2018 Cholesterol Clinical Practice Guidelines: Synopsis of the 2018 American Heart Association/American College of Cardiology/Multisociety Cholesterol Guideline.

Description: In November 2018, the American Heart Association and American College of Cardiology (AHA/ACC) released a new clinical practice guideline on cholesterol management. It was accompanied by a risk assessment report on primary prevention of atherosclerotic cardiovascular disease (ASCVD). Methods: A panel of experts free of recent and relevant industry-related conflicts was chosen to carry out systematic reviews and meta-analyses of randomized controlled trials (RCTs) that examined cardiovascular outcomes. High-quality observational studies were used for estimation of ASCVD risk. An independent panel systematically reviewed RCT evidence about the benefits and risks of adding nonstatin medications to statin therapy compared with receiving statin therapy alone in persons who have or are at high risk for ASCVD. Recommendation: The guideline endorses a heart-healthy lifestyle beginning in childhood to reduce lifetime risk for ASCVD. It contains several new features compared with the 2013 guideline. For secondary prevention, patients at very high risk may be candidates for adding nonstatin medications (ezetimibe or proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) to statin therapy. In primary prevention, a clinician-patient risk discussion is still strongly recommended before a decision is made about statin treatment. The AHA/ACC risk calculator first triages patients into 4 risk categories. Those at intermediate risk deserve a focused clinician-patient discussion before initiation of statin therapy. Among intermediate-risk patients, identification of risk-enhancing factors and coronary artery calcium testing can assist in the decision to use a statin. Compared with the 2013 guideline, the new guideline gives more attention to percentage reduction in low-density lipoprotein cholesterol as a treatment goal and to long-term monitoring of therapeutic efficacy. To simplify monitoring, nonfasting lipid measurements are allowed.

Long-Term Association of Low-Density Lipoprotein Cholesterol With Cardiovascular Mortality in Individuals at Low 10-Year Risk of Atherosclerotic Cardiovascular Disease.

BACKGROUND: The associations of low-density lipoprotein cholesterol (LDL-C) with cardiovascular disease (CVD) and coronary heart disease mortality in an exclusively low estimated 10-year risk group are not well delineated. We sought to determine the long-term associations of various LDL-C and non-high-density lipoprotein cholesterol (HDL-C) thresholds and CVD and coronary heart disease mortality in a large, low 10-year risk cohort. METHODS: The study sample included participants of the CCLS (Cooper Center Longitudinal Study) without a history of CVD or diabetes mellitus and defined as low risk (<7.5%) for 10-year atherosclerotic CVD events at baseline based on Pooled Cohort Risk Assessment Equations. The associations of fasting LDL-C and non-HDL-C with CVD mortality were tested with Cox proportional hazards models. RESULTS: In 36 375 participants (72% men, median age 42) followed for a median of 26.8 years, 1086 CVD and 598 coronary heart disease deaths occurred. Compared with LDL-C <100 mg/dL, LDL-C categories 100 to 129 mg/dL, 130 to 159 mg/dL, 160 to 189.9 mg/dL, and ≥190 mg/dL were associated with a significantly higher risk of CVD death, with hazard ratios of 1.4 (95% CI, 1.1-1.7), 1.3 (95% CI, 1.1-1.6), 1.9 (95% CI, 1.5-2.4), and 1.7 (95% CI, 1.3-2.3), and mean reductions in years free of CVD death of 1.8, 1.1, 4.3, and 3.9, respectively. After adjustment for atherosclerotic CVD risk factors, LDL-C categories 160 to 189 mg/dL and ≥190 mg/dL remained independently associated with CVD mortality, with hazard ratios of 1.7 (95% CI, 1.4-2.2) and 1.5 (95% CI, 1.2-2.1), respectively. In multivariable-adjusted models using non-HDL-C <130 mg/dL as the reference, non-HDL-C 160 to 189 mg/dL, 190 to 219 mg/dL, and ≥220 mg/dL were significantly associated with CVD death, with hazard ratios of 1.3 (95% CI, 1.1-1.6), 1.8 (95% CI, 1.4-2.2), and 1.5 (95% CI, 1.2-2.0), respectively. Restricting the cohort to those with 10-year risk <5% did not diminish the associations of LDL-C and non-HDL-C with CVD mortality. CONCLUSIONS: In a low 10-year risk cohort with long-term follow-up, LDL-C and non-HDL-C ≥160 mg/dL were independently associated with a 50% to 80% increased relative risk of CVD mortality. These findings may have implications for future cholesterol treatment paradigms.

Upper body fat predicts metabolic syndrome similarly in men and women.

BACKGROUND: The metabolic syndrome is a constellation of risk factors including dyslipidemia, dysglycemia, hypertension, a pro-inflammatory state, and a prothrombotic state. All of these factors are accentuated by obesity. However, obesity can be defined by body mass index (BMI), percent body fat, or by body fat distribution. The latter consists of upper body fat (subcutaneous and visceral fat) and lower body fat (gluteofemoral fat). Waist circumference is a common surrogate marker for upper body fat. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) for the years 1999-2006 was examined for associations of metabolic risk factors with percent body fat, waist circumference, and BMI. RESULTS: Associations between absolute measures of waist circumference and risk factors were similiar for men and women. The similarities of associations between waist circumference and risk factors suggests that greater visceral fat in men does not accentuate the influence of upper body fat on risk factors. CONCLUSIONS: Different waist concumference values should not be used to define abdominal obesity in men and women.

Does Dietary Cholesterol Matter?

An ongoing dispute in the nutrition field is whether dietary cholesterol contributes significantly to elevated serum cholesterol and to atherosclerotic disease. Carefully controlled metabolic studies have shown that high-cholesterol intakes cause moderate increases in serum cholesterol levels. It is been difficult to verify this in population studies because of confounding factors. Nonetheless, meta-analysis of controlled studies documents a cholesterol-raising action of dietary cholesterol. Most of this effect occurs in low-density lipoproteins (LDLs), but the cholesterol content of other lipoproteins can be increased as well. Moreover, population studies strongly suggest that dietary cholesterol is atherogenic beyond any rise in LDL concentrations. It must be emphasized that dietary cholesterol is only one of several dietary factors influencing serum cholesterol levels. Others include saturated fatty acids, trans fatty acids, soluble fiber, and total caloric intake. To achieve substantial serum cholesterol lowering, favorable changes in all of these factors must be combined. To maximize cardiovascular risk reduction, a lifetime of a healthy diet is needed. Reduced cholesterol intake is only one of several factors required to achieve such a diet. In addition, reduction of cholesterol absorption can enhance serum cholesterol lowering. This can be attained by the addition of plant sterols or plant stanols to the diet or by use of ezetimibe, a cholesterol absorption blocker. By combining dietary cholesterol reduction with other cholesterol-lowering modalities, it should be possible to substantially reduce atherosclerosis throughout life short of using cholesterol-lowering drugs that act systemically.

Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis.

IMPORTANCE: The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain. OBJECTIVE: To evaluate the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies. DATA SOURCES AND STUDY SELECTION: The MEDLINE and EMBASE databases were searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes included myocardial infarction (MI). Studies were excluded if the duration was less than 6 months or had fewer than 50 clinical events. Studies of 9 different types of LDL-C reduction approaches were included. DATA EXTRACTION AND SYNTHESIS: Two authors independently extracted and entered data into standardized data sheets and data were analyzed using meta-regression. MAIN OUTCOMES AND MEASURES: The relative risk (RR) of major vascular events (a composite of cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, or stroke) associated with the absolute reduction in LDL-C level; 5-year rate of major coronary events (coronary death or MI) associated with achieved LDL-C level. RESULTS: A total of 312 175 participants (mean age, 62 years; 24% women; mean baseline LDL-C level of 3.16 mmol/L [122.3 mg/dL]) from 49 trials with 39 645 major vascular events were included. The RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level was 0.77 (95% CI, 0.71-0.84; P < .001) for statins and 0.75 (95% CI, 0.66-0.86; P = .002) for established nonstatin interventions that work primarily via upregulation of LDL receptor expression (ie, diet, bile acid sequestrants, ileal bypass, and ezetimibe) (between-group difference, P = .72). For these 5 therapies combined, the RR was 0.77 (95% CI, 0.75-0.79, P < .001) for major vascular events per 1-mmol/L reduction in LDL-C level. For other interventions, the observed RRs vs the expected RRs based on the degree of LDL-C reduction in the trials were 0.94 (95% CI, 0.89-0.99) vs 0.91 (95% CI, 0.90-0.92) for niacin (P = .24); 0.88 (95% CI, 0.83-0.92) vs 0.94 (95% CI, 0.93-0.94) for fibrates (P = .02), which was lower than expected (ie, greater risk reduction); 1.01 (95% CI, 0.94-1.09) vs 0.90 (95% CI, 0.89-0.91) for cholesteryl ester transfer protein inhibitors (P = .002), which was higher than expected (ie, less risk reduction); and 0.49 (95% CI, 0.34-0.71) vs 0.61 (95% CI, 0.58-0.65) for proprotein convertase subtilisin/kexin type 9 inhibitors (P = .25). The achieved absolute LDL-C level was significantly associated with the absolute rate of major coronary events (11 301 events, including coronary death or MI) for primary prevention trials (1.5% lower event rate [95% CI, 0.5%-2.6%] per each 1-mmol/L lower LDL-C level; P = .008) and secondary prevention trials (4.6% lower event rate [95% CI, 2.9%-6.4%] per each 1-mmol/L lower LDL-C level; P < .001). CONCLUSIONS AND RELEVANCE: In this meta-regression analysis, the use of statin and nonstatin therapies that act via upregulation of LDL receptor expression to reduce LDL-C were associated with similar RRs of major vascular events per change in LDL-C. Lower achieved LDL-C levels were associated with lower rates of major coronary events.

Adipose tissue and metabolic syndrome: too much, too little or neither.

Obesity is strongly associated with metabolic syndrome. Recent research suggests that excess adipose tissue plays an important role in development of the syndrome. On the other hand, persons with a deficiency of adipose tissue (e.g. lipodystrophy) also manifest the metabolic syndrome. In some animal models, expansion of adipose tissue pools mitigates adverse metabolic components (e.g. insulin resistance, hyperglycaemia and dyslipidemia). Hence, there are conflicting data as to whether adipose tissue worsens the metabolic syndrome or protects against it. This conflict may relate partly to locations of adipose tissue pools. For instance, lower body adipose tissue may be protective whereas upper body adipose tissue may promote the syndrome. One view holds that in either case, the accumulation of ectopic fat in muscle and liver is the driving factor underlying the syndrome. If so, there may be some link between adipose tissue fat and ectopic fat. But the mechanisms underlying this connection are not clear. A stronger association appears to exist between excessive caloric intake and ectopic fat accumulation. Adipose tissue may act as a buffer to reduce the impact of excess energy consumption by fat storage; but once a constant weight has been achieved, it is unclear whether adipose tissue influences levels of ectopic fat. Another mechanism whereby adipose tissue could worsen the metabolic syndrome is through release of adipokines. This is an intriguing mechanism, but the impact of adipokines on metabolic syndrome risk factors is uncertain. Thus, many potential connections between adipose tissue and metabolic syndrome remain to unravelled.

Is There a Role for Coronary Calcium in Patients With Diabetes?

In the primary prevention of atherosclerotic cardiovascular disease (ASCVD), a significant portion of high-risk patients have diabetes. Two decades ago, patients with or without cardiovascular disease were identified as having coronary heart disease (CHD) risk equivalents because prospective studies showed that they were at risk for future CHD events equivalent to that of patients with established CHD. Thus, for patients with CHD, cholesterol guidelines recommended that patients with diabetes should be treated routinely with statins. However, recently, the treatment of diabetes has been greatly improved, and the risk for ASCVD has decreased. For this reason, it may be appropriate to re-evaluate the recommendations for routine use of statins in patients with diabetes. One of the major advances in the risk assessment for ASCVD is the introduction of coronary artery calcium measurement. This report will examine the role of coronary artery calcium scanning for the decision to initiate statin therapy in the primary prevention for patients with diabetes.

Statin therapy for primary prevention in men: What is the role for coronary artery calcium?

Current cholesterol guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD) base statin treatment decisions on multiple risk factor algorithms (e.g., Pooled Cohort Equations [PCEs]). By available PCEs, most older middle-aged men are statin eligible. But several studies cast doubt on predictive accuracy of available PCEs for ASCVD risk assessment. Recent studies suggest that accuracy can be improved by measurement of coronary artery calcium (CAC). This method has the advantage of identifying men at low risk in whom statin therapy can be delayed for several years, provided they are monitored periodically for progression of CAC. Thus, there are two approaches to statin therapy in men ≥ 55 years: first all men could be treated routinely, or second, treatment can be based on the extent of coronary calcium. The latter could allow a sizable fraction of men to avoid treatment for several years or indefinitely. Whether with initial CAC scan or with periodic rescanning, a CAC score ≥ 100 Agatston units is high enough to warrant statin therapy. In otherwise high-risk men (e.g., diabetes, severe hypercholesterolemia, 10-year risk by PCE ≥ 20%), a statin is generally indicated without the need for CAC; but in special cases, CAC measurement may aid in treatment decisions.

Effect of angiotensin receptor blockade on insulin sensitivity and endothelial function in abdominally obese hypertensive patients with impaired fasting glucose.

AngII (angiotensin II) may contribute to cardiovascular risk in obesity via adverse effects on insulin sensitivity and endothelial function. In the present study, we examined the effects of ARB (angiotensin receptor blocker) therapy (losartan, 100 mg/day) on insulin sensitivity and endothelial function in 53 subjects with stage I hypertension, abdominal obesity and impaired fasting glucose. The study design was a randomized double-blinded parallel design placebo-controlled multi-centre trial of 8 weeks duration. We used the hyperinsulinaemic-euglycaemic clamp technique to measure insulin sensitivity (expressed as the 'M/I' value) and RH-PAT (reactive hyperaemia-peripheral arterial tonometry) to measure endothelial function. Additional measures included HOMA (homoeostasis model assessment)-B, an index of pancreatic ß-cell function, and markers of inflammation [e.g. CRP (C-reactive protein)] and oxidative stress (e.g. F2-isoprostanes). ARB therapy did not alter insulin sensitivity [5.2 (2.7) pre-treatment and 4.6 (1.6) post-treatment] compared with placebo therapy [6.1 (2.9) pre-treatment and 5.3 (2.7) post-treatment; P value not significant], but did improve the HOMA-B compared with placebo therapy (P=0.05). ARB therapy also did not change endothelial function [RH-PAT, 2.15 (0.7) pre-treatment and 2.11 (0.7) post-treatment] compared with placebo therapy [RH-PAT, 1.81 (0.5) pre-treatment and 1.76 (0.7) post-treatment; P value not significant]. Markers of inflammation and oxidative stress were not significantly changed by ARB therapy. In conclusion, ARB therapy did not alter peripheral insulin sensitivity or endothelial function in this cohort of patients with essential hypertension, abdominal obesity and impaired fasting glucose, but did improve pancreatic ß-cell function.

A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P< or =5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P< or =0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19) for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8), n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5x10(-6), n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3), n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.

Treatment targets in the management of dyslipidemias: which targets in whom?

The public health approach to prevention of atherosclerotic cardiovascular disease (ASCVD) continues to hold great potential for prevention. This approach includes diets low in saturated fats and cholesterol, maintaining desirable body weight, regular physical activity, and absence of cigarette smoking. But drug therapy is becoming more widely used. Statins have been available for treatment of elevated serum cholesterol for a quarter of a century. They have proven efficacious for reducing risk for atherosclerotic cardiovascular disease (ASCVD). They carry little toxicity, and now that some derivatives are generic, they are inexpensive. Statins have become standard of care for patients with established ASCVD. To achieve further reduction in ASCVD events through cholesterol lowering will require new combinations with older agents and development of new drugs. The future of secondary prevention lies in testing of old and new "add-on" agents. Indications for statin use in primary prevention is less clear-cut. But clinical-trial experience with statins point to enormous potential for reducing ASCVD in the population. At the same time, there are dangers of overuse and turning society into a "drug culture". To abandon the benefits of healthy lifestyles for excessive drug intervention would be unfortunate.

Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults.

CONTEXT: The risk of type 2 diabetes mellitus is heterogeneous among obese individuals. Factors that discriminate prediabetes or diabetes risk within this population have not been well characterized. A dysfunctional adiposity phenotype, characterized by excess visceral fat and insulin resistance, may contribute to diabetes development in those with obesity. OBJECTIVE: To investigate associations between adiposity phenotypes and risk for incident prediabetes and diabetes in a multiethnic, population-based cohort of obese adults. DESIGN, SETTING, AND PARTICIPANTS: Among 732 obese participants (body mass index ≥30) aged 30 to 65 years without diabetes or cardiovascular disease enrolled between 2000 and 2002 in the Dallas Heart Study, we measured body composition by dual energy x-ray absorptiometry and magnetic resonance imaging (MRI); circulating adipokines and biomarkers of insulin resistance, dyslipidemia, and inflammation; and subclinical atherosclerosis and cardiac structure and function by computed tomography and MRI. MAIN OUTCOME MEASURES: Incidence of diabetes through a median 7.0 years (interquartile range, 6.6-7.6) of follow-up. In a subgroup of 512 participants with normal fasting glucose values at baseline, incidence of the composite of prediabetes or diabetes was determined. RESULTS: Of the 732 participants (mean age, 43 years; 65% women; 71% nonwhite), 84 (11.5%) developed diabetes. In multivariable analysis, higher baseline visceral fat mass (odds ratio [OR] per 1 SD [1.4 kg], 2.4; 95% CI, 1.6-3.7), fructosamine level (OR per 1 SD [1.1 µmol/L], 2.0; 95% CI, 1.4-2.7), fasting glucose level (OR per 1 SD [1.1 µmol/L], 1.9; 95% CI, 1.4-2.6), family history of diabetes (OR, 2.3; 95% CI, 1.3-4.3), systolic blood pressure (OR per 10 mm Hg, 1.3; 95% CI, 1.1-1.5), and weight gain over follow-up (OR per 1 kg, 1.06; 95% CI, 1.02-1.10) were independently associated with diabetes, with no associations observed for body mass index, total body fat, or abdominal subcutaneous fat. Among the 512 participants with normal baseline glucose values, the composite outcome of prediabetes or diabetes occurred in 39.1% and was independently associated with baseline measurements of visceral fat mass; levels of fasting glucose, insulin, and fructosamine; older age; nonwhite race; family history of diabetes; and weight gain over follow-up (P < .05 for each) but not with measurements of general adiposity. CONCLUSION: Excess visceral fat and insulin resistance, but not general adiposity, were independently associated with incident prediabetes and type 2 diabetes mellitus in obese adults.

Statin therapy for primary prevention in women: What is the role for coronary artery calcium?

By current guidelines, statin treatment decisions depend on multiple risk factor algorithms (e.g., pooled cohort equations [PCEs]). By available PCEs most older middle-aged women are statin eligible. But several studies cast doubt on reliability of available PCEs for ASCVD risk assessment. An alternative method for risk assessment is a coronary artery calcium (CAC) score. Many older women have zero CAC, which equates to low risk for ASCVD; these women can delay statin therapy for several years before re-scanning. When CAC is 1-99 Agatston units, risk is only borderline high and statin delay also is an option until re-scanning. When CAC is > 100 Agatston units, risk is high enough to warrant a statin. In most women, CAC is the best guide to treatment decisions. In high-risk women (e.g., diabetes and severe hypercholesterolemia), generally are indicated, but CAC can assist in risk assessment, but other risk factors also can aid in treatment decisions.

Prevalence and significance of risk enhancing biomarkers in the United States population at intermediate risk for atherosclerotic disease.

BACKGROUND: Pooled cohort equations (PCEs) estimate 10-year risk for atherosclerotic cardiovascular disease (ASCVD) in US adults. One use is to guide statin eligibility. However, PCEs risk estimate is inaccurate in some US subpopulations. OBJECTIVE: Recent cholesterol guidelines proposed addition of risk enhancing factors to improve risk assessment for selection of statin therapy. This study examines frequencies of several risk enhancing biomarkers in NHANES subjects at intermediate risk (7.5 -<20% 10-year risk for ASCVD) and considers how they may be used to better assess risk for individuals. METHODS: Prevalence of the following biomarkers were determined; elevations in apolipoprotein B-containing lipoproteins, i.e., LDL cholesterol (LDL-C) (160-189 mg/dL), non-HDL-cholesterol (non-HDL-C) (190-219 mg/dL), or total apolipoprotein B (apoB) (≥ 130 mg/dL), serum triglyceride (≥175 mg/dL), hemoglobin A1c (5.7-6.4%), high sensitivity C-reactive protein (2-10 mg/L), and waist circumference ≥ 102 cm, and abnormal estimated glomerular filtration rate (15 - ≤ 60 mg/min/1.73 m2). RESULTS: 25% of NHANES population had intermediate risk. In this subpopulation, 85% had ≥ 1 biomarkers-similarly in women and men-with a third having ≥3 abnormal markers. Frequencies were not age-related, except in those 40-49 years, in whom > 40% had ≥3 abnormal biomarkers. It made little difference whether LDL-C, non-HDL-C or apoB was used as the atherogenic lipoprotein. CONCLUSION: Three or more enhancing risk factors in intermediate risk subjects can complement PCE-estimated 10-year risk and guide the patient-provider discussion toward use of lipid-lowering medication. Future research is needed to integrate risk estimates by PCE and multiple risk enhancers.

Guidelines for the management of hyperlipidemia: How can clinicians effectively implement them?

Guidelines support lowering cholesterol to decrease atherosclerotic cardiovascular disease (ASCVD) risk across the entire lifespan with intensive lifestyle intervention, as well as statin and non-statin pharmacotherapy for those at highest risk. Modest improvements in the initiation, use, and adherence to statin therapy in patients with ASCVD have occurred over the past decades. However, studies continue to document a less than desired implementation of guidelines highlighting a substantial and persistent treatment gap. The success of implementation depends on the consideration of a variety of barriers that exist throughout the healthcare delivery system. Further research is needed to comprehensively evaluate these barriers in order to develop appropriate and sustainable interventions to improve guideline implementation.