Effect of Renin–Angiotensin System Inhibition on Cardiovascular Events in Older Hypertensive Patients with Metabolic Syndrome

doi:10.1016/j.metabol.2013.11.006

Metabolism

Volume 63, Issue 3, March 2014, Pages 392-399

https://doi.org/10.1016/j.metabol.2013.11.006 Get rights and content

Abstract

Objective

Metabolic syndrome (MetS) is associated with cardiovascular disease (CVD). Insulin resistance has been hypothesized as the underlying feature of MetS. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are widely used antihypertensives that may improve insulin sensitivity. The aim of the study is to evaluate the effect of ACEI/ARB on incident CVD events in older hypertensive patients with MetS.

Materials/Methods

We used the Cardiovascular Health Study, a prospective cohort study of individuals > 65 years of age to evaluate ACEI/ARB use and time to CVD events (including coronary and cerebrovascular events). The study included 777 subjects who had hypertension and ATP III-defined MetS, but free of CVD and diabetes at baseline. Cox regression models were used to evaluate the effect of ACEI/ARB as compared to other antihypertensives on the time to the first CVD events.

Results

ACEI/ARB use was associated with a decreased risk of CVD events (adjusted HR = 0.658, 95 % C.I. [0.436–0.993]) compared to other antihypertensives. When CVD endpoints were evaluated separately, use of ACEI/ARB was associated with lower rates of angioplasty and coronary events (HR of 0.129 and 0.530 respectively, with 95 % CI [0.017–0.952] and [0.321–0.875]).

Conclusions

ACEI/ARB use was associated with a lower risk of CVD events in older hypertensive patients with MetS, primarily due to a reduction in coronary events. The potential protective effect of ACEI/ARB on CVD events in older individuals with MetS will need further confirmation from prospective studies.

Introduction

Metabolic syndrome (MetS), a constellation of metabolic risk factors, increases the risk for diabetes and cardiovascular events [1], [2], [3], including cardiovascular disease mortality [4], [5], [6], all-cause mortality [4], [5], [6], and coronary heart disease mortality [6]. The pathogenesis of MetS is complex and incompletely understood, but obesity and insulin resistance contribute to its development [7].

The National Cholesterol Education Program’s (NCEP) Adult Treatment Panel III (ATP) criteria represent the most widely used definition for MetS. MetS, as defined by the ATP III criteria, is estimated to be prevalent in 28% of US adults [8]. The prevalence of MetS increases with age, reaching peak levels in the sixth decade for men and the seventh decade for women [9].

Current pharmacologic management of MetS focuses on the specific risk factors without targeting the underlying insulin resistance [10]. Several lines of evidence suggest that the renin–angiotensin system is both a contributor and target for several risk factors associated with the metabolic syndrome [11]. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) may improve insulin sensitivity [12], [13], [14], decrease the risk of type 2 diabetes [15], improve endothelial function [16], and reduce atherosclerosis and cardiovascular disease risk [17]. Whether ACEI and ARB improve clinical cardiovascular outcomes in hypertensive older patients with MetS is yet to be investigated. The purpose of this study is to evaluate the association between the use of ACEI/ARB and incident cardiovascular events in older adults with hypertension and MetS.

Section snippets

Data Source

We used data from the Cardiovascular Health Study (CHS), a community-based prospective cohort study conducted by the National Heart Lung and Blood Institute (NHLBI) in adults aged 65 and older, to evaluate risk factors for the development and progression of cardiovascular events. The purpose and design of CHS have been published previously [18]. Briefly, the CHS consisted of over 5800 participants randomly selected from Medicare eligibility lists in four U.S. communities in North Carolina,

Results

Of the original 5888 subjects enrolled in the CHS dataset, 1519 subjects had a history of cardiovascular events at baseline (including coronary heart disease, CHF, stroke or TIA). Of the remaining 4369 subjects, 3443 were free from diabetes at baseline. As we were interested in the subjects who used antihypertensive medications, we included in the analysis those who used at least one antihypertensive medication during the study (n = 2412). Out of these individuals, 945 had MetS as defined by ATP

Discussion

MetS is highly prevalent in older individuals [9] and has been associated with future cardiovascular events [1], [2], [3]. ACEIs and ARBs may have beneficial effects on insulin sensitivity [12], [13], [14], the major underlying pathophysiologic feature of MetS. Few studies reported the effect of ACEI/ARB in patients with MetS [28], [29], [30]. These studies were short-term, and the effects of ACEI/ARB on the clinical cardiovascular endpoints were not assessed. Therefore, we sought to determine

Author Contributions

H.H.Z. collected and analyzed data, and drafted the manuscript. K.I.C. designed the study, obtained funding, supervised data collection and analysis, and finalized the manuscript. S.E.H., D.P.M. and P.W.S. contributed to data interpretation and analyses.

Funding

This work was supported in part by National Institutes of Health Grant K23HD049454 (to K.I.C) and Fulbright Scholarship (to H.H.Z.). The Cardiovascular Health Study (CHS) was conducted and supported by the NHLBI in collaboration with the CHS investigators. This manuscript was prepared using a limited access dataset obtained from the NHLBI and does not necessarily reflect the opinions or views of the CHS or the NHLBI.

Conflict of interest

There is no relevant conflict of interest to be disclosed.

Acknowledgments

None.

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We used the National Surgical Quality Improvement Program vascular procedure-targeted database to capture patients undergoing infrainguinal bypass surgery between 2011 and 2015. We defined MetS using the modified MetS criteria: concomitant diabetes, hypertension, and body mass index >30 kg/m². We used multivariable logistic regression analyses to examine the association between MetS and 30-day postoperative morbidity and mortality. We also examined whether preoperative aspirin, statin, and beta blockade modify the effects of MetS on 30-day postoperative outcomes.
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Targets for dyslipidemia in MetS are lowering low-density lipoprotein cholesterols using statins with or without ezetimibe227 and triglycerides by fibrates or niacin.228 To control BP, angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists are considered as first-line therapy, because of their favorable metabolic profile.229,230 In subjects with insulin resistance, metformin can help prevent progression to diabetes, although lifestyle modification may be more effective.231
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Perioperative use of angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEis) in patients undergoing cardiac operations remains controversial. The current practice of discontinuing renin-angiotensin-system inhibitors preoperatively may negate their beneficial effects in vulnerable populations, including patients with metabolic syndrome, who exhibit elevated renin-angiotensin system activity. We hypothesized that preoperative ARB use is associated with reduced incidence of postoperative complications, compared with ACEi or no drug, in patients with metabolic syndrome undergoing coronary artery bypass grafting.
We used propensity matching to derive a cohort of 1,351 patients from 2,998 who underwent coronary artery bypass grafting based on preoperative use of ARBs, ACEis, or no renin-angiotensin-system inhibitors. Our primary end point was a composite of adverse events occurring within 30 days after the operation: new-onset atrial fibrillation/flutter, arrhythmia requiring cardioversion, perioperative myocardial infarction, acute renal failure, need for dialysis, cerebrovascular accidents, acute respiratory failure, or perioperative death.
At least one adverse event occurred in 524 (38.8%) of matched cohort patients (1,184 [39.6% of all patients]). Adjusting for European System for Cardiac Operative Risk Evaluation and metabolic syndrome in the matched cohort, preoperative use of ARBs was associated with a lower incidence of adverse events in patients with metabolic syndrome compared with preoperative use of no renin-angiotensin-system inhibitors (odds ratio, 0.43; 95% confidence interval, 0.19 to 0.99) or ACEis (odds ratio, 0.38; 95% confidence interval, 0.16 to 0.88).
Preoperative use of ARBs, but not ACEis, confers a benefit within 30 days after cardiac operations in patients with metabolic syndrome, suggesting potential efficacy differences of these drug classes in reducing cardiovascular morbidity and death in ambulatory vs surgical patients.
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A persistent question is whether certain anti-hypertensive drugs are preferable for patients with obesity or metabolic syndrome. For example, some investigators [108,109] believe that ACE inhibitors or ARBs should be first-line therapy. These agents do not induce insulin resistance or other metabolic risk factors.
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Metabolic syndrome
2020, Endocrinology (Switzerland)
Hypertension in metabolic syndrome: Novel insights
2020, Current Hypertension Reviews

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Clinical ScienceEffect of Renin–Angiotensin System Inhibition on Cardiovascular Events in Older Hypertensive Patients with Metabolic Syndrome

Abstract

Objective

Materials/Methods

Results

Conclusions

Introduction

Section snippets

Data Source

Results

Discussion

Author Contributions

Funding

Conflict of interest

Acknowledgments

Endocrinol Metab Clin North Am

Am J Hypertens

Am Heart J

Lancet

Ann Epidemiol

Ann Epidemiol

Ann Epidemiol

Ann Epidemiol

J Clin Epidemiol

Ann Epidemiol

Am J Cardiol

Metabolism

J Am Coll Cardiol

Carotid atherosclerosis and coronary heart disease in the metabolic syndrome: prospective data from the Bruneck study

Diabetes Care

The metabolic syndrome and 11-year risk of incident cardiovascular disease in the Atherosclerosis Risk in Communities study

Diabetes Care

Metabolic syndrome and cardiovascular disease in older people: the Cardiovascular Health Study

J Am Geriatr Soc

National Cholesterol Education Program versus World Health Organization metabolic syndrome in relation to all-cause and cardiovascular mortality in the San Antonio Heart Study

Circulation

The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men

JAMA

Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults

Circulation

Clinical Science
Effect of Renin–Angiotensin System Inhibition on Cardiovascular Events in Older Hypertensive Patients with Metabolic Syndrome