NEW ORLEANS — Patients with type 2 diabetes who were treated with once-daily liraglutide experienced significantly greater improvements in glycemic control, compared with patients who were treated with twice-daily exenatide, results from an open-label, multicenter trial showed.
The findings of the Effect of Liraglutide or Exenatide Added to an Ongoing Treatment on Blood Glucose Control in Subjects With Type 2 Diabetes (LEAD-6) were reported at the annual scientific sessions of the American Diabetes Association by Dr. John B. Buse, chief of the division of endocrinology at the University of North Carolina, Chapel Hill. They were simultaneously published online (Lancet 2009 [doi:10.1016/S0140-6736(09)60659-0]).
Liraglutide is an investigational human glucagon-like peptide-1 (GLP-1) analogue, developed by Novo Nordisk Inc., that is undergoing Food and Drug Administration review for approval. Its proposed indication is as an adjunct to diet and exercise and for use in combination therapy with oral antidiabetic agents to improve glycemic control in patients with type 2 diabetes.
Exenatide (Byetta, Amylin Pharmaceuticals Inc.) is an exendin-based GLP-1 receptor agonist approved for use by people with type 2 diabetes who are unsuccessful in controlling their blood sugar levels. Both agents are delivered via subcutaneous injection.
Between August 2007 and April 2008, 464 patients aged 18-80 years with type 2 diabetes were randomized to receive liraglutide 1.8 mg once daily or exenatide 10 mcg twice daily at 132 office-based sites in 15 countries. Patients were eligible for the trial if their hemoblobin A1c levels were 7%-11%, if their body mass index was 45 kg/m2 or less, and if they were on maximally tolerated doses of metformin, sulfonylurea, or both.
The primary end point of LEAD-6 was the difference in HbA1c values between the two treatment groups from baseline to week 26.
At baseline, the mean age of the patients was 56 years, 92% were white, mean BMI was 33 kg/m2, and their mean HbA1c level was 8.2%. Of the 464 patients, 231 received exenatide and 233 received liraglutide.
At 26 weeks, the mean reduction in HbA1c was 1.12% among patients in the liraglutide group, compared with 0.79% among patients in the exenatide group, a statistically significant difference. In addition, significantly more patients in the liraglutide group achieved HbA1c levels of less than 7%, compared with their counterparts in the exenatide group (54% vs. 43%, respectively).
The researchers also found that patients in the liraglutide group achieved significantly greater drops in levels of fasting plasma glucose, compared with those in the exenatide group (1.61 mmol/L vs. 0.60 mmol/L). However, exenatide reduced plasma glucose levels more than did liraglutide after breakfast and dinner meals, which suggests that liraglutide exerts more of its effects in the premeal or fasting period.
Weight reductions in both groups were similar, at about 3 kg.
Both drugs were well tolerated, but patients in the liraglutide group experienced less persistent nausea and less frequent rates of hypoglycemia, compared with those in the exenatide group.
In a commentary accompanying the study, Dr. Christophe E.M. DeBlock and Dr. Luc F. Van Gaal of Antwerp University Hospital, Belgium, expressed concerns about FDA reports of increased rates of pancreatitis associated with liraglutide treatment. “Whether the association is causal and whether it is a class effect of GLP-1 analogues is not clear,” they wrote (Lancet 2009 [DOI:10.1016/S0140-6736(09)60942-9.]) “We recommend not to give GLP-1 analogues to patients at risk for pancreatitis (e.g., with cholecystolithiasis, alcoholism, or hypertriglyceridemia).”
The commentators also pointed to an FDA briefing noting that the risk rate of frequency of papillary thyroid cancer in patients taking liraglutide is 1.6% per 1,000 patient-years of exposure, compared with 0.6% per 1,000 patient-years of exposure in patients taking exenatide. They recommended that future long-term studies of the agents include careful monitoring of thyroid abnormalities.
At the meeting, Dr. Buse said that there were no signs of elevated calcitonin levels (a marker of medullary thyroid carcinoma) in the study participants. “The calcitonin levels were very low on average and indistinguishable between the two groups,” he said.
Dr. Buse disclosed that he has been an investigator, consultant, or speaker for several pharmaceutical companies, including Amylin and Novo Nordisk, the trial's sponsor. Dr. Van Gaal is an adviser to Novo Nordisk and Eli Lilly. Dr. DeBlock declared that he had no conflicts of interest.
Mean reduction in HbA1c was 1.12% in the liraglutide group, compared with 0.79% in the exenatide group. DR. BUSE