Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Abstract

BackgroundThe cardiovascular and long‐term noncardiovascular safety and efficacy of SGLT2 (sodium–glucose cotransporter 2) inhibitors have not been well documented.Methods and ResultsFor cardiovascular outcomes, we performed a meta‐analysis with trial sequential analysis of randomized controlled trials and adjusted observational studies, each with a minimum of 26 weeks and 2000 patient‐years of follow‐up. For long‐term noncardiovascular safety and efficacy outcome analyses, we included only randomized controlled trials with at least 2 years and 1000 patient‐years of follow‐up. Five studies with 351 476 patients were included in cardiovascular outcomes analysis. Meta‐analyses showed that SGLT2 inhibitors significantly reduced the risks of major adverse cardiac events (hazard ratio [HR]: 0.80; 95% confidence interval [CI], 0.69–0.92; P=0.002), all‐cause mortality (HR: 0.67; 95% CI, 0.54–0.84; P<0.001), cardiovascular mortality (HR: 0.77; 95% CI, 0.60–0.98; P=0.03), nonfatal myocardial infarction (HR: 0.86; 95% CI, 0.76–0.98; P=0.02), hospitalization for heart failure (HR: 0.62; 95% CI, 0.55–0.69; P<0.001), and progression of albuminuria (HR: 0.68; 95% CI, 0.58–0.81; P<0.001). No significant difference in nonfatal stroke was found. Analyses limited to randomized controlled trials showed similar findings. Trial sequential analysis provided firm evidence of a 20% reduction in major adverse cardiac events, all‐cause mortality, and hospitalization for heart failure with SGLT2 inhibitors, but evidence remains inconclusive for cardiovascular mortality. Nine randomized controlled trials contributed to long‐term noncardiovascular and efficacy analyses. SGLT2 inhibitors reduced incidence of hypoglycemia and acute kidney injury but increased the risks of urinary tract and genital infections.Conclusions SGLT2 inhibitors showed remarkable cardiovascular‐ and renal‐protective effects and good long‐term noncardiovascular safety with sustained efficacy.

Cardiovascular efficacy and safety of sodium‐glucose co‐transporter‐2 inhibitors and glucagon‐like peptide‐1 receptor agonists: a systematic review and network meta‐analysis

“…Core outcome sets were defined in the protocol of the RCTs, which aimed to reduce selective reporting biases, but in many cases the unavailability of data was in safety (adverse events) outcomes. Despite sparse data for some outcomes, all models appeared to converge from visual analysis of history and trace plots, and the estimates from pairwise analyses and network meta-analyses in the present study were similar to those from meta-analyses conducted previously [10][11][12][13]41]. Furthermore, it was not possible to assess individual treatments in the network but only combined in treatment groups; however, by comparing the class effects of treatments, rather than individual treatment effects, statistical power was increased.…”

Acute renal outcomes with sodium‐glucose co‐transporter‐2 inhibitors: Real‐world data analysis

“…Empagliflozin was significantly associated with a lower risk of composite renal events (OR 0.72, 95% CI 0.60‐0.86), an effect which was largely driven by the EMPA‐REG study . Finally, a meta‐analysis of five trials comprising 13 510 patients revealed lower rates of AKI with SGLT2‐i versus controls (OR 0.80, 95% CI 0.67‐0.96) …”

“…8 Finally, a meta-analysis of five trials comprising 13 510 patients revealed lower rates of AKI with SGLT2-i versus controls (OR 0.80, 95% CI 0.67-0.96). 9 An observational study which included users of SGLT2-i versus non-users in two large cohorts did not find an increased risk of AKI in the inpatient setting with SGLT2-i. 10 Conversely, analysis of the cases reported to the FDA showed an increased risk of AKI with SGLT2-i versus other glucose-lowering agents; however, this database is limited by reporting bias.…”

Glycaemic control in the diabetes and Lifestyle Cohort Twente: A cross‐sectional assessment of lifestyle and pharmacological management on Hba1c target achievement

“…In our opinion, pharmacological therapy should be applied to support lifestyle intervention and should aim to facilitate increasing insulin sensitivity. As important options, glucagon‐like peptide‐1 (GLP‐1) analogues and sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors could be valuable, as they lower HbA1c along with a decrease in body weight and in long‐term cardiovascular risk without increased risk of hypoglycaemia 14, 15…”