(1)
University of Ottawa The Ottawa Hospital, Ottawa, ON, Canada
Diagnosis
Persons with a marked increase in serum levels of cholesterol to >350 mg/dL (9 mmol/L) represent a very small group of individuals in the population at very high risk for developing atherosclerotic coronary disease. Less than 20 % of these individuals (0.1 % of the population) have a genetic abnormality, characterized by cellular low-density lipoprotein cholesterol (LDL-C) receptor deficiency (Brown and Goldstein 1979). Thus, emphasis is now correctly placed on the vast population of individuals with a total serum cholesterol concentration in the range of 200–265 mg/dL (5.5–6.9 mmol/L), in whom the majority of heart attacks occur.
Fasting or Non-fasting LDL-C?
Patients enrolled in the National Health and Nutrition Examination Survey III (NHANES III), a nationally representative cross-sectional survey performed between 1988 and 1994, were stratified based on fasting status (≥8 h or <8 h) and followed for a mean of 14.0 years.
Conclusion—Non-fasting LDL-C has similar prognostic value as that of fasting LDL-C. National and international agencies should consider reevaluating the recommendation that patients fast before obtaining a lipid panel (Doran et al. 2014). The author advise fasting −12 hr for LDL-C in diabetics and for all with elevated triglycerides.
The LDL-C is the main marker and discussion and clinical practice is centered around goal levels depending on risk. The recent guidelines have demoted the LDL-C somewhat; there advice is flawed.
Boekholdt et al. (2014) report a patient-level meta-analysis of data from large statin trials as follows: “in terms of risk reduction, there was a clear relationship between LDL-C level attained and cardiovascular risk, with the major cardiovascular event rate at 1 year increasing incrementally from 4.4 % in those with LDL-C levels <50 mg/dL, to 10.9 % for LDL-C between 50 and <70 mg/dL, 16 % between 70 and <100 mg/dL (1.8 mmol/L), and up to 34.4 % in those with LDL-C 190 mg/dL (4.9 mmol/L). This relationship supports the premise that ‘lower is better’ when it comes to LDL-C goals” (Ben-Yehuda and DeMaria 2014).
The focus should not be on total cholesterol, HDL-C levels, ratios, or calculation of risk.
Most national guidelines agree that the recommended lipoprotein targets of therapy remains the LDL-cholesterol.
It is important to identify the number of CHD risk factors: Framingham 10-year absolute CHD risk, as advised (Goff et al. 2014, the 2013 ACC/AHA guideline). But calculation of risk without LDL numbers is not logical.
Managing risk related to LDL-C is vital in therapy for patients at risk for atherosclerotic cardiovascular disease events given its important etiologic role in atherogenesis (Morris et al. 2014).
Dyslipidemia, particularly increased LDL-C, is the major culprit underlying the development of atheroma in arteries. But why some individuals with severe atheromatous disease do not succumb to acute MI while others with mild to moderate atherosclerotic disease are hit by an acute MI is largely unknown.
The evidence for heritability of AMI is striking, with a positive family history being one of the most important risk factors for this complex trait (Wang et al. 2004). Genetic studies indicate that the heritability of AMI is much more impressive than that of atherosclerotic CAD (Willett 2002; Topol et al. 2001), which in the majority remains stable and without plaque erosion or rupture.
Although more than 50 million American adults have some atheromatous coronary artery disease (CAD), only a small fraction will ever develop erosion, fissuring, or plaque rupture that culminates in AMI (Topol 2005) or sudden death (see Chap. 15 cardiac arrest).
Lifestyle changes must be made to reduce risk (Eckel et al. 2014).
An ideal LDL-C level that carries a reduced risk for CAD events is <100 mg/dL (2.6 mmol/L) for all asymptomatic adults ages 30–80.
Stable CAD, established atherosclerosis, and presence of several risk factors including family history of MI necessitates an LDL-C < 2 mmol/L (77 mg/dL). In many, this ideal is difficult to achieve without drug therapy. For patients with acute coronary syndrome (ACS) or proven ischemia, a level of 1.2–1.6 mmol/L (45–62 mg/dL) is advisable.
HDL-C < 1.0 mmol/L (38 mg/dL) appears to increase CAD risk but is unproven. The LDL-C remains the main marker of risk. Low HDL-C is a novel lipid phenotype that appears to be more prevalent among Asian populations, in whom it is associated with increased coronary risk (Huxley et al. 2011).
Conversion Formula for mg to mmol
LDL-C is calculated by the laboratory, utilizing the total cholesterol (TC) and >12-h fasting triglyceride (TG) as follows: LDL-C mg/dL = TC − HDL-C − (TG ÷ 5). For LDL-C using mmol/L, divide by 2.2 instead of 5. If the TG level is >400 mg/dL (4 mmol/L), the calculation is not valid.
To convert total-C, LDL-C, or HDL-C from mg/dL to mmol/L, divide by 38.5 or multiply by 0.02586.
Secondary Causes of Dyslipidemias
A secondary cause commonly accounts for dyslipidemia, and the following conditions must be sought and treated or regulated:
Dietary
Diabetes mellitus
Hypothyroidism
Nephrotic syndrome
Chronic liver disease
Obesity
Dysgammaglobulinemia (monoclonal gammopathy)
Obstructive jaundice
Biliary cirrhosis
Pancreatitis
Excess alcohol consumption
Estrogens/progesterone
Glycogen storage disorders
Lipodystrophy
Medications
1.
Dietary: Excessive carbohydrate intake; weight gain; increased saturated fat or alcohol intake.
2.
Diseases: Diabetes mellitus, hypothyroidism, pancreatitis, nephrotic syndrome, liver disease (obstructive jaundice, biliary cirrhosis), and monoclonal gammopathy.
3.
Medications: Oral contraceptives and diuretics may unfavorably alter cholesterol and HDL-C cholesterol. The serum lipid alterations produced by beta-blockers have been exaggerated and perhaps exploited. Acebutolol with weak intrinsic sympathomimetic activity (ISA) caused no significant changes in total or HDL-C cholesterol at 24 months.
In the Norwegian timolol multicenter study, timolol decreased total cardiac and sudden deaths regardless of serum lipid levels (Gundersen et al. 1985). Some studies indicate that non-ISA beta-blockers cause no significant alteration of HDL-C (Valimaki et al. 1986), whereas others indicate a small decrease of 5 %. There is no evidence to support the notion that a 5 % decrease in HDL-C increases risks. The variable and mild decrease in the HDL-C (l–7 %) caused by a beta-blocking drug should not persuade against their use because these agents have important salutary effects and a proven role in prolongation of life. Thus, when needed, it is advisable to combine a beta-blocker with statin in patients at high risk for CHD events. Beta-blockers may increase triglyceride levels in some individuals. The evidence linking triglycerides with an increased risk of CHD remains elusive. Markedly raised levels of triglycerides >200 mg/dl appear to be a significant risk factor in women but is unproven. Low HDL-C is a novel lipid phenotype that appears to be more prevalent among Asian populations; it is associated with increased coronary risk.
Dietary Therapy
Dietary therapy is necessary in all patients with hyperlipidemia. In individuals without evidence of CHD or cardiovascular disease, drugs are utilized only after a concerted effort by the physician and patient to lower serum cholesterol adequately. Fortunately, raised levels of triglycerides are virtually always controlled by carbohydrate and alcohol restriction, weight reduction, and exercise. There is no need to add niacin or a fibrate to control triglyceride levels because the risk of myopathy is not justifiable.
1.
Phase I diet: Fat intake reduced to 30 % of food energy with approximately 15 % from saturated fats and 10 % from polyunsaturated. Cholesterol intake should be <300 mg, carbohydrate 55 %, and protein 15 % of calories daily. This modification is recommended for the general population.
2.
Phase III: Intake of fat 20 %, approx 7 % total daily calories from saturated fats, cholesterol 100–150 mg, carbohydrate 65 %, and protein 15 % of calories. The ratio of polyunsaturated fat to saturated fat (P/S) should be near 1.0. The recommendations in the United Kingdom are not as restrictive. For the general population or those at risk, the recommendation is an intake of fat of 35 %, with saturated fat 11 % of food energy. Polyunsaturated acids should reach 7 % with P/S ratio about 0.45 % (10). The UK panel claims that the effects on the population of a P/S ratio of 1.0 or beyond are unknown (Trustwell 1984).
In constructing diets, the following points should be considered. Most studies show that saturated and monounsaturated fats modestly raise the HDL-C concentration; high consumption of polyunsaturated fats lowers the level of HDL-C slightly (Pietinen and Huttunen 1987). A reduction in saturated fat intake from 35–40 % to 20–25 % of energy intake lowers HDL-C concentration irrespective of the type of fat (Pietinen and Huttunen 1987). Depending on the dose, marine (n-3 polyunsaturated) oils may modestly increase HDL-C levels and decrease serum cholesterol and TG levels and platelet aggregation (Sanders and Roshanai 1983). The favorable effects are not consistent, and occasionally a fall in HDL-C concentration occurs (Nestel et al. 1984; Illingworth et al. 1984).
Care is needed to avoid overindulgence because marine oils also contain a significant amount of cholesterol. One hundred grams of cod liver oil contain approximately 19 g of omega-3 fatty acids but 570 mg of cholesterol (Hepburn et al. 1986: 18). One hundred grams of salmon or herring or commercial fish body oils contain approximately 485, 766, and 600 mg cholesterol, respectively. Noncholesterol foods with abundant omega-3 fatty acids include purslane (Portulaca oleracea) (Exler and Wehlrauch 1986), common beans, soybeans, walnuts, walnut oil, wheat-germ oil, butternuts, and seaweed.
A Mediterranean-type diet is strongly recommended: no day without fruit; abundant fresh vegetables, olive oil, avocado, more fiber, fish, nuts, and less meat; butter and cream replaced by polyunsaturated/monounsaturated margarine, non-trans fatty acids. A trial comparing a Mediterranean-based alpha-linolenic acid-rich diet with a postinfarct low-fat diet in the secondary prevention of CHD reported a risk ratio of 0.24 for cardiovascular death and 0.30 for total mortality in the linolenic acid group at 27 months of follow-up (de Lorgeril et al. 1994: 20). The Lyon Heart Study confirmed post-myocardial infarction protection (de Lorgeril et al. 1999).
Nuts such as almonds, walnuts, hazelnuts, and pecans are high in beneficial poly- and monounsaturated fat as well as arginine, the precursor of nitric oxide (NO), which causes vasodilation. Arginine/NO appears to improve endothelial dysfunction and may improve performance in some patients with claudication and also angina (Maxwell et al. 2002).
Trans fatty acids increase LDL-C and must be curtailed. Major sources of food containing trans isomers include margarine, cookies (biscuits), cake and white bread, shortening, some margarine, fried foods, and cookies prepared with these fats (Willett et al. 1994: 24). The effect of intake of trans fatty acids was evaluated in the Nurses’ Health Study of 85,095 women without diagnosed CHD, stroke, or dyslipidemia in 1980. At 8-year follow-up, intake of trans isomers was directly related to the risk of CHD (Willett et al. 1994).
Drug Therapy
The assignment to three categories of risk by the Adult Treatment Panel (ATP 2004) III includes an important 10-year risk score of >20 % or <20 %, which remains clinically helpful (Grundy et al. Expert Panel 2004). The recent guidelines (2013) are complicated and flawed.
Because approximately 66 % of diabetics die of cardiovascular disease, they are considered CHD risk equivalent and to have a 10-year risk for a CHD event >20 %, so do patients with abdominal aortic aneurysm (AAA), peripheral vascular disease (PVD), and significant carotid disease. Guidelines for drug therapy are given in Table 17-1.
Table 17-1
Guidelines for the management of elevated LDL-C cholesterol: when to use drug therapy
CADa
Several risk factorsb
Average risk (one or two risk factors)
Low risk
LDL-C
LDL-C
LDL-C
LDL-C
>100 mg/dL
>130 mg/dL
>160 mg/dL
>180 mg/dLc
(2.5 mmol/L)
(3.5 mmol/L)
(4 mmol/L)
(4.5 mmol/L)
Drug therapy
Drug therapy
Drug therapy
Consider drug therapy
Goal
Goal
Goal
Goal
<80 mg/dL
<100 mg/dL
<120 mg/dL
<130 mg/dL
(<2 mmol/L)
(<2.5 mmol/L)
(<3.0 mmol/L)
(<3.5 mmol/L)
Very high riskd
Goal
<1.8 mmol/Le
<70 mg/dL
The recent guidelines deal mainly with risk assessment and place too much attention on this and unfortunately less emphasis on LDL-C (Goff et al. 2014, the 2013 ACC/AHA guideline).
Many agree that the guidelines should be modified. The guide advises that statins should be commenced in patients whose risk of a heart attack, stroke, or death from CHD (coronary heart disease) in the next 10 years is at least 7.5 %. The risk-factor calculation uses sex, age, race, total cholesterol level, HDL cholesterol level, systolic blood pressure, treatment for high blood pressure, diabetes, and smoking. Strangely, no target on-treatment LDL cholesterol levels are given specified.
Statins
The management of dyslipidemia has been revolutionized with the expanded use of statins (3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors). The statins are competitive inhibitors of HMG-CoA reductase, the key enzyme catabolizing the early rate-limiting step in the biosynthesis of cholesterol within the hepatocyte. The lowering of intracellular cholesterol levels, resulting in a small increase in the number of receptors on the hepatocyte through the process of upregulation, results in increased clearance of circulating LDL-C cholesterol and a decrease in total serum cholesterol levels.
Pleiotropic effects of statins include antithrombotic, anti-inflammatory, decreased hsCRP, and antioxidant-reduced endothelial dysfunction. Violi et al. present experimental data in support of the ability of statins to interfere directly with the clotting system and platelet activation, as well as the clinical settings that suggest that statins exert beneficial effects related to their antithrombotic properties (Violi et al. 2013).
Available statins include atorvastatin, fluvastatin, lovastatin, simvastatin, pravastatin, and rosuvastatin. The more powerful LDL-C-lowering agents, rosuvastatin and atorvastatin, are effective in reducing:
LDL-C cholesterol to goal levels in the majority of patients
Mortality in patients with CHD
The incidence of MI in patients with CHD
Regression in atheroma volume; see ASTEROID AND SATURN trials (Chap. 22)
The risk of stroke
Statins Possess Subtle Differences
The only hydrophilic agent excreted by the kidney is pravastatin. Thus, fewer adverse effects occur from drug interactions compared with lipophilic statins, which are hepatically metabolized see Chap. 21 Interactions.
Lipophilic agents (atorvastatin, lovastatin, and simvastatin) are hepatically metabolized. Interactions may occur with cimetidine, cyclosporine, and other agents that use the cytochrome P-450 pathway (3A4).
Rosuvastatin and fluvastatin engage hepatic 2C9; thus, caution is required particularly with cyclosporine, warfarin, and phenytoin. Rosuvastatin is partly renally eliminated and caution is needed in patients with eGFR < 40 ml/min. Atorvastatin is the only statin recommended for the management of mixed dyslipidemia; the drug decreases triglyceride levels ~10 %.
Atorvastatin has been shown to raise fibrinogen levels by 22 % (Wierbicki et al. 1998).
Contraindications include hepatic dysfunction and concomitant use of nicotinic acid or fibrates, cyclosporin, other cytotoxic drugs, and erythromycin and similar antibiotics.
Avoid in women of childbearing age. They are contraindicated in pregnancy and during lactation.
Advice and Adverse Effects
Hypothyroidism should be managed adequately before starting treatment with a statin.
Increase in hepatic transaminases greater than three times the upper limit of normal occurs in l–2 % of patients receiving average maintenance and maximum dosages of these agents, respectively.
Monitoring of transaminase levels should be done every 4 months, and the drug should be discontinued if levels of these enzymes are raised. If drug treatment is considered essential, patients with an increase less than three times normal can be observed at least twice monthly. Increases of up to fivefold with or without myalgia occur in up to 3 % of patients, and levels >10 times normal with myalgia are observed in <1 %. Myalgia without an increase in creatine kinase (CK) concentration is not uncommon.
Severe myositis with rhabdomyolysis with the risk of renal failure has occurred with the combination of HMG-CoA reductase inhibitors with gemfibrozil, fibrates and also with cyclosporine and colchicine. See Table 17-2.
Table 17-2
Statins: pharmacokinetics and drug interactions
Atorvastatin
Fluvastatin
Pravastatin
Rosuvastatin
Simvastatin
Pharmacokinetics
Lipophilic (L) or hydrophilic (H)
L
Both
H
Both
L
Renal excretion
No
~10 % renal, ~90 % fecal
~60
~20 % renal, ~80 % fecal
No
Renal excretion patient in a renal failure or elderly patienta
No
Yes, if GFR <30 mL/min
Yes; caution if GFR <50 mL/min
Yes, if GFR <30 mL/min: use cautiously if GFR is 31–45 mL/min
No
Cytochrome P-450
3A4
2C9
Not known (multiple pathways)
2C9
3A4
Drug interactions
Warfarinb—INR increased
No
Yes
No
Yes
No
Digoxin level increased
Yes (20 %)
<10 %
No
No
<10 %
Macrolidec antibiotics
Yes
No
No
No
Yes
Antifungal agents
Yes
No
No
No
Yes
Antiviral agents
Yes
No
No
No
Yes
Cyclosporine
Yes
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