Long Term Antihypertensive Exposure and Adverse Metabolic Effects: PEAR Follow-Up Study

One in three deaths in the United States is due to cardiovascular (CV) disease. One in three US adults has hypertension, a major underlying cause of CV disease. Type 2 diabetes (T2D) and dyslipidemia are major contributors of CV morbidity and mortality among hypertensive patients. Thiazide diuretics and beta blockers are first line agents in the treatment of hypertension, but these commonly prescribed antihypertensive classes can contribute to dysfunction of glucose and lipid metabolism. In randomized controlled trials, reductions in CV outcomes due to blood pressure reduction with thiazide diuretic and beta blocker treatment are accompanied by increases in T2D incidence and exacerbation of dyslipidemia. CV morbidity and mortality resulting from persistent antihypertensive-related T2D or dyslipidemia may eventually outweigh benefits from blood pressure reduction, encouraging use of alternate antihypertensive classes especially in high risk patients. An accumulating body of published literature supports that adverse metabolic effects are induced by thiazide diuretics and beta blockers. However, the vast majority of evidence for adverse metabolic effects of antihypertensive drugs utilizes secondary analyses of data from randomized blood pressure reduction trials. To date, no published study has compared short and long term adverse metabolic effects of antihypertensive therapy in the same patient population. The Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study is a randomized, parallel assignment trial to determine genetic influences on blood pressure response to the thiazide diuretic hydrochlorothiazide and the beta blocker atenolol. The PEAR study duration (18 weeks) is not sufficient to assess long term effects (over six months) of these antihypertensive medications. The primary aim of this study is to determine the effects of long term thiazide and beta blocker therapy on glucose and lipid metabolism in the PEAR population, in which short term effects have been assessed. Secondary analyses of this follow-up study include investigating adverse metabolic effects of long term thiazide diuretic and beta blocker therapy on insulin sensitivity and the role of potassium and uric acid in the hyperglycemic effects of thiazide diuretics.