Combined effect of healthy lifestyle and pharmacotherapy on MACE incidence in T2D

In a prospective cohort study among ~98,000 US veterans with T2D, adoption of 6–8 low-risk lifestyle habits and GLP-1RA use were associated with a lower MACE risk, both independently and in combination.

This summary is based on the publication of Nguyen XT, Li Y, Czernichow S, et al. - Combined associations of GLP-1 receptor agonists and a healthy lifestyle with cardiovascular outcomes among individuals with type 2 diabetes: a prospective cohort study. Lancet Diabetes Endocrinol. 2026 Feb 25:S2213-8587(25)00395-X [Online ahead of print]. doi: 10.1016/S2213-8587(25)00395-X

Introduction and methods

Background

Lifestyle modification is the cornerstone of prevention and management of T2D [1,2]. Yet, the long-term effect of combining a healthy lifestyle with pharmacotherapy, in particular GLP-1RAs, on the incidence of MACE in T2D patients is unknown.

Aim of the study

The study aim was to investigate the independent and combined association of adherence to 8 healthy lifestyle habits and GLP-1RA use on MACE risk in T2D patients.

Methods

In a prospective observational cohort study, 98,261 patients with T2D (5426 women and 92,835 men) enrolled in the US Veterans Affairs’ Million Veteran Program in the period January 10, 2011–September 30, 2023 [3], were included. Participants had no previous history of MI, stroke, or advanced CKD. The 8 low-risk lifestyle habits assessed were: healthy eating habits (assessed with the Healthful Plant-Based Diet Index), being physically active, nonsmoking, having restful sleep, no or moderate alcohol intake, good stress management, social connection and support, and no opioid drug addiction. Total follow-up duration was 632,543 person-years.

Outcome

The endpoint was MACE, defined as a composite outcome of nonfatal stroke, nonfatal MI, or CV death.

Main results

• In Cox proportional hazards regression analysis adjusted for possible confounders, such as age, sex, T2D duration, and several covariates updated during follow-up, patients who adopted all 8 low-risk lifestyle habits had a decreased risk of MACE compared with those adopting ≤1 habit (adjusted HR: 0.40; 95%CI: 0.30–0.54).
• All 8 low-risk lifestyle factors were also independently associated with a lower MACE risk compared with nonadherence.
• Participants who ever received GLP-1RA treatment (n=13,394; 13.6%) had a 16% lower MACE risk than nonusers, who received usual care (n=84,867; 86.4%) (adjusted HR: 0.84; 95%CI: 0.76–0.92).
• Both a healthy lifestyle (i.e., adoption of 6–8 low-risk lifestyle habits) and GLP-1RA use were independently associated with a lower MACE risk, with no evidence of significant interactions (P=0.6 for multiplicative interaction and P=0.08 for additive interaction).
• For the lifestyle/pharmacotherapy combination, the lowest MACE risk was observed in participants who adhered to a healthy lifestyle and took GLP-1RAs compared with those with ≤3 low-risk lifestyle habits and no GLP-1RA use (adjusted HR: 0.57; 95%CI: 0.46–0.71).

Conclusion

This prospective observational cohort study among 98,261 US veterans with T2D demonstrated that adherence to low-risk lifestyle habits and GLP-1RA use were independently associated with a low MACE risk. When combined, a healthy lifestyle (i.e., adoption of 6–8 low-risk lifestyle habits) and GLP1RA treatment were associated with a 43% reduced MACE risk compared with a less healthy lifestyle (i.e., ≤3 low-risk lifestyle habits) and no GLP-1RA use.

Find this article online at Lancet Diabetes Endocrinol.

References

1. ElSayed NA, McCoy RG, Aleppo G, et al, and the American Diabetes Association Professional Practice Committee. 10. Cardiovascular disease and risk management: standards of care in diabetes—2025. Diabetes Care 2025; 48 (suppl 1): S207–38.
2. Vodovotz Y, Barnard N, Hu FB, et al. Prioritized research for the prevention, treatment, and reversal of chronic disease: recommendations from the Lifestyle Medicine Research Summit. Front Med (Lausanne) 2020; 7: 585744.
3. Nguyen XT, Li Y, Wang DD, et al, and the VA Million Veteran Program. Impact of 8 lifestyle factors on mortality and life expectancy among United States veterans: the Million Veteran Program. Am J Clin Nutr 2024; 119: 127–35.