Meta-analyses addressing antihypertensive drugs and incident diabetes bring answers and questions

Two studies published in the journals Lancet (Elliott et al) and the Archives of Internal Medicine (Barzilay et al) help to answer questions about the effect some antihypertensive agents can have on the development of diabetes mellitus, but these studies have also raised some new concerns about cardiovascular disease.

The research conducted by Elliott et al utilized a statistical technique called network meta-analysis that the authors said "allows both direct and indirect comparisons to be undertaken, even when 2 of the strategies have not been directly compared." Their data included 22 randomized controlled trials of antihypertensive medications, yielding 143,153 patients without diabetes at randomization; the majority of patients did have hypertension. Traditional meta-analysis was performed in order to identify summary odds ratios of studies comparing 2 drugs directly. These numbers were used in the network meta-analysis to make indirect comparisons between drug classes.

The drugs utilized in the trials included angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs), calcium-channel blockers (CCBs), placebo, beta-blockers, and diuretics.

Barzilay et al conducted a post-hoc analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized study of 42,418 patients with hypertension and ≥1 additional coronary heart disease risk factor; patients were assigned to either a diuretic (chlorthalidone), an ACEI (lisinopril), or a CCB (amlodipine). Other antihypertensive medications could be added to obtain blood pressure goals. Participants without diabetes at baseline (n=18,411) in ALLHAT were included in this study.

At 2 years of follow-up, patients receiving chlorthalidone had the greatest increase in mean fasting glucose level (8.5 mg/dL) compared with those receiving amlodipine (5.5 mg/dL) or lisinopril (3.5 mg/dL) (P<.001 for trend). The risk of developing diabetes was lower with lisinopril (OR=0.55; 95% CI, 0.43–0.70) and amlodipine (OR=0.73; 95% CI, 0.58–0.91) compared with chlorthalidone.

Additionally, patients who developed diabetes, regardless of treatment group, had a statistically significant increased risk of coronary heart disease (HR=1.64; 95% CI, 1.15–2.32). There was no significant increase in any outcome in association with new-onset diabetes among patients taking chlorthalidone, but new-onset diabetes was associated with increased total mortality risk among those taking amlodipine (HR=1.92, 95% CI, 1.07–3.44). and new-onset diabetes was associated with an increased risk of coronary heart disease and heart failure among those taking lisinopril (HR=2.23, 95% CI, 1.07–4.62 and HR=3.66, 95% CI, 1.30–10.32, respectively).

An editorial related to the Barzilay et al study stated that "while the occurrence of new-onset diabetes was an independent predictor of cardiovascular disease, administration of diuretics was not independently associated with cardiovascular risk," and that "thiazide-induced diabetes is a different and benign disease entity compared with either de novo diabetes or that which develops in the context of other antihypertensive agents."

SOURCES

Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007;369:201–207.

Barzilay JI, Davis BR, Cutler JA, et al; for the ALLHAT Collaborative Research Group. Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment. A report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2006;166:2191–2201.

Gorlin R. New-onset diabetes mellitus less deadly than elevated blood pressure? Following the evidence in the administration of thiazide diuretics. Arch Intern Med. 2006;166:2174–2176.