Sodium‐glucose cotransporter‐2 inhibitors for type 2 diabetes mellitus in adults: An overview of 46 systematic reviews

Abstract

Aims To summarize the evidence from systematic reviews (SRs) of randomized controlled trials (RCTs) evaluating the efficacy and safety of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors versus placebo or active comparators for type 2 diabetes mellitus. Materials and Methods We searched six databases between 2014 and 2021. We assessed the quality of evidence using Assessment of Multiple Systematic Reviews (AMSTAR 2) and Grading of Recommendations Assessment, Development and Evaluation (GRADE) and summarized the main outcome results according to their evidence of benefit (PROSPERO ID: CRD42019132431). Results We included 46 SRs, comprising 175 RCTs and 136 096 participants. The results showed “clear evidence of benefit” in relation to: myocardial infarction (odds ratio [OR]/hazard ratio [HR] 0.85 to 0.91); cardiovascular mortality (OR/HR 0.67 to 0.86); heart failure (OR/HR 0.64 to 0.69); albuminuria progression and composite renal outcome (relative risk [RR]/HR 0.55 to 0.63); glycated haemoglobin (HbA1c) versus placebo (mean difference [MD] −0.49% to −0.77% [5.4 to 8.4 mmol/mol]); and weight versus placebo (MD −1.09 kg to −2.99 kg). “Possible benefit” was observed in relation to major adverse cardiovascular events (OR/HR 0.80 to 0.89), all‐cause mortality and nonalcoholic fatty liver disease. SGLT2 inhibitors showed “clear evidence of no effect or equivalence” in relation to stroke and fractures. “Clear evidence of harm” was observed in relation to genital infections (RR/OR 2.06 to 5.25) and ketoacidosis (HR/OR 1.36 to 2.20). Regarding amputation risk and urinary tract infections, we found “no conclusions possible due to lack of evidence”. Conclusions Our results showed that SGLT2 inhibitors have beneficial effects in relation to renal and cardiovascular outcomes (except for stroke), HbA1c and weight. Further studies are needed to assess urinary infections and amputation risk.

Renal Protection with SGLT2 Inhibitors: Effects in Acute and Chronic Kidney Disease

“…[ 22 – 25 ]. Measures of atherosclerotic cardiovascular disease (cardiovascular deaths, non-fatal myocardial infarction and stroke) have also been reduced in some studies with SGLT2 inhibitors: these are reviewed in detail elsewhere in the context of the reciprocating interrelationships of heart and kidney [ 19 – 21 , 26 , 27 ].…”

Safety and Effectiveness of Empagliflozin in Korean Patients with Type 2 Diabetes Mellitus: Results from a Nationwide Post-Marketing Surveillance

“…HbA1c level reduction of −0.62% was confirmed in a meta-analysis of empagliflozin RCTs [ 11 ]. Analysis of 46 systemic reviews, comprising 175 RCTs, confirmed that SGLT2is significantly lowered HbA1c levels from −0.49% to −0.77% [ 12 ]. Interestingly, the glucose-lowering efficacy of SGLT2i was greater in Asian patients than in Caucasian patients [ 13 ].…”

“…Recently, a meta-analysis of randomized controlled trials (RCTs) consistently confirmed the safety of empagliflozin in patients with diabetes [ 11 ]. Empagliflozin also significantly improved glycemic control in patients with T2DM [ 12 ], and greater efficacy was suggested in Asian patients than Caucasian patients based on a comparative meta-analysis [ 13 ].…”

Real‐world data of 12‐month adjunct sodium‐glucose co‐transporter‐2 inhibitor treatment in type 1 diabetes from the German/Austrian DPV registry: Improved HbA1c without diabetic ketoacidosis

“…5 Before dapagliflozin was officially licensed for use in T1D, it was known that DKA is a rare but significant adverse clinical complication of SGTL2i treatment in T2D over the observational time interval analysed in this real-world trial. 1 As a higher DKA rate is generally envisioned in T1D, the fear of this complication in these patients in response to SGLT2i therapy may have prevented healthcare providers from using this type of treatment in more patients with T1D in clinical practice. Of note, in contrast to results from randomized trials with SGLT2is in T1D, this observational trial revealed no increase in the rate of DKA in response to SGLT2i treatment in real-world practice.…”

“…Sodium-glucose co-transporter-2 inhibitors (SGLT2is) represent a class of oral antidiabetic drugs that are used in the treatment of type 2 diabetes (T2D), and more recently have been approved for therapy of heart and kidney failure independent of T2D. 1 Importantly, SGLT2is have shown the capacity to induce reverse cardiac remodelling, 2 together with impressive reductions in cardiovascular, heart failure, and kidney endpoints in outcome trials. 3 SGLT2is lower blood glucose levels independently of insulin action by inhibiting reabsorption of filtered glucose in the proximal tubule to increase urinary glucose excretion.…”