Liraglutide in Type 2 Diabetes

Posted by • July 28th, 2016

Liraglutide in Type 2 Diabetes graphTo assess the long-term effects of liraglutide on cardiovascular outcomes and other clinically important events, the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial was initiated in 2010. Patients with type 2 diabetes who had a glycated hemoglobin level of 7.0% or more were eligible if they either had not received drugs for this condition previously or had been treated with one or more oral antihyperglycemic agents or insulin (human neutral protamine Hagedorn, long-acting analogue, or premixed) or a combination of these agents.

Patients with type 2 diabetes and high cardiovascular risk were assigned to receive either the glucagonlike peptide 1 analogue liraglutide or placebo. In this new Original Article, the rate of first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke was lower with liraglutide.

Clinical Pearl

• What is the mechanism of action of liraglutide?

Liraglutide, an analogue of human glucagon-like peptide 1 (GLP-1), has been approved for the treatment of type 2 diabetes. Its efficacy in lowering glucose levels has been established, and it has been associated with slight reductions in weight and blood pressure.

Clinical Pearl

• Is liraglutide associated with cardiovascular benefit in patients with type 2 diabetes who are at high risk for cardiovascular disease?

In the LEADER trial, patients in the liraglutide group had a lower risk of the primary composite outcome — first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in the time-to-event analysis — and lower risks of death from cardiovascular causes, death from any cause, and microvascular events than did those in the placebo group. The frequencies of nonfatal myocardial infarction and nonfatal stroke were lower in the liraglutide group than in the placebo group, although the differences were not significant.

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 Morning Report Questions

Q: What are some of the adverse events that were associated with liraglutide in the LEADER trial?

A: In the LEADER trial, adverse events leading to the permanent discontinuation of the trial regimen were more common with liraglutide than with placebo. This result appears to have been driven by gastrointestinal disorders in the liraglutide group. There were more episodes of gallstone disease with liraglutide, a finding that has been reported previously. Acute pancreatitis occurred in 18 patients in the liraglutide group and in 23 in the placebo group. There has been considerable interest in a potential association between the use of GLP-1–receptor agonists and pancreatitis and pancreatic cancer, although there is no consistent preclinical, pharmacovigilance, or epidemiologic evidence to date. Among rodents receiving liraglutide, higher rates of thyroid C-cell tumors and hyperplasia have been observed than were observed among control animals. In the LEADER trial, no episodes of C-cell hyperplasia or medullary thyroid carcinoma were observed in patients in the liraglutide group. Randomized trials of this type, despite their size, are not powered to determine the effect of drugs on cancer risk and can therefore neither confirm nor exclude such a possibility.

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Q: How do the results of the LEADER trial compare with those of other trials assessing the cardiovascular safety of newer anti-hyperglycemic therapies?

A: The pattern of cardiovascular benefits that were associated with liraglutide in the LEADER trial appears to differ from that with the sodium–glucose cotransporter 2 inhibitor empagliflozin in the previously reported EMPA-REG OUTCOME trial. The time to benefit emerged earlier in that trial than in the LEADER trial, and the heterogeneity of the direction and magnitude of the effects on the components of the primary composite outcome in that trial contrasts with the consistency of the effect in the LEADER trial. It should be noted that in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, the GLP-1–receptor agonist lixisenatide, which is shorter-acting than and structurally dissimilar to liraglutide, did not show any cardiovascular benefit in patients with diabetes and a recent acute coronary syndrome. There are a number of other trials regarding cardiovascular outcomes in high-risk cohorts of patients with type 2 diabetes in which similar magnitude effects on glycemic control have been shown but without significant benefits with respect to rates of cardiovascular events or death. These include trials with insulin, thiazolidinediones, and DPP-4 inhibitors. The LEADER trial had greater statistical power and included patients with a higher baseline glycated hemoglobin level than did most previous studies. However, no obvious single explanation in terms of either the study designs or the included populations is apparent to explain the divergent findings across this body of medical literature.

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