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Meta-Analysis Evaluates Long-Term Safety of SGLT2’s

Feb 10, 2018

Short-term efficacy and safety of SGLT2 inhibitors have been well established, but what happens with long-lasting use of these medications?

As they are the newest medication class on market for treatment of diabetes, SGLT-2 inhibitors’ influence on both cardiovascular and non-cardiovascular health has not been well documented yet.  Most studies that evaluated the SGLT2 inhibitors had a primary goal of establishing their glucose-lowering abilities, hence not many were concerned with evaluating their impact on cardiovascular and other safety outcomes. One of the studies that is available, published by Bernard Zinman and colleagues, concluded that use of empagliflozin reduced the incidence of cardiovascular events and death when it was added to standard glucose-lowering therapy. Another study, the CANVAS-R trial, argued the benefits of canagliflozin for CV disease to be remarkable with the expense of increased risk of lower leg amputations. In hopes of validating both CV and non-CV safety of SGLT2-i, researchers in China conducted a meta-analysis of the available randomized controlled trials and observational studies; furthermore, to reduce type I errors from occurring, they completed the trial sequential analysis. Their results were recently published by The American Heart Association.


Investigators completed a literature search of Medline, Cochrane, and Embase to screen for available studies. Two independent reviewers assessed eligibility, and a total of 11 studies that were incorporated in the meta-analysis were head-to-head trials, comparing SGLT2’s to either placebo or other antihyperglycemic medications, and had pre-defined CV outcomes.

Researchers set the primary endpoints as the composite of death from cardiovascular causes, nonfatal MI, and nonfatal stroke. Secondary endpoints included each of the primary endpoints as a separate measure, in addition to all-cause mortality, hospitalization for heart failure, and renal microvascular outcomes. Non-CV safety and efficacy of SGLT2’s was examined as well.

The investigators found that across all included studies, patients treated with any SGLT2-i had favorable reduction in composite cardiovascular events and death, hazard ratio of 0.80, p-value of 0.002. After completion of trial sequential analysis (TSA), a firm 20% decrease of primary endpoint was seen with use of SGLT2 inhibitors. Use of SGLT2s was also correlated with a statistically significant decrease in all-cause mortality, HR of 0.67, p-value < 0.001; once again, TSA calculations confirmed the strong 20% reduction. Other secondary endpoints also had more favorable results in patients treated with SGLT2’s. For instance, HR for nonfatal MI was 0.86 favoring the SGLT2 treatment, while SGLT2 therapy also led to fewer hospitalizations for heart failure when compared to other treatments, HR of 0.62. SGLT2 inhibitors lead to beneficial renal microvascular outcomes by slowing the progression of albuminuria, HR of 0.68. However, study researchers found that patients treated with SGLT2 inhibitors did not have statistically significant reductions in nonfatal stroke rates, HR or 0.96, p-value of 0.67.  When comparing hypoglycemia, AKI, and serious adverse events, patients who were treated with SGLT2 inhibitors had overall better outcomes, with the exception of urinary tract and yeast infections.

Xin-Lin Zhang and colleagues report sustained protective cardiovascular outcomes of the entire class of SGLT2 inhibitors. Considering that patients with diabetes are at a high-risk of cardiovascular disease, choosing an antihyperglycemic agent that exerts beneficial cardiovascular outcomes is of a great importance. There are some limitations to the study as recognized by the investigators; mainly, the publication bias that could have occurred in each of the specific studies included in meta-analysis. Nonetheless, since some of the anti-diabetic medications, particularly rosiglitazone and saxagliptin can lead to heart failure, having documented cardiovascular and non-cardiovascular long-term benefits of SGLT2 inhibitors may lead to future changes in practice.

Practice Pearls:

  • Use of SGLT2 inhibitors lead to a strong 20% reduction in composite of death from cardiovascular causes, nonfatal MI, and nonfatal stroke.
  • Statistically significant reduction in all-cause mortality was seen with use of SGLT2 inhibitors, HR = 0.67.
  • SGLT2 inhibitors offer benefits for non-cardiovascular outcomes as well; AKI, hypoglycemia, and serious adverse events were less likely to occur with SGLT2-i treatment when compared to controls.


Xin-Lin Zhang, Qing-Qing Zhu, Yu-Han Chen, et al. “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.” Journal of the American Heart Association. 2018. http://jaha.ahajournals.org/content/7/2/e007165.long.  Accessed Jan 2018.

Bernard Zinman, Christoph Wanner, John Lachin, et al.  “Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes.” New England Journal of Medicine. 2015. http://www.nejm.org/doi/full/10.1056/NEJMoa1504720.  Accessed Jan 2018.

Bruce Neal, Vlado Perkovic, Kenneth Mahaffey, et al. “Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes.” New England Journal of Medicine. 2017.  http://www.nejm.org/doi/full/10.1056/NEJMoa1611925.  Accessed Jan 2018.

Lamija Zimic, PharmD(c), University of South Florida, College of Pharmacy