SGLT2 Inhibitors in Diabetic Patients With Cardiovascular Disease or at High Cardiovascular Risk: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

OBJECTIVE: To investigate the effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with diabetes with cardiovascular disease (CVD) or at high cardiovascular risk. DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). DATA SOURCES: Pubmed, Embase, the Cochrane Library, and ClinicalTrial.gov from their inception to August 28, 2021. REVIEW METHODS: Randomized control trials (RCTs) assess the effects of SGLT2i in patients with diabetes with cardiovascular disease or at high cardiovascular risk. Primary outcomes included the composite outcome of cardiovascular death (CV death) and hospitalization for heart failure (HHF), HHF, and renal composite outcomes. Secondary outcomes included major adverse cardiovascular events (MACE), CV death, all-cause mortality, and change from the baseline in HbA1c. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of primary and secondary outcomes. These subgroups were based on history of heart failure (HF), estimated glomerular filtration rate (eGFR) levels, and history of hypertension (HTN). A meta-analysis was carried out by using fixed effect models to calculate hazard ratio (HR) or mean difference (MD) between the SGLT2i administrated groups and the control groups. RESULTS: Four major studies (n = 42,568) were included. Primary outcomes showed that SGLT2i was associated with significantly lower risk of CV death/HHF (HR, 0.90; 95% confidence interval, 0.84 to 0.98; P for heterogeneity = 0.01), HHF (HR, 0.84; 95% CI, 0.73 to 0.98; p = 0.02), and renal composite outcomes (HR, 0.83; 95%CI, 0.74 to 0.92; p = 0.0007) in patients with diabetes with CVD or at high CV risk. Secondary outcome showed that the use of SGLT2i was associated with significant reduction of the HbA1c level (MD, −0.30; 95% CI, −0.36 to −0.23; p < 0.00001). In subgroup analyses, SGLT2i significantly reduced the risk of renal composite outcomes in patients without history of HF (HR, 0.75; 95% CI, 0.62 to 0.91; p = 0.003 < 0.025). No statistically significant differences were observed in other secondary outcomes and subgroup analyses. CONCLUSIONS: The SGLT2i showed benefits on CV death/HHF, HHF, renal composite outcomes, and HbA1c reduction in patients with diabetes with CVD or at high CV risk. The benefits of improving renal composite outcomes were observed only in patients with diabetes without HF history. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021227400