Pharmacogenetics of antihypertensive drugs and the risk of diabetes

Abstract

The co-existence of high blood pressure and diabetes dramatically and synergistically increases the risk of microvascular and macrovascular complications. In order to reduce morbidity and mortality in these high risk patients, optimal blood pressure goals should be achieved. Angiotensin-converting enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARB) and diuretics(thiazide) are all effective antihypertensive agents in type 2 diabetes mellitus (T2DM) but none of them has shown superiority in either lowering blood pressure or reducing cardiovascular morbidity and mortality in T2DM. The overall aim of this thesis was to gain greater insight into the interaction between antihypertensive drugs, genetic polymorphisms and new onset diabetes (NOD). Despite their superior efficacy in reducing blood pressure, physicians often withhold prescribing thiazide diuretics because of the increased risk of T2DM. In our study with treated hypertensive subjects, the risk of diabetes increased only with increasing thiazide dose. The combination of thiazide with ACEI’s or ARB’s was even less diabetogenic than thiazide monotherapy and the use of potassium supplementation or potassium sparing drugs in combination with thiazides did not show a protection against the development of diabetes. Low-dose thiazide therapy has shown to be the safest treatment in all treatment regimens with regard to the risk of diabetes and this association was also modified by polymorphisms in the salt sensitivity gene and RAAS genes. The response to ACEI’s and ARB’s, which have been proposed as possible protective agents against the development of diabetes in hypertensive subjects, was also modified by genetic variations in the RAAS. Our pharmacogenetic studies demonstrated that genetic variation can explain variation in response to RAAS inhibitors and thiazide diuretics and other antihypertensives with regard to the risk of diabetes mellitus. Based on these findings, we constructed a decision table which should facilitate the process of prescribing an appropriate treatment regimen for hypertensives with increased risk of diabetes, taking into account polymorphisms in relevant genes.