Renin-angiotensin system polymorphisms and the association between use of angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors and the risk of diabetes

Abstract

Introduction.We assessed the influence of genetic polymorphisms in the renin-angiotensin system on the risk of diabetes associated with the use of angiotensin II receptor blockers and angiotensin-converting enzyme (ACE) inhibitors. Materials and methods. We performed a matched case-control study among antihypertensive drug users. Pharmacy records and questionnaires were used to ascertain incident diabetes (cases), antihypertensive drug use, and risk factors. Controls did not (yet) have diabetes. We genotyped ACE (G4656C, which is in complete linkage disequilibrium with the ACE insertion/deletion polymorphism), angiotensinogen (M235T), and angiotensin II type 1 receptor (A1166C). Results. Among 495 cases of incident diabetes and 2,624 controls, homozygous 1166C carriers of angiotensin II type 1 receptor who used angiotensin II receptor blockers had an increased risk of diabetes compared to 1166A carriers (interaction odds ratio 5.3 [95% confidence interval: 1.8-16.1]). Homozygous ACE GG subjects who used ACE inhibitors ≥ 1 defined daily dose/day had a higher risk of diabetes compared to subjects with the ACE C allele (interaction odds ratio 2.3 [95% confidence interval: 1.2-4.5]). Conclusions. Angiotensin II receptor blockers increase the occurrence of diabetes in homozygous 1166C carriers of angiotensin II type 1 receptor, but not in 1166A carriers. ACE inhibitors at doses ≥ 1 defined daily dose/day increase the risk of diabetes among homozygous ACE GG carriers, but not in 4656C carriers. IntroductionDiabetes is a major risk factor for cardiovascular morbidity and mortality and the co-existence of diabetes mellitus in hypertensive patients doubles the risk of cardiovascular events, cardiovascular mortality and total mortality.1,2 A recent metaanalysis assessed that the relative risk reductions of type 2 diabetes mellitus by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) compared to diuretic therapy were 33% and 38%, respectively.3 Although a pooled analysis showed that compared to placebo these risks were not significantly reduced, individual trials have demonstrated small decreased risks of diabetes associated with ARBs and ACE inhibitors. 4 Even if there would be no overall beneficial effect of ACE inhibitors and ARBs on the risk of diabetes, subgroups of patients defined by, for instance genetic variation, might experience more or less benefit from these drugs with regard to the risk of diabetes. The mechanisms through which ACE inhibitors and ARBs reduce the risk of diabetes mellitus remain uncertain, although several mechanisms, such as decreased renal potassium wasting, and improved islet blood flow and pancreatic beta-cell perfusion by reducing angiotensin II-mediated vasoconstriction in the pancreas, have been proposed. 5 Polymorphisms in genes that code for components of the reninangiotensin system (RAS) may influence the response to these agents and risk of diabetes. Spiering et al. 6 found that the CC genotype of the angiotensin II type 1 recept...

Genotypic interactions of renin–angiotensin system genes with diabetes type 2 in a Tunisian population

“…Bozkurt et al (2009a) showed that ARBs increase the occurrence of diabetes in homozygous C carriers, but not in A carriers. The risk of type 2 diabetes due to thiazide use was not increased among CC homozygous subjects (OR = 0.63; 95% CI: 0.28-1.40) compared to A allele carriers (OR = 1.79; 95% CI: 1.43-2.23) (Bozkurt et al 2009b). The CC genotype is associated with a greater sensitivity for Ang II through a greater number of receptor binding sites and affinity for Ang II (Duncan et al 2001).…”

Risk of acute myocardial infarction after discontinuation of antihypertensive agents: a case–control study

“…This database consists of a high CVD risk population including patients with antihypertensive drugs, 15 use of statins and/or hypercholesterolaemia, 16 and diabetes. 17 These subjects were identified from the PHARMO Database Network, a population-based network of healthcare databases that combines the data from different healthcare settings in the Netherlands (www.pharmo.nl). For this study, dispensing data from community pharmacies and hospital discharge diagnoses were used.…”

Association of polymorphisms within the Renin-Angiotensin System with metabolic syndrome in a cohort of Chilean subjects

“…Although contradictory information exists, many authors relate them to various pathological conditions, apparently modulating the development of diseases like hypertension, chronic kidney disease, myocardial infarction and diabetes complications (1,2).…”