Age and Sex Differences in Efficacy of Treatments for Type 2 Diabetes
Authors: Peter Hanlon, Elaine Butterly, Lili Wei, Heather Wightman, Saleh Ali M. Almazam, Khalid Alsallumi, Jamie Crowther, Ryan McChrystal, Heidi Rennison, Katherine Hughes, Jim Lewsey, Robert Lindsay, Stuart McGurnaghan, John Petrie, Laurie A. Tomlinson, Sarah Wild, Amanda Adler, Naveed Sattar, David M. Phillippo, Sofia Dias, Nicky J. Welton, David A. McAllister
Journal: JAMA (2025)

Importance Sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase 4 (DPP4) inhibitors improve hyperglycemia, and SGLT2 inhibitors and GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events (MACEs) among individuals with type 2 diabetes. It is not clear whether efficacy varies by age or sex. Objective To assess whether age or sex are associated with differences in the efficacy of SGLT2 inhibitors, GLP-1 receptor agonists, and DPP4 inhibitors. Data Sources and Study Selection The MEDLINE and Embase databases and US and Chinese clinical trial registries were searched for articles published from inception to November 2022; in August 2024, the search was updated to capture the trial results. Two reviewers screened for randomized clinical trials of SGLT2 inhibitors, GLP-1 receptor agonists, or DPP4 inhibitors vs a placebo or active comparator in adults with type 2 diabetes. Data Extraction and Synthesis Individual participant data and aggregate data were used to estimate age × treatment interactions and sex × treatment interactions in multilevel network meta-regression models. Main Outcome and Measures Hemoglobin A 1c (HbA 1c ) and MACEs. Results Of the 601 eligible trials identified (592 trials with 309 503 participants reported HbA 1c ; mean age, 58.9 [SD, 10.8] years; 42.3% were female and 23 trials with 168 489 participants reported MACEs; mean age, 64.0 [SD, 8.6] years; 35.3% were female), individual participant data were obtained for 103 trials (103 reported HbA 1c and 6 reported MACEs). The use of SGLT2 inhibitors (vs placebo) was associated with less HbA 1c lowering with increasing age for monotherapy (absolute reduction [AR], 0.24% [95% credible interval {CrI}, 0.10% to 0.38%] per 30-year increment in age), for dual therapy (AR, 0.17% [95% CrI, 0.10% to 0.24%]), and for triple therapy (AR, 0.25% [95% CrI, 0.20% to 0.30%]). The use of GLP-1 receptor agonists was associated with greater HbA 1c lowering with increasing age for monotherapy (AR, −0.18% [95% CrI, −0.31% to −0.05%] per 30-year increment in age) and for dual therapy (AR, −0.24% [95% CrI, −0.40% to −0.07%]), but not for triple therapy (AR, 0.04% [95% CrI, −0.02% to 0.11%]). The use of DPP4 inhibitors was associated with slightly better HbA 1c lowering in older people for dual therapy (AR, −0.09% [95% CrI, −0.15% to −0.03%] per 30-year increment in age), but not for monotherapy (AR, −0.08% [95% CrI, −0.18% to 0.01%]) or triple therapy (AR, −0.01% [95% CrI, −0.06% to 0.05%]). The relative reduction in MACEs with use of SGLT2 inhibitors was greater in older vs younger participants per 30-year increment in age (hazard ratio, 0.76 [95% CrI, 0.62 to 0.93]), and the relative reduction in MACEs with use of GLP-1 receptor agonists was less in older vs younger participants (hazard ratio, 1.47 [95% CrI, 1.07 to 2.02]). There was no consistent evidence for sex × treatment interactions with use of SGLT2 inhibitors and GLP-1 receptor agonists. Conclusions and Relevance The SGLT2 inhibitors and GLP-1 receptor agonists were associated with lower risk of MACEs. Analysis of age × treatment interactions suggested that SGLT2 inhibitors were more cardioprotective in older than in younger people despite smaller reductions in HbA 1c ; GLP-1 receptor agonists were more cardioprotective in younger people.