To the best of our knowledge, this is the first study comparing SGLT-2s with a placebo in comprehensive outcomes of primary efficacy and adverse events in cardiovascular diseases in patients with and without T2DM. Cardiovascular diseases include various conditions, such as common coronary artery disease, hypertension, dyslipidaemia, congenital heart disease, valvular disease, and arrhythmia. Accordingly, cardiovascular diseases are a serious threat to human health worldwide. Cardiovascular outcomes, survival, and prognosis in patients with cardiovascular diseases are relatively poor. In a previous meta-analysis, SGLT-2 treatment of patients with T2DM significantly reduced all-cause mortality, cardiovascular mortality, HHF, risk of HF, and renal failure [24–28]. Moreover, among participants with established cardiovascular disease, regardless of the presence or absence of T2DM, SGLT-2s significantly reduce mortality and major adverse cardiovascular events (MACEs) compared with the placebo, and the benefit for the prevention and treatment of HF and renal disease is consistent with that of earlier meta-analyses. The same results were observed in the HFrEF population; however, there were no significant differences in patients with HFpEF and no significant differences between the two groups for most adverse events. The results for the risk of infection, amputation, and hypovolemia should be interpreted with caution.
SGLT-2s were superior to the placebo or other glucose-lowering drugs in terms of the pooled primary efficacy outcomes, including all-cause mortality, cardiovascular mortality, HHF, and renal benefits from EMPA-REG OUTCOME[12, 30], CANVAS-R[13, 31], CANVAS [32, 33], CREDENCE[34, 35], DECLARE-TIMI 58[36, 37], and VERTIS-CV trials [20, 38]. In the EMPA-REG OUTCOME trial, all eligible patients had established cardiovascular disease, and empagliflozin reduced the risk of all-cause mortality by 32%, cardiovascular mortality by 38%, and HHF by 35% compared with the placebo. At the same time, the study confirmed that the dose of empagliflozin did not affect the hazard ratios of cardiovascular outcomes. In the CANVAS and CANVAS-R trials, treatment resulted in reductions of 49% for all-cause mortality, 47% for cardiovascular mortality, 30% for HHF, and 22% for major adverse cardiovascular events. Patients in the canagliflozin group had a lower risk of cardiovascular mortality, HHF, and renal failure than those in the placebo group at a median follow-up of 2.62 years in the CREDENCE trial. In the DECLARE-TIMI 58 trial, dapagliflozin appeared to robustly reduce the risk of cardiovascular mortality or HHF and MACEs in patients with T2DM and previous myocardial infarction. In the VERTIS-CV trial involving patients with T2DM and established atherosclerotic cardiovascular disease, ertugliflozin was shown to be noninferior to the placebo with MACEs. However, the incidence of cardiovascular mortality or HHF did not differ significantly between the two groups. Owing to the diverse properties of different drugs, we cannot exclude the possibility that differences among the agents in this class may result in real differences in clinical outcomes. It is also possible that the effects of individuals are similar because the confidence interval of VERTIS CV overlaps with that of previous trials. Owing to limited literature on the HFpEF population, the role of SGLT-2s in patients with HFpEF remains unclear. In current research on HFpEF, only the subgroup analyses in the DECLARE-TIMI 58 and VERTIS-CV trials suggested a potential impact on HHF or cardiovascular mortality. Two ongoing clinical trials in patients with HFpEF will provide further evidence of its efficacy (NCT03057951 and NCT01297257).
In terms of safety, three available studies showed neutral effects on myocardial infarction and stroke in patients receiving SGLT-2s [39–41]. In an RCT and a nationwide cohort study, the results showed no increased risk of hypoglycaemia with SGLT-2 monotherapy [42, 43]; however, SGLT-2s were associated with approximately twice the risk of diabetic ketoacidosis as DPP4 inhibitors . Accordingly, clinicians should be cautious when combining SGLT-2s with other hypoglycaemic drugs. SGLT-2s reduced the risk of dialysis, transplantation, or death due to kidney disease in individuals with T2DM, with or without basic renal disease, and provided protection against acute kidney injury[45–47]. The use of SGLT-2s was not associated with an increased risk of fracture and amputation compared with other antidiabetics [44, 48–50]. Volume depletion is another major concern, not consistent with recent studies, which showed significant differences between SGLT-2s and other oral hypoglycaemic agents in volume depletion events[51–53], perhaps because of individualised dosing of SGLT-2s. Other potential side effects include urinary tract infection and male/female genital infection, which may be attributed to the selective inhibition of renal proximal tubule glucose reabsorption by SGLT-2s. According to the United States Food and Drug Administration, all manufacturers are required to add a warning of potential infection to the prescribing information and patient medication guide for all SGLT-2s in 2018. Although these adverse events should not mask the overall cardio-renal benefits of SGLT-2s [54–56], individuals at risk of these complications should be monitored closely, and treatment should be reconsidered or discontinued if such complications occur.
Our study had some limitations. First, confounding factors, such as age, sex, regionalism, baseline haemoglobin A1c, estimated glomerular filtration rate, and exposure to cardiovascular disease-related drugs, as well as drug combinations and other potential factors, were difficult to control. Second, articles published in languages other than English were excluded. Third, few RCTs of certain SGLT-2 drugs in the HFpEF population have been published. Finally, this meta-analysis may be underpowered for comparison of long-term adverse events between SGLT-2s and the placebo owing to the different durations of follow up for the included RCTs. Therefore, additional studies are required to confirm our findings.