Age, sex, race, BMI, and duration of diabetes differences in cardiovascular outcomes with glucose lowering drugs in type 2 diabetes: A systematic review and meta-analysis

BACKGROUND: Summarized data of cardiovascular outcomes trials (CVOTs) of sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have shown a reduction in major adverse cardiovascular event (MACE), whether these benefits are extended in certain risk groups (elderly or obese patients or those with a longer duration of diabetes) or certain minorities (Black participants) are not clearly established. We aimed to provide overall hazard ratios (HRs) estimates for MACE of SGLT2i and GLP-1 RAs stratified by age (< 65 years vs. ≥ 65 years and < 75 years vs. ≥ 75 years), sex (male vs. female), race (Black vs. White, Black vs. Asian, and White vs. Asian), body mass index (BMI: < 30 kg/m(2) vs. ≥ 30 kg/m(2)), and duration of diabetes (< 10 years vs. ≥ 10 years). METHODS: We performed a MEDLINE database search from inception up to July 31, 2022 to identify all placebo-controlled phase 3 CVOTs that evaluated the efficacy of SGLT2i and GLP-1 RAs on vascular events at least 1-year after randomisation in participants with type 2 diabetes, and we selected those reporting hazard ratios (HRs) for the specific risk groups for MACE. Differences on MACE in risk groups were examined using a random-effect meta-analysis. The study protocol was registered on PROSPERO (CRD42022347901). FINDINGS: A total of 11 studies fulfilled the prespecified criteria, comprising 96,580 patients with T2D were included. Of these patients, 61,975 (64.2%) were male, 34,605 (35.8%) were female, and race groups included 74,982 (77.6%) White, 7760 (8.0%) Asian, and 4023 (4.2%) Black. In two SGLT2i trials, the HR (95% CI) for long-term diabetes duration more than10 years versus short duration was 0.84 (0.77–0.93) vs. 1.02 (0.89–1.16), respectively (P(interaction) = 0.03). In four SGLT2i trials, the MACE benefit was similar by sex (P(interaction) = 0.13), age (P(interaction) = 0.36), BMI (P(interaction) = 0.69), and race groups (P(interaction) = 0.86 between Black and White, P(interaction) = 0.98 between Black and Asian, and P(interaction) = 0.69 between White and Asian). For GLP-1 RAs, the MACE benefit from the seven trials tended to be greater for Asian (0.71, [0.58–0.87]) than for White (0.87, [0.81–0.94]), (P(interaction) = 0.07). In two GLP-1 RAs trials, the MACE outcome was reduced by 22% (0.78, 0.63–0.95) in elderly patients (≥ 75 years) while no difference was observed in those < 75 years (0.87; 0.75–1.01), (P(interaction) = 0.37). In the remaining risk groups, the MACE benefit was similar by sex (P(interaction) = 0.37), age < 65 years (P(interaction) = 0.80), duration of diabetes (P(interaction) = 0.70), and race (P(interaction) = 0.57 between Black and White, and P(interaction) = 0.15 between Black and Asian), BMI (P(interaction) = 0.78). Risk of bias was lower, and overall heterogeneity was high for sex with SGLT2i, and moderate to low for the remaining comparisons, with a I(2) values ranging from 0% to 54%. INTERPRETATION: In patients with type 2 diabetes at highest risk of cardiovascular disease or established cardiovascular disease, a greater benefit on MACE was found for elderly patients and for Asian individuals compared with White individuals with GLP-1 RAs, and those with a long duration of diabetes with SGLT2i. These findings could help in providing guidance for treatment prescription and facilitate selection and stratification of patients for future CVOTs. Furthermore, pooled individual patient-level data are urgently needed to support our conclusions, and to derive definitive evidence. FUNDING: None.