Effects of newer anti-hyperglycemic agents on cardiovascular outcomes in older adults: systematic review and meta-analysis

Abstract

Background Older adults have higher prevalence of Type 2 diabetes (T2D) and cardiovascular disease. Newer anti-hyperglycemic agents (dipeptidyl peptidase-4 inhibitors [DPP-4i], glucagon-like peptide-1 receptor agonists [GLP-1RA], and sodium/glucose cotransporter 2 inhibitors [SGLT-2i]) demonstrated cardiovascular safety but consistency across older age-groups remains underexplored. In this meta-analysis of randomized controlled trials, we assessed effects of newer anti-hyperglycemic drugs on cardiovascular outcomes in subgroups of older adults. Methods PubMed and Cochrane were searched for cardiovascular outcome trials (CVOTs) testing newer agents until August 31, 2022. (PROSPERO ID CRD42021260167) Studies with ≥ 1000 T2D participants enrolled for ≥12 months were included. Random effect models were used to report relative-risk (RR) for three-point major adverse cardiovascular events (3P-MACE) and its components by age subgroups (65 years; 75 years). The p-value < 0.05 was considered statistically significant. Results For SGLT-2is, five CVOTs (46,969 patients, 45–50% ≥65 years) were included. SGLT-2is reduced risk of MACE (RR;0.91[CI,0.85 – 0.98]); cardiovascular death (CV-death) (RR;0.84[CI,0.73 – 0.96]); and all-cause mortality (ACM) (RR;0.86[CI,0.79 – 0.93]) with no difference in subgroups <65 or ≥65 years. Similar results were observed for subgroups <75 or ≥75 years with 10%, 18% and 15% reduction in MACE, CV-death and ACM respectively, and no significant difference between the age subgroups (p-interaction for MACE=0.74; CV-death=0.97; ACM=0.68). For GLP-1RAs, nine CVOTs (n=64,236, 34–75% ≥65 years) were included. GLP-1RAs reduced risk of MACE (RR;0.89[CI,0.83 – 0.95]), stroke (RR;0.86[CI,0.76 – 0.97]) and ACM (RR;0.90[CI,0.83 – 0.97]) with no significant difference in subgroups <65 or ≥65 years. Additionally, GLP-1RAs reduced risk of MACE (10%), ACM (12%) and CV-death (12%) with no significant difference in age subgroups <75 or ≥75 years. Four CVOTs (n=33,063; 35 – 58% ≥65 years) with DPP-4is were included. There were no significant differences in risk for CV outcomes with DPP-4is compared to placebo in any of the age subgroups. Conclusion The overall cardiovascular outcomes of newer anti-hyperglycemic agents are consistent across the older and younger individuals.