May 21, 2012 (New York, New York) Two studies presented this week at the American Society of Hypertension 2012 Scientific Sessions have shown that therapies designed to reduce body weight in obese patients also result in significant reductions in blood pressure.

In the first, researchers showed that combination treatment with extended-release phentermine/topiramate (Qnexa, Vivus) reduced weight, improved blood pressure, and decreased the progression from prehypertension to hypertension. In the second, laparoscopic adjustable gastric banding also reduced the weight of obese patients, decreased systolic and diastolic blood pressure, and allowed nearly one-quarter of patients to stop taking their antihypertensive medications.

In February 2012, the Food and Drug Administration (FDA) Endocrinologic and Metabolic Drugs Advisory Committee voted 20 to two in favor of approving the phentermine/topiramate combination in patients with a body-mass index (BMI) of >30 or >27 in patients with weight-related comorbidities. A decision from the FDA is expected on July 17, 2012. Speaking with heartwire , the lead investigator on the new analysis, Dr Alok Gupta (Pennington Biomedical Research Center, Baton Rouge, LA), said that he hopes the drug is approved given the epidemic of obesity and hypertension.

"One in three individuals in the US is either overweight or obese," he said. "So we do have a huge need for these people to lose weight, and looking at the results from this clinical trial, as well as others already published, I can tell you that this would be a very welcome addition to a physician's armamentarium to treat obesity. In general, phentermine is generally well tolerated and has been in use for the past 50 years, and topiramate since 1996, so the benefit of using this medicine would be that it's a smaller dose for both components."

Prehypertensive Patients in EQUIP and CONQUER

In the new analysis, Gupta and colleagues pooled data from the EQUIP and CONQUER trials with phentermine/topiramate to analyze the effect of treatment on prehypertensive patients only. EQUIP was a double-blind, placebo-controlled study of 1267 obese subjects randomly assigned to placebo, phentermine/topiramate 3.75 mg/23 mg, or phentermine/topiramate 15 mg/92 mg. The CONQUER trial included 2487 overweight/obese patients with two or more weight-related comorbidities and randomly assigned them to placebo, phentermine/topiramate 7.5 mg/46 mg, or phentermine/topiramate 15 mg/92 mg.

Treatment with all three doses of phentermine/topiramate resulted in a significant reduction in weight when compared with placebo and in significantly more prehypertensive patients losing more than 5% and 10% of their body weight. Compared with placebo, blood-pressure reductions at one year were statistically greater than those achieved with placebo, with 4.7-mm-Hg to 5.7-mm-Hg decreases in systolic blood pressure. The reduction in systolic and diastolic blood pressure did not significantly vary across the three phentermine/topiramate doses.

One-Year Weight Loss and Blood Pressure Changes

Variable Placebo (n=417) Phentermine/topiramate 3.75/23 mg (n=134) Phentermine/topiramate 7.5/46 mg (n=80) Phentermine/topiramate 15/92 mg (n=454)
Mean weight loss (%) -1.4 -5.1 -8.2 -11.2
Subjects achieving >5% weight loss (%) 18.0 43.3 58.8 70.5
Subjects achieving >10% weight loss (%) 5.8 16.4 37.5 49.8
Mean systolic blood pressure change (mmHg) -1.9 -5.3 -4.7 -5.7
Mean diastolic blood-pressure change (mm Hg) -2.1 -1.8 -0.6 -2.8

The researchers also showed that 18.5% of the prehypertensive patients treated with placebo progressed to hypertension compared with 9.7% of patients treated with the low and high doses of phentermine/topiramate and 11.3% of patients treated with the 7.5-mg/46-mg dose (p=0.0008 for all three doses). Roughly 35% to 38% of patients with prehypertension achieved normal blood-pressure levels, a statistically significant improvement compared with placebo (p=0.03 for all three doses). "One would expect that as patients lose weight, they would normalize their blood pressure, especially if they had prehypertension," Gupta told heartwire .

Rates of discontinuation due to adverse events (AE) were 9.7% in the placebo arm and 15.1%, 6.0%, and 16.7% in the groups taking the 3.75/23-mg, 7.5/46-mg, and 15/92-mg doses of phentermine/topiramate, respectively. The most commonly reported AE was tingling or numbness, while upper-respiratory-tract infections, dry mouth, headache, and insomnia were also common.

During the FDA advisory panel, many committee members said the efficacy of the drug is not in question but strongly recommended the initiation and completion of a large morbidity and mortality study to address any potential cardiovascular risks. On the whole, most committee members did not believe the clinical trial was needed to approve the drug, stating that a postapproval study would be sufficient. To heartwire , Dr Barbara Troupin, Vivus vice president of scientific communication and risk management, said the company is planning the morbidity and mortality trial, as well as initiating a risk evaluation and mitigation strategy (REMS) to accompany approval.  

The Lap-Band Procedure

In the second study, Dr Ted Okerson (University of California, Irvine) presented early blood-pressure data from 916 obese patients treated with laparoscopic adjustable gastric banding (Lap-Band, Allergan, CA) in the Helping Evaluate Reduction in Obesity (HERO) study. The study included patients with a BMI 35–40 with weight-related comorbidities or those with a BMI >40 and no comorbidities. The six-month analysis of the five-year clinical trial was designed as a snapshot to determine whether the surgery was having an impact on blood pressure.

Overall, patients lost more than 38 lbs, or nearly 14% of their body weight (p<0.001). BMI also decreased significantly, down from 43.9 at baseline to 38.0 at six months (p<0.001). In addition, systolic and diastolic blood pressure declined 6.9 mm Hg and 2.8 mm Hg, respectively, a significant reduction from baseline. In an analysis of 179 patients with diabetes, 24.6% of patients had their blood pressure controlled at baseline, and this increased to 30.7% at six months, a percentage that Okerson said was still very poor. In contrast, among patients without diabetes, 58.8% had their blood pressure controlled at baseline, and this increased to 75.3% at six months.

For patients taking blood-pressure medications prior to the laparoscopic weight-loss surgery, 75.8% were still taking antihypertensive medications at six months, while one-quarter were not.

Okerson told the conference audience that the six-month data show clinically meaningful and statistically significant reductions in weight loss and blood pressure, and this appeared to be related to the amount of weight that they lost. However, the real test will be the five-year data to determine whether the results are durable or if additional benefits are gained.

The EQUIP/CONQUER analysis was sponsored by Vivus. Okerson is an employee of Allergan in addition to his position at the University of California, Irvine.


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