Liraglutide Leaps Over FDA Safety Hurdle, With Cardiovascular Mortality Reduction to Boot: LEADER

The addition of liraglutide to standard care in the treatment of patients with type 2 diabetes significantly reduced the risk of major cardiovascular events compared with placebo and standard care and this benefit was driven primarily by a reduction in the risk of cardiovascular mortality.

Take Home. Liraglutide Leaps Over FDA Safety Hurdle, With Cardiovascular Mortality Reduction to Boot: LEADER

Those are the main findings from the LEADER study presented today at the American Diabetes Association 2016 Scientific Sessions in New Orleans, LA, and published simultaneously in the New England Journal of Medicine. Overall, treatment with liraglutide (Victoza, Novo Nordisk), a glucagonlike peptide-1 (GLP-1) receptor agonist, reduced the risk of death from cardiovascular causes, nonfatal MI, or nonfatal stroke by 13% compared with placebo.

Importantly, there was a significant 15% relative reduction in all-cause mortality and a 22% relative reduction in cardiovascular mortality among the liraglutide-treated patients compared with the placebo-treated group.

“I do think it’s great that in 2016 when we’re talking to a patient about what to do next in diabetes management, it’s no longer a conversation about only controlling their blood sugar,” senior investigator John Buse, MD (University of North Carolina School of Medicine, Chapel Hill) told TCTMD. “It’s now a conversation that we need to control your blood sugar, but here with these drugs, you can also feel confident it has the potential to improve outcomes you would care about, like kidney disease, heart attack, stroke, and death.”

The reduction in the study’s primary endpoint met criteria for both noninferiority and superiority.  

LEADER, along with a number of other large-scale cardiovascular outcomes studies with diabetic medications, was designed to meet the requirements set out by the US Food and Drug Administration. Following a meta-analysis that highlighted a significantly increased risk of MI with the thiazolidinedione (TZD) rosiglitazone (Avandia, GlaxoSmithKline), a drug with peak sales of $3.3 billion in 2006, the FDA issued guidance for industry in 2008 requiring drug companies to show that their medications do not result in an unacceptable increase in cardiovascular risk.

For Marc Pfeffer, MD (Brigham and Women’s Hospital, Boston, MA), who was not involved in LEADER but led the ELIXA study, which was the cardiovascular safety trial with the GLP-1 receptor agonist lixisenatide (Lyxumia, Sanofi), the FDA requirement has been a win-win for physicians and patients.

“We’re getting a lot of benefits from the FDA guidance looking for safety,” Pfeffer told TCTMD. “Had we not had that, we wouldn’t know about EMPA-REG OUTCOME and LEADER. I think it’s a real tribute to not having surrogates and going for clinical outcome trials. I’d have to put LEADER up as one that will change the practice of medicine in a positive direction.”

Presented in 2015, the EMPA-REG OUTCOME study showed that patients with diabetes and established cardiovascular disease treated with the glucose-lowering agent empagliflozin (Jardiance, Boehringer Ingelheim/Lilly), a sodium glucose cotransporter-2 (SGLT-2) inhibitor, also had a significantly reduced risk of cardiovascular events compared with placebo.  

Sanjay Kaul, MD (Cedars Sinai Medical Center, Los Angeles, CA), who wasn’t involved in the trials but commented on the results for TCTMD, said these two cardiovascular safety studies have now set the standard for treating patients with type 2 diabetes. “Together with the results of the EMPA-REG OUTCOME trial, the LEADER trial results represent a clinical breakthrough in treating type 2 diabetes mellitus and warrant a shift in the treatment paradigm to consider treatment with empagliflozin or liraglutide as a first-line therapy along with metformin in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease,” he wrote in an email.

The topline LEADER results were announced in March and at the time liraglutide was the first GLP-1 analogue shown to reduce the risk of cardiovascular events. In the short period since the results were announced, however, Novo Nordisk released data from the SUSTAIN-6 study, another large-scale cardiovascular outcomes study, showing that their other GLP-1 receptor agonist, semaglutide, which is administered subcutaneously once per week, also lowers the risk of cardiovascular events. In contrast, liraglutide is a once-daily subcutaneous injection.

Following the LEADER

The LEADER trial investigators randomized 9,340 patients with type 2 diabetes who had glycated hemoglobin levels of 7.0% or higher to treatment with liraglutide or placebo plus standard of care (all patients were treated with lifestyle recommendations plus metformin).  Patients were 50 years of age and older and had at least one coexisting cardiovascular condition, such as coronary heart disease, cerebrovascular disease, peripheral vascular disease, chronic kidney disease, or NYHA class II or III heart failure. Patients 60 years of age and older with at least one cardiovascular risk factor were also included in the trial.

After a median follow-up of 3.5 years, active treatment with liraglutide significantly reduced the occurrence of the primary endpoint, a composite of cardiovascular death, nonfatal MI, and nonfatal stroke, compared with patients treated with placebo. As noted, there were also significant reductions in the risk of all-cause and cardiovascular mortality, as well as trends suggesting a reduction in the risk of nonfatal MI, nonfatal stroke, and hospitalization for heart failure. The risk of nephropathy was also significantly reduced.

 Table. Liraglutide Leaps Over FDA Safety Hurdle, With Cardiovascular Mortality Reduction to Boot: LEADER

Speaking with TCTMD, Buse said the one “fly in the ointment” was the numerically higher rate of pancreatic cancer in the liraglutide-treated patients. Overall, pancreatic cancer occurred in 13 patients treated with liraglutide and 5 patients treated with placebo, a nonsignificant difference. Given that the GLP-1 receptor agonists have been previously linked with pancreatitis, there had been some concern the drugs might increase the risk of pancreatic cancer, he explained. However, in this trial, acute pancreatitis occurred less frequently overall with active treatment—18 cases in the liraglutide arm versus 23 in the placebo group—and overall mortality was lowered with liraglutide.    

“It’s not a clear or strong signal for pancreatic cancer,” said Buse.

For Kaul, the increase in the incidence of pancreatic cancer is a concern given the relative short follow-up in the trial. Pfeffer said the finding should be noted, but given the limited follow-up and small numbers in a randomized controlled trial, it’s unlikely researchers would be unable to draw firm conclusions from such studies.

“I think you’re entitled to raise safety questions and this might be the type of thing in the long run [where] postmarketing registries will be a better source of information than the randomized trial,” said Pfeffer.

Buse explained that liraglutide is an analogue of the human GLP-1 peptide, and differs from exenatide (Byetta/Bydureon, AstraZeneca) and lixisenatide, which are derived from the peptide isolated from the Gila monster. In the development program, liraglutide was shown to effectively reduce hemoglobin A1c levels and was associated with a modest reduction in blood pressure and weight. The American Diabetes Association considers liraglutide a second-line agent, along with a half dozen other agents, to be used in patients inadequately controlled on metformin.

The major side effects tend to be gastrointestinal, most notably nausea and vomiting. To date, the GLP-1 agonists are more commonly prescribed by endocrinologists, mainly because the drugs are injected subcutaneously, said Buse. The drug class has not been as widely adopted as the dipeptidyl peptidase-4 (DPP-4) inhibitors, he noted.

ELIXA Neutral, Other Studies Ongoing

Just last year at the ADA meeting, Pfeffer and colleagues presented the results of the ELIXA trial and showed that lixisenatide had a neutral effect on cardiovascular outcomes. To TCTMD, Pfeffer said the two trials—ELIXA and LEADER—differed slightly and this might explain the differential effects on cardiovascular outcomes with two GLP-1 agonists. ELIXA, for example, included patients with type 2 diabetes who recently had an acute coronary syndrome and who had a lower baseline glycated hemoglobin level than those in LEADER.

“LEADER chose more stable patients, followed them longer, and showed a real clinical benefit,” said Pfeffer. “I’m very impressed.”

Buse speculated that because lixisenatide is shorter-acting and structurally dissimilar from liraglutide, this might explain why ELIXA was neutral on cardiovascular outcomes while LEADER was positive. For Kaul, the fact that the results differed between trials isn’t a big surprise, noting there are multiple examples of differential effects with drugs in the same class. Regardless of whether the difference is the result of the structure/function of the molecule or trial design, Kaul told TCTMD “the so-called ‘class’ effect is not of much interest to the regulatory agencies.” Each drug, he said, needs to show its own favorable risk-benefit profile.

Given the positive results with liraglutide, Buse said he suspects the data will add heft to the kinds of complex daily discussions physicians have with patients in practice.  

“It’s also been a bit of an issue with hypertension management—the drugs don’t make you feel any better, and sometimes you actually have side effects. Cholesterol management is the same thing. With cholesterol and hypertension management, at least we’ve been able to say clearly these drugs prevent heart attack and stroke and cardiovascular death. It’s great that we can now start saying that about some of the diabetes drugs.”

Two other cardiovascular safety studies testing other GLP-1 receptor agonists—EXSCEL with exenatide and REWIND with dulaglutide (Lilly)—are currently ongoing.




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Michael O’Riordan is the Managing Editor for TCTMD. He completed his undergraduate degrees at Queen’s University in Kingston, ON, and…

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  • Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;Epub ahead of print.

  • LEADER was sponsored by Novo Nordisk and the National Institutes of Health.
  • Buse reports grants, personal fees, and nonfinancial support from Novo Nordisk during the study period. He also reports grant support from Medtronic, Minimed, Tolerex, Osiris, Halozyme, Johnson & Johnson, Andromeda, Boehringer Ingelheim, GlaxoSmithKline, Astellas, MacroGenics, Intarcia Therapeutics, Scion NeuroStim, and Theranos; grant support, personal fees, and nonfinancial support from Eli Lilly, Bristol-Myers Squibb, GI Dynamics, Merck, AstraZeneca, Sanofi, Lexicon, Orexigen, Takeda, Hoffman LaRoche, and PhaseBio; personal fees and nonfinancial support from Elcylex, Metavention, vTv Pharma, Dance Biopharm, Quest, and Adocia. He also serves on numerous nonprofit boards.
  • Pfeffer has received research grant support from Amgen, Celladon, Novartis, and Sanofi; consulted for Amgen, AstraZeneca, Bayer, DalCor Pharma UK, Genzyme, Lilly, the Medicines Company, MedImmune, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Salix, Sanderling, Sanofi, Takeda, Teva, Thrasos, and Vericel.
  • Kaul reports consulting with Boehringer Ingelheim and Novo Nordisk.