“I think for the pharmaceutical management of obesity, we need tailor-made molecules where we know exactly how they're working.”
With liraglutide, which suppresses appetite, “we know how it works because it mimics a natural hormone we have a lot of knowledge about,” Dr. Astrup said. He also praised liraglutide's route of delivery, a once-daily subcutaneous injection, as another safety plus for the drug rather than a logistical drawback.
“I think an injectable drug will help prevent abuse. It requires a certain commitment from the patient and the physician. The vast majority [of patients in the phase II study] thought it was an easy way to take the drug; it's a kind of hormone replacement therapy for glucagon-like peptide-1.”
The 2-year results on liraglutide he reported involved patients who completed a 20-week, dose-ranging study that also randomized patients to placebo or to orlistat (Lancet 2009;374:1606-16). After completing 52 weeks on their initially assigned medication and dosage, all patients in the four liraglutide arms and the placebo group switched to a 3-mg/day dosage, while patients in the orlistat arm remained on that agent.
In the 2-year, last-observation-carried-forward analysis, average weight loss on liraglutide was 5.3 kg and average loss with orlistat was 2.3 kg.
The most common adverse effect with liraglutide was nausea, which was transient and dose-related.
Treatment with liraglutide also led to a substantial drop in systolic blood pressure and a greater change in lipid levels than seen with orlistat, which Dr. Astrup characterized as a “very positive cardiovascular disease profile,” along with “completely clean” outcomes for psychiatric adverse effects.
The good safety profile for liraglutide contrasted with questionable findings reported for the naltrexone plus bupropion combination, which was the focus of one phase III study with 584 patients treated with 32 mg of sustained-release naltrexone daily plus 360 mg of sustained-release bupropion daily, and a second phase III study with more than 1,100 participants randomized to either of two dosages of naltrexone, 16 mg or 32 mg daily, plus 360 mg/day bupropion. The combined medication regimen showed good efficacy, with 32 mg/day naltrexone plus bupropion producing a 9% average weight loss when used with behavior modification (in the single-dosage study) and a 6% average weight loss (in the two-dosage study), compared with average placebo-group losses of 5% (also with behavior modification) in the first study and 1% in the second.
But at 1 year in the single-dosage 32-mg naltrexone plus 360-mg bupropion study, systolic blood pressure fell an average of 4 mm Hg in the placebo group and an average of 1 mm Hg in the active-drug arm. Average diastolic pressure fell by 3 mm Hg in the placebo arm and 1 mm Hg in the active arm, reported Dr. Dennis Kim, senior vice president for medical affairs at Orexigen Therapeutics, the company developing a fixed-dose naltrexone and bupropion combination (Contrave).
Blood pressure drops were greater with placebo, even though these patients lost less weight than those in the active-drug group. In the other trial of this combination, patients on 32 mg/day naltrexone and bupropion experienced a 2– mm Hg rise over baseline in acute systolic blood pressure during the first 8 weeks, followed by a fall after 12 weeks to an average systolic pressure 1 mm Hg below baseline, according to a poster at the Congress.
Dr. Astrup's study was sponsored by Novo Nordisk, which is developing liraglutide.
Dr. Astrup has received honoraria as a speaker for and adviser to Novo Nordisk and Neurosearch, as well as research grants from both companies; he has also received honoraria as an adviser to Merck and Co. Dr. van der Merwe had no disclosures.
When treating obesity, the cardiometabolic outcome must improve in addition to weight loss.
Source DR. ASTRUP