A sub-analysis of data from a randomized clinical trial comparing the use of angiotensin converting enzyme (ACE) inhibitors plus a diuretic to ACE inhibitors plus a calcium channel blocker found that hypertensive patients receiving the diuretic combination experienced significantly fewer adverse events than normal-weight patients taking the same combination of drugs. However, a study commentary argued that the lower risk should not spur physicians to consider body mass index (BMI) when making hypertension treatment decisions. The study and comment were published online Dec. 6 in Lancet.

Michael A. Weber, MD, associate dean for research at SUNY Downstate College of Medicine in Brooklyn, N.Y., and colleagues investigated the impact of BMI on treatment for hypertension. Using data from the ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial, which compared two combinations of drugs—benazepril plus hydrochlorothiazide or benazepril plus amlodipine—the researchers stratified 11,482 study participants by BMI into obese (BMI, 30 or greater), overweight (BMI, 25 or greater but less than 30) and normal weight (BMI, less than 25) categories. The primary endpoint was a composite of cardiovascular death or non-fatal MI or stroke.  

Overall, 5 percent of obese participants reached the primary endpoint, compared with 6 percent of the overweight group and 7 percent of the normal-weight group. After adjusting for age, sex, diabetes, previous cardiovascular events, stroke and chronic kidney disease, the researchers’ analysis showed that there were some significant differences in rate of adverse events based on BMI classification for the group taking the benazepril/hydrochlorothiazide combination. Normal-weight patients taking benazepril/amlodipine experienced a 43 percent reduction in risk of experiencing the primary endpoint when compared with normal-weight patients taking benazepril/hydrochlorothiazide. Patients who were overweight experienced a 24 percent risk reduction on the amlodipine combination compared with the hydrochlorothiazide combination, and obese patients experienced an 11 percent risk reduction, which the researchers determined was not statistically significant.

According to the study, “cardiovascular outcomes of hypertensive patients differ according to BMI, between thiazide-based treatments (increased risk in non-obese patients) and combinations with calcium channel blockers (no increased risk in non-obese patients). ... Diuretic-based regimens seem to be a reasonable choice in obese patients in whom excess volume provides a rationale for this type of treatment, but thiazides are clearly less protective against cardiovascular events in patients who are lean,” the authors wrote.

Franz H. Messerli, MD, of St. Luke’s Roosevelt Hospital in New York and Sripal Bangalore, MD, of New York University School of Medicine in New York City, disputed those conclusions in their comment accompanying the study. The commenters pointed out that stratifying participants by BMI “is prone to enrich the highest BMI group with people at risk for heart failure.” Noting that ACE inhibitors and diuretics are the cornerstones of heart failure treatment, “the relative greater efficacy of hydrochlorothiazide in the obese patient (versus lean individuals) should not be a surprise,” they wrote.

Furthermore, they cautioned that treatment with diuretics can exacerbate other health risks to which the obese are prone. Diuretic use is associated with increased insulin resistance, intra-abdominal fat accumulation and new-onset diabetes, among other conditions. “Admittedly, diuretic-based metabolic abnormalities are mitigated somewhat in the presence of an ACE inhibitor but seem to persist nonetheless,” they wrote.  

Messerli and Bangalore concluded, “We surmise that thiazide diuretics are contraindicated in obesity, relatively speaking. If the indication is hypertension, amlodipine-based treatment should be used, regardless of body size. Conversely, if the indication is prevention or treatment of left ventricular dysfunction, a diuretic-based regimen should be used, again irrespective of body size. This strategy relegates diuretics to third-line agents for treatment of hypertension, except in patients at risk of heart failure.”