Massive JAMA Network Meta-Analysis: GLP-1 Drugs Protect Hearts More in Younger People, While SGLT2 Inhibitors Protect More in Older People | Research

The takeaway

In 309,503 type 2 diabetes patients across 601 trials, GLP-1 drugs were more cardioprotective in younger people while SGLT2 inhibitors were more cardioprotective in older people — with no significant sex differences for either drug class.

309,503 patients across 601 trials
The largest network meta-analysis of diabetes drug efficacy by age and sex, revealing that GLP-1 and SGLT2 inhibitors have opposite age-dependent cardiovascular protection patterns

What the researchers found

Across 601 trials (309,503 participants for HbA1c; 168,489 for MACE), GLP-1 receptor agonists showed greater cardiovascular risk reduction in younger vs. older people (HR 1.47 per 30-year age increment, 95% CrI 1.07-2.02 — meaning less benefit with age). Conversely, SGLT2 inhibitors showed greater cardiovascular protection in older vs. younger people (HR 0.76 per 30-year increment, 95% CrI 0.62-0.93). For HbA1c, GLP-1 drugs lowered it more in older patients for mono/dual therapy, while SGLT2 inhibitors lowered it less with increasing age. No consistent sex × treatment interactions were found for either drug class.

Why it matters

Clinicians currently choose between GLP-1 drugs and SGLT2 inhibitors based mainly on comorbidities and patient preference. This study adds age as a decision factor: younger high-cardiovascular-risk patients may benefit more from GLP-1 drugs, while older patients may benefit more from SGLT2 inhibitors for heart protection. This could fundamentally change prescribing algorithms for the tens of millions of people with type 2 diabetes worldwide.

How the study worked

Network meta-analysis and meta-regression using individual participant data (103 trials) and aggregate data from 601 eligible randomized controlled trials. Searched MEDLINE, Embase, and clinical trial registries through August 2024. Multilevel network meta-regression models estimated age × treatment and sex × treatment interactions for HbA1c and MACE outcomes.

What this study cannot tell us

Individual participant data were available for only 103 of 601 trials. The age-treatment interaction for MACE was based on only 23 trials reporting this outcome. The credible intervals for some interactions are wide. The analysis focused on drug classes, not individual drugs within classes. The mechanisms underlying the age-dependent differences are not explained. Most trial participants were over 55, limiting conclusions about younger adults.

How to read the evidence

This is a network meta-analysis with individual participant data published in JAMA — the highest tier of evidence synthesis. The massive scale (601 trials, 309K patients), rigorous methodology, and use of individual patient data for age/sex interactions make this among the most authoritative analyses on this topic.

When this study was published

Published in 2025 in JAMA with data updated through August 2024, this is the definitive current analysis of age and sex effects on diabetes drug efficacy.

The bigger picture

This study represents the state of the art in precision medicine for type 2 diabetes. Rather than treating all diabetic patients the same, the data support age-stratified treatment selection — a step toward truly personalized diabetes management. The finding that GLP-1 drugs are more cardioprotective in younger people while SGLT2 inhibitors are more effective in older people suggests different underlying mechanisms of cardiovascular protection that vary in importance across the lifespan.

Questions still open

What biological mechanisms explain why GLP-1 drugs are more cardioprotective in younger people — is it related to GLP-1 receptor density changes with age?
Should clinical guidelines formally recommend age-stratified drug selection between GLP-1 drugs and SGLT2 inhibitors?
Would combining GLP-1 and SGLT2 inhibitors provide optimal cardiovascular protection across all age groups?

Common questions

Should younger vs. older people choose different diabetes medications?

This massive study suggests yes — at least for cardiovascular protection. GLP-1 drugs (like semaglutide and liraglutide) provided greater heart protection for younger type 2 diabetes patients, while SGLT2 inhibitors (like empagliflozin and dapagliflozin) were more cardioprotective in older patients. Both drug classes reduce heart events overall, but the relative benefit shifts with age. Discussing this with your doctor could help optimize your specific treatment plan.

Do GLP-1 drugs work differently for men and women?

No — this study found no significant sex differences in how either GLP-1 drugs or SGLT2 inhibitors work for blood sugar control or cardiovascular protection. Both drug classes appear to be equally effective in men and women. This is reassuring given that women have historically been underrepresented in clinical trials, and provides evidence that current prescribing guidelines apply equally regardless of sex.

Read the original research

Age and Sex Differences in Efficacy of Treatments for Type 2 Diabetes: A Network Meta-Analysis.

JAMA, 333(12), 1062-1073

View on PubMed ↗Publisher’s paper ↗

Citation

Hanlon, Peter; Butterly, Elaine; Wei, Lili; Wightman, Heather; Almazam, Saleh Ali M; Alsallumi, Khalid; Crowther, Jamie; McChrystal, Ryan; Rennison, Heidi; Hughes, Katherine; Lewsey, Jim; Lindsay, Robert; McGurnaghan, Stuart; Petrie, John; Tomlinson, Laurie A; Wild, Sarah; Adler, Amanda; Sattar, Naveed; Phillippo, David M; Dias, Sofia; Welton, Nicky J; McAllister, David A. (2025). Age and Sex Differences in Efficacy of Treatments for Type 2 Diabetes: A Network Meta-Analysis.. JAMA, 333(12), 1062-1073. https://doi.org/10.1001/jama.2024.27402