CVD-REAL Results Suggest that Cardiovascular Benefits of Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors are, Indeed, Real

By Kevin C Maki, PhD


In 2015, the release of the Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial results generated significant surprise and controversy.1 The investigators randomly assigned 7,020 patients with type 2 diabetes mellitus (T2D) to receive 10 or 25 mg/d of empagliflozin or placebo.  Empagliflozin is a sodium-glucose cotransporter-2 inhibitor that reduces renal reabsorption of glucose and sodium, thus increasing urinary losses and reducing the plasma glucose concentration.  The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in the pooled empagliflozin group compared with the placebo group.

The EMPA-REG OUTCOME results showed a 14% reduction (p = 0.04) in the primary outcome in the empagliflozin group.  Despite significant reductions in blood pressure, glycated hemoglobin and body weight, there were no differences between the groups in myocardial infarction or stroke.  However, there were substantial reductions (p ≤ 0.002) in death from cardiovascular causes (38%) and hospitalization for heart failure (35%).

More recently, the results from the Canagliflozin Cardiovascular Assessment Study (CANVAS) program were released in which data were pooled from two placebo-controlled studies of another SGLT-2 inhibitor, canagliflozin, involving 10,142 patients with T2D at high cardiovascular risk.2  The outcome for the primary composite, which was the same as that in EMPA-REG OUTCOME, showed that canagliflozin treatment was associated with a significant 14% reduction, a result that was essentially identical to that in the EMPA-REG OUTCOME study overall.  However, there were some differences between the results for individual components of the composite.


Outcome EMPA-REG OUTCOME (empagliflozin) CANVAS


Hazard Ratio (95% Confidence Interval)
Primary Composite 0.86 (0.74-0.99) 0.86 (0.75-0.97)
Death from Cardiovascular Causes 0.62 (0.49-0.77) 0.87 (0.72-1.06)
Non-fatal Myocardial Infarction 0.87 (0.70-1.09) 0.85 (0.69-1.05)
Non-fatal Stroke 1.24 (0.92-1.67) 0.90 (0.71-1.15)
Hospitalization for Heart Failure 0.65 (0.50-0.85) 0.67 (0.52-0.87)
Death from Any Cause 0.68 (0.57-0.82) 0.87 (0.74-1.01)

The notable differences are for death from cardiovascular causes (38% reduction vs. non-significant 13% reduction) and death from any cause (32% reduction vs. non-significant 13% reduction), for which the results with empagliflozin appeared more favorable, and non-fatal stroke (non-significant 24% increase vs. non-significant 10% reduction), for which the results appeared more favorable for canagliflozin. Or course, such differences could easily be due to random variation, so additional studies are needed with these and other agents in the SGLT-2 inhibitor class.  Large-scale randomized, controlled clinical trials are expensive and time consuming, so it is useful to look at results in the real world for patients prescribed these medications in clinical practice.  Results from such investigations need to be viewed with caution because they are more susceptible to various types of bias and confounding than results from randomized trials.  Nevertheless, they can be useful for evaluating risks and benefits of drug therapies and to further evaluate hypotheses generated from clinical trial data, such as whether there are differences in cardiovascular outcomes between agents in the SGLT-2 inhibitor class.

Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) Methods and Results3

Data were collected from medical claims in the US and several countries in the EU.  A propensity score was used to adjust for SGLT-2 inhibitor initiation.  Hazard ratios were calculated for hospitalization for heart failure, all-cause mortality, and incidence of either outcome among those taking SGLT-2 inhibitors compared with other glucose-lowering drugs (GLD).

Data were included for more than 300,000 patients, half of whom took an SGLT-2 inhibitor and half of whom took other GLDs.  Canagliflozin was the most commonly used SGLT-2 inhibitor (53% of exposure), followed by dapagliflozin (42% of exposure) and empagliflozin (5% of exposure).  Canagliflozin was the most commonly used SGLT-2 inhibitor in the US (76%), whereas dapagliflozin was the most commonly used in Europe (92%); 87% of subjects had no known cardiovascular disease at baseline.

Over 190,164 person-years of follow-up, hazard ratios for hospitalization for heart failure (0.61, 95% CI 0.51-0.73), death (0.49, 0.41-0.57) and either outcome (0.54, 0.48-0.60) were all significantly below the null, indicating that incidence rates for these outcomes were 39-51% lower for SGLT-2 inhibitors compared with other GLDs.  Sensitivity analyses were consistent with the main results, with no evidence of significant heterogeneity across type of SGLT-2 inhibitor or country.


The results of the CVD-REAL investigation support the hypothesis that use of the SGLT-2 inhibitor class reduces risks for heart failure and death in patients with T2D.  The mechanisms responsible for these benefits, which are generally confirmatory (significant reductions or trends) for those observed in the EMPA-REG OUTCOME and CANVAS trials, are not well understood.  The SGLT-2 inhibitor class does not differ markedly from other GLD classes regarding effects on glycemic control.  Additional research will be needed to elucidate mechanisms responsible, which may have implications for the application of this drug class to other high-risk groups who do not have T2D.


  1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.
  2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. 2017; Jun 12. [Epub ahead of print].
  3. Kosiborod M, Cavendar MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017;136:249-259.





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