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 2026·The 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.

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