AT EASD 2016

MUNICH (FRONTLINE MEDICAL NEWS) Liraglutide posted positive secondary endpoints in a large randomized trial, reducing the risk of microvascular events by 16% and protecting renal function in people with type 2 diabetes.

A 22% decreased risk of renal complications was the major driver of microvascular protection in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome) trial, Johannes Mann, MD, said at the annual meeting of the European Association for the Study of Diabetes. Somewhat disappointingly, the glucagonlike peptide–1 (GLP-1) receptor inhibitor didn’t decrease the chance of an eye-related microvascular event, said Dr. Mann of Friedrich Alexander University in Erlangen, Germany.

LEADER randomized 9,340 patients with type 2 diabetes to 1.8 mg or the maximum tolerated dose of subcutaneous liraglutide once daily or to placebo, in addition to standard care (N Engl J Med. 2016 June 13. doi: 10.1056/NEJMoa1603827)

The primary endpoint, reported in June, was a 13% reduction in the risk of a composite cardiovascular outcome (cardiovascular death, nonfatal heart attack, or nonfatal stroke) over 3.8 years of follow-up. This was driven by a 22% reduction in the risk of cardiovascular death; the drug did not significantly impact the other endpoints.

Microvascular and safety endpoints were key secondary outcomes. The study population was already at high risk for renal complications, Dr. Mann said: 20% had a moderate renal impairment at baseline, 20% had microalbuminuria, and 5% had macroalbuminuria.

The renal microvascular endpoint was a composite of several measures: new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, end-stage renal disease, or death from renal failure. It occurred in 7.6% of the liraglutide group and 8.9% of the placebo group. The difference represented a 22% reduction in the time to a first renal event (hazard ratio, 0.78). This was entirely driven by a significant 23% decrease in the chance of new-onset macroalbuminuria (hazard ratio, 0.74), which occurred in 3.4% of the liraglutide group and 4.6% of the placebo group.

There were no significant between-group differences in any of the other renal endpoints, Dr. Mann said.

The eye microvascular endpoint was a composite of vitreous hemorrhage or treatment with photocoagulation or an intravitreal agent. The composite endpoint occurred in 2.3% of the liraglutide group and 2% of the placebo group, which was not a significant difference (HR, 1.15).

The drug was not associated with an increased risk of pancreatitis, with 18 suspected events in the treated group vs. 33 in the placebo group, not a significant difference. None of the cases was time bound; they occurred randomly throughout the trial in both treatment arms, said Michael A. Nauck, MD, of St. Josef Hospital, Bochum, Germany,

But any cases were a cause of concern, Dr. Nauck said, especially since liraglutide, like any GLP-1 agonist, causes increases in the pancreatic enzymes lipase and amylase. Therefore, each suspected case of acute pancreatitis that occurred in either group was fully adjudicated according to three diagnostic criteria: characteristic upper abdominal pain, increased pancreatic enzymes, and imaging findings.

Most of the cases (79% on liraglutide and 58% on placebo) had two of these criteria; the rest fulfilled all three. Any one was enough to prompt a pancreatitis work-up. Pain was the presenting symptom in 40% of liraglutide patients and 74% of placebo patients. Elevated enzymes prompted the work-up in another 40% of liraglutide patients and in 26% of placebo patients. The combination of pain and elevated enzymes was present in 6% of liraglutide patients, and in none of the placebo patients.

But pancreatic imaging was negative in 77% of liraglutide patients and 61% of placebo patients, suggesting that most of the reports did not represent a true acute inflammatory pancreatitis, Dr. Nauck said.

There was no significant liraglutide-associated increase in the risk of any neoplasm, whether malignant (HR, 1.06) or benign (HR, 1.16).

Pancreatic cancer occurred in 13 patients taking liraglutide and 9 taking placebo – not a significant difference. There were numerically fewer cases of prostate cancer and leukemia among those taking the drug, but again, the difference was not statistically significant, and the analysis didn’t control for any confounding factors.

“We are not going to say that liraglutide is in any way protective against these cancers,” Dr. Nauck said.

LEADER was sponsored by Novo Nordisk and the National Institutes of Health. Dr. Nauck is on Novo Nordisk’s advisory panel and speakers board, and receives research funding from the company. Dr Mann is an investigator and consultant for the company.