WHAT’S NEW: Most effective, least expensive
First-line use of thiazide diuretics for hypertension gained major support from the findings of the first ALLHAT report, published in 2002. A year later, JNC7 supported the practice. Yet questions have persisted about whether the choice of initial antihypertensive agent in patients with metabolic syndrome warrants special consideration.
The difference for one patient is small, but when you consider the high prevalence of hypertension, the cumulative benefit at a population level is significant. This subgroup analysis confirms that there is no harm, and potentially a small benefit, in using chlorthalidone as a first-line agent for treating hypertension in patients with metabolic syndrome, regardless of race—despite the measurable and presumably adverse effects of diuretic agents on metabolic measurements.
How large is the benefit of first-line thiazides, overall?
Although, statistically, the relative risks (RR) are not large, the sheer number of patients means that there is significant benefit to the selection of thiazides as first-line treatment in most patients.
CAVEATS: Is stroke a concern? Was follow-up sufficient?
In this study, the only finding of harm in the diuretic group was an increased risk for stroke compared with amlodipine among non-black patients with metabolic syndrome. While this finding does raise some uncertainty, we still think that, on balance, thiazides are the most beneficial, even in this subgroup, as there was a larger benefit in preventing heart failure.
Another theoretical possibility is that follow-up was too short to demonstrate harm from the metabolic effects of thiazides. However, the metabolic effects of thiazides are very small and we believe that the evidence of benefit shown during this study period easily outweighs any such theoretical harms.
We also assume that hydrochlorothiazide, a commonly prescribed thiazide, has the same benefits as chlorthalidone, the medication studied.
Most ALLHAT participants with metabolic syndrome already had diabetes: 67.6% of black participants and 51.8% of non-black participants. Another sub-group analysis of the ALLHAT studied patients with metabolic syndrome without diabetes, and found similar results.19
Of note, lisinopril reduced the onset of diabetes over 5 years (number needed to treat [NNT]=22.2), at the cost of increased heart failure (RR=1.31; 95% confidence interval [CI], 1.04-1.64) and combined cardiovascular disease (RR=1.19; 95% CI, 1.07-1.32). This potentially confounds the claim that thiazides are effective in preventing diabetes, since so many people had it to begin with.
The criteria for metabolic syndrome did not include waist circumference, which is the National Cholesterol Education Program definition. The World Health Organization definition, however, does allow substitution of BMI. Purists would have you believe waist circumference is necessary. In practice, we have come to use BMI as an adequate surrogate. Some say it has, in fact, replaced waist circumference.
CHALLENGES TO IMPLEMENTATION: Inertia
Few interventions are as simple as this. Thiazide diuretics are well tolerated, need to be taken only once daily, and are inexpensive. Because generics are available, little to no pharmaceutical marketing is done to promote their use. The major barriers to implementing this practice may be overcoming clinical inertia, and the message of pharmaceutical marketing on behalf of the more expensive alternatives.
Acknowledgement
We acknowledge Sofia Medvedev, PhD, University HealthSystem Consortium, Oak Brook, IL for analysis of the National Ambulatory Medical Care Survey data.
PURLs methodology
This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at here.
