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Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL)

Results from the ongoing first large real-world evidence study of its kind published in the American Heart Association.

This is a comparative effectiveness study comparing new users of SGLT-2 inhibitors with new users of other glucose-lowering drugs with regard to hospitalization for heart failure and all cause mortality respectively. The study is carried out based on data from six countries: United States, United Kingdom, Germany, Sweden, Denmark, and Norway.

September 2015 the EMPA-REG trial presented data on positive effects of empagliflozin, a SGLT-2 inhibitor on cardiovascular (CV) outcomes. This has created a need for data on how this class of medicines affect CV event rates when used in clinical practice.

The primary aim of this observational study (CVD-REAL) is to compare the risk for hospitalization for heart failure between patients with type 2 diabetes mellitus (T2DM) who are new users of a SGLT-2 inhibitor versus an active comparison group including patients with T2DM who are new users of other glucose-lowering drugs. A secondary aim is to compare all-cause mortality using similar methods. Exploratory aims are to estimate the incidence of acute myocardial infarction and atrial fibrillation in both treatment groups. This is the first of several comparative analyses of CVD-REAL. The study is ongoing and future analyses will be conducted using this dataset as well as data from additional countries. The CVD-REAL study assessed data from more than 300,000 patients across six countries, 87% of whom did not have a known history of cardiovascular disease.

Research was led by Mikhail Kosiborod, M.D. at Saint Luke’s Mid America Heart Institute, in coordination with the CVD-REAL Executive Scientific Committee, and published in the American Heart Association’s flagship journal, Circulation, revealed that patients treated with sodium-glucose co-transporter-2 inhibitor (SGLT-2) medicines experienced a significantly lower risk of hospitalizations for heart failure and death when compared with T2D patients treated with other glucose-lowering drugs (GLDs).

The CVD-REAL study assessed data from more than 300,000 patients across six countries, 87% of whom did not have a known history of cardiovascular disease. The data showed that across this broad population of patients with T2D, treatment with SGLT-2 medicines — canagliflozin, dapagliflozin and empagliflozin — was associated with a 39% lower risk of hospitalization for heart failure (HR 0.61; 95% CI 0.51-0.73; p<0.001) and 51% lower risk of death from any cause (HR 0.49; 95% CI 0.41-0.57; p<0.001), compared with other T2D medicines. For the composite endpoint of hospitalization for heart failure or death from any cause, treatment with SGLT-2 versus other drugs was associated with a 46% lower risk (HR 0.54; 95% CI 0.48-0.60; p<0.001).

Cardiologist Mikhail Kosiborod, M.D., the lead author of the study added that, “T2D remains a major risk factor for cardiovascular disease and overall mortality despite advances in treatment….There is a substantial need to develop treatments that not only lower blood glucose levels, but also reduce the risk of cardiovascular complications, including heart failure. The CVD-REAL study results suggest that SGLT-2 medicines may have a significant impact on reducing those risks and may improve overall outcomes in a much broader population of patients with T2D than previously thought.”

The hospitalizations for heart failure analysis was conducted using anonymized patient data from Denmark, Norway, Sweden, United Kingdom, Germany, and the United States. Of the data reviewed, 53% were on canagliflozin, 42% on dapagliflozin, and 5% on empagliflozin. The analysis of death from any cause was conducted using anonymized patient data from Denmark, Norway, Sweden, United Kingdom and the United States. Of the data reviewed, 42% of patients were on canagliflozin, 51% on dapagliflozin and 7% on empagliflozin. Among patients treated with SGLT-2, the majority in the US received canagliflozin, and the majority in Europe received dapagliflozin; lower risks of hospitalization for heart failure and death associated with SGLT-2 use were seen both in the US and Europe, suggesting that these potential benefits may represent a class effect.

The data for this study were obtained from real-world sources, including medical records, claims databases and national registers, and were not independently adjudicated or verified against source documents. The CVD-REAL study is sponsored by AstraZeneca. This study was validated by the independent academic statistical group at St. Luke’s Mid America Heart Institute, Kansas City, US. While CVD-REAL is a large study with a robust propensity-matching technique, given its observational nature the possibility of residual, unmeasured confounding factors cannot be definitively excluded.

Practice Pearls:

  • Of the data reviewed, 42% of patients were on canagliflozin, 51% on dapagliflozin, and 7% on empagliflozin.
  • Treatment with canagliflozin, dapagliflozin and empagliflozin was associated with a 39% lower risk of hospitalization for heart failure and 51% lower risk of death from any cause, compared with other T2D medicines.
  • The results suggest that the benefits of reducing the risk of death was a class effect.

https://doi.org/10.1161/CIRCULATIONAHA.117.029190: Circulation. 2017;CIRCULATIONAHA.117.029190; Originally published May 18, 2017