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A new look in mixed dyslipidemia

ByChristie M. Ballantyne, MD

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Patients with mixed dyslipidemia are at high risk for coronary heart disease (CHD) events. In particular, diabetic dyslipidemia, characterized by the triad of a high level of triglycerides, a low level of high-density lipoprotein (HDL) cholesterol, and an abundance of atherogenic small, dense low-density lipoprotein (LDL) particles, confers a high risk of CHD events. The National Cholesterol Education Program Adult Treatment Panel III identified diabetes as a CHD risk equivalent requiring aggressive risk-reduction strategies.¹ Although statins are the first step in the treatment of diabetic dyslipidemia, these patients remain at high risk despite statin therapy, presumably due to the elevated level of triglyceride and low HDL level that are not adequately treated by statins.

Please review the following case study of a 62-year-old man with type 2 diabetes for 5 years and the corresponding questions:

A 62-year-old man with type 2 diabetes for 5 years presents for a new patient examination. He has a history of angina. He is an ex-smoker, his body mass index is 28.6 kg/m², and his waist circumference is 40 inches. His current medications are glipizide (10 mg/day) and metformin (1,000 mg twice daily) to treat his diabetes, the combination of lisinopril/hydrochlorothiazide (20 mg/12.5 mg) to treat his hypertension, simvastatin (40 mg/day), and aspirin (325 mg/day). On this regimen, his LDL cholesterol is 69 mg/dL, his HDL cholesterol is 38 mg/dL, and his triglyceride level is 330 mg/dL. He has 1+ protein on urinalysis. His blood glucose level is 160 mg/dL and his HbA1c is 7.3%. He has a normal thyroid stimulating hormone.

According to the Heart Protection Study, patients with diabetes and arterial disease who were randomized to sim vastatin had a 5-year event rate of 31%. ² Therefore, although the patient in the case study is being treated with evidence-based therapies, his residual risk of disease merits intensifying his therapy.

None of these trials based enrollment on an elevation in triglyceride values. In the FIELD study, patients needed a triglyceride level >1 mmol/L (>89 mg/dL) to be enrolled, a level not considered to be elevated.³ The lack of clinical trials designed specifically to test hypotheses in patients with hypertriglyceridemia is disappointing for clinicians who practice evidence-based medicine.

Although colesevelam improves glucose control and would be beneficial in this patient with diabetes, it also increases triglyceride levels, which would be detrimental to this patient with a triglyceride level of 330 mg/dL.

Two CHD prevention trials with fibrates have assessed their efficacy in subgroup analyses of patients with diabetes. Trials of fibrate therapy that included subgroups of patients with diabetes were the primary-prevention Helsinki Heart Study and the secondary-prevention VA-HIT.^4,5

Only 135 patients with diabetes were enrolled in the Helsinki Heart Study, and assignment to active treatment with gemfibrozil was associated with a 68% reduction in the incidence of CHD compared with placebo in this subgroup, a reduction that failed to achieve statistical significance because of low power.

VA-HIT enrolled 627 patients with diabetes, and this subgroup had a statistically significant 24% reduction in CHD events with randomization to gemfibrozil vs. placebo. In VA-HIT, the mean baseline LDL cholesterol was only 112 mg/dL; the mean baseline HDL cholesterol was 32 mg/dL, and mean triglyceride levels at baseline were 160 mg/dL.

Interpretation of FIELD is complex.³ It did not achieve its primary endpoint—a significant reduction in CHD death and nonfatal myocardial infarction (MI) with randomization to fenofibrate vs. placebo. The relative risk reduction on the primary outcome with active therapy was 11% (P =.16), with no benefit of fenofibrate on CHD death but a significant (P =.01) 24% reduction in nonfatal MI. The difficulty in interpreting this study lies in the large number of patients who initiated statin therapy during the trial. Interpretation of the results may have been easier if all patients had been taking a statin at baseline. Nevertheless, subgroup analysis showed no effect of fenofibrate on secondary prevention of CHD (patients with a history of cardiovascular disease in FIELD did not have better results if randomized to fenofibrate), and the patient in the case study has arterial disease. Therefore, the data do not support the use of a fibrate in the case patient.

A trial of combination lipid-modifying therapy, the Action to Control Cardiovascular Risk in Diabetes (ACCORD),⁶ is ongoing. ACCORD is attempting to simultaneously assess degrees of therapy intensity, including glucose control, blood pressure control, and lipid modification, on the incidence of major cardiovascular events in approximately 10,000 patients with type 2 diabetes. In ACCORD, the addition of fenofibrate to baseline simvastatin is being assessed.

A post-hoc analysis of the Coronary Drug Project reveals a favorable effect of monotherapy with high-dose niacin (3 g/day) on the incidence of nonfatal MI compared with placebo in patients with elevated levels of fasting plasma glucose.⁷

The Atherothrombosis Drug Intervention for Metabolic Syndrome with Low HDL/High Triglycerides and its Impact on Global Health Outcomes (AIM HIGH) is an ongoing study in which approximately 3,000 statin-naïve men and women aged 45 years or older with CHD or a CHD risk equivalent are randomized to 40 mg/day simvastatin alone or plus 2,000 mg/day niacin extended release. In both groups, simvastatin can be titrated to 80 mg/day if LDL cholesterol remains >80 mg/dL after 4 weeks. To qualify for inclusion, men must have a baseline HDL cholesterol <40 mg/dL and women must have a baseline HDL cholesterol of <50 mg/dL, and the triglyceride level at baseline must be between 150 mg/dL and 400 mg/dL. The primary outcome is time to a first major adverse cardiovascular event.

In the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive), pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, caused a significant reduction in triglyceride levels (P<.0001), a significant increase in HDL cholesterol levels (P<.0001), and a significant reduction in the LDL cholesterol/HDL cholesterol ratio (P<.0001) compared with placebo in patients with type 2 diabetes.⁸ Pioglitazone failed to significantly reduce the incidence of a composite of vascular events that comprised the primary endpoint but was associated with a significant 16% reduction in the combined risk of death, MI, and stroke (P =.027). Patients treated with pioglitazone experienced a 28% reduction (P =.045) in the incidence of a second MI and a 37% reduction (P =.035) in the occurrence of an acute coronary syndrome.

The GISSI-Prevenzione trial was conducted in 11,324 post-MI patients who were randomly assigned supplements of omega-3 fatty acids, 1 g/day (800 mg to 882 mg of EPA/DHA ethyl esters), vitamin E, 300 mg/day, both, or neither for 3.5 years.⁹ The dosage was not sufficiently high to favorably alter triglyceride levels. Instead, the goal of the study was to observe the biologic effects of omega-3 fatty acids. The primary combined efficacy endpoint was the incidence of death, nonfatal MI, and stroke.

Omega-3 fatty acids were associated with a significant (P<.01) reduction in all cause mortality, which was apparent as early as 90 days. This reduction in mortality is believed to result from a significant (P<.001) reduction in sudden cardiac death.¹⁰ Vitamin E had no effect on any endpoint.

The Japan Eicosapentaenoic Acid (EPA) Lipid Intervention Study (JELIS) is the first large-scale, prospective, randomized trial to combine statins and omega-3 fatty acid therapy to determine whether the combined treatment would afford additional clinical benefits in preventing major coronary events.¹¹

In this open-label trial of 18,645 patients with hypercholesterolemia, 9,326 were assigned to EPA (1,800 mg/day) in addition to statin therapy, and 9,319 were assigned to statin therapy alone. Statin therapy consisted of 10 mg/day prava statin, or 5 mg/day simvastatin. The primary endpoint was the incidence of major coronary events (defined as sudden cardiac death, fatal or nonfatal MI, unstable angina pectoris, and coronary artery bypass graft/percutaneous coronary intervention) at a mean of 4.6 years.

The primary endpoint was achieved in 2.8% patients treated with EPA plus statin compared with 3.5% patients treated with a statin alone, resulting in a 19% reduction (P =.011). This reduction in the primary endpoint was independent of the reduction in total cholesterol and LDL cholesterol.

Conclusion

Patients with mixed dyslipidemia have high residual risk of CHD events even after statin therapy. Although several therapies may be added to statins to further manage dyslipidemia, outcomes data lack information about the use of most of these agents with a statin.

However, evidence shows that fibrates, niacin, and omega-3 fatty acids reduce cardiovascular risk. No completed trials have examined the addition of these agents to statins in patients with mixed hyperlipidemia.

References

1. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults: Executive summary of the Third Report of the National Cholesterol Education Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486–2497.
2. Collins R, Armitage J, Parish S, Sleigh P, Peto R, Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet.2003;361:2005-2016.
3. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849-1861.
4. Koskinen P, Mänttäri M, Manninen V, Huttunen JK, Heinonen OP, Frick MH. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care. 1992;15:820-825.
5. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410-418.
6. www.clinicaltrials.gov/ct/gui/show/NCT00000620?order=29. Last accessed January 17, 2008.
7. Canner PL, Furberg CD, Terrin ML, McGovern ME. Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol. 2005;95:254-257.
8. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279-1289.
9. GISSI Prevenzione investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999;354:447-455. [published correction: Lancet. 2001;357:642.]
10. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002;105:1897-1903.
11. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.