Pharmacological selectivity of SGLT2 inhibitors and cardiovascular outcomes in patients with type 2 diabetes: a meta-analysis

Abstract

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus. However, SGLT2 inhibitors show great variance in pharmacological selectivity to SGLT2 over SGLT1. Reduced functional capacity of SGLT1 is associated with lower risk of heart failure development and mortality in humans. Yet, the clinical relevance of additional pharmacological SGLT1 inhibition is unclear. Purpose To assess whether additional pharmacological SGLT1 blockade adds further benefits to SGLT2 inhibition. Methods In this preregistered meta-analysis, we included randomized placebo-controlled cardiovascular outcome trials (CVOTs) of SGLT2 inhibitors assessing MACE (composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in patients with type 2 diabetes. Hazard ratios (HRs) and 95% confidence intervals (CIs) of prespecified clinical endpoints were pooled using a random-effects model. Interactions were assessed according to low versus high pharmacological SGLT2 selectivity of the given medication. Mixed-effects meta-regression analysis was performed to quantify correlation between pharmacological SGLT2:SGLT1 selectivity ratio and clinical outcomes. Results A total of 6 independent CVOTs comprising 57553 type 2 diabetic patients (mean age 64.6±7.9 years; 36769 [63.9%] men) were included. Overall, SGLT2 inhibitors significantly reduced risk of adverse cardiovascular and renal outcomes, but had no significant impact on the risk of fatal and nonfatal stroke compared with placebo (HR, 0.92; 95% CI, 0.77–1.10; p=0.36; I2=63%). Agents with clinically relevant SGLT1 inhibitory effect (sotagliflozin, canagliflozin) significantly reduced the risk of stroke (HR, 0.78; 95% CI, 0.64–0.94) compared with placebo, whereas those with high SGLT2 selectivity did not (HR, 1.06; 95% CI, 0.92–1.22), yielding a significant interaction (p=0.018). The difference was also significant in patients with estimated glomerular filtration rate (eGFR) lower than 60 mL/min/1.73 m2 (p=0.047). Meta-regression indicated that lower SGLT2:SGLT1 pharmacological selectivity ratio was associated with lower risk of stroke (pseudo-R2=78%; p=0.011), which was evident even after adjusting for baseline eGFR values (p=0.047). Pharmacological selectivity of SGLT2 inhibitors had no significant impact on any other assessed clinical outcomes, including hospitalization for heart failure and all-cause death. Conclusion These hypothesis-generating results indicate that targeting SGLT1 in addition to SGLT2 inhibition might constitute a new avenue for stroke risk reduction in patients with type 2 diabetes. Further confirmatory studies are needed. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This project was supported by grants from the National Research, Development and Innovation Office (NKFIH) of Hungary (K134939 to T.R.), and by the New National Excellence Program of the Ministry of Human Capacities of Hungary (ÚNKP-21-3-II-SE-45 to A.A.S.).