Age and Sex Differences in Efficacy of Treatments for Type 2 Diabetes

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 A1c (HbA1c) and MACEs. Results: Of the 601 eligible trials identified (592 trials with 309 503 participants reported HbA1c; 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 HbA1c and 6 reported MACEs). The use of SGLT2 inhibitors (vs placebo) was associated with less HbA1c 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 HbA1c 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 HbA1c 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 HbA1c; GLP-1 receptor agonists were more cardioprotective in younger people.