An investigational weight loss agent significantly reduced blood pressure, in addition to body weight, a pooled analysis of three randomized trials showed.
Three doses of a controlled release combination of phentermine and topiramate – called Qnexa – significantly reduced systolic blood pressure by 5 to 7 mm Hg after 28 weeks of treatment, according to Suzanne Oparil, MD, of the University of Alabama at Birmingham.
The gains were significantly greater than those seen with placebo (P<0.0001 for all), and persisted through 56 weeks, Oparil reported at the American Society of Hypertension meeting here.
The highest dose also resulted in smaller, but statistically significant, reductions in diastolic blood pressure through 56 weeks.
Phentermine, a stimulant, and topiramate, an anticonvulsant, have been approved individually and are available as generic drugs. Both are known to produce weight loss but they have dose-dependent side effects.
Previous studies have shown that the weight-loss effects of the combination of drugs results in greater weight loss than either one can achieve on its own, and at low enough doses to limit side effects, Oparil said.
She presented a pooled analysis of three randomized, placebo-controlled trials of the investigational single-pill combination in overweight and obese individuals – EQUATE, EQUIP, and CONQUER.
Three doses were evaluated versus placebo – phentermine 3.75 mg/topiramate 23 mg (234 patients), 7.5 mg/46 mg (591 patients), and 15 mg/92 mg (1,582 patients). The mean BMI for each group of patients was 42.5, 36.3, and 38.2.
Another 1,580 patients were taking placebo. The mean BMI was 38.3.
The primary endpoint in each trial was weight loss, but blood pressure was also tracked.
Overall, the mean baseline blood pressure was about 125/79 mm Hg.
About half of the patients in CONQUER had hypertension, as did about a quarter of the patients in each of the other trials.
At week 28, the mean weight loss was 1.9% with placebo, 5.1% with the low dose of the combination, 8% with the middle dose, and 9.9% with the high dose (P<0.0001 for all versus placebo). The weight loss was sustained at 56 weeks.
The mean reductions in blood pressure at 28 weeks in the placebo group and with the increasing doses of phentermine/topiramate were 3.06/1.29 mm Hg, 5.13/1.64 mm Hg, 6.77/3.05 mm Hg, and 6.51/2.82 mm Hg. The reductions in systolic pressure were significantly greater with all three doses of the combination versus placebo, whereas only the highest two doses were superior to placebo for diastolic pressure (P<0.05 for all).
The 56-week findings were similar.
A subgroup analysis of patients with hypertension in CONQUER revealed a similar amount of weight loss and blood pressure reduction as that seen in the overall cohort.
Adverse events were as expected with the agents involved, Oparil said, and included altered taste, back pain, constipation, diarrhea, dizziness, dry mouth, fatigue, headache, insomnia, nasopharyngitis, nausea, tingling, and upper respiratory infection. Tingling and dry mouth occurred in nearly 20% of patients with the highest dose at both the 28- and 56-week follow-ups.
Most adverse events were mild or moderate in severity, Oparil said.
At the two lower doses, there was no change in heart rate, but at the highest dose there was an increase of about 1.5 beats-per-minute.
Discontinuations due to adverse events occurred in 8.5% of those taking placebo and 11.7%, 11.6%, and 17.5% of those in each of the ascending dose groups for the investigational combination.
Franz Messerli, MD, director of the hypertension program at St. Luke’s-Roosevelt Hospital Center in New York City, said the increase in heart rate, even though it was minimal, was concerning.
“We don’t know how significant this is,” said Messerli, an ASH officer, “but I think we should have an outcomes study actually looking at overall cardiovascular events, because obviously weight loss is always welcome. It helps the patient with body image and so on. But it will also reduce heart attacks and strokes. So before we vote here, I think we need an outcomes study.
He admitted, “I have become very skeptical about all weight-losing drugs.”
Primary source: American Society of Hypertension
Oparil S, et al “Once-daily, low-dose, controlled-release phentermine/topiramate improves blood pressure and results in weight loss in overweight/obese patients through 28 weeks” ASH 2010; Abstract LB-OR-02.