The publication of important trials in the treatment of dyslipidemias over the last few years will have an important impact on the management of patients with lipoprotein disorders, especially for the prevention of cardiovascular diseases.
Once the domain of a highly specialized branch of medicine and endocrinology, lipoprotein disorders are an integral part of the everyday care of adult patients. The term dyslipidemia is often preferred, reflecting the fact that a decrease in some lipoprotein lipid levels may be pathogenic – as is the case for high-density lipoprotein cholesterol (HDL-C) or deficiency in chylomicrons. With earlier recognition based on precise laboratory tests, and no longer based solely on clinical signs (corneal abnormalities, xanthelasmas and xanthomas), dyslipoproteinemias present usually without signs or symptoms. Disorders of increased low-density lipoprotein cholesterol (LDL-C) and decreased HDL-C are associated with an increased risk of coronary heart disease (CHD), and severely elevated fasting serum triglyceride level (>10 mmol/l) puts the patient at risk for pancreatitis. Although CHD is manifested clinically in the fourth decade of life, evidence clearly indicates that atherosclerosis, its major cause, is a process that begins early in life and progresses silently for decades. With the growing epidemic of obesity, children are now considered for pharmacological approaches previously reserved for genetic dyslipoproteinemias. This, however, has resulted in unresolved controversy within the medical community.
Proper recognition and management of lipoprotein disorders can reduce cardiovascular and total mortality. This has been demonstrated both in the context of the secondary prevention (treatment of individuals with preexisting disease) and high-risk primary prevention (treatment of individuals in whom there is no evidence of disease).
In the last year, several studies have shown that intensive lipid lowering in high-risk patients is beneficial in terms of reducing major cardiovascular events. However, patients with advanced heart failure and possibly end-stage renal disease do not benefit from statins. More remarkably, the JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial showed that apparently healthy individuals with ‘optimal’ LDL-C levels but an elevated C-reactive protein (CRP) level of more than 2.0 mg/l have a 44% reduction in major cardiovascular events with rosuvastatin 20 mg/day and a 20% reduction in all-cause mortality. This finding will likely prompt a revision of prevention guidelines.
Etiology and classification of lipoprotein disorders
The determination of apolipoproteins (apo), the routine measurement of HDL-C and rapid advances in the molecular and cellular biology of lipid transport pathways has allowed for a more precise diagnosis for severe lipoprotein disorders. In the majority of cases, the dyslipidemia is best classified by the major biochemical abnormality present (i.e., which lipoprotein class is abnormal). These remarkable advances in basic sciences were paralleled by the design of rigorous, large-scale clinical trials with clear (and unambiguous) hard clinical end points that more precisely defined groups of patients that benefit from specific and targeted pharmacological approaches.
Defining ‘normality’ for lipid levels has been fraught with controversy. Normality is usually defined as a biochemical measurement situated between two boundaries of a mean value (±2 standard deviations or the 5th–95th percentile), this concept is not easily applicable to lipoprotein lipids in light of their variation with age, sex and ethnicity. Arbitrary cut points, agreed upon by consensus, determine an abnormal value . Thus, a total cholesterol level of more than 5.0 mmol/l (∼200 mg/dl), a triglyceride level of more than 2.0 mmol/l (180 mg/dl) and a HDL-C level less than 0.9 mg/dl (39 mg/dl) are presently used as clinical cut points. The level of LDL-C at which intervention is recommended depends on the global cardiovascular risk, as determined by the Framingham Heart study Risk Score .
Dyslipidemias can be conceptually considered as primary (including genetic lipoprotein disorders) or secondary to lifestyle and environment, medication, metabolic or endocrine disorders or concomitant diseases (Table 1).
The diagnosis of genetic lipoprotein disorders is made only after ruling out the secondary cause of hyperlipidemia. The major secondary causes of hyperlipidemia in adults are dietary, alcohol intake, oral contraceptives, diabetes mellitus and pharmacological agents (e.g., retinoic acid derivatives, steroids and beta-blockers). The most frequent secondary cause of dyslipoproteinemia is probably the constellation of metabolic abnormalities seen in patients with the metabolic syndrome. The finding of increased visceral fat (abdominal obesity), elevated blood pressure and impaired glucose tolerance often clusters with increased plasma triglycerides and reduced HDL cholesterol level and comprise the major components of the metabolic syndrome [3,4] (Table 2).
Major secondary causes of dyslipidemia
The major secondary causes of dyslipidemia are as follows:
- alcohol intake;
- oral contraceptives;
- diabetes mellitus; and
- pharmacological agents.
Classification of genetic lipoprotein disorders usually requires a biochemical phenotype in addition to a clinical phenotype. Genetic lipoprotein disorders can affect LDL, lipoprotein(a) [Lp(a)], remnant lipoproteins, triglyceride-rich lipoproteins [chylomicrons and very-low-density lipoprotein (VLDL)], or HDL (Table 3).
Clinically, the most important primary hyperlipidemia is familial hypercholesterolemia . The molecular basis of this condition is a functional defect in, or a decrease in the number of, LDL receptors, which leads to decreased clearance of these lipoproteins from the blood and an increase in cholesterol synthesis. The clinical phenotype of familial hypercholesterolemia is characterized by tendinous xanthomas, xanthelasmas and premature corneal arcus. At least four genes [the LDL-receptor, apo B-100, proprotein convertase subtilisin/kexin type 9 (PSCK9) and autosomal recessive hypercholesterolemia – ARH] cause a phenocopy of familial hypercholesterolemia (Table 3).
- Familial hypercholesterolemia recognition is of paramount importance. Lifelong treatment of cholesterol and proper life habits can normalize life expectancy in these individuals.
- WHO clinical criteria for the diagnosis of familial hypercholesterolemia  are as follows:
- tendon xanthomata;
- corneal arcus;
- family (or personal) history of early coronary artery disease (CAD); and
- biochemical measures (i.e., plasma LDL-C).
Diagnosis of lipoprotein disorders
Patients with lipoprotein disorders should undergo comprehensive evaluation and management in the context of a global risk reduction program. The clinical evaluation should include a thorough history, including a complete family history that may reveal clues as to not only the genetic cause but also to the genetic susceptibility to cardiovascular disease. Other risk factors such as obesity, diabetes and cigarette smoking should also be addressed during the clinical evaluation.
Corneal arcus, corneal opacifications, presence of xanthelasmas and xanthomas (in extensor tendons, including hands, elbows, knees, Achilles tendons and palmar xanthomas) should be specifically looked for during the physical examination. The blood pressure, waist circumference, weight and height should be recorded, and signs of arterial compromise sought and a complete cardiovascular examination must be performed. Evaluating the peripheral pulses and determining the ankle-brachial index can reveal clues for the presence of peripheral vascular disease.
The diagnosis of lipoprotein disorders depends on laboratory measurements (Table 4). The fasting lipid profile generally suffices for most lipoprotein disorders, and specialized laboratories can refine the diagnosis and provide expertise for extreme cases. Additional tests often involve considerable expense and may not increase the predictive value beyond that of the lipid profile, though they can help in refining the diagnosis. To assess baseline risk in individuals on lipid-lowering therapy, the medication should be stopped for at least 1 month before a lipid profile is measured. Many advanced lipid tests are available in specialized centers (Table 4) but seldom add to the clinical assessment specified above.
Metabolic syndrome: diagnostic criteria
The most commonly used diagnostic criteria have been those of the National Cholesterol Education Program (NCEP) in which global cardiovascular risk, based on abdominal obesity, dysglycemia, elevated triglycerides and low HDL-C and elevated blood pressure, constitutes the diagnostic criteria . The International Diabetes Federation (IDF) emphasizes abdominal obesity as a major criterion . The IDF emphasized the presence of ethnic and national differences in the definition of abdominal obesity [6,7]. Recent analyses in the US population (1999–2002) showed that the IDF definition leads to a slightly higher prevalence estimate of the metabolic syndrome (39%) than that based on the updated NCEP definition (34.5%), particularly in Mexican–American men .
The above constellation of interrelated metabolic risk factors promotes the development of atherosclerotic cardiovascular disease (CVD). Three mechanisms have been proposed to explain how insulin resistance contributes to increased cardiovascular risk: the effects of mild-to-moderate hyperglycemia, the effects of compensatory hyperinsulinemia and the effects of unbalanced pathways of insulin action. During the last decade, newly discovered adipokinetic pathways have suggested novel pathophysiologic mechanisms linking increased adipose tissue mass with the development of insulin resistance and other components of the metabolic syndrome . In the Insulin Resistance Atherosclerosis Study, the strongest predictor of the metabolic syndrome was waist circumference; thus, abdominal obesity may precede the development of other components of the metabolic syndrome . Likewise, in the San Antonio Heart Study, one-third of patients with both a large waist circumference and high BMI developed the metabolic syndrome during the 8-year follow-up period . Adjusting for fasting insulin concentrations as a surrogate of insulin resistance had only a minor effect on the predictive value of the anthropometric indices. The tendency to increase visceral fat with only modest increases in subcutaneous fat and body weight is especially true in populations from Asia . The adipose tissue of obesity exhibits abnormalities in the production of adipokines, which may separately affect insulin resistance or modify the risk of atherosclerotic CVD or both. These include increased production of inflammatory cytokines such as TNF-α and IL-6, plasminogen activator inhibitor-1 and other bioactive products [12–14]. In addition, levels of the insulin-sensitizing adipokine, adiponectin, are reduced . All of these changes have been implicated in the genesis of metabolic risk factors for CVD.
In recent years, extensive studies have uncovered the importance of systemic low-grade inflammation in the initiation and development of atherosclerosis as well as acute CVD events [16,17,18•]. Circulating levels of several cytokines and acute-phase reactants have been shown to predict CVD, including CRP, IL-6, serum amyloid A, fibrinogen, white blood cell count, D-dimer, plasminogen activator, TNF-α, lipoprotein phospholipase A2, IL-18, metalloproteinase PAPP-A and secretory phospholipase A2 type IIA [19–21]. In addition, systemic inflammation is also associated with atherogenic changes in lipoprotein metabolism including hypertriglyceridemia; elevated triglyceride-rich lipoprotein; small, dense LDL and decreased HDL cholesterol .
Among a wide range of biomarkers, CRP is considered to be the most applicable for clinical use. CRP correlates with the severity of the metabolic syndrome, and several studies support the role of inflammation in the development of the metabolic syndrome . The recently published JUPITER trial lends support to the concept that high-sensitivity hsCRP is a cardiovascular risk marker and should be part of cardiovascular risk stratification [24,25•]. The JUPITER trial examined patients considered at ‘optimum’ LDL-C levels (<3.4 mmol/l or <130 mg/dl) but had an elevated hsCRP level (>2.0 mg/l). With the growing epidemic of obesity, children are now considered for pharmacological approaches previously reserved for genetic dyslipoproteinemias, treated with rosuvastatin 20 mg or placebo. The trial was stopped early because of unequivocal benefit of rosuvastatin in reducing major cardiovascular events by 44–47% (myocardial infarction, cardiovascular death, stroke, hospitalization of unstable angina or revascularization) and all-cause mortality by 20% [25•]. Whether this was due to lipid lowering or to the anti-inflammatory properties of statin therapy remains incompletely understood as LDL was reduced by 50% and hsCRP by 37%.
Another major finding in the last few years has been the concept that ‘lower’ is better in terms of cardiovascular disease prevention in high-risk groups (including the secondary prevention). The cumulative data presented from five large studies [A to Z (Aggrastat to Zocor) , PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) , TNT (Treating to New Targets) , IDEAL (Incremental Decrease in End points through Aggressive Lipid lowering)  and SEARCH (Study for the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) ] show that each mmol/l of LDL-C reduction is associated with a 23% reduction in major cardiovascular events [http://www.ctsu.ox.ac.uk/projects/search/index_html].
Management of lipoprotein disorders
The major reason for treating lipoprotein disorders is to decrease the risk of cardiovascular disease. The therapeutic options consist of lifestyle modifications, dietary modifications, treatment of the secondary causes and drug therapy.
The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) has made recommendations for the treatment of hypercholesterolemia . Target levels depend on overall risk of cardiovascular death or nonfatal myocardial infarction. Patients with CAD or atherosclerosis of other vascular beds (carotids or peripheral vascular disease), adults with diabetes and those patients with an estimated 10-year risk of developing CAD of greater than 20%, fall into a high-risk category and merit aggressive treatment, including medications along with lifestyle modifications, exercise and diet to achieve a primary target of an LDL cholesterol level less than 2.0 mmol/l (80 mg/dl). In patients with triglycerides greater than 200 mg/dl, ATP III presents a secondary target of a non-HDL cholesterol level less than 3.4 mmol/l (130 mg/dl).
A multifaceted lifestyle approach is recommended in the treatment of lipoprotein disorders to reduce risk for CHD. Reduced intakes of saturated fat and cholesterol, weight reduction and increased physical activities are essential parts of this approach. Daily exercise, smoking cessation and stress management are parts of lifestyle changes.
Lifestyle changes are as follows:
- no smoking;
- proper diet (reduced saturated fat);
- weight reduction;
- daily exercise; and
- stress management.
In order to prevent arterial disease, lipid-lowering agents are used with the purpose of ameliorating dyslipidemia. Absorbable drugs [3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, fibric acids and nicotinic acid] reduce plasma VLDLs or low-density lipoproteins (LDLs) or both by a variety of mechanisms. Nonabsorbable agents (anion-exchange resins) interrupt the recirculation of bile acids or reduce the absorption of cholesterol with the gut or both.
Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors)
Statins, the current treatment standard, have proven to be highly efficacious in lowering LDL-C and reducing CHD risk [31,32]. They block the synthesis of cholesterol by inhibiting HMG-CoA reductase, the rate-limiting step in cholesterol synthesis, resulting in decreased synthesis of VLDL and LDL and increased uptake of LDL by receptor-mediated endocytosis. Statins reduce total and LDL-Cs and have a significant effect on triglycerides. They should be started immediately in high-risk group in addition to lifestyle modifications. In low and moderate risk groups, the patients should be given a chance to lower LDL-C through lifestyle modification, usually 3–6 months, after which they should start taking statins if they fail to do so.
In addition to lowering LDL-C, statins cause a mild increase in HDL-C. They also decrease hsCRP levels and have multiple pleiotropic effects .
Statins are generally well tolerated; side effects include reversible elevation in transaminases and myositis, which causes discontinuation of the drug in less than 1% of patients. The currently available drugs are Lescol (fluvastatin; London, UK), 20–80 mg/day; Mevacor (lovastatin; Hunterdon County, New Jersey, USA), 20–80 mg/day; Pravastatin (pravachol; Bristol-Myers-Squibb New York, NY, USA), 20–40 mg/day; Zocor (simvastatin; Merck, Rawway, CT, USA), 10–80 mg/day; Lipitor (atorvastatin), 10–80 mg/day; and Crestor (rosuvastatin; AstraZeneca, London, UK), 5–40 mg/day. Although rosuvastatin may be associated with increased incident type 2 diabetes, cardiovascular morbidity and mortality is nontheless reduced with its use [25•]. Concomitant drugs that interfere with the metabolism of statins by inhibiting the cytochrome P450 3A4 and 2C9 systems can increase plasma concentrations of statins. These include antibiotics, antifungal medications, certain antiviral drugs, grapefruit juice, cyclosporine, amiodarone and several others.
Cholesterol absorption inhibitors
The development of selective inhibitors of intestinal sterol absorption has significantly advanced the treatment of lipoprotein disorders. Ezetimibe is the first such compound. Ezetimibe appears to limit selective uptake of cholesterol and other sterols by intestinal epithelial cells, by interfering with the Niemann–Pick C1-like 1 protein 1 (NPC1L1) . It is particularly indicated for patients with LDL-C levels above target on maximally tolerated statin dose. Ezetimibe lowers LDL-C by about 18% and adds to the effect of statins . Because ezetimibe also prevents the intestinal absorption of sitosterol, it might be the drug of choice in cases of sitosterolemia . The current dose of ezetimibe is 10 mg/day.
Bile acid sequestrants
Bile acid sequestrants lower LDL-C, especially when combined with other cholesterol-lowering drugs. They interrupt the enterohepatic circulation of bile acids by inhibiting their reabsorption in the intestine. Bile acid-binding resins are mainly used as an adjunctive therapy in patients with severe hypercholesterolemia due to increased LDL-C. Colesevelam hydrochloride (HCL) has fewer reported gastrointestinal adverse effects. It has also been demonstrated to modestly improve glycemia in patients with type 2 diabetes [37–39]. It can be used in monotherapy or in combination with an HMG-CoA reductase inhibitor to reduce LDL-C in patients with primary hypercholesterolemia (Fredrickson type IIa). Decreased drug absorption dictates careful scheduling of medications 1 h before or 3 h after the patient takes bile acid-binding resins.
Fibric acid derivatives (fibrates)
Fibrates are structurally and pharmacologically related to the thiazolidinediones, a novel class of antidiabetic drugs that also act on peroxisome proliferator-activated receptors (PPARs) (more specifically PPARγ). Activation of PPARs, especially PPARα, causes transcription of a number of genes on the DNA that facilitate lipid metabolism. It regulates the transcription of the LPL, apo CII and apo AI genes. Both enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL underlie the hypotriglyceridemic effect of fibrates, whereas their effect on HDL metabolism is associated with changes in HDL apolipoprotein expression. The main indication for the use of fibrates is the treatment of hypertriglyceridemia when diet and lifestyle changes are not sufficient. The side effects of fibrates include cutaneous manifestations, gastrointestinal effects (abdominal discomfort, increased bile lithogenicity), erectile dysfunction, elevated transaminases, interaction with oral anticoagulants and elevated plasma homocysteine . Fibrates, especially gemfibrozil, can inhibit the glucuronidation of statins and thus retard their elimination. For this reason, combination of gemfibrozil with statins may increase the risk of myotoxicity. In a subgroup analysis of the fenofibrate trial in diabetic patients [the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial], fenofibrate decreased cardiovascular events in patients with diabetes and features of the metabolic syndrome . To date, however, no trial of combined statin/fibrate has been completed on cardiovascular end points.
Nicotinic acid (niacin)
Niacin is a drug that reduces Lp(a), LDL-C and triglyceride and increases HDL-C and LDL particle size. Niacin (nicotinic acid) is the most potent clinically used agent for increasing plasma HDL and apolipoprotein (apo) A-I. The effect of niacin on LDL-C is more modest. It acts by blocking breakdown of adipose tissue (decreases lipolysis when it is taken in large doses) and decrease in free fatty acids in the blood and, as a consequence, decreased secretion of VLDL and cholesterol by the liver. It inhibits the hepatic production of VLDL and consequently its metabolite LDL also possibly by decreasing apo B production. It raises HDL levels both by reducing lipid transfer of cholesterol from HDL to VLDL and by delaying HDL clearance from kidney. Another property of nicotinic acid is reduction in plasma fibrinogen levels thus altering blood lipid levels. Its major adverse effects are hot flashes, pruritus, gastric irritation, hepatotoxicity and altered glycemic control. Niacin also increases serum homocysteine and uric acid levels. When statins alone have not reduced LDL-C to goal and there is coexistent dyslipidemia or when isolated low HDL-C is being treated, niacin is an excellent choice.
Cholesterol ester transfer protein inhibitors
The inhibition of cholesteryl ester transfer protein (CETP) by pharmacological agents mimics the genetic heterozygous CETP deficiency state. Of several agents tested in human, torcetrapib was the more efficient drug to increase HDL-C. At doses of 120 mg/day, torcetrapib increases HDL-C levels by 40–50% and is generally well tolerated. It has been withdrawn from the market due to increased mortality likely because of off-target side effects. Other CETP inhibitors are under development. It is unclear whether this class of drug will prevent atherosclerosis.
Fish oils are rich in polyunsaturated fatty acids such as eicosapentaenoic acid or docosahexaenoic acid, with the first double on the omega-3 (ω-3) position. These fatty acids lower plasma triglyceride levels and have antithrombotic properties. Although employed in the treatment of hypertriglyceridemia, their use is reserved in cases of severe hypertriglyceridemia refractory to conventional therapy. Fish oils decrease VLDL synthesis and decrease VLDL apo B. The response to fish oils depends on dose, requiring a daily intake of up to 10 g of eicosapentaenoic acid or docosahexaenoic acid for a significant benefit on plasma triglyceride levels.
Phytosterols are derivatives of cholesterol from plants and trees. They interfere with the formation of micelles in the intestine and prevent intestinal cholesterol absorption. They can be obtained as ‘neutraceuticals’ or can be incorporated in soft margarines. These agents may prove useful for the adjunctive management of lipoprotein disorders.
Monitoring of lipid therapy
After initiation of medical therapy, the response should be checked within the first 3 months, along with transaminases and creatinine kinase. Thereafter, clinical judgment should dictate the interval between follow-up visits. Although frequent visits are probably not useful in the detection of serious side effects, they serve to encourage compliance and adherence to diet and lifestyle changes.
Gene therapy is a potential future therapy. Severe, homozygous, monogenic disorders may eventually be treated by gene therapy. The initial trials of gene therapy in cases of homozygous familial hypercholesterolemia have not led to a major improvement and have largely been abandoned. However, the lifelong burden of these rare disorders and the potential for cure make this approach very appealing.
Cardiovascular disease prevention has shown remarkable progress in the last three decades. Public education on cardiovascular risk factors, prompt recognition of symptoms, triage in the emergency department, prompt revascularization and recognition of complications and lethal rhythm disturbances, the secondary prevention efforts with improved diet, smoking cessation, exercise and pharmacological therapies such as aspirin and statins have contributed to a marked reduction in mortality and morbidity in high-risk prevention. The lowering of LDL-C has had a major impact on cardiovascular disease prevention. In the last year, the focus has shifted towards two new paradigms: first, the greater lowering of LDL-C is associated with the greatest clinical benefits, and CRP has been confirmed as a major cardiovascular risk factor that predicts cardiovascular events and influences clinical decision making. Trials of statins in advanced heart failure have failed to show benefit, suggesting that these drugs may not be necessary in patients with this condition [42,43•].
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 189).
1 Grundy SM, Cleeman JI, Merz CNB, et al
. Implications of recent clinical trials for the National Cholesterol
Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110:227–239.
2 Wilson PWF, D'Agostino RB, Levy D, et al
. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97:1837–1847.
3 Grundy SM, Cleeman JI, Daniels SR, et al
. American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome
: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112:2735–2752.
4 Després JP, Lemieux I. Abdominal obesity and metabolic syndrome
. Nature 2006; 444:881–887.
5 World Health Organisation, Human Genetics Programme (1997) Familial Hypercholesterolemia (FH): report of a WHO Consultation, Paris; 3 October 1997; Geneva, Switzerland.
6 Alberti KG, Zimmet P, Shaw J, for the IDF Epidemiology Task Force Consensus Group. The metabolic syndrome
? A new worldwide definition. Lancet 2005; 366:1059–1062.
7 Tan CE, Ma S, Wai D, et al
. Can we apply the National Cholesterol
Education Program Adult Treatment Panel definition of the metabolic syndrome
to Asians? Diabetes Care 2004; 27:1182–1186.
8 Ford ES. Prevalence of the metabolic syndrome
defined by the International Diabetes Federation among adults in the U.S. Diabetes Care 2005; 28:2745–2749.
9 Ruan H, Lodish HF. Regulation of insulin sensitivity by adipose tissue-derived hormones and inflammatory cytokines. Curr Opin Lipidol 2004; 15:297–302.
10 Palaniappan L, Carnethon MR, Wang Y, et al
. Predictors of the incident metabolic syndrome
in adults: the Insulin Resistance Atherosclerosis Study. Diabetes Care 2004; 27:788–793.
11 Han TS, Williams K, Sattar N, et al
. Analysis of obesity and hyperinsulinemia in the development of metabolic syndrome
: San Antonio Heart Study. Obes Res 2002; 10:923–931.
12 Weisberg SP, McCann D, Desai M, et al
. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112:1796–1808.
13 You T, Yang R, Lyles MF, et al
. Abdominal adipose tissue cytokine gene expression: relationship to obesity and metabolic risk factors. Am J Physiol Endocrinol Metab 2005; 288:E741–E747.
14 Juhan-Vague I, Alessi MC, Mavri A, Morange PE. Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk. J Thromb Haemost 2003; 1:1575–1579.
15 Kern PA, Di Gregorio GB, Lu T, et al
. Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes 2003; 52:1779–1785.
16 Ross R. Atherosclerosis? An inflammatory disease. N Engl J Med 1999; 340:115–126.
17 Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21:1876–1890.
18• Lamon BD, Hajjar DP. Inflammation at the molecular interface of atherogenesis: an anthropological journey. Am J Pathol 2008; 173:1253–1264. Three studies
18• [16,17,18•] Three studies
19 Pearson TA, Mensah GA, Alexander RW, et al
. Markers of inflammation and cardiovascular disease. Application to clinical and public health practice. A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107:499–511.
20 Fichtlscherer S, Heeschen C, Zeiher AM. Inflammatory markers and coronary artery disease. Curr Opin Pharmacol 2004; 4:124–131.
21 Hurt-Camejo E, Camejo G, Peilot H, et al
. Phospholipase A2 in vascular disease. Circ Res 2001; 89:298–304.
22 Khovidhunkit W, Memon RA, Reinglod KR, Grunfeld C. Infection and inflammation-induced proatherogenic changes of lipoproteins. J Infect Dis 2000; 181(Suppl 3):S462–S472.
23 Frohlich M, Imhof A, Berg G, et al
. Association between C-reactive protein and features of the metabolic syndrome
: a population-based study. Diabetes Care 2000; 23:1835–1839.
24 Ridker PM, Fonseca FAH, Genest J, et al
, and JUPITER Trial Study Group. Baseline characteristics of participants in the JUPITER Trial, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol
and elevated high-sensitivity C-reactive protein. Am J Cardiol 2007; 100:1659–1664.
25• Ridker PM, Danielson E, Fonseca FAH, et al
. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New Eng J Med 2008; 358:2195–2207. A landmark study supporting the concept that hsCRP is a cardiovascular risk
marker and may be part of cardiovascular risk
26 Larosa JC, Grundy SM, Waters DD, et al
. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. New Eng J Med 2005; 352:1425–1435.
27 Pedersen TR, Faergeman O, Kastelein JJP, et al
. High-dose atorvastatin vs. usual dose simvastatin for secondary prevention after myocardial infarction - the IDEAL study: a randomized controlled trial. JAMA 2005; 294:2437–2445.
28 Cannon CP, Braunwald E, McCabe CH, et al
. Pravastatin or atorvastatin evaluation and infection therapy - thrombolysis in myocardial infarction 22 investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350:1495–1504.
29 SEARCH Study Collaborative Group, Bowman L, Armitage J, et al
. Characteristics of a randomized trial among 12064 myocardial infarction survivors. Am Heart J 2007; 154:815–823.
30 Wiviott SD, de Lemos JA, Cannon CP, et al
. A tale of two trials: a comparison of the post-acute coronary syndrome lipid-lowering trials A to Z and PROVE IT-TIMI 22. Circulation 2006; 113:1406–1414.
31 Baigent C, Keech A, Kearney PM, et al
Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol
-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005; 366:1267–1278.
32 Robinson JG, Smith B, Maheshwari N, Schrott H. Pleiotropic effects of statins: benefit beyond cholesterol
reduction?: A meta-regression analysis. J Am Coll Cardiol 2005; 46:1855–1862.
33 Ridker PM, JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol
and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation 2003; 108:2292–2297.
34 Altmann SW, Davis HR Jr, Zhu LJ, et al
. Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol
absorption. Science 2004; 303:1201–1204.
35 Genest J. Combination of statin and ezetimibe for the treatment of dyslipidemias and the prevention of coronary artery disease. Can J Cardiol 2006; 22:863–868.
36 Kastelein JJ, Akdim F, Stroes ES, et al
, ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008; 358:1431–1443.
37 Bays HE, Goldberg RB, Truitt KE, Jones MR. Colesevelam hydrochloride therapy in patients with type 2 diabetes mellitus treated with metformin: glucose and lipid effects. Arch Intern Med 2008; 168:1975–1983.
38 Goldberg RB, Fonseca VA, Truitt KE, Jones MR. Efficacy and safety of colesevelam in patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-based therapy. Arch Intern Med 2008; 168:1531–1540.
39 Fonseca VA, Rosenstock J, Wang AC, et al
. Colesevelam HCl improves glycemic control and reduces LDL cholesterol
in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care 2008; 31:1479–1484.
40 Sebestjen M, Keber I, Zegura B, et al
. Statin and fibrate treatment of combined hyperlipidemia
: the effects on some novel risk factors. Thromb Haemost 2004; 92:1129–1135.
41 Scott R, O'Brien R, Fulcher G, et al
., on behalf of the FIELD Study Investigators. The effects of fenofibrate treatment on cardiovascular disease risk in 9795 people with type 2 diabetes and various components of the metabolic syndrome
: the FIELD study. Diabetes Care 2009; 32:493–498.
42 Kjekshus J, Apetrei E, Barrios V, et al
, CORONA Group. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007; 357:2248–2261.
43• Gissi-Hf Investigators, Tavazzi L, Maggioni AP, Marchioli R, et al
. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372:1231–1239. Two recent studies showing that statins may not prevent major CVE in advanced heart failure.