Major Finding: In patients on the highest dose of phentermine plus controlled-release topiramate, systolic blood pressure reductions were significantly lower than with placebo: 3.4 mm Hg after 28 weeks in EQUATE, 3.8 mm Hg after 56 weeks in EQUIP, and 3.2 mm Hg after 56 weeks in CONQUER.
Data Source: Pooled analysis of data on 3,985 patients in three clinical trials.
Disclosures: Dr. Oparil disclosed relationships with Vivus as well as with Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Forest, Gilead, Merck, NicOx, Novartis, the Salt Institute, Sanofi-Aventis, and Takeda. Dr. Bakris has reported financial relationships with Abbott, Gilead, GlaxoSmithKline, Merck, Novartis, and other companies.
NEW YORK — An investigational weight-loss agent that combines two drugs slightly reduced blood pressure in an analysis of three large placebo-controlled clinical trials involving a total of 3,985 patients.
The once-daily drug combines a low dose of the generic stimulant phentermine with a low-dose, controlled-release version of the antiepileptic topiramate. The two drugs have been shown previously to cause weight loss by different mechanisms, Dr. Suzanne Oparil said at the meeting.
Higher doses of phentermine are occasionally associated with increased blood pressure, but the combined product appeared to produce enough weight loss—more than 10% of body weight after 56 weeks in two of the studies—to result in modestly lower blood pressure, reported Dr. Oparil, director of the vascular biology and hypertension program at the University of Alabama at Birmingham.
“We really need a well-tolerated, safe, and effective weight-loss treatment,” commented Dr. Oparil, a past president of ASH who conducted the analysis as a consultant to Vivus, which is developing the combined agent under the brand name Qnexa.
But some physicians at the ASH meeting said they were not entirely convinced of the agent's safety. At the highest dose, a heart rate increase of about 1.5 beats per minute was observed. And none of the trials used 24-hour ambulatory blood pressure monitoring.
“I would want to see data on the drug's effect on 24-hour blood pressure,” said Dr. George L. Bakris, professor of medicine and director of the Hypertension Center at the University of Chicago.
The 56-week EQUIP trial enrolled 1,267 obese adults and compared the high-dose combination (phentermine 15 mg and topiramate 92 mg) and a low-dose combination (phentermine 3.75 mg and topiramate 23 mg) with placebo. The 28-week EQUATE trial (enrolled 756 obese adults and compared the high-dose formulation and a mid-dose formulation (phentermine 7.5 mg and topiramate 46 mg) with placebo and with the respective single agents. The 56-week CONQUER trial enrolled 2,487 overweight and obese adults with two or more weight-related comorbidities: increased waist circumference, type 2 diabetes, elevated triglycerides, and elevated blood pressure. It compared the high-dose and mid-dose combinations with placebo. Of the total 4,510 patients who were initially enrolled in the three trials, 3,985 completed the studies.
In Dr. Oparil's pooled analysis of the three trials, the mean weight loss at week 28 was 1.9% of total body weight for the 1,579 patients on placebo, 5.1% for the 234 patients on the lowest dose of the drug, 8.0% for the 591 patients on the middle dose, and 9.9% for the 1,581 patients on the highest dose. All three active-treatment groups had significantly more weight loss, compared with the placebo group.
In the two trials that went to 56 weeks, CONQUER and EQUIP, weight loss reached 10.4% of body weight with the highest dose, compared with 1.5% with placebo, also a significant difference.
The reductions in systolic blood pressure in patients on the high-dose combination, compared with placebo, were 3.4 mm Hg after 28 weeks in EQUATE, 3.8 mm Hg after 56 weeks in EQUIP, and 3.2 mm Hg after 56 weeks in CONQUER; all three reductions were statistically significant. Significant reductions in systolic blood pressure also were seen with some of the lower doses of the combined product. For diastolic blood pressure, only two of the higher-dose groups had reductions that were significantly greater than that seen with placebo.
“In the hypertensive subgroup [of CONQUER], there were significant and dose-related reductions in both systolic and diastolic blood pressure,” Dr. Oparil said. In that subgroup, the mean drop in systolic blood pressure was 6.9 mm Hg for the 256 patients given the middle dose of the drug and 9.1 mm Hg for the 514 patients given the highest dose of the drug; both reductions were significantly greater than the 4.9–mm Hg reduction in the 516 patients on placebo. Reductions in diastolic blood pressure in these patients were 5.2 mm Hg for the middle dose and 5.8 mm Hg for the highest dose; both reductions were significantly greater than the 3.9–mm Hg drop with placebo.