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A substudy of a "real-world" observational analysis found better cardiovascular outcomes for Scandinavian patients starting SGLT2 inhibitors compared with other glucose-lowering drugs.

In the CVD-REAL Nordic study, use of SGLT2 inhibitors was associated with significant reductions in major adverse cardiovascular events (HR 0.78, 95% CI 0.69-0.87) and cardiovascular mortality (HR 0.53, 95% CI 0.40-0.71) in just under a year compared with use of other drugs, Anna Norhammar, MD, of the Karolinska Institute in Stockholm, and colleagues .

The drug class was also tied to a reduction in all-cause mortality (HR 0.51, 95% CI 0.45-0.58) and hospitalizations for heart failure (HR 0.70, 95% CI 0.61 to 0.81), but it had no effects on non-fatal MI or stroke, they reported.

Both the EMPA-REG and CANVAS trials have shown a reduction in cardiovascular morbidity and mortality for empagliflozin (Jardiance) and canagliflozin (Invokana), respectively, and researchers have been exploring whether the cardiovascular benefits may be class effect of SGLT2 inhibitors.

The CVD-REAL observational study aimed to look at the question using "real-world" data from Scandinavia as well as the U.S., the U.K., and Germany. , showed that use of SGLT2 inhibitors was associated with a lower rate of hospitalization for heart failure and overall mortality.

CVD-REAL Nordic focuses on Scandinavia, where national registries help make the data more detailed and complete than elsewhere. Importantly, the dapagliflozin (Farxiga) accounts for the majority of SGLT2 use in those countries, a drug for which cardiovascular outcomes have not yet been reported. The ongoing DECLARE-TIMI 58 trial is poised to release results in 2018; in the meantime, dapagliflozin drugmaker AstraZeneca .

In CVD-REAL Nordic, 22,830 patients with type 2 diabetes started on an SGLT2 inhibitor in 2012-2013, while 68,490 patients started on other glucose-lowering medications. Their mean age was 61. The researchers used propensity matching for comparisons.

Overall, 94% of the total SGLT2-inhibitor exposure time was for dapagliflozin; 5% was for empagliflozin and 1% for canagliflozin.

Norhammar and colleagues noted that the outcomes for cardiovascular mortality were similar for those with cardiovascular disease at baseline and those without -- but the reduction in major adverse cardiovascular events was seen only in those with a history of heart disease (HR 0.70, 95% CI 0.59-0.83 versus HR 0.90, 95% CI 0.76-1.07).

Although the study is limited by its observational nature, the researchers still concluded that their results are consistent with those seen in the EMPA-REG and CANVAS trials and suggest a class effect of cardiovascular risk reduction with SGLT2 inhibitors.

In an accompanying editorial, David Fitchett, MD, of St. Michael's Hospital in Toronto, agreed that the data suggest a class effect for SGLT2 inhibitors, but data from randomized controlled trials are needed before making any final conclusions.

"Although the direction of benefit observed in CVD-REAL Nordic is probably real, the magnitude of the benefit is likely to be exaggerated because of channeling bias," Fitchett wrote. "CVD-REAL Nordic provides some additional support for a class effect for SGLT2 inhibitors ... but the results must be considered within the limitations of observational studies. Only with the results of the DECLARE-TIMI 58 study ... will we have definitive evidence for the cardiovascular benefit and safety of dapagliflozin."

A spokesperson for AstraZeneca said the DECLARE trial will now read out in 2018 instead of 2019 because the trial is event-driven and the company has confirmed a new reporting date.

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