Defense Date

2009

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacy

First Advisor

Kai Cheang

Abstract

Background: Insulin resistance may play a pathogenic role in cardiovascular disease (CVD). Resistance to insulin has been associated with obesity, hypertension, and abnormal glucose and lipid metabolism. The constellation of these features among insulin resistant subjects has been called the metabolic syndrome. Prevalence of the metabolic syndrome increases with age and is most common in the elderly. Different criteria have been proposed to define the metabolic syndrome (ATP, WHO, AACE, EGIR). Current management of metabolic syndrome focuses on the specific risk factors that the patient may have without targeting the underlying insulin resistance. Angiotensin Converting Enzyme Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB) are widely used antihypertensive medications that may improve insulin sensitivity. We hypothesize that they can be used to reduce the long term cardiovascular complications in elderly hypertensive subjects with evidence of insulin resistance. In this study, we determined the effect of ACEI/ARB on the long term development of CVD in hypertensive non-diabetic elderly patients with the metabolic syndrome, as well as in patients with insulin resistance. Methods: Our research project utilizes the Cardiovascular Health Study (CHS) dataset. This dataset is a community based observational study where elderly participants were randomly selected and followed up for 11 years and the time to any cardiovascular event was recorded. In our project, we included hypertensive, non-diabetic individuals, with evidence of metabolic syndrome or insulin resistance, but had not experienced cardiovascular events at baseline. Cox regression model was used to evaluate the effect of ACEI/ARB on the time to the first cardiovascular event compared to the other antihypertensive medications adjusting for possible confounders such as age, race, gender, smoking status, triglycerides, LDL levels, systolic blood pressure, development of diabetes, congestive heart failure (CHF) and the number of anti-hypertensives. Results: In elderly hypertensive non-diabetic subjects with the metabolic syndrome according to the ATP and the WHO criteria, the hazard ratio for CVD associated with the use of ACEI/ARB was 0.65 or 0.68 (with 95 % C.I. of [0.45, 0.98], and [0.48, 0.96]) respectively when compared to the group exposed to the other anti-hypertensives. When the metabolic syndrome was defined according to the AACE and EGIR, the use of ACE/ARB was associated with hazard ratios for CVD equal to 0.74 and 0.899, respectively (with 95 % C.I. of [0.54, 1.09] and [0.61, 1.34]) compared to the use of the other anti-hypertensives. Hypertensive non-diabetic elderly subjects who were insulin resistant as evidenced by a HOMA-IR in the upper quartile, had a hazard ratio for CVD of 0.78 (95 % C.I. [0.56, 1.09]) associated with the use of ACEI/ARB compared to the use of other anti-hypertensives. Conclusions: The effect of ACEI/ARB on the development of cardiovascular events differs according to the definition of the metabolic syndrome. Elderly hypertensive patients with the metabolic syndrome, defined by ATP and WHO, seem to have lower risk of CVD with ACEI/ARB compared to the other antihypertensive medications. However, this association is not significant in elderly hypertensive patients in the upper quartile of HOMA and in patients with the metabolic syndrome as defined by AACE and EGIR criteria.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

December 2009

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