The SGLT2 inhibitor Jardiance significantly reduced the risk for cardiovascular death and all-cause mortality in adults with type 2 diabetes and an established history of cardiovascular disease, according to study findings presented at the 51st European Association for the Study of Diabetes Annual Meeting.
In announcing the findings from the EMPA-REG Outcome trial, a randomized, double-blind, placebo-controlled trial in 42 countries, researchers said that Jardiance (empagliflozin, Boehringer Ingelheim), when combined with standard care, reduced the risk for CV death by 38% compared with placebo, with no significant difference in the risk for non-fatal myocardial infarction or stroke. Patients treated with empagliflozin also experienced a 32% reduction in all-cause mortality risk and a 35% reduction in risk for hospitalization for heart failure, according to researchers.
“[The results] were very surprising,” Silvio Inzucchi, MD, professor of endocrinology and director of the Yale Diabetes Center at Yale School of Medicine, told Endocrine Today. “I did not predict it. In fact, I’m on record as saying I thought the results of the study would be [risk] neutral ... I was shocked.”
Inzucchi and colleagues analyzed data from 7,020 adults with type 2 diabetes, a BMI of 45 kg/m² or less, an HbA1c between 7% and 10% and an established history of CVD (mean age, 63 years; 72% men; mean HbA1c, 8%; mean BMI, 30.6 kg/m²). Within the cohort, 76% of participants had an established history of coronary artery disease; 46% of participants had a history of MI; between 9.5% and 10.5% of participants had a history of cardiac failure. Between 80% and 81% of participants were using ACE inhibitors; between 75% and 78% of participants were using statins.
Participants were randomly assigned 10 mg empagliflozin (n = 2,345), 25 mg empagliflozin (n = 2,342) or placebo (n = 2,333). Primary endpoint was defined as the time to first occurrence of either CV death, non-fatal MI or non-fatal stroke; the trial continued until at least 691 participants experienced a primary outcome event. Researchers used Cox proportional hazards to analyze CV outcomes, following participants for an average of 3.1 years.
During the treatment period, patients experienced a reduced risk for CV death, with an HR of 0.65 for patients assigned 10 mg empagliflozin (95% CI, 0.5-0.85) and an HR of 0.59 for patients assigned 25 mg empagliflozin (95% CI, 0.45-0.77), for a combined HR of 0.62 (95% CI, 0.49-0.77). The HR for non-fatal MI was 0.87 (95% CI, 0.7-1.09), while the HR for non-fatal stroke was 1.24 (95% CI, 0.92-1.67).
Hospitalization for heart failure also decreased for patients assigned empagliflozin (combined HR = 0.65; 95% CI, 0.5-0.85); patients also saw a reduction in all-cause mortality (combined HR = 0.68; 95% CI, 0.57-0.82).
There was an increased rate for genital infections in patients assigned empagliflozin; however, there was no increase in the frequency of hypoglycemia, diabetic ketoacidosis or acute kidney injury, the researchers said. The researchers also noted no increase in bone fractures, which has been an adverse event of special interest in similar trials.
“EMPA-REG studied a particularly high-risk group of people, and I think this is extremely important to remember,” Hertzel C. Gerstein, MD MSc, FRCPC, an endocrinology professor in the department of medicine at McMaster University, said in commentary following the presentation of study data. “[Empagliflozin] clearly reduces CV death without any doubt at all. It’s very clear, and starts to reduce these outcomes within 3 months.”
The mechanism behind the reduction in CV risk was debated during the presentation, with researchers speculating that the diuretic properties of the drug, combined with the beneficial effects of improved blood pressure, lower HbA1c values and weight loss, may have led to the reduction in CV risk and ultimately, CV death.
“But it has be something else as well,” Inzucchi said after the presentation. “A lot of it is speculation and it’s very challenging to come up with an answer ... a possibility is maybe, by doing a little of this and a little of that, you do right by patients. Weight goes down a little, blood pressure goes down a little, glucose goes down a little, and [the drug doesn’t] result in hypoglycemia. So maybe the quadruple benefit of lower blood pressure, weight and glucose, without hypoglycemia, can somehow add up and lead to a benefit. We need help from the cardiology community and scientists to really hash through this data.”
“The EMPA-REG trial has identified a therapy that can save many lives and reduce much suffering,” Gerstein said. “The results were unexpected and they are clearly going to open up new research.”
Results from the findings were also published in the New England Journal of Medicine. – Regina Schaffer
Inzucchi, S, et al. “Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.” Presented at: 51st EASD Annual Meeting; Sept. 14-18, 2015; Stockholm.
Zinman B, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1504720.
Disclosure: Inzucchi reports consulting for and receiving non-financial support from Boehringer Ingelheim, Eli Lilly, Intarcia, Janssen, Lexicon, Novo Nordisk, Merck, Poxel, Sanofi/Regerson and Takeda.