Real-world data show clinical benefit of empagliflozin, which is likely a class effect

Lower Risk of Heart Failure and Death in Patients Initiated on SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study

Literature - Kosiborod M, Cavender MA, Fu AZ, et al. - Circulation 2017; published online ahead of print


Higher HbA1c levels are associated with an increased cardiovascular disease (CVD) risk, however intensive glucose control has not been related to a reduction of heart failure (HF) development and of cardiovascular (CV)- or all-cause death so far [1,2].

In the EMPA-REG OUTCOME study, there was a substantial reduction in CV death and hospitalization for heart failure (HHF) in type 2 diabetes mellitus (T2DM) patients with established atherosclerotic CVD, who were randomized to the SGLT-2 inhibitor empagliflozin [3,4]. There was only a small difference in HbA1c levels between empagliflozin- and placebo-treated patients, therefore the clinical benefit cannot be explained by glucose-lowering. Although mechanisms explaining the EMPA-REG OUTCOME study results are unclear, the question remains whether the clinical benefits related to SGLT-2 inhibitor treatment are reproducible in clinical practice.

In this real-world practice international study (6 countries), the risk for HHF, death and the combined endpoint of HHF or death was assessed in T2DM patients treated with SGLT-2 inhibitors (n=166,033) or with other glucose-lowering drugs (oGLDs, n=1,226,221). This was done to confirm the CV benefits with SGLT-2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) in real-world setting, to determine whether there is a class effect and to verify the effects in T2DM patients with a broader CV risk profile than this in the EMPA-REG OUTCOME study, which only included patients with established CVD.

Main results

  • Compared to patients on oGLDs, patients initiated on SGLT-2 inhibitors were younger, less likely to have chronic kidney disease or CV complications, more likely to have microvascular disease, more likely to receive statins, anti-hypertensive drugs, and other glucose-lowering medication classes at baseline, and less likely to receive loop diuretics.
  • The baseline characteristics were well-balanced between groups post-matching and the standardized differences for most variables were <10%.
  • The mean age was 57 years, 44% were women, 13% had established CVD, 67% of patients received statins, 80% anti-hypertensive medications, 74% ACEi/ARBs, and 79% metformin.
  • The initiation of SGLT-2 inhibitor vs. oGLD was associated with a lower risk of HHF (pooled HR 0.61, 95% CI 0.51–0.73, P<0.001) and a lower risk of death (pooled HR 0.49, 95% CI 0.41–0.57, P<0.001), as well as with a lower risk of the composite outcome of HHF or death (pooled HR 0.54, 95% CI 0.48–0.60, P<0.001).
  • Sensitivity analysis including multivariate adjustment, stepwise removal of specific oGLD classes and comparisons within geographic region, yielded similar results.


In a large multinational study, treatment of T2DM patients with SGLT-2 inhibitors versus oGLDs was associated with lower rates of HHF and death in a real-world setting. Since the overwhelming majority of patients did not have established CVD, this suggests that the benefits of SGLT-2 inhibitors on the prevention of heart failure may extend to lower-risk patients than those enrolled in randomized trials so far. Moreover, as there is substantial variation in SGLT2 inhibitor use between geographic regions and no heterogeneity in results was observed across counties, this suggests that there is likely a class effect for SGLT-2 inhibitors.


1. Bertoni AG, Hundley WG, Massing MW, et al. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care. 2004;27:699-703.

2. Matsushita K, Blecker S, Pazin-Filho A, et al. The association of hemoglobin a1c with incident heart failure among people without diabetes: The atherosclerosis risk in communities study. Diabetes. 2010;59:2020-2026.

3. Zinman B, Wanner C, Lachin JM, et al, Investigators E-RO. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New Engl J Med. 2015;373:2117-2128.

4. Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the empa-reg outcome trial. Eur Heart J. 2016;37:1526-1534.

Find this article online at Circulation

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