Louisville Metabolic and Atherosclerosis Research Center

AimsApproximately two-thirds of obesity-related mortality is attributable to cardiovascular disease (CVD). The aim of this analysis is to examine predicted CVD risk reduction following weight loss in persons with obesity for primary prevention between tirzepatide and semaglutide, and projected CVD events that could be potentially prevented in the USA.Methods and resultsSURMOUNT-5 was a Phase 3b, open-label, randomized trial conducted in participants with obesity and without Type-2 diabetes, comparing tirzepatide (10 or 15 mg) with semaglutide (1.7 or 2.4 mg) and administered via weekly subcutaneous injection. Predicted 10-year CVD risks were compared between treatments at baseline and up to 72 weeks post-treatment among participants without prior CVD. The impact of cardiovascular risk reduction was estimated as the projected preventable CVD events over 10 years for tirzepatide and semaglutide in the USA. The average predicted 10-year CVD risk score before treatment was 9.3%. Treatment with tirzepatide was associated with significantly greater reduction in predicted 10-year CVD risk compared with semaglutide (absolute reduction from baseline of 2.4% and 1.4%, respectively, P < 0.001). Translating risk reduction to the US population who met treatment eligibility criteria and without prior CVD (∼85 million), an estimated 2 million CVD events could be potentially prevented over 10 years after 72 weeks of tirzepatide treatment, vs. 1.15 million with semaglutide.ConclusionIn SURMOUNT-5, treatment with tirzepatide was associated with greater predicted 10-year CVD risk reduction compared with semaglutide. This post hoc analysis suggests tirzepatide treatment may provide greater benefit in primary prevention of CVD than semaglutide in people with obesity and overweight.RegistrationClinicalTrials.gov: NCT05822830

BackgroundMaridebart 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.MethodsWe 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.ResultsWe 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.ConclusionsIn 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.)

AimsThis randomized, double‐blind, placebo‐controlled Phase 2b study aimed to assess the efficacy, safety, and tolerability of danuglipron (PF‐06882961), an oral small‐molecule glucagon‐like peptide‐1 (GLP‐1) receptor agonist, in adults with obesity.Materials and MethodsEligible participants (aged 18–75 years; with obesity, without diabetes) were randomized to receive danuglipron or placebo twice daily (BID) for 26 or 32 weeks. Danuglipron was escalated to doses of 40–200 mg BID in 1‐, 2‐, or 4‐week intervals. Assessments included body weight, waist circumference, and safety evaluations.ResultsOverall, 628 participants were randomized; of 626 receiving study treatment (placebo, n = 90; danuglipron, n = 536), 39.3% completed treatment. Approximately 38% of participants discontinued treatment because of adverse events (AEs) and 22% discontinued for other reasons. The primary endpoint was the change in weight from baseline to the end of treatment; all danuglipron groups demonstrated statistically significant reductions with least squares mean percentage decreases from baseline ranging from −5.0% (90% confidence interval [CI] −6.8%, −3.2%) to −12.9% (90% CI −16.1%, −9.5%) relative to placebo. Danuglipron was considered safe. Consistent with the mechanism, the most frequently reported events were nausea and vomiting, and increased rates of gastrointestinal AEs were generally observed at higher doses. Most events were reported as mild, and no other dose‐related trends were observed in safety endpoints.ConclusionsIn participants with obesity, danuglipron resulted in statistically significant and clinically meaningful reductions in body weight versus placebo over 26 or 32 weeks. The overall safety profile observed in this study was consistent with expectations for the mechanism, although discontinuation rates due to AEs were higher than anticipated across all treatment groups, including placebo.ClinicalTrials.gov identifier: NCT04707313.

IntroductionBatoclimab is an anti-neonatal fragment crystallizable receptor monoclonal antibody in clinical development for the treatment of autoimmune diseases. In phase II trials, batoclimab resulted in dose-dependent reductions in pathogenic immunoglobulin G autoantibodies; however, dose-related increases in low-density lipoprotein cholesterol and other lipids were observed.ObjectiveThis study examined the relationship between batoclimab treatment and lipid levels, and whether increases in low-density lipoprotein cholesterol could be mitigated by coadministration with atorvastatin, a widely used cholesterol-lowering agent.MethodsIn this phase I, randomized, fixed-sequence, single-blind trial, 70 healthy participants received subcutaneous injections of batoclimab at various doses or placebo for 6 weeks. Open-label oral atorvastatin was coadministered in a subset of participants receiving batoclimab 340 mg or 680 mg weekly, starting 14 days before the first dose of the study drug, and continuing through the 6-week treatment period and 8-week safety follow-up. Key endpoints included changes in lipid parameters and atorvastatin pharmacokinetics.ResultsDose-dependent increases in total cholesterol and low-density lipoprotein cholesterol were observed with batoclimab doses ≥ 255 mg weekly, comparable to previous observations, whereas coadministration of atorvastatin 10 mg or 40 mg daily mitigated these changes. Batoclimab had little effect on atorvastatin pharmacokinetics. Dose-dependent decreases in serum albumin up to 37% were observed with batoclimab doses ≥ 255 mg weekly, returning to near-baseline levels 4 weeks after stopping batoclimab. As expected, coadministration of atorvastatin did not meaningfully impact the albumin level. The majority of adverse events were mild in severity.ConclusionsAtorvastatin can mitigate clinically significant increases in low-density lipoprotein cholesterol that may occur with batoclimab treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-025-01549-2.

Patients with coronary artery disease (CAD) and diabetes are identified as a high cardiovascular risk group both in Russia and abroad. Having similar paths of development and progression of atherosclerosis and atherothrombosis, these diseases potentiate each other's thrombogenesis mechanisms. As a result, cardiovascular ischemic events occur, making a significant contribution to the mortality rates of this group of patients. Influencing the risk of thrombus formation is one of the key links on the way to improving the prognosis of patients with CAD and diabetes. Modern antithrombotic therapy, including not only the antiplatelet agent aspirin, but also the anticoagulant rivaroxaban at a dose of 2,5 mg, allows for the maximum impact on the development of atherothrombosis, thereby reducing the risks of cardiovascular events and all-cause death. The aim of the review was to analyze the potential of reducing the all-cause death risk by prescribing the main drug groups that are part of the therapy of patients with CAD and diabetes.

To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus. This was a phase 3, multicenter, open-label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment-induced anti-insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment-induced AIA development to the prespecified margins. The percentages of participants positive for treatment-induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of -2.1 percentage points and a 90% CI (-7.6%, 3.5%) (predefined similarity margins: -10.7%, 10.7%). The difference in glycated haemoglobin was -0.08% (90% CI, -0.23, 0.06). The overall percentage of participants with any treatment-emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups. GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy,and safety, based on the current study.