The effect of sodium‐glucose transport protein 2 inhibitors on mortality and heart failure in randomized trials versus observational studies

Abstract

Aim Randomized clinical trials (RCTs) allocating type 2 diabetes patients to treatment with sodium‐glucose transport protein 2 (SGLT‐2) inhibitors or placebo have found significant effects on the risk of heart failure and modest effects on mortality. In the wake of the first trials, a number of observational studies have been conducted, some of these reporting a mortality reduction of 50% compared to active comparators. In this review, we systematically assess and compare the results on all‐cause mortality, cardiovascular mortality and heart failure hospitalization observed in RCTs with the results obtained in observational studies. Method We performed a systematic bibliographical search including cardiovascular outcome trials and observational studies assessing the effect of SGLT‐2 inhibitors on mortality and heart failure. Results Seven RCTs and 23 observational studies were included in the current review. The observed heterogeneity between study results for all‐cause mortality (p‐interaction < 0.001) and cardiovascular mortality (p‐interaction < 0.001) was explained by study type, whereas this was not the case for heart failure (p‐interaction = 0.18). Conclusion Methodological considerations such as the omission of important confounders, immortal‐time bias and residual confounding such as unmeasured social economic inequality may be the cause of the inflated results observed in observational studies and that calls for caution when observational studies are used to guide treatment of patients with type 2 diabetes.

A real-world study on SGLT2 inhibitors and diabetic kidney disease progression

“…Despite reducing doses, the benefits accrued from using SGLT2is remained strong. Third, we could not avoid indication and time-related biases where those patients prescribed SGLT2is tend to have better predefined outcomes [ 40 , 41 ]. The systematic differences in baseline characteristics between treatment-exposed and unexposed groups departed from what we usually observed in RCTs.…”

Sodium‐glucose co‐transporter‐2 inhibitors in type 2 diabetes: Are clinical trial benefits for heart failure reflected in real‐world clinical practice? A systematic review and meta‐analysis of observational studies

“…Our study also supports the findings of previous meta-analyses of observational studies, which showed that SGLT2 inhibitors are associated with reduced odds/risk of heart failure events compared with people treated with other glucose-lowering medications. However, three of the previous analyses did not stratify included studies by the presence of baseline CVD, [62][63][64] while another only reported risk for studies with populations with 20%-30% incidence of CVD. 65 Our review includes more recently published studies, across more countries, which provides more data on high and low cardiovascular risk groups, making it possible for us to explore differences between these groups more comprehensively.…”