The hypertension field has been troubled by repeated observations that normal weight patients have more cardiovascular (CV) events than obese patients. Now a new analysis of a large hypertension trial confirms this finding but also suggests that it may be explained by either an adverse effect of diuretics or a protective effect of calcium-channel blockers in non-obese hypertensives.
Michael Weber and colleagues analyzed data from more than 11,000 patients randomized in the ACCOMPLISH trial to shed light on this problem. In 2008 the main results of the trial showed that the combination of benazepril and amlodipine (calcium channel blocker group, CCB) was superior to the combination of benazepril and hydrochlorothiazide (diuretic group) in reducing CV events in high risk hypertensive patients.
The new analysis, published online in the Lancet, confirmed earlier observations and found significant differences in outcome based on weight. However, the differences in outcome occurred mostly in the diuretic group. In the diuretic group, the rate for the primary endpoint was significantly different between the groups (30.7 events per 1,000 patient-years in normal weight patients, 21.9 in overweight patients, and 18.2 in obese patients, p=0.0034). In the CCB group the rates were not significantly different (18.2, 16.9, and 16.5).
To explain their finding the investigators proposed that “hypertension in obese and lean patients is probably mediated by different forms of underlying pathophysiology.” Obese patients, who are more likely to have increased plasma volume and cardiac output, will be responsive to diuretics, while lean patients are more likely to have involvement of the sympathetic and renin-angiotensin systems. They concluded that “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. An alternative therapeutic regimen that includes a calcium channel blocker such as amlodipine, which works equally well across all BMI categories, provides an advantage with respect to clinical outcomes in patients who are not obese.”
In an accompanying comment, Franz Messerli and Sripal Bangalore write that the effectiveness of hydrochlorothiazide in obese people in ACCOMPLISH “has little if anything to do with obesity per se, but simply reflects the fact that among obese patients there was a preponderance of individuals at risk for heart failure who were prone to respond well to diuretic treatment.” They argue that “amlodipine-based treatment should be used irrespective of body size” for the indication of hypertension. Diuretics, on the other hand, should be used for the prevention of left-ventricular dysfunction.
Here is the press release from the Lancet:
Body mass index may determine which blood pressure treatments work best
According to new research published Online First in The Lancet, body mass index (BMI) may influence which blood pressure medications work best at reducing the major complications of high blood pressure (strokes, heart attacks, and death). The findings suggest that diuretic drugs seem to be a reasonable choice for obese patients, but significantly increase the risk of cardiovascular events in non-obese individuals. Calcium channel blockers, meanwhile, work equally well in people in all weight groups, including lean individuals.
“These findings could change the way high blood pressure (hypertension) is treated and should be of practical help to clinicians in selecting the type of combination treatment most likely to benefit individual patients”*, says Michael Weber from the State University of New York’s Downstate Medical Center who led the research. “Importantly, they suggest that hypertension in obese and lean patients is probably mediated by different forms of underlying disease processes.”
Weber and colleagues conducted a subanalysis of the international ACCOMPLISH trial that compared the impact of two single-pill drug combinations**—benazepril (ACE inhibitor) plus the diuretic hydrochlorothiazide, and benazepril plus amlodipine (calcium channel blocker)— on the long-term health of people with high blood pressure at high risk of heart disease.
The researchers grouped 11482 participants according to three body mass index categories (normal weight, overweight, and obese) to assess the effects of body mass index and different treatment regimens on heart-related events (cardiovascular deaths, hearts attacks, and strokes).
The analysis showed that in people assigned to the diuretic combination a normal BMI was associated with significantly worse outcomes—a 68% higher event rate—than a high BMI.
In contrast, the benazepril and amlodipine combination was equally effective across all weight categories. What is more, compared with the diuretic regimen, the combination of benazepril and amlodipine significantly reduced heart-related events in normal weight (difference 43%) and overweight (24%) individuals.
Both treatments worked as well in obese people, with no major difference in outcomes recorded between the two regimens.
Weber speculates that, “Higher cardiovascular event rates in lean patients reported in hypertension clinical trials might have reflected the types of antihypertensive treatments that were used. 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.”
However, he cautions, “Our observations might not be fully generalisable to all types of treatments…since they were driven predominantly by findings in one (the diuretic-based) of our two treatment groups.”*
Contrary to the conclusion of Weber and colleagues, Franz Messerli from Columbia University College of Physicians and Surgeons in New York and Sripal Bangalore from New York University School of Medicine, New York argue in a linked Comment that diuretic-based regimens are not a suitable choice in obese patients. They conclude, “If the indication is hypertension, amlodipine-based treatment should be used irrespective 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—a position recognised in the latest UK guidelines.”
Notes to Editors:
*Quotes direct from author and cannot be found in text of Article.
**ACE inhibitors reduce blood pressure by preventing the conversion of the hormone angiotensin I into angiotensin II, and thus averting the narrowing of blood vessels caused by angiotensin II. Diuretics work by clearing the body of excess fluid and sodium, while calcium channel blockers relax blood vessels by slowing the flow of calcium into arterial smooth muscle cells.
THis is an interesting subgroup analysis that like other subgroup analyses should be interpreted cautiously until further evidence is available.