Effects on Insulin Action of Adding Low-Dose Thiazide to Angiotensin-Converting Enzyme Inhibitor in Essential Hypertension

Abstract

Abstract-Concern exists regarding adverse metabolic effects of antihypertensive agents. In the United States, diuretics are recommended first-line but additional agents, usually angiotensin-converting enzyme (ACE) inhibitors, are often required to meet blood pressure targets. We have previously shown that the combination of low-dose diuretic with an ACE inhibitor has detrimental effects on insulin action compared with ACE inhibitor alone in hypertensive type 2 diabetic patients. Our aim was to establish whether similar effects occur in nondiabetic hypertensive patients using this combination. A randomized doubleblind placebo-controlled crossover design was used. After a 6-week run-in, when regular antihypertensive medications were withdrawn and placebo substituted, patients received captopril 50 mg twice daily with either bendroflumethiazide 1.25 mg (CB) or placebo (CP) for 12 weeks with a 6-week wash-out between treatments. Insulin action was assessed by hyperinsulinemic euglycemic clamp after the 6-week run-in and at the end of each treatment period. There were no differences between treatments in fasting glucose or insulin concentrations. Glucose infusion rates required to maintain euglycemia were the same with each treatment (CP 22.1±2.

Metabolic Impact of Adding a Thiazide Diuretic to Captopril

“…In summary, the use of thiazides has been clearly linked to new-onset diabetes in clinical trials and impairments in insulin sensitivity, especially in those at increased risk such as overweight, hypertensive individuals, as seen in the current study (7). While these observational results from a relatively small cohort should be viewed cautiously, the use of mechanistic clamp studies in larger cohorts will be necessary to help elucidate the pancreatic beta cell and insulin sensitive tissue effects of diuretics and/or RAAS blockers.…”

“…In this issue of Hypertension , McHenry et al (7) build upon their previous work (8) exploring the addition of an ACEi captopril to bendrofluazide and utilizing hyperinsulinemic, euglycemic clamps to evaluate insulin sensitivity. The authors utilized a prospective randomized, cross-over design with a 6 week wash-in followed by 12 weeks of treatment in each arm with clamp studies to evaluate glucose disposal and endogenous glucose production as a marker of hepatic insulin sensitivity.…”

“…In the current study (7), the authors utilize a similar paradigm of mildly hypertensive, overweight (e.g BMI ~29kg/m 2 ) individuals but this time randomize to 1.25 mg of bendrofluazide instead of the 5 mg and as a blood pressure (BP) control doxazosin was used when systolic BP was >160 mmHg and diastolic BP >95 mm Hg. Only 12 out of 23 enrolled patients completed the study protocol but notably, there were no differences in BP, glycemic, or lipid measures between the two treatment groups.…”

Induction of Type 2 Diabetes Mellitus with Antihypertensive Therapy: Is There Any Role of Alpha Adducin, ACE, and IRS-1 Gene?

“…One study has shown that low-dose addition of thiazide diuretic to ACEI therapy does not have a significant effect on insulin action and hence on the glucose turnover in the body. This study suggested that the use of thiazides in low doses is safe [39]. The retrospective longitudinal cohort study on seven antihypertensive drug classes (ACEIs, ARBs, CCBs, diuretics, β-blockers, α-blockers, and vasodilators) demonstrated the independent association of diuretics, β-blockers, and calcium channel blockers with increased risk of NOD, whereas ACEIs, ARBs, α-blockers, and vasodilators were not associated with the risk of NOD [40].…”