Should Body Weight Influence Choice of Antihypertensive Therapy? 1

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.
Click here to read the press release from the Lancet…

Hydrochlorothiazide and Nifedipine Linked To Increased Incidence Of Lip Cancer Reply

The antihypertensive drugs hydrochlorothiazide and nifedipine have been linked to a significantly increased risk for lip cancer in a new study published in the Archives of Internal Medicine. The link is plausible, write the authors, since the drugs are known to be photosensitizing.

Using a large cohort from the Kaiser Permanente system, researchers at Kaiser Permanente and Stanford identified 712 patients with lip cancer and 22,904 matched controls. Here are the odds ratios for people with at least a 5-year exposure to antihypertensive drugs compared with no use:

  • hydrochlorothiazide: 4.22 (2.82-6.31)
  • hydrochlorothiazide-triamterene: 2.82 (1.74-4.55)
  • lisinopril: 1.42 (0.95-2.13)
  • nifedipine: 2.50 (1.29-4.84)
  • atenolol: 1.93 (1.29-2.91)

The atenolol result was no longer significant when the use of other drugs was taken into account. The authors note that because lip cancer is “a relatively infrequent form of cancer, it is not surprising that associations with antihypertensive drugs have not been observed in large clinical trials.”

In their conclusion, the authors say physicians who prescribe “photosensitizing drugs should ascertain whether patients are at high risk of lip cancer because of their fair skin and long-term sun exposure and discuss lip protection with them. Although not confirmed by clinical trials, likely preventive measures are simple: a hat with a sufficiently wide brim to shade the lips and lip sunscreens.”

In an accompanying editor’s note, Mitchell Katz wrote that ”it is likely that patients receiving these agents are also at increased risk of basal cell and squamous cell cancers of the skin (these cancers are not tracked by the cancer registry used for this study). The findings are important because simple interventions, such as lip protector, sunscreen, large-brim hats, rash guard swim shirts, and avoiding times of the day when the sun is most intense, are likely to decrease the harmful effects of the sun for everyone, regardless of whether they are receiving a photosensitizing agent. When initiating use of photosensitizing agents for our patients, we need to remind them of these simple measures to avoid sun exposure.”