Reducing type 2 diabetes mortality: empagliflozin study

The results of a large study of the impact of empagliflozin (Jardiance) on cardiovascular outcomes were recently published. Here are some key takeaways.

In September, the results of a large multi-site, multi-national study of the impact of empagliflozin (Jardiance) on cardiovascular outcomes were published in the New England Journal of Medicine. The results of this trial are quite encouraging and suggest strategies for improving a number of important clinical endpoints including:

  • Cardiovascular mortality;

  • All-cause mortality; and

  • Congestive heart failure episodes and admissions.

Study population and design

This study was a randomized trial of empagliflozin at two different doses vs. placebo. All patients received other medications for lowering blood glucose and treating blood pressure and cholesterol.

A total of 7,020 patients were randomized and treated at 590 centers in 42 countries. All of the patients in the study had established cardiovascular disease and glycated hemoglobin levels of 7.0 or greater. Most patients in the study had long-standing Type 2 diabetes and were at high risk for cardiovascular events.

In the intervention, patients received either 10mg or 25mg per day of empagliflozin. The average time in the study was 3.1 years. All patients received other treatments for diabetes and cardiovascular risk factors.

Empagliflozin is an inhibitor of sodium glucose co-transporter 2 (SGLT2), which interferes with absorption of glucose in the kidneys resulting in excretion of glucose in the urine. Other drugs in the SGLT2 class include canagliflozin (Invokana) and dapagliflozin (Farxiga). All of these drugs are approved for lowering of glucose in Type 2 diabetes and may be used as either mono or combination therapy.

Next: The study results




The primary study outcome was a composite outcome including death from cardiovascular causes, nonfatal myocardial information and nonfatal stroke. The key secondary outcome was the composite measure plus hospitalization for unstable angina.

Use of empagliflozin significantly reduced the risk of death from cardiovascular causes, risk of death from all causes, and rates of hospitalization for congestive heart failure. The key secondary outcome was not achieved.

OutcomeHazard Ratio
Death from cardiovascular disease0.62 (p<0.001)
Death from any cause0.68 (p<0.001)
Hospitalization for congestive heart failure0.65 (p<0.002)


Separation between the intervention and placebo arms of the trial was observed almost immediately and continued to widen over time.

The most striking finding was the impact of the intervention on death from cardiovascular causes. Also of importance is the impact on hospitalization for congestive heart failure. Although not all subgroups showed benefit using the composite primary endpoint, all subgroups did show a statistically significant reduction in cardiovascular mortality.


Much of the literature on diabetes treatment is focused on improving risk factors such as increased glycated hemoglobin, blood pressure and lipid management. To date there has been little evidence on the impact of specific treatments on the most important outcomes to patients. This trial is a good start, and has important implications for both treatment and future studies on Type 2 diabetes.

Patient specific outcomes can be broadly classified as clinical outcomes (survival, prevention of untoward events, reduction in symptoms and avoidance of toxicity) and personal outcomes (quality of life, patient experience with care). Although this study does not address the personal outcomes it provides very important evidence for treating patients at high risk for poor clinical outcomes.

Earlier this year, another study appearing in the International Journal of Clinical Practice addressed the issue of whether treatment with SGLT2 inhibitors should be initiated early in the course of diabetes.

The study author argues that a favorable safety profile coupled with impacts on multiple risk factors make a good case for placing these drugs earlier in the treatment guidelines. The author does mention the lack of outcome evidence. This new study addresses that lack of evidence for patients with more advanced disease. It does not look at outcomes for diabetics with early disease but it is still an important step forward.

The empagliflozin study emphasizes the importance of managing the entire set of risk factors including glucose levels. The study makes a good case for treating high risk individuals with empagliflozin, although I suspect that many physicians will want to have some confirmation of this through other studies and publications.

Whether this is a class effect or is specific to this drug is currently unknown but similar trials are underway with the other drugs in this class. Depending on the results, the accumulation of multiple studies may help to answer the question of whether the results are durable and whether all of the drugs in this class have efficacy in preventing cardiovascular mortality.

Next: What's next?


What’s next?

We should keep an eye out for new developments in this therapeutic category. More outcome studies are needed and we anticipate that studies specifically on the other SGLT2 drugs will be published in the next two years. Of particular importance will be whether these studies stimulate more work on cardiovascular outcomes and the determinants of better outcomes for patients including for patients with earlier stages of disease. We may also see more utilization of SGLT2 inhibitors in high risk patients. This could prompt the American Diabetes Association and others to reconsider the current guidelines, especially for patients with very high risk and known cardiovascular disease.

Edmund Pezalla, MD, MPH, is vice president and national medical director for pharma- ceutical policy and strategy, Aetna.