TREATMENT OF DIABETES
Details of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial of the glucose-lowering drug liraglutide (Victoza, Novo Nordisk), showing that it significantly reduced the rates of major adverse cardiovascular events in type 2 diabetes patients at elevated cardiovascular risk, were reported today.
The study is the second suchmandated FDA cardiovascular safety study for a diabetes drug to show cardiovascular benefit, rather than just lack of harm, on top of standard therapy in type 2 diabetes patients at high cardiovascular risk after the EMPA-REG trial, and the first with an agent from the glucagonlike peptide 1 (GLP-1) receptor agonist class. Results of a previous trial with another GLP-1 agonist, ELIXA, were neutral.
Experts here said that LEADER andEMPA-REG may now begin to change the landscape of diabetes therapy, giving doctors a somewhat clearer choice when deciding which drug to use second line after metformin in type 2 diabetes.
The results from the multicenter, international study were presented June 13, 2016 here at the American Diabetes Association (ADA) 2016 Scientific Sessions and were published online simultaneously in the New England Journal of Medicine, by Steven P Marso, MD, of University of Texas Southwestern Medical Center, Dallas, and colleagues.
LEADER began in 2010 and followed 9340 high-risk adults with type 2 diabetes for 3.5 to 5 years, who were randomly assigned to receive either a subcutaneous injection of liraglutide 1.8 mg once daily (or the maximum tolerated dose) or placebo along with standard treatment.
The primary end point was the first occurrence of the three-point major adverse cardiac event (MACE) components: cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke.
The degree of risk reduction for MACE was 13% (occurring in 608 of 4668 patients taking liraglutide) vs 14.9% (in 694 of 4672 taking placebo) (P = .01 for superiority), including a 22% lower rate of cardiovascular death (4.7 vs 6.0%, P = .007), Dr Marso reported in a press briefing held at the ADA meeting in advance of a special 2-hour symposium devoted to the findings.
The number of patients who would be needed to treat to prevent one event in 3 years was 66 for the MACE composite and 98 for death from any cause.
Liraglutide also reduced HbA1c, body weight, and hypoglycemia, and its safety profile was similar to what has been seen in previous trials, with gastrointestinal adverse events and increases in heart rate being the most common.
New Trials Inform Clinical Choice of Second Drug for Type 2 Diabetes
Coming on the heels of the cardiovascular benefit seen for the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) in the EMPA-REG trial, the LEADER findings have experts talking about a “new era” in the management of type 2 diabetes.
While most agree that metformin remains the first-line drug of choice, these new landmark study data are starting to better inform the clinical choice of second drug based on characteristics beyond their glucose-lowering capacity, speakers said during the press briefing. Continue Reading
“In type 2 diabetes, most of us agree that under most circumstances metformin is the drug of choice,” briefing moderator Robert H Eckel, MD, of the University of Colorado, Denver, said, noting that additional potential cardiovascular and also anticancer benefits have been seen with that drug as well.
However, he said, “It’s interesting, with LEADER the benefit for cardiovascular death is very similar to what statins do. I think with validation, it could potentially change practice….I’d like to see second and third trials for both [liraglutide and empagliflozin]. Keep in mind there are 25 or 30 trials for statins showing benefit,” said Dr Eckel, who was not involved in LEADER or EMPA-REG.
Senior investigator of LEADER, John Buse, MD, of the University of North Carolina, Chapel Hill, added: “I think this changes the conversation with patients. Now, instead of just saying we’re giving you this drug to manage your hyperglycemia in diabetes, [we can say] this drug also has the potential to modify your risk for cardiovascular disease and death.
“It was beyond our expectations that we would be able to demonstrate cardiovascular efficacy,” he told the press briefing.
Asked to comment, Simon Heller, MD, professor of clinical diabetes, University of Sheffield, United Kingdom, toldMedscape Medical News, “I think we are in a different era now. People die from hypoglycemia, whether by insulin or sulfonylureas. We shouldn’t forget that.
“These drugs [liraglutide and empagliflozin] don’t cause hypoglycemia and have other effects that may be beneficial. I agree absolutely we need to confirm with other studies, but I think we’re definitely going to see a shift toward modern therapies.”