News Article
Investigational Drug Bests Approved Weight-Loss Treatments
Tesofensine, an investigational agent that inhibits the presynaptic uptake of noradrenaline, dopamine, and serotonin, produced twice the weight loss of currently approved obesity drugs in a 6-month phase II study.
In the study funded by the drug's manufacturer, NeuroSearch A/S, a total of 203 nondiabetic obese individuals were initially randomized to receive placebo or tesofensine in daily doses of either 0.25, 0.50, or 1.0 mg. They were also instructed to follow a diet with an energy deficit of 300 kcal and to gradually increase their physical activity up to 30-60 minutes per day.
The 161 patients who completed the study included 39 in the placebo group and 43, 44, and 35 subjects in the 0.25-, 0.50-, and 1.0-mg groups, respectively. All had a body mass index between 30 and 40 kg/m².
In the intention-to-treat population, there was a 2.0% decrease in body weight in the placebo group from baseline to 6 months. Mean weight loss above that with placebo was 4.5% for the group receiving 0.25 mg tesofensine, 9.2% for the 0.5-mg group, and 10.6% for the 1.0-mg group. The outcome was nearly the same for those completing the study, with 4.7%, 9.2%, and 10.4% weight loss above that of placebo, respectively. The difference in weight loss between 0.5 mg and 1.0 mg tesofensine was not significant, said Dr. Arne Astrup of the University of Copenhagen and his associates (Lancet 2008 Oct. 23 [doi:10.1016/S0140-6736(08)61525-1]).
The reduction in body weight was primarily due to a reduction in body fat, as shown by a reduction in waist circumference and sagittal diameter. After discontinuation of treatment from week 24 to week 32, body weight increased significantly in all tesofensine groups, by 0.5% in the placebo group, 0.82% in the 0.25-mg tesofensine group, 2.26% in the 0.5-mg group, and 3.81% in the 1.0-mg group.
Consistent with the weight loss, tesofensine reduced fasting triglyceride and total cholesterol concentrations, but only the 0.25-mg dose produced a significant drop in LDL cholesterol. And, although plasma glucose was not affected, tesofensine was associated with reductions in plasma insulin levels and hemoglobin A
The 0.25- and 0.5-mg tesofensine doses had no effect on blood pressure, but the 1.0-mg dose significantly increased both systolic and diastolic blood pressure. There was a significant dose-dependent increase in heart rate with tesofensine, from 4.7 more beats per minute with 0.25 mg to 7.8 with 0.5 mg and 8.5 with 1.0 mg, compared with an increase of 0.4 beats per minute with placebo.
The profile of mood states did not show an effect of tesofensine on total mood disturbance, tension, anxiety, depression, dejection, fatigue, or inertia, compared with placebo, but the 1.0-mg dose did appear to increase anger and hostility, while both the 0.5-mg and 1.0-mg doses increased confusion. All tesofensine doses improved vigor and activity, compared with placebo, while quality of life scores were also significantly improved with the 0.5-mg and 1.0-mg doses, Dr. Astrup and his associates reported.
Depressed mood was reported in 6.1% of the 1.0-mg tesofensine group and in 6.0% of the 0.5-mg group, vs. 1.9% with 0.25 mg and none with placebo. These numbers were not statistically significant, they noted.
Gastrointestinal adverse events reported with tesofensine included dry mouth, nausea, abdominal pain, constipation, hard feces, and diarrhea. Nausea was reported in 9.6% of the placebo patients, 17.3% with 0.25 mg, 20.0% with 0.5 mg, and 22.4% with 1.0 mg; and dry mouth in 11.5%, 23.1%, 42.0%, and 59.2%, respectively. Aside from those two, rates of the other gastrointestinal adverse events above that of placebo were seen only in the 1.0-mg group. Insomnia, sleep disturbance, and dizziness were also more common with tesofensine, particularly in the 1.0-mg group. Insomnia was reported by 26.5% of the 1.0-mg group and 12% of the 0.5-mg group, vs. 3.8% with 0.25 mg and 1.9% with placebo.
The proportion of patients with serious adverse events did not differ between tesofensine and placebo. However, more patients in the tesofensine group had serious adverse events related to the intervention, and in the 1.0-mg group, more patients discontinued the treatment as a result.
These 6-month weight loss results can be compared with the 2.9-kg weight loss produced by orlistat, 4.2 kg with sibutramine, and 4.7 kg by rimonabant (BMJ 2007;335:1194-9; Lancet 2007;370:1706-13). The lowest tested dose of tesofensine produced a weight loss similar to that of sibutramine and rimonabant treatment over 6-24 months. However, this phase II study was much smaller than any of the trials of those agents.
"Our findings need to be confirmed in larger phase III trials and direct head-to-head comparisons with approved weight-loss compounds is needed before any conclusion about comparative efficacy can be made," the investigators said.
Dr. Astrup receives honoraria from NeuroSearch and also owns stock in the company.
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