Hypercholesterolemia. The evidence supports use of statins

Using statins to treat older men and women with coronary artery disease (CAD) and hypercholesterolemia reduces the risk of all-cause mortality, cardiovascular mortality, coronary events, coronary revascularization, stroke, Intermittent claudication, and congestive heart failure. The target serum low-density lipoprotein (LDL) cholesterol level is < 100 mg in older patients with CAD, prior stroke, peripheral arterial disease, extracranial carotid arterial disease, abdominal aortic aneurysm, diabetes meilitus, and the metabolic syndrome. Statins are also effective in reducing cardiovascular events in older persons with hypercholesterolemia without cardiovascular disease. Consider using statins in older persons without cardiovascular disease but with a serum LDL cholesterol > or = 130 mg/dL, or a serum high-density lipoprotein cholesterol < 50 mg/dL. Data from the Heart Protection Study favor treating patients at high risk for vascular events with statins regardless of age or initial serum lipids.     

Treatment of older persons with hypercholesterolemia with and without cardiovascular disease

Hypercholesterolemia is a risk factor for new coronary events in older men and women. Secondary prevention trials have demonstrated in persons with coronary artery disease (CAD) and hypercholesterolemia that statin drugs reduced in older persons all-cause mortality, cardiovascular mortality, coronary events, coronary revascularization, stroke, and intermittent claudication. Statins have also been shown to slow progression of coronary atherosclerotic plaques in persons with CAD, to reduce restenosis after coronary stent implantation, and to decrease myocardial ischemia in persons with CAD. Older men and women with CAD, prior atherothrombotic brain infarction, peripheral arterial disease, or extracranial carotid arterial disease and a serum low-density lipoprotein (LDL) cholesterol level higher than 125 mg/dl despite diet should be treated with statin drug therapy to lower the serum LDL cholesterol level below 100 mg/dl. Primary prevention trials have shown that statins were also effective in reducing cardiovascular events in older persons with hypercholesterolemia. On the basis of data from the Air Force/Texas Coronary Atherosclerosis Prevention Study, the physician should consider using statins in persons aged 65-80 years without cardiovascular disease with a serum LDL cholesterol level above 130 mg/dl and serum high-density lipoprotein cholesterol level below 50 mg/dl.     

Pharmacologic therapy of lipid disorders in the elderly

Older men and women with coronary artery disease, prior stroke, peripheral arterial disease, and extracranial carotid arterial disease with a serum low-density lipoprotein (LDL) cholesterol >125 mg/dL despite diet should be treated with lipid-lowering drug therapy, preferably with statins, to reduce the serum LDL cholesterol to <100 mg/dL. If statin drug therapy does not lower the serum LDL cholesterol to <100 mg/dL in older persons with coronary artery disease, a bile acid binding resin, such as cholestyramine, should be added, since this drug does not increase the incidence of myositis in persons taking statins. The physician should use statins to treat older persons without atherosclerotic cardiovascular disease with a serum LDL cholesterol=160 mg/dL plus one major risk factor, or a serum LDL cholesterol=130 mg/dL plus a serum high-density lipoprotein (HDL) cholesterol <50 mg/dL. Gemfibrozil may be useful in reducing the incidence of coronary events in persons with coronary artery disease whose primary lipid abnormality is a low serum HDL cholesterol level. There are no good data supporting treatment of hypertriglyceridemia unassociated with increased LDL cholesterol or decreased HDL cholesterol for prevention of cardiovascular disease.     

Effect of statins on mortality and cardiovascular events in elderly high-risk persons

Review of: MRC/BHF Heart Protection Study of Cholesterol Lowering with Simvastatin in 20,536 High‐Risk Individuals: a Randomized Placebo‐Controlled Trial. Lancet 2002;360:7–22. PURPOSE: To determine the effect of simvastatin 40 mg daily versus placebo on all‐cause mortality and cardiovascular events in high‐risk persons with serum total cholesterol levels of 135 mg/dL or greater. BACKGROUND: Pooled data from three secondary prevention trials of patients with coronary artery disease (CAD) and two primary prevention studies showed that treatment of hypercholesterolemia with statins caused a 31% reduction in major coronary events (95% confidence interval (CI) = 26–36%) and a 21% reduction in all‐cause mortality (95% CI = 14–28%). 1 The secondary prevention trials included 4,444 persons (23% aged 65–70) treated with simvastatin in the Scandinavian Simvastatin Survival Study, 2 , 3 4,159 persons (31% aged 65–75) treated with pravastatin in the Cholesterol and Recurrent Events Trial, 4 - 6 and 9,014 persons (39% aged 65–75) treated with pravastatin in the long‐term Intervention with Pravastatin in Ischaemic Disease Trial. 7 The two primary prevention studies included 6,595 middle‐aged men up to 64 years of age treated with pravastatin in the West of Scotland Coronary Prevention Study 8 and 6,605 persons (22% aged 65–73) treated with lovastatin in the Air Force/Texas Coronary Atherosclerosis Prevention Study. 9 The absolute risk reduction in major coronary events per 1,000 persons treated in these five studies was 33 (13–52) for women versus 37 (29–44) for men and 44 (30–58) for persons aged 65 and older versus 32 (24–40) for younger persons. 1 METHODS: The Heart Protection Study included 20,536 persons (15,454 men and 5,082 women) aged 40 to 80 (5,806 aged 70–80) with serum total cholesterol of 135 mg/dL or greater and prior myocardial infarction (MI) (8,510 persons), other CAD (4,876 persons), or no CAD (7,150 persons). Of the 7,150 participants without CAD, 1,820 had cerebrovascular disease, 2,701 had peripheral arterial disease (PAD), and 3,982 had diabetes mellitus. Although treated hypertension was present in 8,457 persons, only 237 persons were included on the basis of hypertension alone. Patients were randomized to simvastatin 40 mg daily or double‐blind placebo. Mean follow‐up was 5 years. Average compliance was 85% for the simvastatin‐treated group, and 17% of the placebo group took a statin during the 5‐year study. RESULTS: During the 5‐year study, simvastatin reduced serum total cholesterol 46 mg/dL, serum low‐density lipoprotein (LDL) cholesterol 39 mg/dL, and serum triglycerides 12 mg/dL and increased serum high‐density lipoprotein (HDL) cholesterol 1 mg/dL Simvastatin caused a 13% reduction in all‐cause mortality (95% CI = 6–19%), a 17% reduction in any vascular death (95% CI = 9–25%), a 27% reduction in major coronary events (95% CI = 21–33%), a 25% reduction in any stroke (95% CI = 15–34%), a 24% reduction in coronary or noncoronary revascularization (95% CI = 17–30%), and a 24% reduction in any major vascular event (95% CI = 19–28%). Simvastatin significantly reduced the first major vascular event in patients with MI, other CAD, or no CAD; in patients with cerebrovascular disease, PAD, diabetes mellitus, treated hypertension, or no hypertension; in men and in women; in patients aged 40 to 64, 65 to 69, and 70 to 80; in patients with low or high serum total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides; in smokers and nonsmokers; and in patients treated with and without aspirin, beta blockers, and angiotensin‐converting enzyme inhibitors. In the 3,500 persons with an initial serum LDL cholesterol of less than 100 mg/dL, reduction of serum LDL cholesterol from 97 mg/dL to 65 mg/dL by simvastatin caused a similar reduction in risk, as did treating patients with higher serum LDL cholesterol levels. Five years of simvastatin therapy prevented MI, stroke, and revascularization in 70 to 100 per 1,000 treated patients. CONCLUSION: In patients with serum total cholesterol of 135 mg/dL or higher at high risk for vascular events, simvastatin 40 mg daily significantly reduced all‐cause mortality, vascular death, major coronary events, coronary or noncoronary revascularization, and any major vascular event regardless of initial levels of serum lipids, age, or gender.     

Management of hyperlipidemia with statins in the older patient

Numerous randomized, double-blind, placebo-controlled studies and observational studies have demonstrated that statins decrease mortality and major cardiovascular events in older high-risk persons with hypercholesterolemia. The Heart Protection Study found that statins decreased mortality and major cardiovascular events in high-risk persons regardless of the initial level of serum lipids, age, or gender. The updated National Cholesterol Education Program (NCEP) III guidelines state that in very high-risk patients, a serum low-density lipoprotein (LDL) cholesterol level of <70 mg/dl is a reasonable clinical strategy, regardless of age. When a high-risk person has hypertriglyceridemia or low serum high-density lipoprotein cholesterol, consideration can be given to combining a fibrate or nicotinic acid with an LDL cholesterol-lowering drug. For moderately high-risk persons (2 or more risk factors and a 10-year risk for coronary heart disease of 10% to 20%), the serum LDL cholesterol should be decreased to <100 mg/dl. When LDL cholesterol-lowering drug therapy is used to treat high-risk persons or moderately high-risk persons, the serum LDL cholesterol should be decreased at least 30% to 40%.     

Small dense low‐density lipoprotein cholesterol is a promising biomarker for secondary prevention in older men with stable coronary artery disease

Aim

The study objective was to investigate whether small dense low‐density lipoprotein cholesterol (sdLDL‐C) is superior to low‐density lipoprotein cholesterol (LDL‐C) and other biomarkers to predict future cardiovascular events (CE) in secondary prevention.

Methods

sdLDL‐C measured by a homogeneous assay, remnant lipoprotein cholesterol, LDL particle diameter and other biomarkers were compared in 345 men aged ≥65 years with stable coronary artery disease. Baseline LDL‐C was 100.5 ± 30.1 mg/dL. CE including cardiovascular death, onset of acute coronary syndrome, need for arterial revascularization, hospitalization for heart failure, surgery procedure for cardiovascular disease and hospitalization for stroke were monitored for 5 years.

Results

CE occurred in 96 patients during the study period. LDL‐C, sdLDL‐C non‐high‐density lipoprotein cholesterol, apolipoprotein B, remnant lipoprotein cholesterol, glucose, glycated hemoglobin and brain natriuretic peptide were significantly higher; LDL particle diameter and apolipoprotein A‐1 were significantly lower in patients with than in those without CE. Age‐adjusted Cox regression analysis showed that sdLDL‐C per 10 mg/dL, but not LDL‐C, was significantly associated with CE (HR 1.206, 95% CI 1.006–1.446). A significant association of sdLDL‐C and incident CE was observed in statin users (HR 1.252, 95% CI 1.017–1.540), diabetes patients (HR 1.219, 95% CI 1.018–1.460), patients without diabetes (HR 1.257, 95% CI 1.019–1.551) and patients with hypertriglyceridemia (HR 1. 376, 95% CI 1.070–1.770).

Conclusions

sdLDL‐C was the most effective predictor of residual risk of future CE in stable coronary artery disease patients using statins and in high‐risk coronary artery disease patients with diabetes or hypertriglyceridemia. Geriatr Gerontol Int 2018; 18: 965–972 .     

Association between isolated hypercholesterolemia, isolated hypertriglyceridemia and coronary artery disease in south Indian type 2 diabetic patients

Very high prevalence rates of coronary artery disease have been reported among Indians. The aim of this study was to determine the relative importance of isolated hypercholesterolemia, isolated hypertriglyceridemia, isolated high low-density lipoprotein and isolated low high-density lipoprotein in coronary artery disease among South Indian type 2 diabetic subjects. The study group comprised of 17,885 type 2 diabetic patients attending our institute. A history of documented myocardial infarction was considered as the diagnostic criteria for coronary artery disease. Isolated hypercholesterolemia was defined as serum cholesterol over 200 mg/dL with normal serum triglyceride levels (< or = 200 mg/dL); isolated hypertriglyceridemia was defined as serum triglyceride level over 200 mg/dL with normal serum cholesterol levels (< or = 200 mg/dL). Isolated low high-density lipoprotein was defined as one below 35 mg/dL with normal serum triglyceride levels. Isolated high low-density lipoprotein cholesterol was defined as one over 150 mg/dL with normal serum triglyceride levels. Normolipidemia was defined as serum cholesterol and serum triglyceride both upto 200 mg/dL, high-density lipoprotein 35 mg/dL or above and low-density lipoprotein upto 150 mg/dL. The prevalence of coronary artery disease was significantly high among patients with isolated hypercholesterolemia (4.1%; p < 0.001), isolated high low-density lipoprotein (4.5%; p < 0.001) and isolated low high-density lipoprotein (3.9%; p = 0.005) compared to normolipidemic individuals (2.8%), but not in those with isolated hypertriglyceridemia (3.4%). The odds ratios for coronary artery disease increased with each quartiles of isolated cholesterol, isolated low-density lipoprotein cholesterol and total cholesterol to high-density lipoprotein ratio and reached statistical significance in the last quartile (p < 0.05). There was no significant increase in the odds ratios for coronary artery disease in relation to quartiles of isolated triglycerides. For isolated low high-density lipoprotein, when the last quartile was taken as the reference, the odds ratio for coronary artery disease in the first quartile reached statistical significance (p = 0.03). Multivariate regression analysis revealed age (odds ratio 1.06; p < 0.001), male sex (odds ratio 1.7; p < 0.001), hypercholesterolemia (odds ratio 1.26; p = 0.07) and high low-density lipoprotein levels (odds ratio 1.22; p = 0.043) to be strongly associated with coronary artery disease. Among South Indian type 2 diabetic subjects, serum isolated hypercholesterolemia and high low-density lipoprotein cholesterol but not isolated hypertriglyceridemia appear to be associated with coronary artery disease.     

Clinical characteristics, risk factors, and medical treatment of 561 patients with peripheral arterial disease followed in an academic vascular surgery clinic

The charts of all 561 patients (69% men and 31% women, mean age 71 +/- 10 years) with peripheral arterial disease (PAD) followed in an academic vascular surgery clinic were reviewed. Coexistent coronary artery disease (CAD) was present in 364 of 561 patients (65%). Of the 561 patients with PAD, 442 (79%) were current or exsmokers, 385 (69%) had hypertension, 225 (40%) had diabetes, 358 (64%) had a serum low-density lipoprotein (LDL) cholesterol > or =100 mg/dL, and 228 (41%) had a serum high-density lipoprotein cholesterol <40 mg/dL. Cilostazol or pentoxifylline was given to 301 of 301 patients (100%) with intermittent claudication. Aspirin or clopidogrel was given to 501 of 561 patients (89%) with PAD. Statins were given to 282 of 358 patients (79%) with PAD and an increased serum LDL cholesterol. If CAD was present, beta blockers were given to 301 of 364 patients (83%) and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers to 303 of 364 patients (83%).     

Achieving optimum lipid-lowering goals in patients with vascular disease

Individuals with established cardiovascular disease are at high risk for serious adverse ischemic events. Fortunately, effective control of serum cholesterol levels, especially low-density lipoprotein (LDL), can significantly reduce cardiovascular morbidity and mortality. To achieve these benefits, the evidence-based National Cholesterol Education Program-Adult Treatment Panel III Guidelines recommend an LDL goal of less than 100 mg/dL with a secondary non-high-density lipoprotein (HDL) goal of less than 130 mg/dL. The more aggressive optional goals are an LDL less than 70 mg/dL and a non-HDL of less than 100 mg/dL. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) exert potent LDL-lowering as well as pleiotropic effects, and these agents have consistently reduced cardiac mortality and myocardial infarction in trials of secondary prevention. Should a statin drug alone fail to achieve the goal due to resistance or patient intolerance, combination drug therapy can be used. Combination therapy may also help achieve secondary goals for the reduction of non-HDL cholesterol levels.     

Rationale and design of REDUCE‐IT: Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial

Residual cardiovascular risk persists despite statins, yet outcome studies of lipid‐targeted therapies beyond low‐density lipoprotein cholesterol (LDL ‐C) have not demonstrated added benefit. Triglyceride elevation is an independent risk factor for cardiovascular events. High‐dose eicosapentaenoic acid (EPA ) reduces triglyceride‐rich lipoproteins without raising LDL ‐C. Omega‐3s have postulated pleiotropic cardioprotective benefits beyond triglyceride‐lowering. To date, no large, multinational, randomized clinical trial has proved that lowering triglycerides on top of statin therapy improves cardiovascular outcomes. The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE‐IT ; NCT01492361 ) is a phase 3b randomized, double‐blinded, placebo‐controlled trial of icosapent ethyl, a highly purified ethyl ester of EPA , vs placebo. The main objective is to evaluate whether treatment with icosapent ethyl reduces ischemic events in statin‐treated patients with high triglycerides at elevated cardiovascular risk. REDUCE‐IT enrolled men or women age ≥45 years with established cardiovascular disease or age ≥50 years with diabetes mellitus and 1 additional risk factor. Randomization required fasting triglycerides ≥150 mg/dL and <500 mg/dL and LDL ‐C >40 mg/dL and ≤100 mg/dL with stable statin (± ezetimibe) ≥4 weeks prior to qualifying measurements. The primary endpoint is a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary endpoint is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Several secondary, tertiary, and exploratory endpoints will be assessed. Approximately 8000 patients have been randomized at approximately 470 centers worldwide. Follow‐up will continue in this event‐driven trial until approximately 1612 adjudicated primary‐efficacy endpoint events have occurred.     

High-density vs low-density lipoprotein cholesterol as the risk factor for coronary artery disease and stroke in old age

BACKGROUND: A high total serum cholesterol level does not carry a risk of cardiovascular mortality among people 85 years and older and is related to decreased all-cause mortality. At this old age, there are few data on fractionated lipoprotein levels in the determination of cardiovascular disease risk. The aim of this study was to evaluate the relationships between low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels and mortality from specific causes among people in the oldest age categories. METHODS: Between September 1, 1997, and September 1, 1999, a total of 705 inhabitants in the community of Leiden, the Netherlands, reached the age of 85 years. Among these old people, we initiated a prospective follow-up study to investigate determinants of successful aging. A total of 599 subjects participated (response rate, 87%) and all were followed up to September 2001. Serum levels of total, LDL, and HDL cholesterol were assessed at baseline along with detailed information on comorbid conditions. The main outcome measure was all-cause and specific mortality risk. RESULTS: During 4 years of follow-up, 152 subjects died. The leading cause of death was cardiovascular disease, with similar mortality risks in all tertiles of LDL cholesterol level. In contrast, low HDL cholesterol level was associated with a 2.0-fold higher risk of fatal cardiovascular disease (95% confidence interval [CI], 1.2-3.2). The mortality risk of coronary artery disease was 2.0 (95% CI, 1.0-3.9) and for stroke it was 2.6 (95% CI, 1.0-6.6). Both low LDL cholesterol and low HDL cholesterol concentrations were associated with an increased mortality risk of infection: 2.7 (95% CI, 1.2-6.2) and 2.4 (95% CI, 1.1-5.6), respectively. The risks were unaffected by comorbidity. CONCLUSION: In contrast to high LDL cholesterol level, low HDL cholesterol level is a risk factor for mortality from coronary artery disease and stroke in old age.     

Implications of the heart protection study for reducing coronary events in high-risk patients

The Heart Protection Study tested the effectiveness of 40 mg/d of simvastatin in preventing total mortality and cardiovascular mortality in 20,536 high-risk adults, of whom there were 13,386 with known coronary heart disease and 7150 with cerebrovascular or peripheral vascular disease and/or diabetes. The study used a double-blind, placebo-controlled design and a 5-year period of observation. Those with total serum cholesterol less than 135 mg/dL were excluded. The simvastatin-treated cohort experienced 13% fewer deaths from all causes due entirely to the 17% reduction in cardiovascular deaths. Myocardial infarctions were reduced by 38%, stroke by 25%, and all major cardiovascular endpoints by 24%. The benefits were statistically significant in women and men, in diabetic patients, in those over age 70 years, and in those with low-density lipoprotein cholesterol below 100 mg/dL at baseline.     

Magnitude and management of hypercholesterolemia in the adult population of Spain, 2008-2010: The ENRICA Study

Introduction and objectives

Only a few studies have reported nationwide population-based data on the magnitude and control of hypercholesterolemia. This work examines the prevalence and management of hypercholesterolemia in Spain.

Methods

Cross-sectional study conducted from June 2008 to October 2010 on 11 554 individuals representative of the population aged ≥18 years in Spain. Study participants provided 12-h fasting blood samples, which were analyzed in a central laboratory with standardized methods.

Results

In the whole population, 50.5% had hypercholesterolemia (total cholesterol ≥200 mg/dL or drug treatment) and 44.9% high levels of low-density lipoprotein cholesterol (≥130 mg/dL or drug treatment), with no substantial sex-related differences. Moreover, 25.5% of men showed high-density lipoprotein cholesterol <40 mg/dL and 26.4% of women high-density lipoprotein cholesterol <50 mg/dL. Also, 23.2% of men and 11.7% of women had triglycerides ≥150 mg/dL. Frequency of dyslipidemia increased up to 65 years, except for low high-density lipoprotein cholesterol which did not vary with age. Among those with high low-density lipoprotein cholesterol, 53.6% knew of it and 44.1% of them received lipid-lowering treatment; among the latter, 55.7% had a controlled level (13.2% of all hypercholesterolemics). Control of high low-density lipoprotein cholesterol increased with age and with the number of visits to the specialist physician, but was lower among diabetics (odds ratio=0.38; 95% confidence interval, 0.28-0.53) and patients with cardiovascular disease (odds ratio=0.55; 95% confidence interval, 0.33-0.92).

Conclusions

About half of the Spanish population has elevated serum cholesterol; moreover, cholesterol control is poor, particularly among those with highest cardiovascular risk, such as diabetics or patients with cardiovascular disease.Full English text available from:www.revespcardiol.org     

Dietary glycemic index, dietary glycemic load, blood lipids, and C-reactive protein

Carbohydrate quantity and quality may influence the risk of cardiovascular disease through blood lipid concentrations and inflammation. We measured dietary glycemic index (GI) and dietary glycemic load (GL) among 18137 healthy women > or = 45 years old without diagnosed diabetes using a food-frequency questionnaire. We assayed fasting total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol; LDL/HDL cholesterol ratio; triacylglycerols (TG); and C-reactive protein (CRP). We evaluated associations with dietary GI and GL using a cross-sectional design, adjusting for age, body mass index, lifestyle factors, and other dietary factors. Dietary GI was significantly associated with HDL and LDL cholesterol, LDL/HDL cholesterol ratio, TG, and CRP (comparing top to bottom quintile difference in HDL cholesterol = -2.6 mg/dL, LDL cholesterol = 2.2 mg/dL, LDL/HDL cholesterol ratio = 0.16, TG = 12 mg/dL, and CRP = 0.21 mg/L). Dietary GL was associated with HDL cholesterol, LDL/HDL cholesterol ratio, and TG (comparing top to bottom quintile HDL cholesterol = -4.9 mg/dL, LDL/HDL cholesterol ratio = 0.24, and TG = 13 mg/dL). Differences in blood lipids and CRP between extreme quintiles of dietary GI and GL were small, but may translate into a clinically meaningful difference in cardiovascular risk.     

Oxidized low density lipoprotein is a prognostic marker of transplant-associated coronary artery disease

Retrospective studies identified oxidized low density lipoprotein (LDL) in the blood as a diagnostic marker of coronary artery disease (CAD). This prospective study sought to determine the prognostic value of oxidized LDL for CAD in cardiac transplant patients. Oxidized LDL was measured in 99 cardiac transplant patients with normal coronary angiograms at baseline and was measured again after a median follow-up of 2 years at the time of a second angiogram. Twenty-one patients developed angiographically detectable cardiac transplant vasculopathy (cases), and 78 individuals did not (controls). Cases had significantly higher baseline plasma levels of oxidized LDL than did controls: 1.18+/-0.70 versus 0.57+/-0.20 mg/dL (mean+/-SD, P<0.0001). The increase of oxidized LDL at the end of the follow-up was significantly higher in cases than in controls: 0. 75+/-0.73 mg/dL versus 0.14+/-0.27 mg/dL (P<0.0001). Baseline levels of oxidized LDL predicted cardiac transplant vasculopathy (chi(2)=16, P<0.0001) independent of pretransplant ischemic cardiomyopathy, time after transplantation, age, and serum levels of LDL and high density lipoprotein cholesterol. The development of transplant CAD was associated with a further increase of plasma levels of oxidized LDL (chi(2)=14, P=0.0002). Oxidized LDL is a prognostic marker of transplant CAD.     

CHD: a major burden in type 2 diabetes

Patients with type 2 diabetes have a two- to four-fold greater risk of cardiovascular mortality than non-diabetic individuals. In order to prevent coronary events in the diabetic population, it is important to treat modifiable cardiovascular risk factors. Data from the Multiple Risk Factor Intervention Trial (MRFIT) show that serum cholesterol level, systolic blood pressure level and cigarette smoking were significant predictors of cardiovascular disease mortality in men with and without diabetes. At every risk factor level, the absolute risk of age-adjusted coronary death rate was three times greater for diabetic men than non-diabetic men (p<0.0001). Patients with diabetes have an abnormal (dyslipidaemic) lipoprotein profile with high levels of very low density lipoprotein cholesterol and triglycerides, and a low level of high density lipoprotein cholesterol. Although levels of total cholesterol or low density lipoprotein (LDL) cholesterol do not differ significantly between patients with and without diabetes, those with diabetes have higher levels of atherogenic small dense LDL particles. MRFIT data show that at any serum cholesterol level, diabetes confers two-three times the risk for a coronary event. These findings constitute the rationale for considering hypolipaemic therapy, e.g. with HMG-CoA reductase inhibitors (statins), in diabetic patients with dyslipidaemia, particularly in those with evidence of coronary heart disease. Evidence shows that statins significantly lower cholesterol, exhibit beneficial effects on many components of atherosclerosis, and can significantly reduce the incidence of stroke.     

Risk stratification and prognostic implication of plasma biomarkers in nondiabetic patients with stable coronary artery disease: the role of high-sensitivity C-reactive protein

STUDY OBJECTIVES: To evaluate the implication of plasma biomarkers to future cardiovascular events in nondiabetic patients with stable coronary artery disease (CAD).Designs and settings: Prospective, follow-up study at a tertiary referral center.Patients and measurement: Serial plasma biomarkers including high-sensitivity C-reactive protein (hsCRP), homocysteine, soluble adhesion molecules, von Willebrand factor, and lipid profiles were determined before coronary angiograms in a series of nondiabetic CAD patients with stable angina. Among them, 75 consecutive patients who received coronary revascularization (48 coronary interventions and 27 coronary bypass surgeries) later and another 75 age- and gender-matched patients who preferred medical treatment were both enrolled. In patients of each group, major cardiovascular events including cardiac death, nonfatal myocardial infarction, new or repeated coronary revascularization, and hospitalization for unstable angina, stroke, or peripheral artery disease were prospectively followed up for at least 6 months. RESULTS: Patients were followed up to 40 months (median, 18 months). The incidences of major cardiovascular events were similar between the two groups. For patients with medical treatment, plasma levels of hsCRP, homocysteine, low-density lipoprotein, and the ratio of total cholesterol (TC) to high-density lipoprotein cholesterol (HDL-C) were significantly higher in those with cardiovascular events than those without. However, only hsCRP > 0.1 mg/dL (relative risk [RR], 2.78; 95% confidence interval [CI], 1.21 to 6.41; p = 0.016) and TC/HDL-C ratio > 4.8 (RR, 2.42; 95% CI, 1.04 to 5.65; p = 0.041) were independent predictors by multivariable analysis. For patients with revascularization, basal plasma hsCRP levels were higher in those with cardiovascular events than those without (p = 0.04). However, no biochemical markers could predict future major cardiovascular events in these patients. CONCLUSIONS: In nondiabetic patients with CAD, basal plasma hsCRP levels were increased with future cardiovascular events regardless of different treatment strategies. Both plasma hsCRP level and TC/HDL-C ratio independently predict future cardiovascular events, confirming the role of plasma biomarkers in clinical risk stratification especially in patients with medical treatment.     

Primary cardiovascular events and serum lipid levels in elderly Japanese with hypercholesterolemia undergoing 6-year simvastatin treatment: a subanalysis of the Japan lipid intervention trial

OBJECTIVES: To determine the relationship between serum lipid levels and the incidence of coronary events in older Japanese hypercholesterolemic patients without prior coronary heart disease (CHD). DESIGN: Post hoc subanalysis of the results in the Japan Lipid Intervention Trial. SETTING: A large-scale cohort observational study conducted throughout Japan. PARTICIPANTS: Men aged 35 to 70 and postmenopausal women younger than 70 with serum total cholesterol (TC) level of 220 mg/dL or greater treated for 6 years with low-dose simvastatin (52,421 total patients). After exclusion of 5,127 patients because of prior CHD and 4,934 patients because of incomplete data, 42,360 patients were divided into an older (9,860 patients, aged 65-70, mean age 67.1) and younger (32,500 patients, younger than 65, mean age 54.9) group and analyzed. MEASUREMENTS: Fasting serum lipid levels were measured every 6 months. Major coronary events, including fatal or nonfatal myocardial infarction, and sudden cardiac death as the primary endpoint and other cardiovascular diseases, including onset of angina pectoris, cerebrovascular events, and any causes of death, as the secondary endpoints were monitored. RESULTS: Simvastatin treatment in older patients was as safe and effective as in younger patients. Incident rates of major coronary events were 1.30 per 1,000 patient-years in the older group and 0.80 per 1,000 patient-years in the younger group. The incidence of a major coronary event was correlated to serum TC and low-density lipoprotein cholesterol (LDL-C) levels in both groups. The absolute risk of major coronary events in the older group was higher than in the younger group at any level of LDL-C, whereas the relative risk increased by 1.7% with an elevation of each 1 mg/dL LDL-C level in both groups. In the older group, the risk of major coronary events also increased as triglyceride level increased, whereas the risk decreased as high-density lipoprotein cholesterol level increased above 60 md/dL. CONCLUSION: The LDL-C level-dependent increase of relative risk of CHD was similar in elderly and younger patients, whereas the absolute risk at any LDL-C level in elderly patients was higher than in younger patients.     

Evaluation of Low-Density Lipoprotein Particle Number Distribution in Patients With Type 2 Diabetes Mellitus With Low-Density Lipoprotein Cholesterol <50 mg/dl and Non-High-Density Lipoprotein Cholesterol <80 mg/dl

Many patients with type 2 diabetes mellitus (T2DM) have relatively normal levels of low-density lipoprotein (LDL) cholesterol yet have increased risk for cardiovascular events. Distribution of lipoprotein subclasses in patients with T2DM who have achieved very low levels of LDL cholesterol (<50 mg/dl) or non-high-density lipoprotein (HDL) cholesterol (<80 mg/dl) have not been extensively examined. The aim of this study was to assess variations in lipoprotein particle concentration in patients with diabetes with "very low" LDL cholesterol and non-HDL cholesterol levels to elucidate the drivers of residual cardiovascular risk. Data were selected from a single large clinical laboratory database. Cases were patients with T2DM diagnosis codes (International Classification of Diseases, Ninth Revision, codes 250 to 250.93). Lipoprotein particle concentrations were analyzed using nuclear magnetic resonance spectroscopy. The Friedewald equation was used to calculate LDL cholesterol. Among the 1,970 patients with T2DM, the mean age was 61 years, and approximately 51% were men. At LDL cholesterol concentrations <50 mg/dl (triglyceride <150 mg/dl and HDL cholesterol >40 mg/dl), 16% had LDL particle concentrations <500 nmol/L, 70% had concentrations of 500 to 1,000 nmol/L, and 14% had concentrations >1,001 nmol/L. At non-HDL cholesterol levels <80 mg/dl, 8% had LDL particle concentrations <500 nmol/L, 67% had concentrations of 500 to 1,000 nmol/L, and 25% had concentrations >1,001 nmol/L. In conclusion, despite attainment of LDL cholesterol <50 mg/dl or non-HDL cholesterol <80 mg/dl, patients with diabetes exhibited significant variation in LDL particle levels, with most having LDL particle concentrations >500 nmol/L, suggesting the persistence of potential residual coronary heart disease risk.     

Detection and evaluation of dyslipoproteinemia

Screening for dyslipoproteinemias should be undertaken in all individuals older than 20 years of age at least once every 5 years. The initial screening, as recommended by the Adult Treatment Guidelines Panel of the National Cholesterol Education Program, is to determine the concentration of total blood cholesterol. This initial determination can be made on blood obtained in the nonfasting state. Further evaluation of the patient's lipoprotein concentrations is dependent upon the presence of other cardiovascular risk factors. in the absence of definite coronary heart disease, hypertension, diabetes mellitus, a family history of coronary artery disease, cigarette smoking, or severe obesity, the patient with a total blood cholesterol concentration less than 200 mg/dL requires no specific instruction and should have a repeated screening performed within 5 years. Patients with blood cholesterol concentrations greater than 200 mg/dL should have their lipoprotein profiles determined if they have atherosclerotic cardiovascular disease or two other cardiovascular disease risk factors. The lipoprotein profile includes the determination of fasting cholesterol and triglyceride and HDL cholesterol concentrations. From these values, the LDL cholesterol concentration can be calculated. This LDL cholesterol concentration is central in selecting the appropriate therapy. HDL cholesterol concentrations may be useful in evaluating patients with ischemic heart disease. Concentrations of HDL cholesterol less than 35 mg/dL are associated with increased risk for coronary artery disease. Although there is currently no convincing evidence that support the specific treatment of depressed HDL cholesterol concentrations, therapy directed to modulating lipoprotein metabolism in patients with heart disease and low HDL concentrations may be of benefit. Patients with recurrent abdominal pain, pancreatitis, and eruptive xanthomatosis frequently have fasting hypertriglyceridemia concentrations exceeding 1000 mg/dL. These patients should be identified in order to effectively reduce their triglyceride concentrations, which can prevent these complications.