Age and sex differences in efficacy of treatments for type 2 diabetes: A network meta-analysis

Importance
Sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor analogues (GLP1ra) and dipeptidyl peptidase-4 inhibitors (DPP4i) improve hyperglycemia, and SGLT2i and GLP1ra reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes. It is not clear whether efficacy varies by age or sex.

Objective
Assess whether age or sex are associated with differences in efficacy of SGL2i, GLP1ra and DPP4i.

Data sources
Medline, Embase, trial registries.

Study selection
Two reviewers screened for randomized controlled trials of SGLT2i, GLP1ra, or DPP4i compared with placebo/active comparator, in adults with type 2 diabetes. 64 Data extraction and synthesis We used individual participant data and aggregate-level data to estimate age-treatment and sex-treatment interactions in Bayesian multi-level network meta-regressions. Main Outcome and Measures HbA1c and MACE.

Results
We identified 601 eligible trials [592 trials with 309,503 participants reporting HbA1c, mean age 59.0, SD (10.7) years, 43.1% female; 23 trials with 168,489 participants reporting MACE, mean age 64.0, SD (8.6) years, 44.0% female] and obtained individual participant data for 103 trials (103 reporting HbA1c and 6 reporting MACE). For SGLT2i, the magnitude of HbA1c reduction versus placebo was attenuated in older compared with younger participants (absolute 4 reduction 0.24%; 95% credible interval (CrI) 0.10-0.38, 0.17%; 95% CrI 0.10-0.24 and 0.25%; 95% CrI 0.20-0.30 less HbA1c lowering per 30-year increment in age for monotherapy, dual therapy, and triple therapy, respectively). GLP1ra was associated with greater absolute HbA1c lowering with increasing age in monotherapy and dual-therapy (-0.18%; 95% CrI -0.31 to -0.05 and -0.24%; 95% CrI -0.40 to -0.07 HbA1c lowering per 30-yer increment respectively) but not triple therapy (0.04%; 95% CrI -0.02 to 0.11 per 30-year increment). DPP-4i was associated with slightly better absolute HbA1c lowering in dual-therapy for older people (-0.09%; 95% CrI -0.15 to -0.03 HbA1c lowering per 30-year increment), but the 95% CrIs included the null for mono and triple therapy (-0.08%; 95% CrI -0.18 to 0.01 and -0.01%; 95% CrI -0.06 to 0.05 respectively). The relative reduction in MACE with SGLT2i was greater in older compared with younger participants (HR 0.76; 95% CrI 0.62-0.93 per 30-year increment in age), whereas the opposite was found with GLP1ra (HR 1.47; 95% CrI 1.07-2.02 per 30-year increment in age). The credible intervals for sex-treatment interactions included the null for SGLT2i and GLP1ra.

Conclusions and Relevance
SGLT2i, GLP1ra, and DPP4i were associated with HbA1c lowering across age and sex groups. SGLT2i and GLP-1ra were associated with lower risk of MACE, with findings suggesting SGLT2i were more cardioprotective in older than younger people despite smaller HbA1c reductions, whereas GLP-1ra were more cardioprotective in younger individuals.