Combined associations of GLP-1 receptor agonists and a healthy lifestyle with cardiovascular outcomes among individuals with type 2 diabetes: a prospective cohort study.

PubMed1 Apr 2026The lancet. Diabetes & endocrinology● 7/10i

Combined associations of GLP-1 receptor agonists and a healthy lifestyle with cardiovascular outcomes among individuals with type 2 diabetes: a prospective cohort study.

Nguyen XT, Li Y, Czernichow S, Rassy N, Houghton SC et al.

GLP-1 receptor agonists combined with comprehensive lifestyle interventions reduced MACE risk by 43% compared to poor lifestyle habits without GLP-1 therapy in adults with type 2 diabetes. Prospective cohort study of 98,261 US veterans over 632,543 person-years of follow-up. This provides the first large-scale evidence quantifying the additive cardiovascular benefit of combining GLP-1 therapy with multiple lifestyle factors beyond diet and exercise alone.

Strategic Signal

This real-world evidence strengthens the medical narrative for GLP-1s beyond glycemic control, positioning them as foundational cardiovascular risk reduction tools when combined with lifestyle interventions. The 16% MACE reduction aligns with dedicated CVOT trials but in a broader, real-world population. Payers like CMS will likely view this favorably for coverage decisions, as it demonstrates value in preventing costly cardiovascular events when paired with lifestyle programs. This supports integrated care models that combine pharmaceutical and behavioral interventions, potentially influencing formulary positioning and value-based contracting discussions.

GLP-1CardiovascularType 2 diabetesReal-world evidence

Original Abstract

BACKGROUND: The long-term combined effects of lifestyle habits and GLP-1 receptor agonists on cardiovascular outcomes are unknown. We aimed to examine the combined association of GLP-1 receptor agonist use and adherence to eight lifestyle habits with cardiovascular outcomes. METHODS: We did a prospective cohort study of individuals with type 2 diabetes enrolled within the US Veterans Affairs' Million Veteran Program between Jan 10, 2011, and Sept 30, 2023. Participants had no previous history of myocardial infarction, stroke, or advanced chronic kidney disease. The eight low-risk lifestyle habits assessed were a higher quality diet, being physically active, not smoking, restful sleep, no heavy alcohol intake, good stress management, social connection and support, and no opioid use disorder. We assessed the risk of major adverse cardiovascular events (MACE), defined as non-fatal stroke or myocardial infarction, or cardiovascular death, according to GLP-1 receptor agonist use and low-risk lifestyle habits using Cox proportional hazard regression models. FINDINGS: Of the 963 753 veterans enrolled, a total of 98 261 participants were included in the study with 632 543 person-years of follow-up, during which 10 443 people developed MACE. Multivariable-adjusted hazard ratio (HR) of MACE was 0·40 (95% CI 0·30-0·54) when comparing participants adhering to all eight low-risk lifestyle habits to those adopting one habit or less. Multivariable-adjusted HR of MACE was 0·84 (0·76-0·92) when comparing users of GLP-1 receptor agonists with non-users. Participants using GLP-1 receptor agonists and adhering to six to eight low-risk lifestyle factors had a 43% lower risk of MACE than did those with three or fewer low-risk lifestyle factors and no GLP-1 receptor agonist use (0·57; 0·46-0·71). INTERPRETATION: Adherence to low-risk lifestyle habits combined with GLP-1 receptor agonist use was associated with a greater reduction in MACE risk than either approach alone, underscoring the importance of integrating lifestyle modification with pharmacotherapy in type 2 diabetes management. FUNDING: Department of Veterans Affairs.

View original source ↗

Related signals

Strategic Signal

FDA1 Apr 2026New Drug Approval (NDA/BLA)High impact● 10/10i

FDA Approves Foundayo (Orforglipron) — New Drug Approval (NDA/BLA)

FDA approved orforglipron (Foundayo, Eli Lilly) for type 2 diabetes -- a once-daily oral small-molecule GLP-1 receptor agonist. Orforglipron is the first non-peptide oral GLP-1 approved in the US; oral semaglutide (Rybelsus, Novo Nordisk) has been approved for T2D since 2019 and expanded to obesity in January 2026. Unlike Rybelsus, orforglipron requires no fasting or water volume restrictions before dosing.

GLP-1Type 2 diabetesPricing/accessEli Lilly Novo Nordisk

Strategic Signal

Clinical Trial19 Mar 2026Phase 3High impact● 9/10i

Efficacy and Safety of Tirzepatide Once Weekly in Participants Without Type 2 Diabetes Who Have Obesity or Are Overweight With Weight-Related Comorbidities: A Randomized, Double-Blind, Placebo-Controlled Trial (SURMOUNT-1)

Phase 3 SURMOUNT-1 tests once-weekly tirzepatide at three doses versus placebo in adults without type 2 diabetes who have obesity or are overweight with comorbidities. The randomized, double-blind trial targets 2,539 participants with primary efficacy assessment at 72 weeks. This represents tirzepatide's pivotal obesity trial against placebo, potentially supporting Eli Lilly's bid to compete directly with Wegovy in the non-diabetic obesity market. A prediabetes subgroup continues long-term to assess diabetes prevention.

Weight lossGLP-1Eli Lilly

Strategic Signal

Clinical Trial17 Apr 2026Phase 3High impact● 8/10i

A Phase 3, Open-Label Study of Once Daily LY3502970 Compared With Insulin Glargine in Adult Participants With Type 2 Diabetes and Obesity or Overweight at Increased Cardiovascular Risk

Phase 3 open-label trial compared once-daily oral orforglipron versus insulin glargine in people with type 2 diabetes and obesity or overweight at increased cardiovascular risk. The study enrolled 2,749 participants with primary endpoint of time to first major adverse cardiovascular event, completed in March 2026. Eli Lilly is positioning orforglipron as a cardiovascular outcomes option in high-risk populations, directly competing with established insulin therapy in this indication. This represents the first cardiovascular outcomes trial for orforglipron following its April 2026 FDA approval for type 2 diabetes.

GLP-1Type 2 diabetesWeight lossCardiovascularEli Lilly

Strategic Signal

Clinical Trial13 Apr 2026Phase 3High impact● 8/10i

A Phase 3, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Retatrutide Compared to Tirzepatide in Adults Who Have Obesity

Eli Lilly is conducting a Phase 3 head-to-head trial comparing retatrutide versus tirzepatide in adults with obesity. The double-blind study targets 800 participants over 89 weeks with primary endpoint of percent body weight change, completing December 2026. This represents the first direct comparison between Eli Lilly's next-generation triple receptor agonist retatrutide and its approved dual agonist tirzepatide in obesity. The trial positions Eli Lilly to potentially establish superiority claims for retatrutide ahead of expected regulatory submissions.

GLP-1Weight lossDrug comparisonsEli Lilly