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

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.

Figure 1. Study design

Randomization occurred at baseline (Week 0), followed by forced titration of doses at Week 4, 8, and 12. HCTZ=hydrochlorothiazide; R=randomization; S=screening.

Figure 2. Patient Disposition

Postprandial glucose (A) and insulin (B) after OGTT challenge at baseline and end of study. EOS=end of study

Figure 2. Patient Disposition

Postprandial glucose (A) and insulin (B) after OGTT challenge at baseline and end of study. EOS=end of study

Figure 2. Patient Disposition

Postprandial glucose (A) and insulin (B) after OGTT challenge at baseline and end of study. EOS=end of study

Figure 3

Pearson product correlations between postprandial insulin and postprandial glucose at 30 (A) and 120 (B) min at the end of the study.

Figure 3

Pearson product correlations between postprandial insulin and postprandial glucose at 30 (A) and 120 (B) min at the end of the study.