Question Does the efficacy of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase 4 inhibitors vary by age and sex among individuals with type 2 diabetes?
Findings In this systematic review and network meta-analysis of 601 eligible trials (including 103 trials with individual participant data), there was a greater reduction in the risk of major adverse cardiovascular events when comparing older vs younger participants taking sodium-glucose cotransporter 2 inhibitors despite smaller reductions in hemoglobin A1c. Sex was not associated with differences in efficacy for any agent.
Meaning Newer glucose-lowering drugs were efficacious across age and sex groups. Sodium-glucose cotransporter 2 inhibitors were more cardioprotective in older than in younger people
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
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