Thiazide-Like Diuretic Suitable in Patients With Hypertension and Metabolic Syndrome

Despite a less favorable metabolic profile, a thiazide-like diuretic yielded similar or possibly superior cardiovascular disease outcomes in older patients with hypertension and metabolic syndrome vs treatment with calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors.

The results from a subgroup analysis from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).  "Optimal initial antihypertensive drug therapy in people with the metabolic syndrome is unknown," write Henry R. Black, MD, from the New York University School of Medicine in New York, NY, and colleagues from ALLHAT. "Concerns have been raised that diuretics should not be used because they have unfavorable effects on insulin sensitivity and increase the risk of new-onset diabetes and adverse clinical outcomes. Calcium channel blockers (CCBs), which are metabolically neutral, and ACE inhibitors and angiotensin receptor blockers (ARBs), which improve insulin action, are considered by many to be the initial drugs of choice."

The purpose of this subgroup analysis of ALLHAT was to compare metabolic, cardiovascular, and renal outcomes in patients without diabetes and with or without metabolic syndrome who were initially assigned to treatment of hypertension with a thiazide-like diuretic (chlorthalidone), a calcium channel blocker (amlodipine), or an ACE inhibitor (lisinopril).
At 4 years of follow-up, the incidence of newly diagnosed diabetes (fasting blood glucose levels >126 mg/dL) in patients who had metabolic syndrome at baseline was 17.1% with chlorthalidone, 16.0% with amlodipine (P = .49, chlorthalidone vs amlodipine), and 12.6% with lisinopril (P < .05, lisinopril vs chlorthalidone). For participants without metabolic syndrome, the rate of newly diagnosed diabetes at 4 years was 7.7% with chlorthalidone, 4.2% with amlodipine, and 4.7% with lisinopril (P < .05 for both comparisons).

In participants with metabolic syndrome, relative risks (RRs) for outcomes were not different for amlodipine vs chlorthalidone. However, the risk for heart failure was higher in participants without metabolic syndrome (RR for amlodipine vs chlorthalidone, 1.55; 95% confidence interval [CI], 1.25 – 1.35).

In participants with metabolic syndrome, outcomes were superior with chlorthalidone vs lisinopril for heart failure (RR, 1.31; 95% CI, 1.04 – 1.64) and for combined cardiovascular disease (RR, 1.19; 95% CI, 1.07 – 1.32). There was no apparent significant interaction between treatment group and metabolic syndrome.

"Despite a less favorable metabolic profile, thiazide-like diuretic initial therapy for hypertension offers similar, and in some instances possibly superior, CVD [cardiovascular disease] outcomes in older hypertensive adults with metabolic syndrome, as compared with treatment with CCBs and ACE inhibitors," the study authors write. "This was true in spite of the mildly increased fasting glucose levels and higher level of incident diabetes in those treated with the thiazide-like diuretics compared with the other two medications. These findings are consistent with those in the overall ALLHAT cohort and in the subgroup with diabetes, as previously reported."

Practice Pearls:

• Whereas calcium channel blockers tend to be metabolically neutral, diuretics can have a negative impact on insulin sensitivity and increase the risk for incident diabetes. However, ACE inhibitors and angiotensin receptor blockers can improve the metabolic action of insulin.
• Despite being associated with a higher rate of incident diabetes in ALLHAT, chlorthalidone promoted superior cardiovascular outcomes vs lisinopril among adults with the metabolic syndrome.

Diabetes Care. Feb. 2008;31:353-360.