Fasting Glucose Increases in Older Adults With Hypertension Regardless of Treatm

Fasting glucose (FG) levels increase in older adults with hypertension regardless of whether they are treated with chlorthalidone, amlodipine, or lisinopril. This comes from the results of an analysis from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) reported in the November 13 issue of the Archives of Internal Medicine. Although the risk of developing FG levels higher than 125 mg/dL was modestly greater with chlorthalidone, there was no conclusive or consistent evidence that this diuretic-associated increase in risk for diabetes increased the risk for clinical events.

Robert Phillips, MD, director of the Heart and Vascular Center of Excellence at the University of Massachusetts Memorial Medical Center in Worcester, states that, "Many patients with hypertension eventually develop diabetes. "Physicians and others interested in the individual and public health are guided by the principle of primum non nocere — first, do no harm. The initial reports from the ALLHAT trial showed that there was more diabetes associated with thiazide-diuretic treatment, and the authors sought to determine if this was harmful."

The objective of this analysis was to compare the effect of first-step antihypertensive drug therapy with thiazide-type diuretic, calcium-channel blocker (CCB), or angiotensin-converting enzyme (ACE) inhibitor on FG levels and to determine the risks for cardiovascular and renal disease associated with elevated FG levels and incident diabetes mellitus in these 3 treatment groups. The investigators performed post hoc subgroup analyses from ALLHAT among nondiabetic participants who were randomized to treatment with chlorthalidone (n = 8419), amlodipine (n = 4958), or lisinopril (n = 5034). Mean follow-up was 4.9 years.
Corresponding author Barry R. Davis, MD, PhD, of the University of Texas School of Public Health, Coordinating Center for Clinical Trials in Houston stated that, "Mean fasting glucose levels increased during ALLHAT follow-up in all treatment groups." "There was no significant association of fasting glucose level change at 2 years with subsequent coronary heart disease [CHD], stroke, cardiovascular disease, total mortality, or end-stage renal disease."

At year 2, the chlorthalidone group had the greatest increase in mean FG levels (+8.5 mg/dL [0.47 mmol/L] vs +5.5 mg/dL [0.31 mmol/L] for amlodipine and +3.5 mg/dL [0.19 mmol/L] for lisinopril). The odds ratios for developing diabetes at 2 years were 0.55 with lisinopril vs chlorthalidone (95% confidence interval [CI], 0.43 – 0.70), and 0.73 with amlodipine vs chlorthalidone (95% CI, 0.58 – 0.91; P <.01). Incident diabetes at 2 years was not significantly associated with clinical outcomes, except for CHD (risk ratio [RR], 1.64; P = .006), but RR was lower and nonsignificant in the chlorthalidone group (1.46; P = .14).

"The diuretic did not appear to be the culprit responsible for the increased CHD risk associated with new-onset DM [diabetes mellitus]," Dr. Phillips says. "Rather surprisingly, development of DM during treatment with ACE inhibitors was associated with an increased risk of CHD and congestive heart failure, and development of DM during treatment with CCB was associated with increased mortality. We need to be cautious about the clinical implications, but I do believe that they suggest that diuretic-induced hyperglycemia is relatively benign. Conversely, if diabetes develops on an ACE or CCB, it suggests that that patient has developed insulin resistance despite being on drugs that tend to improve insulin sensitivity, and hence the consequences are more dire."

Strengths of this study, according to Drs. Davis and Phillips, are the large sample size providing much greater statistical power to recognize associations and differences between medications and the relatively long duration of follow-up. Limitations are the retrospective design, and follow-up possibly insufficient to detect the adverse effects of thiazide-induced hyperglycemia.

"I think that [the ALLHAT analysis] will help physicians to feel more comfortable about using low-dose thiazide therapy as either the initial drug choice as or part of combination therapy," Dr, Phillips said. "If hyperglycemia or frank diabetes does develop, many physicians would stop the diuretic and substitute another agent to see if the hyperglycemia would resolve. One can’t argue with that approach, but actually we do not know if it is the correct action to take."

"These results should reinforce the recommendations of the Joint National Committee on Hypertension that diuretics should be considered as a first-line treatment of hypertension and should be part of any multidrug regimen for hypertension," Dr. Davis concluded.
Arch Intern Med. 2006;2174-2176, 2191-2201.

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