The Food and Drug Administration has approved liraglutide as a once-daily injection for the treatment of type 2 diabetes. But the endorsement came with significant caveats. The drug has a boxed warning about thyroid C-cell tumors observed in preclinical rodent studies, no permission for first-line use, and significant postmarketing requirements.
Liraglutide, a human glucagonlike peptide 1 (GLP-1) receptor agonist that promotes glucose-dependent insulin secretion, will be marketed by Novo Nordisk Inc. under the name Victoza. It was licensed for use in combination with diet, exercise, and certain other glucose-lowering medications, but not as initial therapy in patients who have not achieved adequate glucose control on diet and exercise alone. Liraglutide is the second in the class of GLP-1 receptor agonists to be approved in the United States. The first one, exenatide (Amylin/Lilly's Byetta), was approved in 2005.
Liraglutide's label states that the dosage should be initiated at 0.6 mg for the first week; this beginning regimen is intended to reduced gastrointestinal symptoms, not to achieve glycemic control. After 1 week, the dosage increases a therapeutic level of 1.2 mg, and then to 1.8 mg if glycemic control has not been achieved.
In the five clinical trials—involving more than 3,900 patients—reviewed by the FDA, liraglutide-treated patients showed clinically and statistically significant improvements in hemoglobin A1c and fasting plasma glucose (FPG), compared with placebo and had no adverse effects on blood pressure. Those trials examined liraglutide as monotherapy and as add-on therapy to metformin, sulfonylurea, metformin plus sulfonylurea, and metformin plus thiazolidinedione, according to the prescribing information.
In another trial of 464 patients that compared liraglutide with exanitide, the mean reduction in HbA1c was 1.12% in patients in the liraglutide group, compared with 0.79% in patients in the exenatide group, a statistically significant difference. In addition, significantly more patients in the liraglutide group (54%) achieved HbA1c levels of less than 7%, compared with the exenatide patients (43%) (Lancet 2009;374:39-47).
In all five of the FDA-evaluated studies, pancreatitis occurred more often in patients on liraglutide than in those taking other diabetes medicines, a finding reported with exenatide. The package label will state that liraglutide should be stopped if there is severe abdominal pain with or without nausea and vomiting, and should not be restarted if pancreatitis is confirmed. It should be used with caution in people with a history of pancreatitis, the FDA said in a statement.
The most common side effects observed with liraglutide were headache, nausea, and diarrhea. Other side effects included allergic-like reactions including urticaria.
Last April, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 8-5 that the available cardiovascular safety data on liraglutide were adequate to rule out an unacceptable increase in cardiovascular risk when compared with other diabetes drugs. However, the FDA approval requires the manufacturer to conduct postmarketing cardiovascular safety studies, as is now the case with most glucose-lowering drugs. (The advisory panel was not asked to vote on whether liraglutide should be approved, only about the cardiovascular safety.)
The boxed warning states that liraglutide “causes thyroid C-cell tumors at clinically relevant exposures in rodents,” based on two preclinical carcinogenicity studies that linked liraglutide to thyroid tumors in rats and mice, some of them malignant. The risk was significantly increased among the rats that received a liraglutide dose 8 times higher than what humans would receive, according to the FDA statement. “It is unknown whether Victoza causes thyroid C-cell tumors, including medullary thyroid carcinoma, in humans, as human relevance could not be determined by clinical or nonclinical studies,” the label states. Novo Nordisk is required to conduct a 5-year epidemiological analysis of a health claims database to evaluate thyroid cancer, other cancers, hypoglycemia, pancreatitis, and allergic reactions.
Novo Nordisk is also required to establish a cancer registry to monitor the rate of medullary thyroid cancer in the United States over the next 15 years. The boxed warning states that liraglutide should not be used in people already at risk for medullary thyroid cancer, such as those who have a family history of it or who have Multiple Endocrine Neoplasia syndrome type 2.
Also included in the approval is a Risk Evaluation and Mitigation Strategy (REMS) consisting of a Medication Guide and a Communication Plan to help patients and providers understand the potential risks of liraglutide and to ensure that its benefits continue to outweigh the risk of acute pancreatitis and the potential risk of medullary thyroid cancer. As part of the REMS, the communic
As part of the REMS, the communication plan for health care professionals highlights appropriate patient selection, along with a reminder to promptly evaluate patients who develop symptoms suggestive of pancreatitis.
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