ENDOCRINE TODAY July 2007
New Paradigms in Dyslipidemia Management: Taking the Patient Beyond LDL Cholesterol Reduction

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Introduction Diagnosing hypertriglyceridemia and developing dyslipidemia treatment goals Vera Bittner, MD, MSPH The importance of triglycerides in assessing and managing CHD risk Judith Hsia, MD Beyond LDL cholesterol targets: combination therapies for dyslipidemia management Roger S. Blumenthal, MD

Introduction

Although LDL cholesterol remains the primary therapeutic target in patients with dyslipidemia, the National Cholesterol Education Program Adult Treatment Panel III guidelines list non-HDL cholesterol as a secondary target. The guidelines also recommend the optimization of other CHD risk factors including lowering triglyceride levels to <150 mg/dL and raising HDL cholesterol levels to >40 mg/dL in men and >50 mg/dL in women. Statin monotherapy may help patients with dyslipidemia achieve target LDL cholesterol levels; however, combination therapy is often needed to attain secondary treatment goals.

Vindico Medical Education conducted a symposium at the 2007 Annual Meeting of the American College of Cardiology held in New Orleans. An esteemed faculty utilized an interactive case-based format to provide an overview of the epidemiology of dyslipidemia, apply risk assessment tools and explore combination treatment options. This monograph includes a case presentation and a matching quiz allowing you, the cardiologists and endocrinologists, the opportunity to test your knowledge.

Alan J. Garber, MD, PhD Endocrine Today Chief Medical Editor

Carl J. Pepine, MD Today in Cardiology Chief Medical Editor

Vera Bittner, MD, MSPH, Course Director, is professor of medicine and section head of Preventive Cardiology at the University of Alabama in Birmingham, Ala. Roger S. Blumenthal, MD, is associate professor of Medicine, Director of Preventive Cardiology and Medical Director at Johns Hopkins Heart Health at Timonium and Associate medical director of the Johns Hopkins Sibling Study at the Johns Hopkins University in Baltimore, Md. Judith Hsia, MD, is professor of Medicine and director of the Lipid Research Clinic at George Washington University in Washington, DC.

Diagnosing hypertriglyceridemia and developing dyslipidemia treatment goals
Vera Bittner, MD, MSPH

Hypertriglyceridemia affects approximately one-third of the population and can lead to serious medical conditions such as non-coronary atherosclerosis, coronary heart disease and pancreatitis. This article discusses the definitions and characteristics of this condition as well as treatment goals established by the Adult Treatment Panel III for adults with hypertriglyceridemia.

Definition and prevalence

In 2002, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) updated its definition of hypertriglyceridemia.¹ Triglyceride levels below 150 mg/dL are considered normal; levels between 150 mg/dL and 199 mg/dL are considered borderline high; levels between 200 mg/dL and 499 mg/dL are considered high; and those above 500 mg/dL are designated as very high.

Overall, hypertriglyceridemia affects between 25% and 36% of the U.S. population.² According to data from the National Health and Nutrition Examination Survey (NHANES) taken between 1988 and 1994, 35.9% of men and 24.6% of women had hypertriglyceridemia, with an overall rate of 30.2%. NHANES data collected between 1999 and 2000 found these rates to be 35.6% in men, 29.9% in women and 32.6% overall.²

Familial syndromes leading to high triglyceride levels

Hypertriglyceridemia is a heterogeneous disorder with a number of causes.³ Several familial, inherited syndromes can cause high levels of triglycerides, the most common of which is familial combined hyperlipidemia. This genetic condition occurs in approximately one in 200 people and results in high levels of LDL cholesterol, very low density lipoprotein (VLDL) cholesterol and apolipoprotein B (apoB) levels. Triglyceride levels typically range from 150 mg/dL to 500 mg/dL in these patients, who are at increased risk for coronary heart disease (CHD).

“Overall, hypertriglyceridemia affects between 25% and 36% of the U.S. population.” — Vera Bittner, MD, MSPH

Familial dysbetalipoproteinemia is another inherited condition that can cause hypertriglyceridemia. Patients with this condition have a characteristic genotype in which the apoE protein is the E2-E2 variant, causing the protein to have less affinity for some of the lipoprotein receptors. Decreased affinity leads to impaired catabolism of the remnants. This disorder does not tend to manifest itself unless the patient has a second cause of high remnant levels such as obesity, diabetes, hypothyroidism or alcoholism. Lipoprotein particles have abnormal composition in these patients, which means that the typical formula used to determine LDL cholesterol (Friedewald formula) cannot be used.

Familial hypertriglyceridemia results in high VLDL levels and high chylomicrons. Triglyceride levels in these patients are typically between 250 mg/dL and 1,000 mg/dL, with higher levels occurring in patients with the high chylomicron variety. Some controversy remains as to the degree to which this condition is associated with an increased risk of early CVD.

Familial chylomicronemia is another inherited hypertriglyceridemic disorder. Adult cardiologists generally do not see patients with this condition because lipid abnormalities in these patients with absent or dysfunctional lipoprotein lipase or apoC-II become apparent in early childhood. The main risk in these patients is pancreatitis rather than CHD due to the high triglyceride levels, which range from 1,000 mg/dL to 10,000 mg/dL.

Secondary causes

Myriad secondary causes of hypertriglyceridemia should be considered for each patient. Hypertriglyceridemia should not be treated as a primary condition when it is a secondary manifestation of a disorder that can be managed with lifestyle or medications. In particular, treatments should focus on controlling primary disease states such as obesity, metabolic syndrome, diabetes, nephrotic syndrome, kidney disease and hypothyroidism. Furthermore, any medication affecting triglyceride levels such as tamoxifen, steroids, immunosuppressants, beta-blockers, retinoids, protease inhibitors and atypical antipsychotics should be stopped if possible. Finally, addressing lifestyle issues such as physical inactivity, high carbohydrate intake and excessive alcohol intake can help improve hypertriglyceridemia.

Composition and transport of triglycerides

Triglyceride molecules consist of a glycerol backbone and three fatty acids, which are transported by various lipoprotein particles. Some of these particles (ie, chylomicrons) are too large to get into the artery wall and are, therefore, not directly atherogenic. In contrast, some of the smaller chylomicron remnants and VLDL remnants are highly atherogenic and can deliver a substantial amount of cholesterol to the artery wall.

Lipoproteins differ significantly in composition. Triglyceride-rich lipoprotein particles include chylomicrons and VLDL, whereas LDL and HDL particles contain much smaller amounts of triglycerides. As VLDL particles get metabolized in the circulation, they become more cholesterol enriched and can actually deliver more cholesterol per particle to the artery wall than an LDL particle in patients with high triglycerides.

Assessing atherogenicity of plasma

Two simple measurements are available to determine atherogenicity of plasma: ApoB and non-HDL-cholesterol levels (Figure 1). Both measures are independent predictors of CHD as documented in multiple prospective studies. ApoB is the apolipoprotein common to all triglyceride-rich lipoprotein particles and to LDL particles. This measure thus provides an estimate of all potentially atherogenic particles. Most hospitals and free-standing laboratories do not offer apoB as a routine measurement.

Figure 1: Atherogenic Particles Figure 1. Atherogenic particles include VLDL, VLDLR, IDL, LDL, and small, dense LDL. Atherogenic measurements include apoB and non-HDL-C. Source: Figure courtesy of Vera Bittner, MD, MSPH.

A second and more practical option is to measure non-HDL cholesterol. It can be calculated easily from a standard lipid profile by subtracting HDL cholesterol from total cholesterol and is highly correlated with apoB measurements. Patients do not have to fast, because neither total cholesterol nor HDL cholesterol changes significantly after a meal.

ATP III treatment goals for non-HDL cholesterol are set 30 mg/dL higher than for LDL cholesterol. For high-risk, moderate-risk and low-risk patients, LDL levels should be targeted at <100 mg/dL, <130 mg/dL and <160 mg/dL, respectively. Simply adding 30 mg/dL to each of these numbers yields the non-HDL cholesterol target values for high-, moderate- and low-risk patients, respectively.⁴

Lifestyle modification is crucial in the management of mixed dyslipidemia, hypertriglyceridemia and metabolic syndrome. Maintaining a calorically balanced diet without excess carbohydrate or fat is desirable, as is avoiding excessive alcohol intake. Regular physical activity offers significant benefits by activating lipoprotein lipase, stimulating the metabolism of triglyceride-rich lipoproteins.¹

NCEP ATP III treatment goals

Physicians should keep in mind the varying treatment goals for hypertriglyceridemia based on given triglyceride levels in presenting patients.

Most patients fall into the borderline high range (150 mg/dL to 199 mg/dL). According to NCEP ATP III,¹ the primary treatment goal for these individuals remains achievement of LDL cholesterol goals. Lifestyle changes are the primary treatment method in this group. Specifically, smoking cessation, restriction of alcohol use, increased physical activity, control of body weight and avoidance of high carbohydrate intake (>60% of calories) are recommended. Triglycerides themselves are not a primary target for drug therapy in these individuals and statins are a good option to achieve LDL cholesterol targets. Niacin, fibrates, bile acid resins and omega-3 fatty acids are choices for patients with other associated lipid abnormalities.

Although the LDL cholesterol target is still the primary treatment goal for patients in the high triglyceride range (200 mg/dL to 499 mg/dL), a non-HDL cholesterol target is an important secondary goal. Lifestyle changes and statins are still effective in this group; however, combination drug therapy is often required. A statin can be combined with niacin, a fibrate or omega-3 fatty acids. Patients should be carefully monitored. The combination of a statin and a fibrate can cause myopathy.

In approximately 3% of patients with hypertriglyceridemia, the triglyceride level is in the very high range (>500 mg/dL). Among these patients, the focus of treatment should shift from prevention of CVD to prevention of pancreatitis. It will be nearly impossible to normalize levels in patients with extremely high triglyceride levels. Lowering triglyceride levels to <500 mg/dL is sufficient to prevent pancreatitis. To achieve this goal, a low-fat diet (<15% of total calories from fat) and medium chain triglycerides (to replace long chain triglycerides) are recommended for patients with triglyceride levels >1,000 mg/dL. In addition to lifestyle changes, fibrates and niacin are appropriate medications. Statins should not be used as a first-line agent and bile acid sequestrants should be avoided because they tend to increase triglyceride levels. Finally, patients with lipoprotein lipase or apoC-II deficiency will not typically respond to drug therapy.

Figure 2: Quiz: Test your knowledge of lipid profiles, clinical histories and physical findings   A.  25 year-old patient with history of pancreatitis     B.  50 year-old patient with recent history of bypass graft and the following labs: TC 400 mg/dL, TG 100 mg/dL, HDL 45 mg/dL     C.  40 year-old with claudication and the following labs: TC 500 mg/dL, TG 500 mg/dL, HDL 39 mg/dL     D.  40 year-old with a recent history of MI and the following labs: TC 180 mg/dL, HDL 22 mg/dL, TG 105 mg/dL     A.  25 year-old patient with a history of pancreatitis     B.  50 year-old patient with recent history of coronary artery bypass graft and the following labs: TC 400 mg/dL, TG 100 mg/dL, HDL 45 mg/dL     C.  40 year-old with claudication and the following labs: TC 500 mg/dL, TG 500 mg/dL, HDL 39 mg/dL     D.  40 year-old with a recent history of MI and the following labs: TC 180 mg/dL, HDL 22 mg/dL, TG 105 mg/dL     Answer Key. 1.A: Lipemia retinalis and pancreatitis typically occur in patients with triglyceride levels in the 1000s who have a familial syndrome. 2.C: Palmar xanthomas typically occur in patients with type III hyperlipidemia, in which the total cholesterol and triglyceride levels are approximately the same.   Figure 2. Test your knowledge and match the physical finding shown in the picture with the corresponding clinical history and lipid profile. Source: Figure courtesy of Vera Bittner, MD, MSPH

Summary

Because hypertriglyceridemia is not always the primary target for treatment, it is often overlooked in day to day clinical practice. Close attention to underlying causes of hypertriglyceridemia and specific therapy as indicated can help prevent progression of non-coronary atherosclerosis and CHD and prevent pancreatitis.

References

1. ATP III. Third report of the National Cholesterol Education Program expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421.
2. Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among U.S. adults. Diabetes Care. 2004;27:2444-2449.
3. Dunbar RL, Rader DJ. Demystifying triglycerides: a practical approach for the clinician. Cleve Clin J Med. 2005;72:661-680.
4. Grundy SM, Cleeman JI, Bairy-Merz CN, et al. Implications of recent clinical trials for the national cholesterol education program adult treatment panel III guidelines. Circulation. 2004;110:227-239.

The importance of triglycerides in assessing and managing CHD risk
Judith Hsia, MD

Although triglycerides often take a back seat to cholesterol levels, hypertriglyceridemia is an independent risk factor for coronary heart disease. This article discusses risk assessment tools as well as complications and treatment approaches to dyslipidemia, and, more specifically, hypertriglyceridemia.

Problems with risk scores

Health care providers generally assess individual patient risk using the Framingham risk score that estimates the 10-year risk of myocardial infarction or death caused by coronary heart disease (CHD). The Framingham risk algorithm includes the following factors: age, sex, total cholesterol, HDL-cholesterol, smoking status, diabetes, blood pressure (BP) and whether hypertension is treated.^1,2 The National Cholesterol Education Program (NCEP) further recommends assessment of non-HDL cholesterol as a secondary treatment goal and evaluation of patients for the presence of the metabolic syndrome, both of which reflect the risk associated with hypertriglyceridemia.

“...calculated non-HDL cholesterol is a measure of the cholesterol contained within atherogenic apoB-containing lipoproteins including LDL, IDL and triglyceride-rich VLDL.” — Judith Hsia, MD

Non-HDL cholesterol is calculated by subtracting HDL cholesterol from total cholesterol; calculated non-HDL cholesterol is a measure of the cholesterol contained within atherogenic apoB-containing lipoproteins including low-density lipoprotein (LDL), intermediate-density lipoprotein (IDL) and triglyceride-rich very-low-density lipoprotein (VLDL). NCEP non-HDL cholesterol targets are 30 mg/dL above LDL targets. The metabolic syndrome is a cluster of risk factors that confers atherosclerotic risk. Individuals with three of the following characteristics are defined as having the metabolic syndrome: waist circumference >35” for Caucasian women or >40” for Caucasian men in the U.S. population, systolic BP >130 mm Hg or diastolic BP >85 mm Hg, glucose >100 mg/dL, HDL <50 mg/dL for women or <40 mg/dL for men, and/or triglycerides >150 mg/dL.

Triglycerides as CHD risk predictor

A number of studies have demonstrated risks associated with elevated triglyceride levels.^3,4 In a study of 4,639 men with no history of myocardial infarction or stroke, the relative risks for CHD were 1.6 (P=.02) for those with triglyceride levels of 105 mg/dL to 166 mg/dL and 2.6 (P=.001) for patients with triglycerides >166 mg/dL compared with patients who had triglyceride levels <105 mg/dL.³ Triglyceride levels independently predicted CHD risk after adjustment for LDL and HDL cholesterol (Figure 1). Furthermore, CHD risk increased sixfold among individuals with triglycerides >200 mg/dL and an LDL-HDL ratio >5.

Figure 1: Triglyceride Levels and CHD Risk Figure 1. Elevated triglyceride levels significantly increase CHD risk. This correlation remains significant after adjusting for LDL and HDL cholesterol levels.3

A meta-analysis of 29 studies that included more than 260,000 individuals found a hazard ratio of 1.72 for CHD cases among patients with triglyceride levels in the upper tertile compared with those in the bottom tertile.⁴ This analysis included adjustments for a variety of other factors including total cholesterol levels, age and smoking status. Collectively, these results support the importance of hypertriglyceridemia as an independent predictor of CHD risk; furthermore, these data suggest that the magnitude of risk with hypertriglyceridemia is similar to that of traditional risk factors such as hypertension.

Non-HDL cholesterol levels

Non-HDL cholesterol levels should be calculated as part of CHD risk assessment. In one study of more than 4,400 men and women, non-HDL cholesterol was a better predictor of cardiovascular disease (CVD) mortality than LDL cholesterol in both sexes.⁵ CVD risk increased in men by 19% with a 30 mg/dL increase in non-HDL cholesterol and by 15% with a 30 mg/dL increase in LDL cholesterol; corresponding CVD risks in women increased by 11% and 8%, respectively.

Another recent study of more than 5,700 patients identified a strong, positive graded association between non-HDL cholesterol and CHD risk at every level of LDL cholesterol.⁶ This relationship suggested that non-HDL cholesterol is a stronger predictor of CHD risk than LDL cholesterol, even though lowering LDL cholesterol remains the primary therapeutic target in dyslipidemia.

Even though calculation of non-HDL cholesterol is specifically recommended only in individuals with high triglycerides, the predictive value of non-HDL cholesterol is present across the spectrum of triglyceride levels.

Metabolic syndrome

The degree of risk associated with the metabolic syndrome is highly variable, depending on the number of criteria for the metabolic syndrome present and their severity. With the increasing prevalence of obesity, prediabetes and frank diabetes mellitus in the United States, the metabolic syndrome is increasing in prominence as a high-risk phenotype. In the National Health and Nutrition Examination Survey, the metabolic syndrome was more prevalent among older Americans and Hispanics.⁷ Weight loss and physical activity are the standard therapeutic recommendations for patients with the metabolic syndrome,⁸ underscoring the lack of clinical trials demonstrating risk reduction with pharmacologic interventions.

Triglycerides and statin therapy

How beneficial is statin therapy in patients with hypertriglyceridemia? In the Heart Protection Study, simvastatin-treated patients with low triglyceride levels had a significantly lower CVD event rate of 18.3% during 5 years of follow up compared with statin-treated patients with high triglycerides, who had an event rate of 23.2% (Figure 2).⁹ Data analyzed from the Cholesterol and Recurrent Events (CARE) and Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trials demonstrated coronary event rates of 20.3% in pravastatin-treated patients with low triglyceride levels and 24.7% in those with high triglycerides (Figure 2).¹⁰ Therefore, hypertriglyceridemia may modulate statin efficacy.

Figure 2: CVD Risk in Statin-Treated Patients from the HPS* and CARE/LIPID Studies** Figure 2. Statin therapy did not eliminate the CVD risk associated with high triglyceride levels in the HPS and CARE/LIPID studies.9,10 *HPS = Heart Protection Study   **CARE = Cholesterol and Recurrent Events Study **LIPID = Long-Term Intervention with Pravastatin in Ischemic Disease Study

Summary

The National Heart, Lung and Blood Institute is currently trying to move toward global cardiovascular risk assessment and management. However, until that system is in place, cardiologists and all physicians will need to work within the limitations of the tools available.

Hypertriglyceridemia predicts CHD risk, independent of HDL and LDL cholesterol levels and other traditional risk factors. A simple way to include triglycerides in risk assessment of individual patients is to calculate non-HDL cholesterol, as recommended by the NCEP guidelines. Although LDL cholesterol remains the primary therapeutic target, non-HDL cholesterol is an important secondary target of therapy. Management of non-HDL cholesterol includes lifestyle modification and pharmacologic interventions beyond statin treatment.

The case study on page 10 demonstrates the application of risk assessment tools over the course of 10 years in a patient with a high lifetime risk despite a low Framingham risk score.

References

1. Adult Treatment Panel III. Estimate of 10-year risk for coronary heart disease: Framingham point scores. http://www.nhlbi.nih.gov/guidelines/cholesterol/risk_tbl.htm.
2. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97(18):1761-1762.
3. Assmann G, Schulte H, von Eckardstein A. Hypertriglyceridemia and elevated lipoprotein(a) are risk factors for major coronary events in middle-aged men. Am J Cardiol. 1996;77:1179-1184.
4. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;115:450-458.
5. Cui Y, Blumenthal RS, Flaws JA, et al. Non-high-density lipoprotein cholesterol levels as a predictor of cardiovascular disease mortality. Arch Int Med. 2001;161:1413-1419.
6. Liu J, Sempos CT, Donahue RP, et al. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol. 2006;98:1363-1368.
7. Ford ES, Giles, WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among U.S. adults. Diabetes Care. 2004;27(10):2444-2449.
8. National Cholesterol Educational Program on the Detection, Evaluation and Treatment of High Blood Cholesterol in adults. Circulation. 2002;106:3143-3421.
9. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowing with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;360:7-22.
10. Sacks FM, Tonkin AM, Shepherd J, et al. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project. Circulation. 2000;102:1893-1900.

PRESENTATION EM is a 40-year-old African American woman who is worried because her cousin was just diagnosed with diabetes. Subjective:   Non-smoker, sedentary Family history of diabetes, but not coronary heart disease; Medications: acetaminophen and an H2-blocker prn Objective:   5'3", 225 lb, BMI: 39.9, waist circumference: 38.5" BP: 132/88 mm Hg Total cholesterol: 191 mg/dL, HDL: 51 mg/dL, LDL: 95 mg/dL, triglycerides: 224 mg/dL Fasting glucose: 98 mg/dL Assessment (Framingham):   Points   Age (40): 0       TC (191): 3       HDL (51): 0       BP (132/88) untreated: 2       Diabetes (no): 0       Smoking status (no): 0         Point total: 5     10-year CHD risk: <1% Actual Risks:   Lifestyle factors (obese, sedentary) Pre-hypertension Hypertriglyceridemia High normal fasting glucose At risk for metabolic syndrome, future diabetes, significant lifetime risk of CHD PATIENT PRESENTATION 5 YEARS LATER: AGE 45 YEARS Subjective:   Non-smoker, still sedentary Brother (aged 54 years) just underwent angioplasty Medications now include HCTZ 12.5 mg daily Objective:   5'3", 245 lb, BMI: 43.3, waist circumference: 40.2" BP: 168/96 mm Hg TC: 210 mg/dL, HDL: 38 mg/dL, non-HDL: 172 mg/dL, TG: 298 mg/dL Fasting glucose: 121 mg/dL, HbA1C: 6.3% Assessment (Framingham):   Points   Age (45): 3       TC (210): 6       HDL (38): 2       BP (168/96) treated: 6       Diabetes (no): 0       Smoking status (no): 0         Point total: 17     10-year CHD risk: 5% Actual Risks:   Lifestyle factors (obese, sedentary) Major risk factors (hypertension, family history of premature CHD, IFG) All five criteria for metabolic syndrome:     Low HDL-C     High triglycerides     Increased waist circumference     Hypertension     Impaired fasting glucose PATIENT PRESENTATION 10 YEARS LATER: AGE 50 YEARS Subjective:   Non-smoker, still sedentary Medications:   HCTZ 12.5 mg/day, amlodipine 10 mg/day, metformin 500 mg twice daily, atorvastatin 20 mg/day Objective:   BMI: 44.2 BP: 150/90 mm Hg Total cholesterol: 164 mg/dL, HDL: 32 mg/dL, non-HDL: 132 mg/dL, triglycerides: 310 mg/dL Fasting glucose: 102 mg/dL Assessment (Framingham):   Points   Age (50): 6       TC (164): 2       HDL (32): 2       BP (150/90) treated: 5       Diabetes (no): 0       Smoking status (no): 0         Point total: 15     10-year CHD risk: 3%* *Decrease in 10-year CHD risk is attributed to treatment of hypertension and dyslipidemia; however, lifetime risk remains very high

Beyond LDL cholesterol targets: combination therapies for dyslipidemia management
Roger S. Blumenthal, MD

Although the primary therapeutic goal of dyslipidemia management remains focused on LDL cholesterol lowering, other facets of cardiovascular risk now point toward secondary goals. This article discusses combination therapies targeted toward lowering triglyceride and non-HDL cholesterol levels in patients who have already reached LDL cholesterol goals.

LDL cholesterol: The primary target

The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines indicate LDL cholesterol as the primary therapeutic target while stressing the importance of continuous counseling on lifestyle modification.¹ Figure 1 lists LDL cholesterol goals based on coronary heart disease (CHD) risk as determined by Framingham risk analysis.

For example, a 79-year-old man with diabetes, hypertension treated with enalapril and a recent history of non-ST-segment elevated myocardial infarction (non-STEMI) would be considered very high risk, and, therefore, have a minimum NCEP ATP III therapeutic LDL cholesterol target <100 mg/dL and an optional goal of <70 mg/dL.

Once the target LDL cholesterol level is set and lifestyle modifications are put into place, first-line therapy with a statin is initiated. If the LDL cholesterol target is not met after 6 weeks of statin therapy, the next step is typically to titrate the statin up to a higher dose. Although different classes of agents are available to further lower LDL cholesterol, this article focuses on combination therapies used to achieve secondary therapeutic targets after the primary LDL cholesterol goal is met.

Therefore, assume that high-dose statin therapy lowered LDL cholesterol to 68 mg/dL in the hypothetical patient discussed above. Should treatment stop here now that LDL goal has been reached?

Figure 1: LDL Cholesterol Goals Based on CHD Risk Equivalents Figure 1. According to the NCEP ATP-III treatment guidelines, LDL-C goals are <100 mg/dL for patients with a CHD risk >20%, <130 mg/dL for those with a CHD risk of 10% to 20% and <160 mg/dL for patients with 0-1 risk factors; corresponding non-HDL-C goals are <130 mg/dL, <160 mg/dL, and <190 mg/dL, respectively. Figure courtesy of Roger S. Blumenthal, MD

Secondary goals: Targeting non-HDL cholesterol and triglycerides

What steps should be taken after meeting target LDL cholesterol levels? Achieving secondary therapeutic goals is important, especially among high-risk individuals. As mentioned above, an important secondary goal in most patients is lowering the non-HDL cholesterol (determined by subtracting the HDL cholesterol from total cholesterol). Although further lowering of LDL cholesterol can move a patient toward this goal, often, the best way of achieving this goal is to focus on lowering triglyceride levels. Statin-based combination therapy is a good option in these patients.

Bile acid sequestrants

Although adding a bile acid sequestrant such as colesevelam to statin therapy may seem a logical step for dyslipidemia management, these agents are not good options in patients with elevated triglycerides. In one study, 94 patients with a total cholesterol >160 mg/dL were randomized to receive placebo, colesevelam 3.8 g daily, atorvastatin 10 or 80 mg daily or colesevelam 3.8 mg + atorvastatin 10 mg daily. After 4 weeks of treatment, patients treated with atorvastatin 80 mg (53%) and those treated with combination therapy (48%) had significantly greater reductions in LDL cholesterol levels than did patients treated with either atorvastatin 10 mg (38%) or colesevelam (12%) (P<.01). However, only patients treated with atorvastatin 10 mg or 80 mg had significant reductions in triglyceride levels (24% and 33%; P<.05); colesevelam monotherapy increased triglycerides by 12%.² These results indicate that, although colesevelam and statin combination therapy may provide a good approach for patients who require significant LDL cholesterol lowering, this combination is not appropriate in patients with high triglyceride levels.

Fibrates

Another combination option includes the addition of a fibrate such as fenofibrate or gemfibrozil to a statin. One study involved the randomization of 120 patients with type 2 diabetes and elevated LDL cholesterol (>130 mg/dL), low HDL cholesterol (<40 mg/dL) and elevated triglycerides (200 mg/dL to 399 mg/dL) to receive atorvastatin 20 mg daily, micronized fenofibrate 200 mg daily or a combination of the two.³ Among the 40 patients in each group, 80% of atorvastatin-treated patients, 5% of fibrate-treated patients and 97.5% of combination-treated patients (P<.05 vs. monotherapy) reached goal LDL cholesterol levels (<100 mg/dL). Furthermore, 75% of atorvastatin-treated patients, 92.5% of fibrate-treated patients and 100% of combination-treated patients (P<.0001 vs. baseline) reached triglyceride goals (<200 mg/dL) and 60% of patients in the combination therapy group reached a target HDL level of >45 mg/dL (P<.0001 vs. baseline). The atorvastatin-fenofibrate combination had favorable effects on the lipid profile in these patients with type 2 diabetes.

However, certain risks associated with fibrates and combinations of statins and fibrates should be weighed against the benefits. A study examining the incidence of rhabdomyolysis with statins and fibrates found that, although the overall incidence of rhabdomyolysis is low, certain combinations can raise the risk significantly.⁴ For example, combining cerivastatin with gemfibrozil resulted in an incidence rate of 1,035 per 10,000 person-years (95% CI, 389-2117); cerivastatin has been subsequently withdrawn from the market. The incidence of rhabdomyolysis associated with atorvastatin and fenofibrate was significantly lower, however, with an incidence rate of 22.45 per 10,000 person-years (95% CI, 0.57-125). Risk for myalgia and myositis also exists with these combinations. Fenofibrate is clearly the preferred fibrate when a statin is also prescribed.

Niacin

Adding niacin (nicotinic acid) to a statin is another option in dyslipidemia management. In the HDL Atherosclerosis Treatment Study (HATS), patients who received simvastatin and niacin had a 42% reduction in LDL cholesterol and a 26% increase in HDL cholesterol compared with baseline.⁵ Patients treated with combination therapy also experienced a reduction in average stenosis. Although the HATS population included only 160 participants, a much larger study is now under way to more fully determine the potential of adding niacin to a statin.

Aside from flushing, the main risk associated with niacin-based therapy is insulin sensitivity, and higher doses (>3 g/day) can worsen hyperglycemia among patients with type 2 diabetes.⁶ Recent research has shown, however, that lowering the dose of niacin may yield clinically relevant results without exacerbating hyperglycemia.⁷

Omega-3 fatty acids

“Currently, the AHA recommends using 2 g to 4 g daily of the omega-3 fatty acids EPA and DHA for patients who require lowering of triglyceride levels.” — Roger S. Blumenthal, MD

Omega-3 fatty acids may also be given in combination with a statin. Currently, the American Heart Association recommends using 2 g to 4 g daily of the omega-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) for patients who require lowering of triglyceride levels.⁸ These agents have been shown to lower triglycerides both as monotherapy and in combination,⁹ and they have few drug interactions.¹⁰ In one study, 59 patients with coronary heart disease and triglycerides >205 mg/dL (2.3 mmol/L) who were taking simvastatin 10 mg to 40 mg daily were randomized to receive prescription omega-3 fatty acids 2 g twice daily or placebo for 24 weeks.⁹ Omega-3 fatty acids significantly lowered triglycerides by 20% to 30% ( P<.005) and very-low density lipoprotein (VLDL) cholesterol by 30% to 40% (P<.005) compared with both baseline and placebo at 3, 6 and 12 months. Treatment with omega-3 fatty acids was safe and effective in these patients.

Summary

Secondary causes of dyslipidemia should always be considered. Next, risk should be assessed as the first step to establishing treatment goals. The primary goal should always be reaching the established LDL cholesterol target. Combination therapy should be considered when necessary to achieve secondary goals such as triglyceride and non-HDL cholesterol levels.

References

1. Adult Treatment Panel III. Executive summary of the third report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
2. Hunninghake D, Insull W, Toth P, et al. Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively. Atherosclerosis. 2001;158:407-416.
3. Athyros VG, Papageorgiou AA, Athyrou VV, Demitriadis DS, Kontopoulos AG. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes and combined hyperlipidemia. Diabetes Care. 2002;25(7):1198-1202.
4. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA. 2004;292:2585-2590.
5. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592.
6. Garg A, Grundy SM. Nicotinic acid as therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. JAMA. 1990;264:723-726.
7. Elam MB, Hunninghake DB, Davis KB, et al. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: a randomized trial. JAMA. 2000;284:1263-1270.
8. Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation. 2006;114:82-96.
9. Durrington PN, Bhatnagar D, Mackness MI, et al. An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridemia. Heart. 2001;85:544-548.
10. McKenney JM, Swearingen D, Di Spirito M, et al. Study of the pharmacokinetic interaction between simvastatin and prescription omega-3-acid ethyl esters. J Clin Pharmacol. 2006;46:785-791.