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In patients with type 2 diabetes and chronic kidney disease, weekly semaglutide significantly reduced risks of major kidney events, cardiovascular events, and death from any cause while slowing loss of kidney function.

Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide produced greater reductions in symptoms, physical limitations, and body weight than placebo at 1 year.

Tirzepatide, a dual incretin agonist of the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors, has favorable effects on glycemic control and body weight. The effects on cardiovascular outcomes are uncertain. We conducted an active-comparator-controlled, double-blind, noninferiority trial in which patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomly assigned in a 1:1 ratio to receive a weekly subcutaneous injection of tirzepatide (up to 15 mg) or dulaglutide (1.5 mg), an agent that has been shown to reduce the incidence of cardiovascular events. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke and was tested for noninferiority of tirzepatide to dulaglutide with a margin of 1.05 for the upper limit of the 95.3% confidence interval for the hazard ratio. An upper limit of less than 1.00 was considered to indicate superiority of tirzepatide to dulaglutide. A total of 13,299 patients underwent randomization; 134 were subsequently excluded because they did not meet inclusion criteria. The modified intention-to-treat population thus included 6586 patients in the tirzepatide group and 6579 in the dulaglutide group. The mean (±SD) age of the patients was 64.1±8.8 years, 29.0% were women, the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 32.6±5.5, the mean glycated hemoglobin level was 8.4±0.9%, and the mean duration of diabetes was 14.7±8.8 years. A primary end-point event occurred in 801 patients (12.2%) in the tirzepatide group and 862 (13.1%) in the dulaglutide group (hazard ratio, 0.92; 95.3% confidence interval, 0.83 to 1.01; P = 0.003 for noninferiority; P = 0.09 for superiority). The incidence of adverse events appeared to be similar in the two groups, although more gastrointestinal adverse events were observed in the tirzepatide group. Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, tirzepatide was noninferior to dulaglutide with respect to a composite of death from cardiovascular causes, myocardial infarction, or stroke. (Funded by Eli Lilly; SURPASS-CVOT ClinicalTrials.gov number, NCT04255433.).

Dulaglutide and liraglutide, both glucagon-like peptide-1 (GLP-1) receptor agonists, improve glycaemic control and reduce weight in patients with type 2 diabetes. In a head-to-head trial, we compared the safety and efficacy of once-weekly dulaglutide with that of once-daily liraglutide in metformin-treated patients with uncontrolled type 2 diabetes. We did a phase 3, randomised, open-label, parallel-group study at 62 sites in nine countries between June 20, 2012, and Nov 25, 2013. Patients with inadequately controlled type 2 diabetes receiving metformin (≥1500 mg/day), aged 18 years or older, with glycated haemoglobin (HbA1c) 7·0% or greater (≥53 mmol/mol) and 10·0% or lower (≤86 mmol/mol), and body-mass index 45 kg/m2 or lower were randomly assigned to receive once-weekly dulaglutide (1·5 mg) or once-daily liraglutide (1·8 mg). Randomisation was done according to a computer-generated random sequence with an interactive voice response system. Participants and investigators were not masked to treatment allocation. The primary outcome was non-inferiority (margin 0·4%) of dulaglutide compared with liraglutide for change in HbA1c (least-squares mean change from baseline) at 26 weeks. Safety data were collected for a further 4 weeks' follow-up. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01624259. We randomly assigned 599 patients to receive once-weekly dulaglutide (299 patients) or once-daily liraglutide (300 patients). 269 participants in each group completed treatment at week 26. Least-squares mean reduction in HbA1c was −1·42% (SE 0·05) in the dulaglutide group and −1·36% (0·05) in the liraglutide group. Mean treatment difference in HbA1c was −0·06% (95% CI −0·19 to 0·07, pnon-inferiority<0·0001) between the two groups. The most common gastrointestinal adverse events were nausea (61 [20%] in dulaglutide group vs 54 [18%] in liraglutide group), diarrhoea (36 [12%] vs 36 [12%]), dyspepsia (24 [8%] vs 18 [6%]), and vomiting (21 [7%] vs 25 [8%]), with similar rates of study or study drug discontinuation because of adverse events between the two groups (18 [6%] in each group). The hypoglycaemia rate was 0·34 (SE 1·44) and 0·52 (3·01) events per patient per year, respectively, and no severe hypoglycaemia was reported. Once-weekly dulaglutide is non-inferior to once-daily liraglutide for least-squares mean reduction in HbA1c, with a similar safety and tolerability profile. Eli Lilly and Company.

Maridebart cafraglutide (known as MariTide) is a long-acting peptide-antibody conjugate that combines glucagon-like peptide-1 receptor agonism and glucose-dependent insulinotropic polypeptide receptor antagonism and that is intended for the treatment of obesity. We conducted a phase 2, double-blind, randomized, placebo-controlled, dose-ranging trial that included 11 groups as two cohorts. Participants with obesity (obesity cohort) were randomly assigned in a 3:3:3:2:2:2:3 ratio to receive maridebart cafraglutide subcutaneously at a dose of 140, 280, or 420 mg every 4 weeks without dose escalation; 420 mg every 8 weeks without dose escalation; 420 mg every 4 weeks with 4-week dose escalation; 420 mg every 4 weeks with 12-week dose escalation; or placebo. Participants with obesity with type 2 diabetes (obesity-diabetes cohort) were randomly assigned in a 1:1:1:1 ratio to receive maridebart cafraglutide at a dose of 140, 280, or 420 mg every 4 weeks (all without dose escalation) or placebo. The primary end point was the percent change in body weight from baseline to week 52. We enrolled 592 participants. In the obesity cohort (465 participants; female sex, 63%; mean age, 47.9 years; mean body-mass index [BMI, the weight in kilograms divided by the square of the height in meters], 37.9), the mean percent change in body weight from baseline to week 52 on the basis of the treatment policy estimand (intention-to-treat approach) ranged from -12.3% (95% confidence interval [CI], -15.0 to -9.7) to -16.2% (95% CI, -18.9 to -13.5) with maridebart cafraglutide, as compared with -2.5% (95% CI, -4.2 to -0.7) with placebo. In the obesity-diabetes cohort (127 participants; female sex, 42%; mean age, 55.1 years; mean BMI, 36.5), the mean percent change in body weight from baseline to week 52 on the basis of the treatment policy estimand ranged from -8.4% (95% CI, -11.0 to -5.7) to -12.3% (95% CI, -15.3 to -9.2) with maridebart cafraglutide, as compared with -1.7% (95% CI, -2.9 to -0.6) with placebo. The mean change in the glycated hemoglobin level on the basis of the treatment policy estimand in this cohort was -1.2 to -1.6 percentage points in the maridebart cafraglutide groups and 0.1 percentage points in the placebo group. Gastrointestinal adverse events were common with maridebart cafraglutide, although less frequent with dose escalation and a lower starting dose. No unexpected safety signals emerged. In this phase 2 trial, once-monthly maridebart cafraglutide resulted in substantial weight reduction in participants with obesity with or without type 2 diabetes. (Funded by Amgen; ClinicalTrials.gov number, NCT05669599.).

In a trial in patients with cardiovascular disease and overweight or obesity but no diabetes, semaglutide was superior to placebo in lowering the risk of major adverse cardiovascular events at a mean follow-up of 39.8 months.

Aims/hypothesis The aim of this study was to evaluate the efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes insufficiently controlled with diet and exercise alone. Methods The Peptide Innovation for Early Diabetes Treatment (PIONEER) 11 trial was a double-blind, randomised, Phase IIIa trial conducted across 52 sites in the China region (mainland China and Taiwan), Hungary, Serbia and Ukraine. Eligible participants were ≥18 years (≥20 years in Taiwan), had a diagnosis of type 2 diabetes with HbA 1c 53–86 mmol/mol (7.0–10.0%) and were not receiving any glucose-lowering drugs. After a 4-week run-in period in which participants were treated with diet and exercise alone, those who fulfilled the randomisation criteria were randomised (1:1:1:1) using a web-based randomisation system to receive once-daily oral semaglutide 3 mg, 7 mg or 14 mg or placebo for 26 weeks (using a 4-week dose-escalation regimen for the higher doses). Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary and confirmatory secondary endpoints were change from baseline to week 26 in HbA 1c and body weight (kg), respectively. Safety was assessed in all participants exposed to at least one dose of the trial product. Results Between October 2019 and October 2021, a total of 774 participants were screened and 521 participants were randomised to oral semaglutide 3 mg ( n =130), 7 mg ( n =130), 14 mg ( n =130) or placebo ( n =131); most participants (92.5%, n =482) completed the trial, with 39 participants prematurely discontinuing treatment. The number of participants contributing to the trial analyses was based on the total number of participants who were randomised at the beginning of the trial. The majority of participants were male (63.7%), and the mean age of participants was 52 years. At baseline, mean HbA 1c and body weight were 63 mmol/mol (8.0%) and 79.6 kg, respectively. Oral semaglutide resulted in significantly greater reductions in HbA 1c than placebo at week 26 ( p <0.001 for all doses). The estimated treatment differences (ETDs [95% CIs]) for oral semaglutide 3 mg, 7 mg and 14 mg vs placebo were –11 (–13, –9) mmol/mol, –16 (–18, –13) mmol/mol and –17 (–19, –15) mmol/mol, respectively. The corresponding ETDs in percentage points (95% CI) vs placebo were –1.0 (–1.2, –0.8), –1.4 (–1.6, –1.2) and –1.5 (–1.8, –1.3), respectively. Significantly greater reductions in body weight were also observed for oral semaglutide 7 mg and 14 mg than for placebo at week 26 (ETD [95% CI] –1.2 kg [–2.0 kg, –0.4 kg; p <0.01] and –2.0 kg [–2.8 kg, –1.2 kg; p <0.001], respectively), but not for oral semaglutide 3 mg (ETD [95% CI] –0.0 kg [–0.9 kg, 0.8 kg; not significant]). Similar reductions in HbA 1c and body weight were observed in the Chinese subpopulation, which represented 74.9% of participants in the overall population. Adverse events (AEs) occurred in between 65.4% and 72.3% of participants receiving oral semaglutide (for all doses) and 57.3% of participants with placebo. Most AEs were mild to moderate in severity, with few serious AEs reported; the most commonly reported AEs were gastrointestinal-related and were more frequent with semaglutide (all doses) than with placebo. The proportion of AEs was slightly higher in the Chinese subpopulation. Conclusions/interpretation Oral semaglutide resulted in significantly greater reductions in HbA 1c across all doses and in significant body weight reductions for the 7 mg and 14 mg doses when compared with placebo in predominantly Chinese participants with type 2 diabetes insufficiently controlled by diet and exercise alone. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. Trial registration ClinicalTrials.gov NCT04109547. Funding Novo Nordisk A/S. Graphical Abstract

Background Oral semaglutide is a tablet co-formulation of the human glucagon-like peptide-1 (GLP-1) analog semaglutide with the absorption enhancer sodium N -(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The absorption of coadministered oral drugs may be altered due to enhancement by SNAC, potential gastric emptying delay by semaglutide, or other mechanisms. Two one-sequence crossover trials investigated the effect of oral semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin. Methods In trial 1, 52 healthy subjects received lisinopril (20 mg single dose) or warfarin (25 mg single dose) with subsequent coadministration with SNAC alone (300 mg single dose), followed by oral semaglutide 20 mg once daily (steady state). In trial 2, 32 healthy subjects received digoxin (500 μg single dose) or metformin (850 mg twice daily for 4 days), with subsequent coadministration with SNAC alone followed by oral semaglutide, as in trial 1. Results There were no apparent effects of oral semaglutide on area under the plasma concentration–time curve (AUC) and maximum plasma concentration ( C max ) for lisinopril, warfarin, and digoxin. The AUC of metformin was increased by 32% (90% confidence interval 1.23–1.43) by oral semaglutide coadministration versus metformin alone, whereas the C max was unaffected. SNAC alone did not affect exposure of lisinopril, warfarin, digoxin, or metformin. Adverse events were in line with those previously observed for GLP-1 receptor agonists. Conclusions Oral semaglutide or SNAC alone did not appear to affect the exposure of lisinopril, warfarin, or digoxin, and, based on its wide therapeutic index, the higher metformin exposure with oral semaglutide was not considered clinically relevant.

Glucagon, an essential regulator of glucose homeostasis, also modulates lipid metabolism and promotes weight loss, as reflected by the wasting observed in glucagonoma patients. Recently, coagonist peptides that include glucagon agonism have emerged as promising therapeutic candidates for the treatment of obesity and diabetes. We developed a novel stable and soluble glucagon receptor (GcgR) agonist, which allowed for in vivo dissection of glucagon action. As expected, chronic GcgR agonism in mice resulted in hyperglycemia and lower body fat and plasma cholesterol. Notably, GcgR activation also raised hepatic expression and circulating levels of fibroblast growth factor 21 (FGF21). This effect was retained in isolated primary hepatocytes from wild-type (WT) mice, but not GcgR knockout mice. We confirmed this link in healthy human volunteers, where injection of natural glucagon increased plasma FGF21 within hours. Functional relevance was evidenced in mice with genetic deletion of FGF21, where GcgR activation failed to induce the body weight loss and lipid metabolism changes observed in WT mice. Taken together, these data reveal for the first time that glucagon controls glucose, energy, and lipid metabolism at least in part via FGF21-dependent pathways.

In this randomized trial, adults with obesity treated with weekly tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, had major weight loss over 72 weeks.