Thiazide Diuretics Alone or With β-Blockers Impair Glucose Metabolism in Hypertensive Patients With Abdominal Obesity
Randomized clinical trials in patients with hypertension and other cardiovascular disease risk factors have shown that antihypertensive therapy with thiazide diuretics and β-blockers is associated with an increased incidence of new-onset diabetes mellitus and other metabolic abnormalities.1,2 There is growing evidence that those patients with central obesity and other components of the cardiometabolic syndrome are especially prone to new-onset diabetes mellitus.1–5 In persons with abdominal obesity, hypertension, and impaired fasting glucose, there is a 3- to 5-fold increase in the risk for incident diabetes mellitus.4 In this context, there is growing evidence of an association between antihypertensive induced new-onset diabetes mellitus and associated increases in cardiovascular disease morbidity and mortality from stroke and myocardial infarction.6
In the present issue of Hypertension,7 the impact of abdominal obesity on the incidence of adverse metabolic effects accompanying antihypertensive therapy was examined in a population of hypertensive patients treated with atenolol and/or hydrochlorothiazide (HCTZ). A total of 395 middle-age patients, without diabetes mellitus and/or heart disease (considered low-risk hypertensive patients), participating in the Pharmacogenomic Evaluation of Antihypertensive Responses Study, were included. Patients were randomly assigned to HCTZ or atenolol, and the medication was titrated up to the maximum study dose (25 mg of HCTZ or 100 mg of atenolol). Combination therapy with these 2 agents was instituted if target blood pressure <120/70 mm Hg was not achieved with either drug. The mean duration of monotherapy and combination therapy was 6 weeks, respectively. At baseline, abdominal obesity was present in 58% of the study population, and within this cohort, 20% had impaired fasting glucose at baseline compared with 40% at the end of the study. Hypertensive patients with abdominal obesity, exposed to HCTZ alone or in combination with atenolol, had a significantly increased frequency of impaired fasting glucose and insulin resistance, measured by homeostasis model assessment-insulin resistance, as well as new-onset diabetes mellitus. Indeed, new-onset diabetes mellitus occurred in 6% of the cohort with abdominal obesity and in 2% of those without abdominal obesity. Multivariate logistic regression analysis showed that the use of HCTZ, female sex, and baseline uric acid levels strongly predicted the incidence of new-onset diabetes mellitus in hypertensive patients manifesting abdominal obesity. Thus, results from this investigation complement earlier studies, which report that hypertensive patients with abdominal obesity and accompanying metabolic abnormalities are especially vulnerable to the development of new-onset diabetes mellitus with HCTZ and/or β-blocker antihypertensive therapy.
The use of thiazide diuretics has been shown to be associated with adverse metabolic effects, including hypokalemia, hypomagnesemia, hyperuricemia, dyslipidemia, and impaired glucose metabolism.1 Our understanding of the mechanisms involved in thiazide diuretic- and β-blocker-induced abnormalities of glucose metabolism is incomplete and evolving1,2 (Figure). In previous trials, the baseline predictors of new-onset diabetes mellitus during treatment with antihypertensives included increasing age, female sex, minority ethnicity, body mass index, and waist circumference; elevated fasting and postprandial glucose; low high-density lipoprotein cholesterol; presence of left ventricular hypertrophy; and the degree of elevation of both diastolic and systolic blood pressures.1–4 The relative impact of various predisposing factors appears to differ for diuretics versus that for β-blockers. For example, hypokalemia and hypomagnesemia appear to contribute to a dose-related diabetogenic potential of thiazide diuretics.1 Low serum levels of these cations have been reported to be associated with both impairment of β-cell insulin secretion and insulin metabolic signaling in skeletal muscle, liver, and adipose tissue1 (Figure). In this regard, neither baseline potassium nor change in potassium with treatment predicted either impaired fasting glucose or new-onset diabetes mellitus in the current study.7 However, hyperuricemia did emerge as a relatively important risk factor for impaired glucose metabolism and new-onset diabetes mellitus.7
Increased systemic and tissue inflammations are increasingly recognized as important factors contributing to the pathogenesis of thiazide diuretic-induced impairment of glucose metabolism, especially in those hypertensive persons with abdominal obesity and other components of the cardiometabolic syndrome5,6 (Figure). For example, in a recent study, the use of HCTZ, compared with an angiotensin receptor blocker or placebo, was associated with impaired insulin sensitivity in a cohort of abdominally obese hypertensive patients.8 Impaired insulin sensitivity paralleled increased fat deposition in the liver and was associated with augmented inflammatory markers. Thiazide diuretic therapy has also been shown to increase C-reactive protein and plasminogen activator inhibitor 1, to elevate components of the renin-angiotensin-aldosterone system, and to reduce adiponectin, an adipocyte-derived factor that improves insulin metabolic signaling1,4 (Figure). Indeed, abdominal obesity is also associated with elevated aldosterone levels, and there is emerging evidence that aldosterone promotes insulin resistance by increasing oxidative stress and inflammation in insulin-sensitive tissues.1 Accordingly, although not measured in the current study, it is likely that aldosterone levels were high in the patients with abdominal obesity treated with HCTZ and/or atenolol.7
Nonvasodilating β-blockers, such as atenolol and metoprolol, have been reported to worsen insulin sensitivity, alter lipid metabolism, and cause weight gain.9,10 Other potential mechanisms through which these conventional β-blockers impair glucose metabolism include decreased exercise, decreased skeletal muscle blood flow, decreased islet cell insulin secretion, and the antagonistic effects of blockade of the β2 receptor on insulin metabolic signaling9,10 (Figure). The newer vasodilating β-blockers, such as carvedilol and nebivolol, do not appear to have these negative metabolic properties.10 To this point, Bakris et al9 examined the impact of 2 commonly prescribed β-blockers in type 2 diabetic hypertensive patients. Using homeostasis model assessment-insulin resistance measurements, these investigators reported detriments in insulin sensitivity in those persons who were treated with metoprolol when compared with individuals treated with carvedilol. In addition, hemoglobin A1C measurements were significantly higher in the metoprolol-treated group. Interestingly, the persons treated with carvedilol did not gain as much weight as those treated with metoprolol. Similarly, nebivolol, another vasodilating β-blocker, that reduces vascular oxidative stress and increases bioavailable NO, does not cause deterioration in insulin sensitivity even in overweight hypertensive patients with the cardiometabolic syndrome.10 These disparate data, with vasodilating versus conventional β-blocker therapy, suggest that reduced blood flow, particularly in the skeletal muscle microcirculation, is an important mechanism for the insulin resistance engendered by nonvasodilating β-blockers (Figure). Thus, the use of newer vasodilating β-blocker agents might result in fewer metabolic adverse effects, especially in those hypertensive patients with accompanying abdominal obesity and associated metabolic abnormalities.10
In summary, the use of thiazides and conventional nonvasodilating β-blockers has been clearly linked to impaired carbohydrate metabolism, especially in those at increased risk, such as the hypertensive patients with abdominal obesity, as reported in the current study.7 The recognition of the various risk factors that predispose hypertensive patients to diabetes mellitus, in relation to the specific antihypertensive agents, should help the clinician to better choose an antihypertensive regimen that avoids weight gain and other factors that contribute to impaired glucose metabolism. In this regard, the combination of thiazide diuretics and conventional β-blockers should be used with care in overweight, hypertensive patients.
Sources of Funding
J.R.S. is funded by the National Institutes of Health, the Department of Veterans’ Affairs, Novartis, and Forest Laboratory grants. C.M. has a Fellows Grant from Forest Laboratories.
J.R.S. is on the research advisory boards of Novartis and Forest Laboratories.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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Cooper-DeHoff RM, Wen S, Beitelshees AL, Zineh I, Gums JG, Turner ST, Gong Y, Hall K, Parekh V, Chapman AB, Boerwinkle E, Johnson JA. Impact of abdominal obesity on incidence of adverse metabolic effects associated with antihypertensive medications. Hypertension. 2010; 55: 61–68.
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Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, Raskin P, Wright JT Jr, Oakes R, Lukas MA, Anderson KM, Bell DSH; for the GEMINI investigators. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA. 2004; 292: 2227–2236.