Effects Of Sodium Glucose Cotransporter-2 Inhibitors In Treatment Of Type 2 Diabetes On Cardiovascular Safety

Aim: To access the effects of sodium glucose cotransporter-2(SGLT2) inhibitors on cardiovascular safety in patients of type 2 diabetes mellitus.Methods: According to the purpose of this systemic review, we searched EMBASE, the Cochrane Library, Pub Med, Web O f Science, CNKI, WANG FANG, VIP, C BM from inception to December 2015 for data from prospective randomized controlled trials assessing the cardiovascular effects of SGLT2 treatment compared with controls. Eligible studies were screened according to inclusion and exclusion criteria. We extracted data from trails including SGLT2 inhibitor vs placebo,SGLT2 inhibitor vs other antihyperglycemic drugs(AHD),SGLT2 inhibitor combined with other AHD vs placebo combined with the same AHD, SGLT2 inhibitor combined with other AHD vs another antihyperglycemic drug combined with the same AHD. The primary cardiovascular outcome of interest was major adverse cardiovascular events(MAC E), consisting of cardiovascular death, nonfatal myocardial infarction(MI) and stroke, and acute coronary syndromes and/or heart failure reported as serious adverse events. Secondary outcomes included fatal and nonfatal MI and stroke, all-cause and cardiovascular mortality. Q uality assessment used the Cochrane Collaboration's tool for assessing risk of bias. Statistical analysis was performed by the Revman5.3 software of Cochrane Collaboration. We will compare outcome measures for dichotomous(binary) data using Odds Ratio(OR) with 95% confidence intervals(CI). An I2 of more than 50% was considered to indicate heterogeneity, that could be solved by sensitivity analysis, subgroup analysis as well as randomized effect model and the data without heterogeneity(I2<50%) could be pooled using fixed effect model. Statistical significance was assumed at the P?0.05 level.Results: Forty two randomized, controlled trials(RCTs) involving 30142 patients with type 2 diabetes mellitus were included in the analysis. The included trails period was ranged from 12 weeks to 162 weeks. The meta-analysis showed that compared with placebo, SGLT2 inhibitors had less incident of major cardiovascular events(MAC E) [P=0.03,M-H OR=0.86, 95%CI(0.75,0.99),I 2=0%];The difference in incidence of stroke between SGLT2 inhibitors and placebo did not reach statistical significance [P=0.21,M-H OR=1.20, 95%CI(0.91,1.58), I 2=0%]; SGLT2 inhibitors was similar to placebo in incidence of myocardial infarction(MI) [P=0.25,M-H OR=0.89, 95%CI(0.72,1.09),I 2=0%]; The incidence of all-cause death or cardiovascular death in SGLT2 inhibitors were lower than placebo[P<0.0001,M-H OR=0.67, 95%CI(0.56,0.87),I 2=0%],[P<0.0001,M-H OR=0.61, 95%CI(0.49,0.77), I 2=0%],respectively. SGLT2 inhibitors combined with AHD had less incident of MACE compared with placebo combined with the same AHD [ P=0.02, M-H OR=0.65, 95%CI(0.46,0.92),I 2=1%]; SGLT2 inhibitors combined with other AHD was less to placebo combined with same AHD in incidence of MI[P=0.02,M-H OR=0.45, 95%CI(0.22,0.89),I 2=0%]; The difference in incidence of stroke, all-cause death, CV death between SGLT2 inhibitors combined with other AHD and placebo combined with same AHD did not reach statistical significance [P=0.22,M-H OR=0.67, 95%CI(0.35,1.27),I 2=0%],[P=0.99,M-H OR=1.00, 95%CI(0.50,1.99),I 2=0%],[P=0.58,M-H O R=1.43, 95%CI(0.40,5.08),I 2=0%]. SGLT2 inhibitors combined with AHD had less incident of MACE compared with another antihyperglycemic drug combined with the same AHD[P=0.009,M-H OR=0.60, 95%CI(0.41,0.88),I 2=14%]; SGLT2 inhibitors combined with other AHD was less to another antihyperglycemic drug combined with the same AHD in incidence of MI[P=0.003,M-H OR=0.28, 95%CI(0.12,0.64),I 2=0%]; The difference in incidence of stroke, all- cause death, CV death between SGLT2 inhibitors combined with other AHD and another antihyperglycemic drug combined with the same AHD did not reach statistical significance [ P=0.64, M-H OR=0.86, 95%CI(0.45,1.64),I 2 =39% ],[ P=0.96, M-H OR=0.98, 95%CI(0.41,2.30),I 2=0%],[P=0.81,M-H OR=0.83, 95%CI(0.20,3.55),I 2=24%].Conclusion: The present meta-analysis suggests the protection of SGLT2 inhibitors against cardiovascular outcomes and death. Although there are some limitations in this data, we expect that there will be more high quality evidence provided by large sample and long duration RCTs to assess cardiovascular safety of the SGLT2 inhibitors in T2 DM.