A large observational study suggests a class-effect of cardiovascular protection.
Heart Safer on SGLT2 Diabetes Drugs, Real-World Data Says
MACE, deaths, HF hospitalizations lower in Scandinavian observations
by Kristina Fiore, Deputy Managing Editor, MedPage Today
August 14, 2017
This article is a collaboration between MedPage Today® and The American Heart Association
Real-world data from Scandinavian databases affirmed that people taking diabetes drugs in the SGLT2 class -- largely dapagliflozin (Farxiga) there -- were less likely to have or die from cardiovascular events, extending evidence from recent positive trials.
Starting SGLT2 inhibitors compared with other glucose-lowering drugs was associated with fewer major adverse cardiovascular events (HR 0.78, 95% CI 0.69-0.87) and less cardiovascular mortality (HR 0.53, 95% CI 0.40-0.71) in just under a year in the Nordic substudy of the CVD-REAL observational study.
SGLT2 drugs were also associated with a substantial reduction in risk of all-cause mortality (HR 0.51, 95% CI 0.45-0.58) as well as fewer hospitalizations for heart failure (HR 0.70, 95% CI 0.61 to 0.81) not fewer non-fatal MIs or strokes, Anna Norhammar, MD, of the Karolinska Institute in Stockholm, and colleagues reported online in Lancet Diabetes & Endocrinology.
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 a 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. That study, reported in May, 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 funded this observational study.
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.
The study was funded by AstraZeneca. The authors disclosed financial relationships with AstraZeneca and other diabetes drugmakers.