Angiotensin receptor blocker/diuretic combination preserves insulin responses in obese hypertensives

James R Sowers, Leopoldo Raij, Ishwaral Jialal, Brent M Egan, Elizabeth O Ofili, Rita Samuel, Dion H Zappe, Das Purkayastha, Prakash C Deedwania, James R Sowers, Leopoldo Raij, Ishwaral Jialal, Brent M Egan, Elizabeth O Ofili, Rita Samuel, Dion H Zappe, Das Purkayastha, Prakash C Deedwania

Abstract

Background: Thiazide diuretics can impair glucose metabolism and increase new-onset diabetes. Adding an angiotensin receptor blocker to diuretics may protect against these metabolic effects; however, the mechanism of this protection is unclear.

Method: To explore potential mechanisms, a 16-week multicenter trial was conducted to ascertain the relative glucose metabolism effects of combined hydrochlorothiazide and angiotensin receptor blocker (valsartan) therapy compared with hydrochlorothiazide and calcium channel blocker (amlodipine) treatment in 412 centrally obese hypertensive individuals (BMI = 35 +/- 7 kg/m, seated BP = 159 +/- 8/94 +/- 8 mmHg, and mean age 56 years). Individuals were randomized to valsartan/hydrochlorothiazide, with force-titration to 320/25 mg or hydrochlorothiazide, with titration to hydrochlorothiazide 25 mg and amlodipine 10 mg, respectively. Changes from baseline to week 16 in fasting and 2-h postprandial glucose and insulin levels after an oral glucose load were measured.

Results: At week 16, clinic blood pressure reductions were similar (P > 0.05) in both groups. Fasting and 2-h glucose levels increased (P < 0.05) with the amlodipine combination but not with the valsartan combination. In concert with these glucose responses, postprandial insulin increases from baseline were substantially greater with valsartan than with amlodipine plus hydrochlorothiazide group (P = 0.001). The glucose responses were inversely related to insulin responses at the study conclusion.

Conclusion: The novel observation of this investigation was that the combination of valsartan and hydrochlorothiazide was associated with greater glucose-stimulated insulin secretory and lesser glycemic excursion responses than the amlodipine combination group. Thus, this data suggests that adding an angiotensin receptor blocker attenuates the negative effects of thiazides on pancreatic beta-cell glucose-induced insulin secretion.

Trial registration: ClinicalTrials.gov NCT00439738.

Conflict of interest statement

Conflict(s) of Interest/Disclosure(s)

JRS has NIH and VA funding and has served as a consultant for Novartis Pharmaceuticals Corporation and Forest Pharmaceuticals. Research funding grants were provided to University of Missouri by Novartis Pharmaceuticals Corporation and Forest Pharmaceuticals.

LR has served as a consultant and speaker for Novartis Pharmaceuticals Corporation.

IJ has served as a consultant for Novartis Pharmaceuticals Corporation.

BE has served as a consultant and speaker for Novartis Pharmaceuticals Corporation, Pfizer Inc. and GlaxoSmithKline. Research support received from Novartis Pharmaceuticals Corporation and AstraZeneca Pharmaceuticals.

EO has served as a consultant and speaker for Novartis Pharmaceuticals Corporation. She has served as a consultant for Bristol-Myers Squibb, Nitromed and Sanofi-Aventis and speaker for Merck Pharmaceuticals.

PCD has served as a consultant and speaker for Novartis Pharmaceuticals Corporation, Forest, GlaxoSmithKline and Pfizer. Research support received from Novartis Pharmaceuticals Corporation and AstraZeneca Pharmaceuticals.

RS, DZ and DP are employees at Novartis Pharmaceuticals Corporation