assessed the impact of fixed‐ratio combination basal insulin + GLP‐1RA treatment on β‐cell function. Materials and Methods: We analysed data from 351 participants in the LixiLan‐G trial (NCT02787551) randomized to receive iGlarLixi (insulin glargine 100 U/ml + lixisenatide) or to continue daily/weekly GLP‐1RA, both on top of metformin. Participants received a 2‐h meal tolerance test before randomization and at study end (26 weeks), with timed plasma glucose and C‐peptide determinations. β‐cell function parameters were resolved using mathematical modelling. Results: In the GLP‐1RA group (n = 162), both body weight and glycated haemoglobin decreased at week 26, yet none of the insulin secretion/β‐cell function parameters changed significantly. In contrast, in the iGlarLixi group (n = 189), glycated haemoglobin decreased significantly more than in the GLP‐1RA group (p <.0001) despite an increase in body weight (+1.7 ± 3.9 kg, p <.0001). Fasting and stimulated insulin secretion decreased at Week 26 (both p <.0001 vs. GLP‐1RA), while β‐cell glucose sensitivity increased by a median 35% (p =.0032 vs. GLP‐1RA). The incremental meal tolerance test glucose area showed a larger reduction with iGlarLixi versus GLP‐1RA (p <.0001). Conclusions: In people with type 2 diabetes on metformin, 26‐week treatment with iGlarLixi resulted in a marked improvement in β‐cell function concomitant with sparing of endogenous insulin release and a reduction in meal absorption. [ABSTRACT FROM AUTHOR]

Exogenous insulin has been the mainstay treatment for individuals living with type 1 diabetes (T1D). Although there has been tremendous growth in both pharmacological and technological advancements, insulin monotherapy has proven to be insufficient for maintaining optimal glycaemic targets for most adults with T1D. At present, there is still no breakthrough for the treatment of T1D. Adjunctive pharmacotherapies might therefore complement insulin management to achieve better glycaemic control, while possibly offering additional benefits. Recent interest in re‐purposing glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), a leading antihyperglycaemic medication class approved for type 2 diabetes, has prompted the field to seek extended potential for the T1D population. The adjunctive use of GLP‐1RAs has been at the forefront of T1D research, albeit with some conflicting trial findings to date. However, the potential of GLP‐1 agonism for T1D may have been underestimated, possibly from missed opportunities or categorized effects. Moreover, some GLP‐1RAs have demonstrated extra‐pancreatic potential with emerging multi‐organ protection involving the heart, kidneys, liver and brain in varied cohorts, which may bode well for the growing T1D profile of comorbid complications. This narrative review aims to summarize and critically appraise the current evidence‐based literature from large‐scale randomized controlled trials and closed‐loop system pilot studies that examined GLP‐1RAs as adjunctive therapy for T1D. Furthermore, we outline uncharted opportunities with GLP‐1 agonism using versatile approaches in selected T1D populations that may inspire and re‐direct future research in this field. [ABSTRACT FROM AUTHOR]

Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) have become agents of choice for people with type 2 diabetes (T2D) with established cardiovascular disease or in high‐risk individuals. With currently available GLP‐1 RAs, 51%‐79% of subjects achieve an HbA1c target of less than 7.0% and 4%‐27% lose 10% of body weight, illustrating the need for more potent agents. Three databases (PubMed, Cochrane, Web of Science) were searched using the MESH terms 'glucagon‐like peptide‐1 receptor agonist', 'glucagon receptor agonist', 'glucose‐dependent insulinotropic peptide', 'dual or co‐agonist', and 'tirzepatide'. Quality of papers was scored using PRISMA guidelines. Risk of bias was evaluated using the Cochrane assessment tool. An HbA1c target of less than 7.0% was attained by up to 80% with high‐dose GLP‐1 RAs and up to 97% with tirzepatide, with even up to 62% of people with T2D reaching an HbA1c of less than 5.7%. A body weight loss of 10% or greater was obtained by up to 50% and up to 69% with high‐dose GLP‐1 RAs or tirzepatide, respectively. The glucose‐ and weight‐lowering effects of the GLP‐1/glucagon RA cotadutide equal those of liraglutide 1.8 mg. Gastrointestinal side effects of high‐dose GLP‐1 RAs and co‐agonists occurred in 30%‐70% of patients, mostly arising within the first 2 weeks of the first dose, being mild or moderate in severity, and transient. The development of high‐dose GLP‐1 RAs and the dual GLP‐1/glucose‐dependent insulinotropic peptide RA tirzepatide resulted in increasing numbers of people reaching HbA1c and body weight targets, with up to 62% attaining normoglycaemia with 15‐mg tirzepatide. Whether this will also translate to better cardiovascular outcomes and affect treatment guidelines remains to be studied. [ABSTRACT FROM AUTHOR]

Aim: To assess the comparative cardiovascular and renal effectiveness of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors versus glucagon‐like peptide‐1 (GLP‐1) receptor agonists in routine clinical practice. Materials and Methods: A cohort study of nationwide registers from Sweden, Denmark, and Norway, including 87 525 new users of SGLT2 inhibitors and 63 921 new users of GLP‐1 receptor agonists, was conducted using data from 2013‐2018. Co‐primary outcomes, analysed using an intention‐to‐treat exposure definition, were major adverse cardiovascular events (MACE; myocardial infarction, stroke, and cardiovascular death), heart failure (hospitalization or death because of heart failure), and serious renal events (renal replacement therapy, hospitalization for renal events, and death from renal causes). Results: Use of SGLT2 inhibitors versus GLP‐1 receptor agonists was associated with a higher risk of MACE (adjusted incidence rate: 15.2 vs. 14.4 events per 1000 person‐years; HR 1.07 [95% CI 1.01‐1.15]), a similar risk of heart failure (6.0 vs. 6.0 events per 1000 person‐years; HR 1.02 [0.92‐1.12]), and a lower risk of serious renal events (2.9 vs. 4.0 events per 1000 person‐years; HR 0.76 [0.66‐0.87]). In as‐treated analyses, the HR (95% CI) was 1.11 (1.00‐1.24) for MACE, 0.88 (0.74‐1.04) for heart failure, and 0.60 (0.47‐0.77) for serious renal events. In secondary outcome analyses, use of SGLT2 inhibitors versus GLP‐1 receptor agonists was not associated with statistically significant differences for the risk of myocardial infarction (HR 1.09 [95% CI 1.00‐1.19]), cardiovascular death (HR 0.97 [95% CI 0.84‐1.12]), death from renal causes (HR 0.75 [95% CI 0.41‐1.35]), or any cause death (HR 1.01 [95% CI 0.94‐1.09]), while the risk of stroke was higher (HR 1.14 [95% CI 1.03‐1.26]), and the risk of renal replacement therapy (HR 0.74 [95% CI 0.56‐0.97]) and hospitalization for renal events (HR 0.75 [95% CI 0.65‐0.88]) were lower among users of SGLT2 inhibitors. Conclusions: Use of SGLT2 inhibitors versus GLP‐1 receptor agonists was associated with a similar risk of heart failure and a lower risk of serious renal events, while use of GLP‐1 receptor agonists versus SGLT2 inhibitors was associated with a slightly lower risk of MACE. In as‐treated analyses, the associations with MACE and serious renal events increased in magnitude, and the HR for heart failure tended towards a protective association for SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

C) Effects of GLP-1RA's on GGT concentration in patients with NASH compared to placebo. BACKGROUND Non-alcoholic steatohepatitis (NASH) is manifested by ectopic fat accumulation on the liver tissue without a secondary cause. FIGURE S1: PRISMA 2009 flow diagram (8).FIGURE S2: A) Effects of GLP-1RA's on AST concentration in patients with NASH compared to placebo. In addition, we compared for the first time the secondary markers of NASH other than aminotransferase levels, which may be utilized to supplement the results of GLP-1RA treatment on histological aspects of NASH. [Extracted from the article]

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]

In a phase 2 trial of once‐weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo, the dual glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1 receptor agonist tirzepatide dose‐dependently reduced HbA1c and body weight in patients with type 2 diabetes. In this post hoc analysis, inflammation, endothelial dysfunction, and cellular stress biomarkers were measured at baseline, 4, 12, and 26 weeks to evaluate the additional effects of tirzepatide on cardiovascular risk factors. At 26 weeks, tirzepatide 10 and 15 mg decreased YKL‐40 (also known as chitinase‐3 like‐protein‐1), intercellular adhesion molecule 1 (ICAM‐1), leptin, and growth differentiation factor 15 levels versus baseline, and YKL‐40 and leptin levels versus placebo and dulaglutide. Tirzepatide 15 mg also decreased ICAM‐1 levels versus placebo and dulaglutide, and high‐sensitivity C‐reactive protein (hsCRP) levels versus baseline and placebo, but not dulaglutide. GlycA, interleukin 6, vascular cell adhesion molecule 1, and N‐terminal‐pro hormone B‐type natriuretic peptide levels were not significantly changed in any group. YKL‐40, hsCRP, and ICAM‐1 levels rapidly decreased within 4 weeks of treatment with tirzepatide 10 and 15 mg, whereas the decrease in leptin levels was more gradual and did not plateau by 26 weeks. In this hypothesis‐generating exploratory analysis, tirzepatide decreased several biomarkers that have been associated with cardiovascular risk. [ABSTRACT FROM AUTHOR]