ELIXA Published: Reiterates CV Safety of Lixisenatide in Diabetes

Marlene Busko

December 03, 2015

Results of the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, a cardiovascular safety study of the glucose-lowering agent lixisenatide (Lyxumia, Sanofi), first presented at the American Diabetes Association (ADA) 2015 Scientific Sessions this summer—have been published in the New England Journal of Medicine.

The study showed that in patients with type 2 diabetes who had a recent acute coronary syndrome, the glucagonlike peptide-1 (GLP-1)-receptor agonist did not lead to any increased cardiovascular adverse events compared with placebo.

"The results were totally neutral in every aspect, including heart failure," lead author Marc A Pfeffer, MD, PhD, of the cardiovascular medicine division at Brigham and Women's Hospital, in Boston, Massachusetts, told Medscape Medical News. "We really turned the data upside down looking for an adverse effect and didn't see it."

Lixisenatide, a once-daily injectable agent, has been available in Europe, Japan, Australia, and Mexico since 2013.

However the agent is not yet approved in the United States; based on the results from ELIXA and other phase 3 efficacy and safety trials, Sanofi submitted a new drug application to the Food and Drug Administration (FDA) on September 29, 2015.

Since 2008 the FDA has required cardiovascular-safety studies for all new type 2 diabetes drugs, and ELIXA was designed to satisfy this requirement.

This is the first GLP-1 receptor agonist to have cardiovascular safety data reported to the FDA, Dr Pfeffer noted.

How Does ELIXA Sit With EMPA-REG?

More recently, another cardiovascular-outcomes trial with a diabetes agent from a different drug class has caused great excitement, as it was the first to show a cardiovascular benefit (ie, a glucose-lowering agent prevented cardiovascular deaths compared with placebo).

In the landmark Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial, 39 patients needed to be treated with the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) for 3 years to prevent one cardiovascular death.

EMPA-REG, first presented at the European Association for the Study of Diabetes (EASD) 2015 meeting in mid-September and simultaneously published online (N Engl J Med. 2015;373:2117-2128), was also an FDA-mandated cardiovascular-safety study.

Some experts had said it was futile to expect an antidiabetic drug to show a benefit in CV-safety trials, since these are relatively short, and physicians are allowed to use any combination of drugs to lower glucose in the placebo and study-drug arms.

Then, "magically, this other [drug, empagliflozin,] with a different mechanism, [showed a survival benefit]," Dr Pfeffer observed.

Since more than one antidiabetic agent may be needed to control blood glucose, these new drugs will give physicians and patients more choices, he added, noting "It's pretty exciting that cardiovascular outcomes can be improved."

Neutral Effect of Lixisenatide on CV Outcomes and No Serious Adverse Drug Reactions

ELIXA aimed to see whether lixisenatide was safe in patients with type 2 diabetes who were at very high risk of having a cardiovascular event, since they had had an acute coronary syndrome within the past 180 days.

"GLP-1 agonists [even] seemed to have some cardiovascular promise," Dr Pfeffer noted. Some studies had suggested that patients might lose weight, have less proteinuria, and have slightly lower blood pressure.

Between 2010 and 2013, ELIXA randomized 6068 adults with type 2 diabetes in 49 countries. Most patients had a recent non–ST-segment-elevation myocardial infarction (39%) or ST-segment-elevation myocardial infarction (43%), and the rest (17%) had unstable angina.

At a median of 25 months, the primary composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina occurred in 13.4% of the lixisenatide patients and 13.2% of the control patients (hazard ratio [HR], 1.02; P < .001 for noninferiority, P = .81 for superiority).

There were no significant between-group differences in the rate of hospitalization for heart failure (HR, 0.96) or the rate of death (HR, 0.94).

Lixisenatide was not associated with a higher rate of serious adverse events or severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions, compared with placebo.

Well-Controlled CV Risk Factors in Type 2 Diabetes

It's important for diabetic patients to have tools to lower glucose to prevent complications of retinopathy, neuropathy, and nephropathy, and ELIXA showed that lixisenatide can be "another tool to [safely] lower glucose in the long run," Dr Pfeffer said.

"The neutral cardiovascular profile associated with lixisenatide will inform physicians' and patients' decisions regarding the use of this agent as an adjunctive therapy to control the glycated-hemoglobin level safely, with no observed augmentation of the risks of hypoglycemia or pancreatitis," he and his colleagues summarize.

And importantly, patients in this and other cardiovascular-safety trials of new antiglycemic agents have very well-controlled CV risk factors, Dr Pfeffer pointed out.

Not so long ago, diabetes treatment was focused solely on managing glucose, but "one of the benefits that has come out of this intense cardiovascular-outcome-trial effort in the…field of diabetes is the emphasis on [treating] the whole patient," he noted.

"If you look at table 1 of any of the publications, including ELIXA, I think the investigators…in all of these trials can be proud that [in addition to] addressing HbA1c," blood pressure and LDL cholesterol, for example, are "very nicely controlled."

In ELIXA, the mean baseline systolic blood pressure was 130 mm Hg and the mean LDL cholesterol was 78 mg/dL, he noted.

"We're now looking at all the risk factors, and glucose is just one of many....I'm very proud of the whole pattern of research," he concluded.

The study was supported by Sanofi. Dr Pfeffer reports grant support and personal fees from Sanofi during the conduct of the study; grant support from Celladon, grant support and personal fees from Amgen and Novartis; and personal fees from AstraZeneca, Bayer, Genzyme, Lilly, the Medicines Company, MedImmune, Medtronic, Merck, Novo Nordisk, Relypsa, Roche, Salix, Sanderling, Takeda, Teva, Thrasos, and Vericel outside the submitted work. In addition, Dr Pfeffer reports that Brigham and Women's Hospital holds patents related to the use of inhibitors of the renin-angiotensin system in selected survivors of MI and European patents licensed to Novartis. Disclosures for the coauthors are listed on the journal website.

N Engl J Med. 2015;373:2247-2257. Abstract

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