SGLT2 inhibitors in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials balancing their risks and benefits

Abstract

Aims/hypothesis Cardiovascular outcome trials (CVOTs) have demonstrated the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i). However, serious adverse drug reactions have been reported. The risk/benefit ratio of SGLT2i remains unquantified. We aimed to provide an estimation of their risk/benefit ratio in individuals with type 2 diabetes. Methods We conducted a systematic review (MEDLINE, up to 14 September 2021) and meta-analysis. We included randomised CVOTs assessing SGLT2i in individuals with type 2 diabetes with or without other diseases. We used the Cochrane 'Risk of bias' assessment tool. The primary outcomes were overall mortality, major adverse cardiovascular events (MACE), hospitalisation for heart failure (HHF), end-stage renal disease (ESRD), amputation, diabetic ketoacidosis (DKA) and reported genital infections. For each outcome, we estimated the incidence rate ratio (IRR) with a 95% CI; we then computed the number of events expected spontaneously and with SGLT2i. Results A total of 46,969 participants from five double-blind, placebo-controlled international trials (weighted mean follow-up 3.5 years) were included. The prevalence of previous CVD ranged from 40.6% to 99.2%. The definition of reported genital infections ranged from 'genital mycotic infection' to 'genital infections that led to discontinuation of the trial regimen or were considered to be serious adverse events'. The number of included studies for each outcomes was five. The use of SGLT2i decreased the risk of allcause death (IRR 0.86 [95% CI 0.78, 0.95]), MACE (IRR 0.91 [95% CI 0.86, 0.96]), HHF (IRR 0.69 [95% CI 0.62, 0.76]) and ESRD (IRR 0.67 [95% CI 0.53, 0.84]), and increased the risk of DKA (IRR 2.59 [95% CI 1.57, 4.27]) and genital infection (IRR 3.50 [95% CI 3.09, 3.95]) but not of amputation (IRR 1.23 [95% CI 1.00, 1.51]). For 1000 individuals treated over 3.5 years, SGLT2i are expected, on average, to decrease the number of deaths from 70 to 61, to prevent nine MACE, 11 HHF and two cases of ESRD, while inducing two DKA occurrences and 36 genital infections; 778 individuals are expected to avoid all the following outcomes: MACE, HHF, ESRD, amputation, DKA and genital infection. Conclusions/interpretation Our study is limited to aggregate data. In a population of individuals with type 2 diabetes and a high CVD risk, the cardiovascular and renal benefits of SGLT2i remain substantial despite the risk of DKA and even the hypothetical risk of amputation.

Mendelian randomization revealing the protective effect of sodium-glucose cotransporter 2 inhibition on prostate cancer with verified evidence from electronic healthcare and biological data

“…A few epidemiology studies supported the protective role of SGLT2 inhibitors on prostate cancer risk 13,51 . A recent systematic review of RCTs provided weak evidence of an effect of SGLT2 inhibitors on cancers 52 . Only one phase I trial was registered in clinicaltrial.gov (NCT04887935), which aims to investigate the safety of dapagliflozin, one type of SGLT2 inhibitors, for men considered at high risk of prostate cancer.…”

The Effect of Clinically Indicated Liraglutide on Pericoronary Adipose Tissue in Type 2 Diabetic Patients

“…Not only GLP-1 receptor agonists [47] but also sodium glucose cotransport 2 inhibitors (SGLT2i) [48] and metformin [49] have shown to increase SIRT6 expression and exhibit antiinflammatory effects on cardiac plaque. Moreover, GLP-1 receptor agonists [50], SGLT2i [51], and metformin [52] have shown to significantly reduce the rate of major adverse cardiovascular events in T2DM. In the current study, there was no significant difference in SGLT2i usage between the two groups.…”

Editorial: New mechanisms and drugs for the treatment of cardiovascular disease with diabetes

“…Oral metformin use was associated with improved cardiovascular health as defined by 5 indicators (smoking, body mass index, physical activity, blood pressure, and total cholesterol). While sodium-glucose co-transporter 2 inhibitor (SGLT2i) has been reported to reduce risks of major adverse cardiovascular events and heart failure hospitalization in patients with type 2 diabetes ( 6 ), the potential mechanisms are still elusive. Xi et al examined cardiovascular effects of 12-week treatment of empagliflozin (a frequently used SGLT2i) in 24 male rats with streptozocin-induced diabetes through a multi-omics approach.…”