help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Garg, A.
Right arrow Articles by Simha, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Garg, A.
Right arrow Articles by Simha, V.
Related Collections
Right arrow Metabolism
Right arrow Lipid
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 5 1581-1589
Copyright © 2007 by The Endocrine Society

UPDATE

Update on Dyslipidemia

Abhimanyu Garg and Vinaya Simha

Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for Human Nutrition, The University of Texas Southwestern Medical Center at Dallas, and the Veterans Affairs North Texas Health Care System, Dallas, Texas 75390

Address all correspondence and requests for reprints to: Abhimanyu Garg, M.D., Professor of Internal Medicine, Chief, Division of Nutrition and Metabolic Diseases, Endowed Chair in Human Nutrition Research, Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9052. E-mail: abhimanyu.garg{at}utsouthwestern.edu.


   Abstract
Top
 Abstract
Introduction
 Genetics of Dyslipidemia
 Acquired Causes of Dyslipidemias
 Treatment Guidelines
 Recent Status of the...
 Beyond LDL Cholesterol Reduction
 Conclusions
 Note Added in Proof
 References
 
Recently, considerable progress has been made in understanding the genetic basis of dyslipidemias and in studying the safety and efficacy of lipid-lowering drugs for coronary heart disease (CHD) prevention. Novel loci have been identified for monogenic hypercholesterolemia, such as low-density lipoprotein (LDL) receptor (LDLR)-associated protein, proprotein convertase subtilisin-like kexin type 9, and ATP-binding cassette transporters ABCG5 and ABCG8. LDLR-associated protein promotes clustering of LDLRs into clathrin-coated pits for LDL uptake; proprotein convertase subtilisin-like kexin type 9 is involved in LDLR degradation; and ABCG5 and 8 pump sterols out of the hepatic and intestinal cells into bile and intestinal lumen, respectively. A novel gene encoding apolipoprotein AV, an activator of lipoprotein lipase, has also been linked to familial hypertriglyceridemia. Linkage of familial combined hyperlipidemia to upstream stimulatory factor 1 remains controversial. Recent guidelines of the Adult Treatment Panel III emphasize intensive reduction of LDL or non-high-density lipoprotein cholesterol in patients at high risk of CHD. However, of the four recently concluded trials comparing high- vs. low-dose statin therapy, only two showed an unequivocal reduction in cardiovascular endpoints. Because intensive statin therapy can increase the risk of myopathy and hepatotoxicity, it is important to consider its risk-benefit ratio in individual patients. Restriction of dietary saturated and trans-fat and cholesterol, along with increased intake of soluble fiber, can also achieve substantial LDL cholesterol lowering. Fibrates may reduce the risk of acute pancreatitis in severely hypertriglyceridemic patients and may be beneficial for CHD prevention. However, the safety and efficacy of combined therapy of fibrates and statins needs to be established.


   Introduction
Top
 Abstract
 Introduction
Genetics of Dyslipidemia
 Acquired Causes of Dyslipidemias
 Treatment Guidelines
 Recent Status of the...
 Beyond LDL Cholesterol Reduction
 Conclusions
 Note Added in Proof
 References
 
IN THE LAST few years, much has been added to our understanding of the genetic basis of dyslipidemias and the role of different molecular players in the pathogenesis of these disorders. New information has also emerged regarding the efficacy and safety of intensive lipid-lowering therapies from many large-scale randomized clinical trials. In the current update, we provide a brief overview of these advances and discuss their implications in decision-making regarding the clinical management of patients with dyslipidemias.


   Genetics of Dyslipidemia
Top
 Abstract
 Introduction
 Genetics of Dyslipidemia
Acquired Causes of Dyslipidemias
 Treatment Guidelines
 Recent Status of the...
 Beyond LDL Cholesterol Reduction
 Conclusions
 Note Added in Proof
 References
 
Hypercholesterolemia as well as hypertriglyceridemia in the vast majority of patients are either secondary to diet, obesity, medications, or other disorders affecting lipoprotein metabolism, or are polygenic in origin. However, recent discoveries of novel loci for both monogenic hypercholesterolemias and hypertriglyceridemia have led not only to increasing recognition of these disorders, but also to a better understanding of the pathways involved in lipid metabolism.

Monogenic hypercholesterolemias

All the known genes defective in patients with monogenic hypercholesterolemias are involved in the receptor-mediated uptake of low-density lipoproteins (LDL) by the LDL receptor (LDLR) in the hepatocytes (Fig. 1Go). As a result of the seminal work of Goldstein and Brown (1), autosomal dominant familial hypercholesterolemia (FH) (OMIM no. 143890) has been well recognized to be due to mutations in LDLR gene and is one of the most common inherited metabolic diseases with a frequency of approximately 1:500 for heterozygotes and approximately 1:1,000,000 for homozygotes or compound heterozygotes. Recent studies reveal that, among patients meeting the clinical criteria for monogenic hypercholesterolemia, LDLR mutations have been reported in 52–76% of patients (2, 3, 4, 5) (Table 1Go). Loss of function or reduced LDLR number in the hepatocytes results in reduced clearance of plasma LDL and a 2- to 3-fold elevation in LDL cholesterol levels in heterozygous FH patients. Approximately half of these patients develop tendon xanthomas, xanthelasmas, and premature corneal arcus, and coronary heart disease (CHD) occurs in the fourth or fifth decades. Homozygous or compound heterozygous patients have a greater than 5-fold increase in plasma LDL cholesterol levels and often develop severe atherosclerosis before the age of 20 yr.


Figure 1
View larger version (21K):
[in this window]
[in a new window]

  		FIG. 1. LDLRs undergo posttranslational processing in the endoplasmic reticulum and are then transported to the cell membrane where they bind to LDL particles through specific interaction with ApoB. PCSK9 is secreted from the hepatocytes and binds to LDLR on the surface of hepatocytes. The ligand-bound LDLRs (some with and some without PCSK9) are then mobilized to the clathrin-coated pits and then internalized with the help of LDLRAP1. After endocytosis, the LDL particle dissociates from the LDLR and is degraded in the lysosomes to release free cholesterol. Some of the free cholesterol and other noncholesterol sterols contained in LDL particles are extruded from the apical cell surface through the sterolins, ABCG5 and ABCG8. The LDLRs are either recycled back to the cell membrane or lysed by the attached PCSK9. Thus, various mechanisms that can result in hypercholesterolemia include: 1) impaired LDLR formation or function; 2) defective ApoB leading to impaired binding of LDL particles to LDLR; 3) defective LDLRAP1 interfering with endocytosis of ligand bound LDLR; 4) abnormally increased PCSK9 activity leading to excessive LDLR catabolism; 5) defective sterolins leading to increased intracellular phytosterol and cholesterol accumulation in hepatocytes and increased absorption through enterocytes (data not shown).

 

View this table:
[in this window]
[in a new window]

  		TABLE 1. Relative frequency and clinical features of various types of monogenic hypercholesterolemia

 
Familial defective apolipoprotein B (FDB; OMIM no. 144010), an autosomal codominant disorder due to mutations in apolipoprotein B (APOB) gene, is indistinguishable from FH due to LDLR mutations. The frequency of heterozygous FDB in the European population generally ranges from 1:500 to 1:700 (6, 7). Certainly, the frequency of APOB mutations in patients with hypercholesterolemia phenotype is reported to be much less than LDLR mutations and varies from 0–11% (2, 4, 5, 8). Currently, eight more missense mutations in the LDLR binding domain of the APOB have been identified since the original identification of defective LDL binding (9) and its R3500Q mutation (2, 10, 11). Recent data reveal that, compared with FH patients with LDLR mutations, FDB patients have lower LDL cholesterol levels by 20–25% (2), respond better to statins, and have lower risk of CHD (12). This difference could be due to normal clearance of very-low-density lipoprotein (VLDL) remnants through apolipoprotein E (apo E)-mediated uptake in FDB, whereas in FH patients with LDLR mutations, clearance of both LDL and VLDL remnants may be affected (13). Only five FDB patients with homozygous APOB mutations have been reported and, interestingly, their LDL cholesterol levels (6.9 to 8.5 mmol/liter or 267 to 329 mg/dl) were only modestly higher than those of heterozygous patients and were substantially lower than those seen in homozygous FH patients with LDLR mutations (14, 15, 16, 17). Interestingly, two women (31 and 69 yr old) and a 54-yr-old man with homozygous APOB mutations had no tendon xanthomas or CHD.

The third locus for autosomal dominant hypercholesterolemia, proprotein convertase subtilisin-like kexin type 9 (PCSK9), was cloned recently by Abifadel et al. (OMIM no. 607786) (18). PCSK9 is a serine protease that degrades hepatic LDLR in the endosomes (19, 20); and, interestingly, gain-of-function missense mutations such as S127R, F216L, D374Y and N157K are associated with hypercholesterolemia (18, 21, 22). The clinical features of these patients are also similar to FH patients with LDLR mutations (23, 24). Interestingly, some loss-of-function PCSK9 variants (especially prevalent in African-Americans) have been recently reported to be associated with low levels of plasma LDL cholesterol and reduced risk of CHD (25, 26).

The fourth locus for monogenic hypercholesterolemia, LDLR adaptor protein (LDLRAP1 or ARH), was positionally cloned in pedigrees with autosomal recessive hypercholesterolemia (ARH) (27) (OMIM no. 603813). LDLRAP1 promotes the clustering of LDLRs into the clathrin-coated pits on the basolateral surface of hepatocytes by coupling the cytoplasmic tail of LDLR to structural components of the clathrin-coated pit (28) and thus is essential for LDLR-mediated endocytosis. Inactivating mutations in LDLRAP1 lead to retention of LDLRs on the apical surface, thus severely reducing LDL uptake. ARH is a rare disorder with clustering of cases in Sardinia (29) but has been reported from other regions as well (30, 31). Serum LDL cholesterol levels in ARH patients have been reported to be lower or similar to those seen in patients with homozygous LDLR mutations (32), but no difference was seen in the prevalence of planar, tuberous, or tendon xanthomas. Interestingly, ARH patients had markedly reduced prevalence of CHD compared with those with homozygous LDLR mutations (32). For example, none of the ARH patients less than 20 yr old had CHD, whereas nine of 21 patients with homozygous LDLR mutations had CHD (32). Recently Jones et al. (33) demonstrated that hepatic VLDL remnant clearance is intact in ARH-deficient mice, which may explain the lower cholesterol levels in these patients.

Another rare autosomal recessive disorder in which elevations of serum cholesterol might be observed along with markedly elevated plasma levels of plant sterols (such as sitosterol and campesterol) is called sitosterolemia or phytosterolemia (OMIM no. 210250). Patients can develop tendon xanthomas, xanthelasmas, and premature CHD. Mutations in two adjacent ATP-binding cassette transporters, ABCG8 (sterolin-2) and ABCG5 (sterolin-1), that regulate sterol transport at the apical surface of hepatocytes and enterocytes have been identified in patients with sitosterolemia (34, 35). ABCG5 and ABCG8 dimerize to form a functional complex necessary for efflux of dietary cholesterol and noncholesterol sterols from the intestine and liver (36). Thus, mutations in either of these two genes lead to increased absorption and accumulation of cholesterol and plant sterols. Unlike other forms of FH, patients with sitosterolemia respond well to restriction in dietary cholesterol and phytosterols.

Finally, about 17–33% of patients with a clinical diagnosis of monogenic hypercholesterolemia based on elevated total plasma cholesterol concentration greater than 7.5 mmol/liter (~300 mg/dl) in the proband, together with either tendon xanthoma in the proband or in a first-degree relative or the presence of premature CHD or hypercholesterolemia in a first-degree relative (37), do not harbor any disease-causing variants in the known loci, suggesting either the possibility of additional hypercholesterolemia loci or the lack of robustness in mutational screening currently employed by various laboratories (4, 5).

Genetics of familial hypertriglyceridemia

Besides well-known loci for type 1 and type III hyperlipidemia, i.e. lipoprotein lipase (LPL) and apolipoprotein CII (APOC2), and apolipoprotein E (APOE), respectively, recently homozygous mutations (Q148X and Q139X) in the apolipoprotein AV (APOA5) gene have been reported to cause severe hypertriglyceridemia in two male probands presenting with chylomicronemia and recurrent pancreatitis from ages 5 and 34, respectively (38, 39) (OMIM no. 606368). In the heterozygous state, these mutations predispose to hypertriglyceridemia, likely in association with other functional polymorphisms in either APOA5 or other genes, or other factors such as age, abdominal obesity, or diabetes. Apo AV appears to augment LPL-mediated hydrolysis of VLDL and chylomicron triglycerides by binding these lipoproteins to the proteoglycans on the vascular endothelium, thus bringing them in close proximity to LPL. It may also directly modulate LPL activity by stabilizing its dimeric structure (40, 41).

Besides LPL, APOC2, APOE, and APOA5, all the loci identified for syndromes of lipodystrophies, such as 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) for the autosomal recessive congenital generalized lipodystrophy and lamin A/C (LMNA), peroxisome proliferator-activated receptor-{gamma} (PPARG), and v-AKT murine thymoma oncogene homolog 2 (AKT2) for the autosomal dominant familial partial lipodystrophy, are associated with severe hypertriglyceridemia due to various different molecular mechanisms (42, 43). Many patients with genetic lipodystrophies develop chylomicronemia-related acute pancreatitis as well as cutaneous xanthomas.

Genetics of familial combined hyperlipidemia (FCHL)

FCHL was described as a putative autosomal dominant disorder characterized by either isolated or combined elevations of plasma total cholesterol and triglycerides with at least one first-degree relative also displaying varying degree of dyslipidemia. However, no single gene has yet been identified as a causative factor, and it is not clear whether this is truly a monogenic disorder. Recently, the upstream stimulatory factor 1 (USF1) gene on chromosome 1q21-q23 was linked to FCHL and metabolic syndrome traits in Finnish, Dutch, Mexican, and Chinese patients (44, 45, 46, 47), and there was much enthusiasm for its role as a candidate gene for this disorder (48, 49). However, the association with the different traits is not consistent (44, 47), and the pathogenesis of FCHL may involve a complex interaction of several genetic and environmental factors.

Familial hypoalphalipoproteinemia (FHA)

The three major genes regulating high-density lipoprotein (HDL) metabolism whose mutations cause FHA are apolipoprotein A-I (APOAI), ATP binding cassette A1 (ABCA1), and lecithin:cholesterol acyltransferase (LCAT). Apo A-I is the major protein constituent of the HDL particle, and homozygous or compound heterozygous mutations leading to complete Apo A-I and HDL deficiency (HDL cholesterol levels < 10 mg/dl) have been reported in about two dozen subjects (50, 51, 52). However, premature CHD was noted in only about half of these subjects. Interestingly, a heterozygous APOAI mutation (Apo A-IMilano), which reduces HDL cholesterol levels by half, does not predispose to atherosclerosis (53). Other heterozygous Apo A-I mutations cause variable reductions in HDL cholesterol levels and have no consistent association with CHD (54, 55).

ABCA1 mediates the efflux of cellular cholesterol and phospholipids to the nascent lipid-free Apo A-I particle. More than 50 structural variants have been identified (56), and homozygous defects lead to Tangier disease, which is characterized by accumulation of lipid-laden macrophages in the reticuloendothelial system and low HDL cholesterol levels (~5 mg/dl in homozygous patients and ~25 mg/dl in heterozygous carriers). The clinical features include enlarged, orange-colored tonsils, peripheral neuropathy, and premature CHD (57, 58). However, some patients with Tangier disease have been reported to be free of atherosclerotic disease (59, 60), which could be due to concomitant decrease in LDL cholesterol levels. But, Clee et al. (61) recently reported increased CHD risk associated with both heterozygous and homozygous ABCA1 mutations (odds ratios of 3.5 and 5.9, respectively).

Mutations in LCAT, which catalyzes the esterification of free cholesterol, interfere with the maturation of nascent HDL particles. Homozygous mutations in LCAT lead to marked reduction in HDL cholesterol levels (5–10% of normal), corneal opacifications (fish eye disease), and renal disease, whereas heterozygous carriers show no clinical features except for reduced HDL cholesterol levels (~50% of normal) (56, 58). The association between LCAT deficiency and atherosclerosis is not clear.


   Acquired Causes of Dyslipidemias
Top
 Abstract
 Introduction
 Genetics of Dyslipidemia
 Acquired Causes of Dyslipidemias
Treatment Guidelines
 Recent Status of the...
 Beyond LDL Cholesterol Reduction
 Conclusions
 Note Added in Proof
 References
 
As mentioned before, dyslipidemia is more often secondary to other causes than a primary genetic defect. Even in patients with known genetic disorders, it is important to consider secondary factors that may affect lipid levels. These include obesity; lifestyle influences such as diet, exercise, smoking, and alcohol use; endocrine disorders such as diabetes mellitus and hypothyroidism; and liver and renal diseases. Another important cause for elevated lipids is the use of pharmacological agents. Drugs such as diuretics, ß blockers, glucocorticoids, retinoic acid derivatives, and interferons {alpha}, ß, and {gamma} are well known to increase serum triglycerides. Cyclosporine can increase LDL cholesterol levels, and sirolimus and HIV 1 protease inhibitors can cause severe hypertriglyceridemia. Bexarotene, a new retinoid X receptor selective retinoid, causes hypertriglyceridemia in up to 80% of patients (62). Tamoxifen, by virtue of its estrogenic effects, can also cause severe hypertriglyceridemia in susceptible individuals (63) but reduces LDL cholesterol levels. Aromatase inhibitors can modestly raise LDL cholesterol levels, especially in comparison with tamoxifen (64, 65, 66, 67). Severe hypertriglyceridemia has also been reported anecdotally with the use of asparaginase, capecitabine, and propofol (68, 69, 70).


   Treatment Guidelines
Top
 Abstract
 Introduction
 Genetics of Dyslipidemia
 Acquired Causes of Dyslipidemias
 Treatment Guidelines
Recent Status of the...
 Beyond LDL Cholesterol Reduction
 Conclusions
 Note Added in Proof
 References
 
Therapeutic lifestyle changes including those to diet and exercise constitute the cornerstone of management of dyslipidemic patients (71). Restriction of dietary cholesterol, saturated and trans-fat, along with liberal intake of dietary fiber and plant sterols can lower LDL cholesterol, and high intake of omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) can reduce serum triglycerides. Recently, Jenkins et al. (72) reported 28% reduction in LDL cholesterol levels with a diet that was low in saturated fat and cholesterol and especially rich in soluble fiber, plant sterols, soy protein, and nuts. Because weight reduction can further lower LDL cholesterol and triglycerides and raise HDL cholesterol levels, maximal improvement in dyslipidemia should be attempted with lifestyle intervention before consideration is given to lipid-lowering drugs.

The recent guidelines of the National Cholesterol Education Program’s Adult Treatment Panel III (ATP III) on the management of high blood cholesterol are summarized in Table 2Go (71, 73). Although LDL cholesterol remains the primary target of therapy, for those with elevated serum triglyceride concentrations, non-HDL cholesterol, which contains both LDL and VLDL cholesterol, has been suggested as an additional target. The management approach suggested by the ATP III is based upon calculation of the risk of CHD in an individual patient. However, recent demonstration of low rates of CHD in individuals with lifelong low LDL cholesterol levels due to loss-of-function PCSK9 mutations strongly argues for early and lifelong reduction of LDL cholesterol levels in susceptible subjects (74).


View this table:
[in this window]
[in a new window]

  		TABLE 2. Updated Adult Treatment Panel III recommendations for management for high blood cholesterol (73 )

 
On the basis of additional evidence, especially data from the Heart Protection Study (HPS) (75) and the Pravastatin or Atorvastatin Evaluation and Infection – Thrombolysis in Myocardial Infarction 22 (PROVE IT – TIMI 22) (76) trial, the original ATP III guidelines (71) were updated in 2004 (73); this report introduced an optimal LDL cholesterol goal of less than 70 mg/dl (1.8 mmol/liter) for patients at very high risk of CHD and recommended drug therapy for these patients even if baseline LDL cholesterol levels were less than 100 mg/dl (2.6 mmol/liter) (73). Such patients include those with established CHD plus one of the following: 1) multiple major risk factors (especially diabetes); 2) severe and poorly controlled risk factors; 3) multiple risk factors of the metabolic syndrome; or 4) acute coronary syndromes.

These recommendations were based on the subgroup analysis of the HPS, which showed beneficial reduction in CHD risk even in those with baseline LDL cholesterol less than 100 mg/dl. Similarly, the PROVE IT – TIMI 22 trial compared more intensive LDL cholesterol reduction (to 62 mg/dl) using 80 mg atorvastatin daily to less intensive reduction (to 95 mg/dl) using 40 mg pravastatin daily in patients with acute coronary syndrome and showed significant 16% reduction (P < 0.005) in atherosclerotic events including death from any cause, myocardial infarction, unstable angina, coronary revascularization, and stroke (76).


   Recent Status of the Intensive Statin Therapy for High-Risk CHD Patients
Top
 Abstract
 Introduction
 Genetics of Dyslipidemia
 Acquired Causes of Dyslipidemias
 Treatment Guidelines
 Recent Status of the...
Beyond LDL Cholesterol Reduction
 Conclusions
 Note Added in Proof
 References
 
Although there are no clinical trials that specifically tested the efficacy and safety of LDL cholesterol reduction to less than 70 mg/dl in very-high-risk patients with CHD (77), since the new ATP-III recommendations, results of three other trials comparing an intensive LDL cholesterol-lowering approach (approaching an LDL cholesterol level of 70 mg/dl) to a moderate LDL cholesterol-lowering approach (to ~100 mg/dl) using different doses of statins have been published. These include the Treating to New Targets (TNT) and the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trials in patients with stable CHD and the Aggrastat-to-Zocor (A-to-Z) trial in patients with acute coronary syndromes (78, 79, 80). Although the A-to-Z and IDEAL trials failed to achieve statistically significant reduction in the primary end points of cardiovascular events with intensive therapy compared with moderate therapy, only the TNT trial revealed a significant 21% reduction in cardiovascular events. However, a recent meta-analysis of the four trials does suggest a 16% reduction in the incidence of coronary death or any cardiovascular event with LDL cholesterol reduction to 75 mg/dl with high-dose statin therapy compared with LDL cholesterol reduction to 101 mg/dl with moderate-dose statin therapy (81).

It is important to realize the limitations of high-dose statin therapy. Compared with the low-dose statin therapy, intensive statin therapy has been associated with increased incidence of discontinuation, hepatotoxicity (0.2–1.1% vs. 0.9–3.3%, respectively) and myalgia (1.1–4.7% vs. 1.8–4.8%, respectively) (76, 78, 79, 80). The incidence of severe myopathy and rhabdomyolysis was rare despite high-dose statins. Although, in the TNT study, there was a higher number of deaths from noncardiovascular causes in the high-dose atorvastatin group compared with the low-dose atorvastatin group and this difference approached statistical significance (3.2 vs. 2.5%, respectively; P = 0.06), a similar increase was not observed in the IDEAL and PROVE-IT trials with high-dose atorvastatin. It must be kept in mind that the incidence of side effects with the high-dose statins might be higher in clinical practice than that reported in these clinical trials due to careful selection of patients in these trials. For example, patients with previous intolerance to statins were excluded in the IDEAL study (79); in the TNT trial (78) those with intolerance to statin during the run-in phase were excluded (~4% of enrolled patients); and in the PROVE-IT study (76) approximately 25% of the patients were on prior statin therapy.

In many patients with marked hypercholesterolemia or severe hypertriglyceridemia, it is not feasible to achieve the desired levels of LDL or non-HDL cholesterol using monotherapy with either maximal doses of statins or fibrates. Thus, often clinicians have to resort to combination therapy. For those with high LDL cholesterol levels, various combinations of statins, bile acid binding sequestrants, ezetimibe, niacin, and sitostanol can be used, whereas for others with severe hypertriglyceridemia, combination of statins, fibrates, and fish oils must be used. It must be realized that, first, there is lack of documented clinical trial evidence for the efficacy of many of these combination regimens in the prevention of hard end points of CHD and, second, many of these regimens, especially combination of statins and fibrates, are associated with increased risk of serious myopathy and rhabdomyolysis and therefore should be used with great caution. Recently, an inhibitor of microsomal triglyceride transfer protein (involved in chylomicron formation in the intestine and VLDL formation in the liver) was reported to lower LDL cholesterol levels by 51% in patients with homozygous FH due to LDLR mutations; however, marked elevation in liver fat and severe elevations of serum aminotransferases were noted (82). This therapy remains experimental at this time. Another potential therapeutic target is the inhibition of PCSK9, which may increase LDL clearance by reducing degradation of LDLRs.


   Beyond LDL Cholesterol Reduction
Top
 Abstract
 Introduction
 Genetics of Dyslipidemia
 Acquired Causes of Dyslipidemias
 Treatment Guidelines
 Recent Status of the...
 Beyond LDL Cholesterol Reduction
Conclusions
 Note Added in Proof
 References
 
There is no clear consensus on the benefits of targeting other facets of dyslipidemia such as hypertriglyceridemia and low levels of HDL cholesterol. It is, however, well known that severe hypertriglyceridemia (serum triglycerides > 1000 mg/dl) can predispose to acute pancreatitis and needs immediate therapy. Among all the lipid parameters, triglycerides are most responsive to lifestyle interventions such as diet and exercise. Extremely low-fat diets (<10–15% of total calories) should be recommended in all patients with severe hypertriglyceridemia before starting pharmacological interventions such as fibrates, niacin, or omega-3 polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid). The benefit of treating mild to moderate hypertriglyceridemia on CHD mortality is still not entirely clear, although elevated serum triglycerides are considered to be an independent risk factor (83, 84). Certainly, non-HDL cholesterol levels reflect increases in VLDL cholesterol levels in hypertriglyceridemic patients and are one of the targets of therapy identified by The National Cholesterol Education Program. The Veterans Affairs High Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) reported that gemfibrozil was effective for secondary prevention in patients with CHD and low HDL cholesterol levels, especially for those with diabetes and insulin resistance (85). Similarly, two smaller trials showed angiographic improvement with bezafibrate and gemfibrozil therapy (86, 87). However, the enthusiasm for fibrate use has been considerably dampened by results of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, which reported a nonsignificant 11% reduction in the primary end point of CHD events in type 2 diabetics treated with fenofibrate (200 mg daily) compared with those on placebo for 5 yr (88). However, a significant reduction in total cardiovascular events was achieved with fenofibrate therapy (P = 0.035). Interestingly, in the FIELD trial, many more patients on placebo initiated statin therapy during the trial (17%) than those on fenofibrate (8%), which could have confounded the results. Fenofibrate therapy was found to be associated with an uncommon but increased risk of pancreatitis, deep vein thrombosis, and pulmonary embolism as well as increases in plasma creatinine by 10–12 µmol/liter (0.11 to 0.14 mg/d) and homocysteine by 3.7 µmol/liter (88).

Low HDL cholesterol is well recognized as an independent risk factor for CHD, but there is not much hard clinical evidence to support benefits of HDL-raising therapies. Only small clinical trials have been conducted in patients with low HDL cholesterol using combination therapy with niacin and simvastatin/colestipol, and these showed improvements in surrogate CHD end points of angiographic assessment of atherosclerotic coronary artery lesions (89, 90). However, whether the angiographic regression noted in these studies is due to the 29–41% increase in HDL cholesterol or a 31–43% reduction in LDL cholesterol or a combination of the two is not clear. Niacin causes flushing and it can deteriorate glycemic control in patients with diabetes and has the potential for hepatotoxicity, therefore prompting a search for other HDL cholesterol-raising therapies (91).

The cholesterol ester transfer protein (CETP) inhibitor, torcetrapib, has been shown to increase HDL cholesterol levels by 16–91% in a dose-dependent manner (92), but phase III clinical trials of this drug were recently stopped because 82 patients taking torcetrapib and atorvastatin died, compared with only 52 deaths in those on atorvastatin alone (93). Whether this increased mortality was due to torcetrapib-induced increases in blood pressure or other side effects is not clear. Also it is possible that CETP inhibition may produce dysfunctional and atherogenic HDL particles. Finally, it is not clear whether other CETP inhibitors under development will be beneficial in reducing CHD risk.

Recently, weekly iv infusions of recombinant Apo A-IMilano/phospholipid complexes for 5 wk were reported to significantly reduce atheroma volume in patients with acute coronary syndromes (94). Apo A-1Milano is a mutant (Arg173Cys) form associated with longevity and absence of atherosclerosis. However, further confirmation of efficacy of Apo A-IMilano therapy in larger studies with clinical outcomes data are required before it can be accepted as a novel therapeutic strategy.

Because Apo A-I is a large protein, it needs to be administered iv. The development of small Apo A-I mimetic peptides, which can be administered orally, offers an interesting alternative (95). A synthetic peptide D4F, which contains 18 D-amino acids (which, unlike L-amino acids, are resistant to gastrointestinal degradation) binds lipids in a manner similar to Apo A-I and accelerates the early steps in reverse cholesterol transport without any effect on HDL cholesterol levels. D4F therapy reduces the size of atherosclerotic lesion in animal models (96, 97), and a phase I human trial is currently underway.


   Conclusions
Top
 Abstract
 Introduction
 Genetics of Dyslipidemia
 Acquired Causes of Dyslipidemias
 Treatment Guidelines
 Recent Status of the...
 Beyond LDL Cholesterol Reduction
 Conclusions
Note Added in Proof
 References
 
Recent advances in unraveling the molecular basis of monogenic dyslipidemias have improved our knowledge of lipoprotein metabolism and can be exploited to develop novel therapies. Although the current guidelines recommend aggressive lowering of LDL (or non-HDL) cholesterol in patients with very high risk of CHD, further clinical trial evidence is required to ratify these recommendations. Marked lowering of LDL or non- HDL cholesterol might require combination therapies, and clinicians must be aware of serious side effects of such intervention.


   Note Added in Proof
Top
 Abstract
 Introduction
 Genetics of Dyslipidemia
 Acquired Causes of Dyslipidemias
 Treatment Guidelines
 Recent Status of the...
 Beyond LDL Cholesterol Reduction
 Conclusions
 Note Added in Proof
References
 
Recent data from two new trials failed to show any benefit of the CETP inhibitor, torcetrapib, on the progression of coronary or cartotid atherosclerosis over a 2-yr period, despite a nearly 50-60% increase in HDL cholesterol levels (99, 100).


   Acknowledgments
 
We thank Scott M. Grundy, M.D., Ph.D., and Jonathan Cohen, Ph.D., for their helpful discussions and Sarah Mayhew for preparing the illustration.


   Footnotes
 
This work was supported by the National Institutes of Health Grants R01-DK54387 and R01-DK63656, and by the Southwestern Medical Foundation.

Abbreviations: Apo A-I, Apolipoprotein A-I; APOA5, apolipoprotein AV; APOB, apolipoprotein B; APOC2, apolipoprotein CII; APOE, apolipoprotein E; ARH, autosomal recessive hypercholesterolemia; CETP, cholesterol ester transfer protein; CHD, coronary heart disease; FCHL, familial combined hyperlipidemia; FDB, familial defective apolipoprotein B; FH, familial hypercholesterolemia; FHA, familial hypoalphalipoproteinemia; HDL, high-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; LDL, low-density lipoprotein; LDLR, LDL receptor; LDLRAP1, LDLR adaptor protein; LPL, lipoprotein lipase; PCSK9, proprotein convertase subtilisin-like kexin type 9; VLDL, very-low-density lipoprotein.

Received February 6, 2007.

Accepted March 29, 2007.


   References
Top
 Abstract
 Introduction
 Genetics of Dyslipidemia
 Acquired Causes of Dyslipidemias
 Treatment Guidelines
 Recent Status of the...
 Beyond LDL Cholesterol Reduction
 Conclusions
 Note Added in Proof
 References
 

  1. Goldstein JL, Brown MS 1979 The LDL receptor locus and the genetics of familial hypercholesterolemia. Ann Rev Genet 13:259–289[CrossRef][Medline]
  2. Fouchier SW, Kastelein JJ, Defesche JC 2005 Update of the molecular basis of familial hypercholesterolemia in The Netherlands. Hum Mutat 26:550–556[CrossRef][Medline]
  3. van Aalst-Cohen ES, Jansen AC, Tanck MW, Defesche JC, Trip MD, Lansberg PJ, Stalenhoef AF, Kastelein JJ 2006 Diagnosing familial hypercholesterolaemia: the relevance of genetic testing. Eur Heart J 27:2240–2246[Abstract/Free Full Text]
  4. Humphries SE, Whittall RA, Hubbart CS, Maplebeck S, Cooper JA, Soutar AK, Naoumova R, Thompson GR, Seed M, Durrington PN, Miller JP, Betteridge DJ, Neil HA 2006 Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. J Med Genet 43:943–949[Abstract/Free Full Text]
  5. Tosi I, Toledo-Leiva P, Neuwirth C, Naoumova RP, Soutar AK 2006 Genetic defects causing familial hypercholesterolaemia: Identification of deletions and duplications in the LDL-receptor gene and summary of all mutations found in patients attending the Hammersmith Hospital Lipid Clinic. Atherosclerosis, in press
  6. Humphries SE, Talmud PJ 1995 Hyperlipidaemia associated with genetic variation in the apolipoprotein B gene. Curr Opin Lipidol 6:215–222[Medline]
  7. Cladaras C, Hadzopoulou-Cladaras M, Nolte RT, Atkinson D, Zannis VI 1986 The complete sequence and structural analysis of human apolipoprotein B-100: relationship between apoB-100 and apoB-48 forms. EMBO J 5:3495–3507[Medline]
  8. Gasparovic J, Basistova Z, Fabryova L, Wsolova L, Vohnout B, Raslova K 2006 Familial defective apolipoprotein B-100 in Slovakia Are differences in prevalence of familial defective apolipoprotein B-100 explained by ethnicity? Atherosclerosis, in press
  9. Vega GL, Grundy SM 1986 In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia. J Clin Invest 78:1410–1414[Medline]
  10. Soria LF, Ludwig EH, Clarke HR, Vega GL, Grundy SM, McCarthy BJ 1989 Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 86:587–591[Abstract/Free Full Text]
  11. Soufi M, Sattler AM, Maerz W, Starke A, Herzum M, Maisch B, Schaefer JR 2004 A new but frequent mutation of apoB-100-apoB His3543Tyr. Atherosclerosis 174:11–16[CrossRef][Medline]
  12. Fouchier SW, Defesche JC, Kastelein JJ, Sijbrands EJ 2004 Familial defective apolipoprotein B versus familial hypercholesterolemia: an assessment of risk. Semin Vasc Med 4:259–264[CrossRef][Medline]
  13. Schaefer JR, Scharnagl H, Baumstark MW, Schweer H, Zech LA, Seyberth H, Winkler K, Steinmetz A, Marz W 1997 Homozygous familial defective apolipoprotein B-100. Enhanced removal of apolipoprotein E-containing VLDLs and decreased production of LDLs. Arterio Thromb Vasc Biol 17:348–353[Abstract/Free Full Text]
  14. Gallagher JJ, Myant NB 1995 The affinity of low-density lipoproteins and of very-low-density lipoprotein remnants for the low-density lipoprotein receptor in homozygous familial defective apolipoprotein B-100. Atherosclerosis 115:263–272[CrossRef][Medline]
  15. Ceska R, Vrablik M, Horinek A 2000 Familial defective apolipoprotein B-100: a lesson from homozygous and heterozygous patients. Physiol Res 49 (Suppl 1):S125–S30
  16. Marz W, Baumstark MW, Scharnagl H, Ruzicka V, Buxbaum S, Herwig J, Pohl T, Russ A, Schaaf L, Berg A, Bohles HJ, Usadel KH, Groß W 1993 Accumulation of "small dense" low density lipoproteins (LDL) in a homozygous patients with familial defective apolipoprotein B-100 results from heterogenous interaction of LDL subfractions with the LDL receptor. J Clin Invest 92:2922–2933[Medline]
  17. Funke H, Rust S, Seedorf U, Brennhausen B, Chirazi A, Motti C, Assmann G 1992 Homozygosity for familial defective apolipoprotein B-100 (FDB) is associated with lower plasma cholesterol concentrations than homozygosity for familial hypercholestrolemia (FH). Circulation 86:I-691 (Abstract)
  18. Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derre A, Villeger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C 2003 Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34:154–156[CrossRef][Medline]
  19. Park SW, Moon YA, Horton JD 2004 Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem 279:50630–50638[Abstract/Free Full Text]
  20. Maxwell KN, Fisher EA, Breslow JL 2005 Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci USA 102:2069–2074[Abstract/Free Full Text]
  21. Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, Skolnick MH, Hopkins PN, Hunt SC, Shattuck DM 2004 A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum Genet 114:349–353[CrossRef][Medline]
  22. Leren TP 2004 Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet 65:419–422[CrossRef][Medline]
  23. Varret M, Rabes JP, Saint-Jore B, Cenarro A, Marinoni JC, Civeira F, Devillers M, Krempf M, Coulon M, Thiart R, Kotze MJ, Schmidt H, Buzzi JC, Kostner GM, Bertolini S, Pocovi M, Rosa A, Farnier M, Martinez M, Junien C, Boileau C 1999 A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32. Am J Hum Genet 64:1378–1387[CrossRef][Medline]
  24. Haddad L, Day IN, Hunt S, Williams RR, Humphries SE, Hopkins PN 1999 Evidence for a third genetic locus causing familial hypercholesterolemia. A non-LDLR, non-APOB kindred. J Lipid Res 40:1113–1122[Abstract/Free Full Text]
  25. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH 2005 Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 37:161–165[CrossRef][Medline]
  26. Cohen JC, Boerwinkle E, Mosley Jr TH, Hobbs HH 2006 Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 354:1264–1272[Abstract/Free Full Text]
  27. Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, Calandra S, Bertolini S, Cossu F, Grishin N, Barnes R, Cohen JC, Hobbs HH 2001 Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 292:1394–1398[Abstract/Free Full Text]
  28. Garuti R, Jones C, Li WP, Michaely P, Herz J, Gerard RD, Cohen JC, Hobbs HH 2005 The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits. J Biol Chem 280:40996–41004[Abstract/Free Full Text]
  29. Arca M, Zuliani G, Wilund K, Campagna F, Fellin R, Bertolini S, Calandra S, Ricci G, Glorioso N, Maioli M, Pintus P, Carru C, Cossu F, Cohen J, Hobbs HH 2002 Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: a clinical and molecular genetic analysis. Lancet 359:841–847[CrossRef][Medline]
  30. Harada-Shiba M, Takagi A, Miyamoto Y, Tsushima M, Ikeda Y, Yokoyama S, Yamamoto A 2003 Clinical features and genetic analysis of autosomal recessive hypercholesterolemia. J Clin Endocrinol Metab 88:2541–2547[Abstract/Free Full Text]
  31. Abera AB, Marais AD, Raal FJ, Leisegang F, Jones S, George P, Henderson HE 2007 Autosomal recessive hypercholesterolaemia: discrimination of ARH protein and LDLR function in the homozygous FH phenotype. Clin Chim Acta 378(1–2):33–37
  32. Pisciotta L, Oliva CP, Pes GM, Di Scala L, Bellocchio A, Fresa R, Cantafora A, Arca M, Calandra S, Bertolini S 2006 Autosomal recessive hypercholesterolemia (ARH) and homozygous familial hypercholesterolemia (FH): a phenotypic comparison. Atherosclerosis 188:398–405[CrossRef][Medline]
  33. Jones C, Garuti R, Michaely P, Li WP, Maeda N, Cohen JC, Herz J, Hobbs HH 2007 Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia. J Clin Invest 117:165–174[CrossRef][Medline]
  34. Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, Kwiterovich P, Shan B, Barnes R, Hobbs HH 2000 Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290:1771–1775[Abstract/Free Full Text]
  35. Lee MH, Lu K, Hazard S, Yu H, Shulenin S, Hidaka H, Kojima H, Allikmets R, Sakuma N, Pegoraro R, Srivastava AK, Salen G, Dean M, Patel SB 2001 Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet 27:79–83[Medline]
  36. Hazard SE, Patel SB 2007 Sterolins ABCG5 and ABCG8: regulators of whole body dietary sterols. Pflugers Arch 453:745–752[CrossRef][Medline]
  37. 1991 Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ 303:893–896
  38. Oliva CP, Pisciotta L, Li Volti G, Sambataro MP, Cantafora A, Bellocchio A, Catapano A, Tarugi P, Bertolini S, Calandra S 2005 Inherited apolipoprotein A-V deficiency in severe hypertriglyceridemia. Arterio Thromb Vasc Biol 25:411–417[Abstract/Free Full Text]
  39. Marcais C, Verges B, Charriere S, Pruneta V, Merlin M, Billon S, Perrot L, Drai J, Sassolas A, Pennacchio LA, Fruchart-Najib J, Fruchart JC, Durlach V, Moulin P 2005 Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment. J Clin Invest 115:2862–2869[CrossRef][Medline]
  40. Merkel M, Loeffler B, Kluger M, Fabig N, Geppert G, Pennacchio LA, Laatsch A, Heeren J 2005 Apolipoprotein AV accelerates plasma hydrolysis of triglyceride-rich lipoproteins by interaction with proteoglycan-bound lipoprotein lipase. J Biol Chem 280:21553–21560[Abstract/Free Full Text]
  41. Merkel M, Heeren J 2005Give me A5 for lipoprotein hydrolysis! J Clin Invest 115:2694–2696
  42. Agarwal AK, Garg A 2006 Genetic disorders of adipose tissue development, differentiation, and death. Ann Rev Genomics Hum Genet 7:175–199[CrossRef][Medline]
  43. Garg A 2004 Acquired and inherited lipodystrophies. N Engl J Med 350:1220–1234[Free Full Text]
  44. Huertas-Vazquez A, Aguilar-Salinas C, Lusis AJ, Cantor RM, Canizales-Quinteros S, Lee JC, Mariana-Nunez L, Riba-Ramirez RM, Jokiaho A, Tusie-Luna T, Pajukanta P 2005 Familial combined hyperlipidemia in Mexicans: association with upstream transcription factor 1 and linkage on chromosome 16q24.1. Arterio Thromb Vasc Biol 25:1985–1991[Abstract/Free Full Text]
  45. Ng MC, Miyake K, So WY, Poon EW, Lam VK, Li JK, Cox NJ, Bell GI, Chan JC 2005 The linkage and association of the gene encoding upstream stimulatory factor 1 with type 2 diabetes and metabolic syndrome in the Chinese population. Diabetologia 48:2018–2024[CrossRef][Medline]
  46. Pajukanta P, Lilja HE, Sinsheimer JS, Cantor RM, Lusis AJ, Gentile M, Duan XJ, Soro-Paavonen A, Naukkarinen J, Saarela J, Laakso M, Ehnholm C, Taskinen MR, Peltonen L 2004 Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nat Genet 36:371–376[CrossRef][Medline]
  47. van der Vleuten GM, Isaacs A, Hijmans A, van Duijn CM, Stalenhoef AF, de Graaf J 2007 The involvement of upstream stimulatory factor 1 in Dutch patients with familial combined hyperlipidemia. J Lipid Res 48:193–200[Abstract/Free Full Text]
  48. Naukkarinen J, Ehnholm C, Peltonen L 2006 Genetics of familial combined hyperlipidemia. Curr Opin Lipidol 17:285–290[Medline]
  49. Suviolahti E, Lilja HE, Pajukanta P 2006 Unraveling the complex genetics of familial combined hyperlipidemia. Ann Med 38:337–351[CrossRef][Medline]
  50. Ikewaki K, Matsunaga A, Han H, Watanabe H, Endo A, Tohyama J, Kuno M, Mogi J, Sugimoto K, Tada N, Sasaki J, Mochizuki S 2004 A novel two nucleotide deletion in the apolipoprotein A-I gene, apoA-I Shinbashi, associated with high density lipoprotein deficiency, corneal opacities, planar xanthomas, and premature coronary artery disease. Atherosclerosis 172:39–45[CrossRef][Medline]
  51. Yokota H, Hashimoto Y, Okubo S, Yumoto M, Mashige F, Kawamura M, Kotani K, Usuki Y, Shimada S, Kitamura K, Nakahara K 2002 Apolipoprotein A-I deficiency with accumulated risk for CHD but no symptoms of CHD. Atherosclerosis 162:399–407[CrossRef][Medline]
  52. Pisciotta L, Miccoli R, Cantafora A, Calabresi L, Tarugi P, Alessandrini P, Bittolo Bon G, Franceschini G, Cortese C, Calandra S, Bertolini S 2003 Recurrent mutations of the apolipoprotein A-I gene in three kindreds with severe HDL deficiency. Atherosclerosis 167:335–345[CrossRef][Medline]
  53. Sirtori CR, Calabresi L, Franceschini G, Baldassarre D, Amato M, Johansson J, Salvetti M, Monteduro C, Zulli R, Muiesan ML, Agabiti-Rosei E 2001 Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study. Circulation 103:1949–1954[Abstract/Free Full Text]
  54. von Eckardstein A, Funke H, Henke A, Altland K, Benninghoven A, Assmann G 1989 Apolipoprotein A-I variants. Naturally occurring substitutions of proline residues affect plasma concentration of apolipoprotein A-I. J Clin Invest 84:1722–1730[Medline]
  55. Strobl W, Jabs HU, Hayde M, Holzinger T, Assmann G, Widhalm K 1988 Apolipoprotein A-I (Glu 198—-Lys): a mutant of the major apolipoprotein of high-density lipoproteins occurring in a family with dyslipoproteinemia. Pediat Res 24:222–228[Medline]
  56. Miller M, Rhyne J, Hamlette S, Birnbaum J, Rodriguez A 2003 Genetics of HDL regulation in humans. Curr Opinion Lipidol 14:273–279[CrossRef][Medline]
  57. Singaraja RR, Brunham LR, Visscher H, Kastelein JJ, Hayden MR 2003 Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene. Arterio Throm Vasc Biol 23:1322–1332[CrossRef]
  58. Hovingh GK, de Groot E, van der Steeg W, Boekholdt SM, Hutten BA, Kuivenhoven JA, Kastelein JJ 2005 Inherited disorders of HDL metabolism and atherosclerosis. Curr Opin Lipidol 16:139–145[Medline]
  59. Ho Hong S, Rhyne J, Zeller K, Miller M 2002 Novel ABCA1 compound variant associated with HDL cholesterol deficiency. Biochim Biophys Acta 1587:60–64[Medline]
  60. Hovingh GK, Kuivenhoven JA, Bisoendial RJ, Groen AK, van Dam M, van Tol A, Wellington C, Hayden MR, Smelt AH, Kastelein JJ 2004 HDL deficiency and atherosclerosis: lessons from Tangier disease. J Intern Med 255:299–301[CrossRef][Medline]
  61. Clee SM, Kastelein JJ, van Dam M, Marcil M, Roomp K, Zwarts KY, Collins JA, Roelants R, Tamasawa N, Stulc T, Suda T, Ceska R, Boucher B, Rondeau C, DeSouich C, Brooks-Wilson A, Molhuizen HO, Frohlich J, Genest Jr J, Hayden MR 2000 Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes. J Clin Invest 106:1263–1270[Medline]
  62. Assaf C, Bagot M, Dummer R, Duvic M, Gniadecki R, Knobler R, Ranki A, Schwandt P, Whittaker S 2006 Minimizing adverse side-effects of oral bexarotene in cutaneous T-cell lymphoma: an expert opinion. Br J Dermatol 155:261–266[CrossRef][Medline]
  63. Milionis HJ, Liberopoulos EN, Elisaf MS 2001 Tamoxifen-induced hypertriglyceridemia in association with diabetes mellitus. Diabetes Metab 27:160–163[Medline]
  64. Bundred NJ 2005 The effects of aromatase inhibitors on lipids and thrombosis. Br J Cancer 93(Suppl 1):S23–S27
  65. Conte P, Frassoldati A 2007 Aromatase inhibitors in the adjuvant treatment of postmenopausal women with early breast cancer: Putting safety issues into perspective. Breast J 13:28–35[CrossRef][Medline]
  66. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS 2005 Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60–62[CrossRef][Medline]
  67. Thurlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A 2005 A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747–2757[Abstract/Free Full Text]
  68. Keung YK, Rizk R, Wu XY, Cobos E 1999 Drug-induced hypertriglyceridemia with and without pancreatitis. South Med J 92:912–914[Medline]
  69. Kurt M, Babaoglu MO, Yasar U, Shorbagi A, Guler N 2006 Capecitabine-induced severe hypertriglyceridemia: report of two cases. Ann Pharmacother 40:328–331[Abstract/Free Full Text]
  70. Bustamante SE, Appachi E 2006 Acute pancreatitis after anesthesia with propofol in a child with glycogen storage disease type IA. Paediatr Anaesth 16:680–683[CrossRef][Medline]
  71. 2001 Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 285:2486–2497
  72. Jenkins DJ, Kendall CW, Marchie A, Faulkner DA, Wong JM, de Souza R, Emam A, Parker TL, Vidgen E, Lapsley KG, Trautwein EA, Josse RG, Leiter LA, Connelly PW 2003 Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive protein. JAMA 290:502–510[Abstract/Free Full Text]
  73. Grundy SM, Cleeman JI, Merz CN, Brewer Jr HB, Clark LT, Hunninghake DB, Pasternak RC, Smith Jr SC, Stone NJ 2004 Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 110:227–239[Abstract/Free Full Text]
  74. Brown MS, Goldstein JL 2006 Biomedicine. Lowering LDL–not only how low, but how long? Science 311:1721–1723[Abstract/Free Full Text]
  75. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. 2002 Lancet 360:7–22[CrossRef][Medline]
  76. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM 2004 Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 350:1495–1504[Abstract/Free Full Text]
  77. Hayward RA, Hofer TP, Vijan S 2006 Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Intern Med 145:520–530[Abstract/Free Full Text]
  78. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK 2005 Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 352:1425–1435[Abstract/Free Full Text]
  79. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J 2005 High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 294:2437–2445[Abstract/Free Full Text]
  80. de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, Rouleau JL, Pedersen TR, Gardner LH, Mukherjee R, Ramsey KE, Palmisano J, Bilheimer DW, Pfeffer MA, Califf RM, Braunwald E 2004 Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 292:1307–1316[Abstract/Free Full Text]
  81. Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E 2006 Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 48:438–445[Abstract/Free Full Text]
  82. Cuchel M, Bloedon LT, Szapary PO, Kolansky DM, Wolfe ML, Sarkis A, Millar JS, Ikewaki K, Siegelman ES, Gregg RE, Rader DJ 2007 Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med 356:148–156[Abstract/Free Full Text]
  83. Miller M, Seidler A, Moalemi A, Pearson TA 1998 Normal triglyceride levels and coronary artery disease events: the Baltimore Coronary Observational Long-Term Study. J Am Coll Cardiol 31:1252–1257[Abstract/Free Full Text]
  84. Jeppesen J, Hein HO, Suadicani P, Gyntelberg F 1998 Triglyceride concentration and ischemic heart disease: an eight-year follow-up in the Copenhagen Male Study. Circulation 97:1029–1036[Abstract/Free Full Text]
  85. Rubins HB, Robins SJ, Collins D, Nelson DB, Elam MB, Schaefer EJ, Faas FH, Anderson JW 2002 Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch Intern Med 162:2597–2604[Abstract/Free Full Text]
  86. Ericsson CG, Nilsson J, Grip L, Svane B, Hamsten A 1997 Effect of bezafibrate treatment over five years on coronary plaques causing 20% to 50% diameter narrowing (The Bezafibrate Coronary Atherosclerosis Intervention Trial [BECAIT]). Am J Cardiol 80:1125–1129[CrossRef][Medline]
  87. Frick MH, Syvanne M, Nieminen MS, Kauma H, Majahalme S, Virtanen V, Kesaniemi YA, Pasternack A, Taskinen MR 1997 Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Lopid Coronary Angiography Trial (LOCAT) Study Group. Circulation 96:2137–2143[Abstract/Free Full Text]
  88. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesaniemi YA, Sullivan D, Hunt D, Colman P, d’Emden M, Whiting M, Ehnholm C, Laakso M 2005 Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366:1849–1861[CrossRef][Medline]
  89. Stewart BF, Brown BG, Zhao XQ, Hillger LA, Sniderman AD, Dowdy A, Fisher LD, Albers JJ 1994 Benefits of lipid-lowering therapy in men with elevated apolipoprotein B are not confined to those with very high low density lipoprotein cholesterol. J Am Coll Cardiol 23:899–906[Abstract]
  90. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ 2001 Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 345:1583–1592[Abstract/Free Full Text]
  91. Forrester JS, Shah PK 2006 Emerging strategies for increasing high-density lipoprotein. Am J Cardiol 98:1542–1549[CrossRef][Medline]
  92. Clark RW, Sutfin TA, Ruggeri RB, Willauer AT, Sugarman ED, Magnus-Aryitey G, Cosgrove PG, Sand TM, Wester RT, Williams JA, Perlman ME, Bamberger MJ 2004 Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib. Arterio Thromb Vasc Biol 24:490–497[Abstract/Free Full Text]
  93. Tanne JH 2006 Pfizer stops clinical trials of heart drug. BMJ 333:1237
  94. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, Eaton GM, Lauer MA, Sheldon WS, Grines CL, Halpern S, Crowe T, Blankenship JC, Kerensky R 2003 Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 290:2292–2300[Abstract/Free Full Text]
  95. Navab M, Anantharamaiah GM, Reddy ST, Fogelman AM 2006 Apolipoprotein A-I mimetic peptides and their role in atherosclerosis prevention. Nat Clin Pract Cardiovasc Med 3:540–547[CrossRef][Medline]
  96. Li X, Chyu KY, Faria Neto JR, Yano J, Nathwani N, Ferreira C, Dimayuga PC, Cercek B, Kaul S, Shah PK 2004 Differential effects of apolipoprotein A-I-mimetic peptide on evolving and established atherosclerosis in apolipoprotein E-null mice. Circulation 110:1701–1705[Abstract/Free Full Text]
  97. Navab M, Anantharamaiah GM, Reddy ST, Hama S, Hough G, Frank JS, Grijalva VR, Ganesh VK, Mishra VK, Palgunachari MN, Fogelman AM 2005 Oral small peptides render HDL antiinflammatory in mice and monkeys and reduce atherosclerosis in ApoE null mice. Circulation Res 97:524–532[Abstract/Free Full Text]
  98. Marks D, Thorogood M, Neil HA, Humphries SE 2003 A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 168:1–14[CrossRef][Medline]
  99. Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Tuzcu EM 2007 Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 356:1304–11316[Abstract/Free Full Text]
  100. Kastelein JJ, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ, Revkin JH, Grobbee DE, Riley WA, Shear CL, Duggan WT, Bots ML 2007 Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med, in press