Abstract
Background Glucose lowering agents that reduce the risk of major cardiovascular events would be considered a major advance. Despite the reduction of cardiovascular risk by sodium-glucose cotransporter 2 inhibitors (SGLT-2i) has been confirmed by some large randomized controlled studies and systematic reviews, exact indicators of cardiovascular risk remained controversial. Whether consistent results can be obtained in clinical practice is unclear. Therefore, in this meta-analysis, we examined the real-world effect of SGLT-2i on cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM).Methods We did a real-world systematic review and meta-analysis of cardiovascular outcome of SGLT-2i in patients with T2DM. We searched PubMed and Embase for trials published up to October 23, 2019. Data search and extraction were completed with a standardized data form and any discrepancies were resolved by consensus. The primary outcome was major adverse cardiovascular events (MACE) and all-cause mortality (ACM). Secondary outcomes were hospitalization for heart failure (HHF), atrial fibrillation (AF), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), unstable angina (UA), heart failure (HF). Odds ratio (OR) with 95% CIs were pooled across trials, and cardiovascular outcomes were stratified by baseline incidence of cardiovascular disease (CVD), usage rate of cardiovascular benefit drug, follow-up period and region.Results Fourteen trials enrolling 3,157,259 patients were included. SGLT-2i reduced MACE (OR, 0.71; 95% CI 0.67,0.75, P<0.001) and ACM (OR, 0.53; 95% CI 0.49,0.57, P<0.001) compared to other glucose lowering drugs (oGLD). Compared with oGLD, SGLT-2i had significantly lowered the risk of HHF (OR, 0.56; 95% CI 0.46,0.68, P<0.001), MI (OR, 0.77; 95% CI 0.73,0.81, P<0.001), stroke (OR, 0.75; 95% CI 0.72,0.78, P<0.001), CVM (OR, 0.58; 95% CI 0.49,0.69, P<0.001) and HF(OR, 0.56; 95% CI 0.48,0.67, P<0.001), but there was no benefit from UA or AF. Subgroup analysis showed SGLT-2i reduced the risk of MACE, ACM, HHF, MI, stroke, CVM and HF with a similar benefit regardless of the incidence of CVD was (20-30)% or < 15%, (15-30)% and <15% have been treated with GLP-1 receptor agonists (GLP-1RA), >80% and<70% have been treated with statins or both GLP-1RA and statins. SGLT-2i reduced the risk of ACM in low-risk population (P<0.001). No inconsistencies were found when stratification was performed at 1 or (3-4) years of follow-up. SGLT-2i showed similar cardiovascular benefits in the Nordic countries, Asia and the United States.Conclusions The predominant impact of SGLT-2i is on cardiovascular outcome driven predominantly by reduction in MACE, ACM, HHF, MI, stroke, CVM, HF, but not UA or AF. SGLT-2i have robust benefits on reducing MACE, ACM, HHF, MI, stroke, CVM and HF regardless of a history of usage rate of GLP-1RA and/or statins and /or metformin.
Generalizability of sodium-glucose co-transporter-2 inhibitors cardiovascular outcome trials to the type 2 diabetes population: a systematic review and meta-analysis
