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Jardiance reduces risk for CV death, all-cause mortality in adults with type 2 diabetes and CVD history
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.”
Silvio Inzucchi
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
Reference:
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.
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It’s surprising to see this magnitude of benefit, and the pattern is interesting as well. The short answer is, we don’t know what the mechanism is. The reduction in heart failure and death — not in myocardial infarction and stroke — is quite different than typical anti-ischemic therapies that we’re used to, like statins. It’s surprising to see the two “hard” endpoints of death and heart failure — often the hardest to impact — have these huge findings. This looks like a heart failure-type drug. This fits a pattern seen before in heart failure with a diuretic-type mechanism. The diuretic [effect] fits the heart failure benefit. The timing fits with the immediate reduction in heart failure. The death curves track along that same pattern. The Sprint trial results also loom large in everyone’s thoughts, where targeting systolic blood pressure at 120 mm Hg [reduced risk for MI, heart failure, stroke and cardiovascular death]… I think that factors in here. There was a reduction in weight and a pretty substantial reduction in blood pressure. To me, the mechanism may also involve glucose reduction. Weight is also impacted, and the fact that waist circumference was impacted shows that the weight is not simply fluid, but it’s also a metabolic (response), and you do have a negative calorie balance with this class of drugs. My sense is that all those factors contribute to the mechanism. This is not just an antiglycemic drug. This is a multifactorial agent, each of which may have contributed to the substantial benefit.
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This study shows that one drug in a new class of drugs (SGLT2 inhibitors) is not only safe in terms of cardiovascular disease outcomes but also beneficial. Is this the molecule or the drug class? This remains to be validated.
Many CVD risk factors changed favorably in the empagliflozin group including weight, waist circumference, uric acid, blood pressure and HDL. Atherosclerosis is a multifactorial disease and additional statistical modeling of these data would be nice to see.
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The mortality findings from the EMPA-REG Outcomes study are very important for the field. Altogether, there were 463 deaths from all causes in EMPA-REG OUTCOME (HR for empagliflozin vs. placebo = 0.68; P < .0001). This was driven primarily by a 38% reduction in deaths from CV. In addition, there was a significant and clinically important reduction in hospitalizations for HF (HR = 0.65; P = .0017). There has never been a trial in diabetes, old or new, that has shown such a remarkable benefit on these outcomes.
There are several interesting metabolic and BP effects of the SGLT2 inhibitors. However, it is hard to associate these changes with the striking outcomes on both mortality and HF hospitalizations. The drug, and the class, clearly lower both systolic and diastolic BP, and that occurred in the EMPA-REG OUTCOME trial as well. Yet, there was no stroke benefit — in fact, the point estimate favored placebo for nonfatal stroke (HR = 1.24; P = .164). SGLT2 inhibitors have a mild diuretic effect; this could be one of the pharmacologic effects that lowered HF admissions and possibly CV mortality. Empagliflozin also had beneficial effects on body weight, HbA1c, uric acid levels and HDL, but these were all fairly modest changes and it would be far-fetched to think that any of these clinical factors could have caused such a dramatic effect on all-cause and CV mortality.
Of course, there are many other analyses that the investigators can do in the future to determine the impact of BP and the other parameters mentioned above on CV outcomes. I look forward to seeing those in secondary presentations and publications in the near future.
The findings from this trial may eventually elevate the use of SGLT2 inhibitors to a more dominant role in the initial therapy of type 2 diabetes treatment, particularly when patients also have CVD. It may take another positive trial with an SGLT2 inhibitor (eg, CANVAS) to influence guidelines for the management of type 2 diabetes, however.
The primary reason that EMPA-REG OUTCOME was conducted was to assess for the potential of CV harm based on a 2008 FDA guidance. It is the fifth major CV outcomes trial to be completed (others included SAVOR-TIMI 53, EXAMINE, TECOS and ELIXA). All five of these studies have demonstrated noninferiority for the primary endpoint (typically CV death, MI and stroke, sometimes including hospitalization for unstable angina) when comparing the antihyperglycemic drug to placebo. The findings from EMPA-REG OUTCOME were both unexpected and fortunate for the drug, and perhaps the class of SGLT2 inhibitors, considering the study duration was only about 3 years with 7,020 patients with type 2 diabetes and CVD. Perhaps the academic cardiology and endocrinology communities can encourage that future studies of drugs for the treatment of type 2 diabetes should be larger and focus on the potential for efficacy in lowering CV events rather than noninferiority. This means larger sample size and longer duration of follow-up.