COMMENTARY: SYMPOSIUM ON DYSLIPIDEMIA

A new approach to atherogenic dyslipidemia

Charles A. Reasner, MD

VOL 117 / NO 4 / APRIL 2005 / POSTGRADUATE MEDICINE

Dr Reasner is on the speakers' bureau for Kos Pharmaceuticals, Inc, Pfizer Inc, and Takeda Pharmaceuticals America, Inc. He discloses no unlabeled uses of any product mentioned in this article.

Reasner CA. A new approach to atherogenic dyslipidemia. Postgrad Med 2005;117(4):13-6

As a clinical endocrinologist, I spend 80% of my time seeing patients who have type 2 diabetes. Most of my patients are insulin-resistant and have the metabolic syndrome. Cardiovascular disease will develop in most of these patients. In this symposium, Dr Rosenson, Dr McGovern, and I discuss the treatment of the atherogenic dyslipidemia seen in insulin-resistant patients.

In the article "Cholesterol Lowering in Diabetes," Dr Rosenson outlines what may be viewed as the state-of-the-art approach to dyslipidemia, which focuses on therapy with statins to decrease low-density lipoprotein cholesterol (LDL-C) levels. Dr McGovern's article, "Taking Aim at HDL-C," previews methods for raising high-density lipoprotein cholesterol (HDL-C) levels, which I believe will be the next target of lipid treatment. Both articles, written by academic cardiologists, provide important insights for primary care physicians. In this commentary, I add a few thoughts from the perspective of an endocrinologist.

The disease process

Once we understand the pathogenesis of atherogenic dyslipidemia, it becomes clear that the prevalence of low HDL-C levels, hypertriglyceridemia, and a predominance of small, dense LDL particles will increase in direct relation to the growing rate of obesity in the United States (see figure 3 in Dr. McGovern's article). As abdominal obesity increases, free fatty acids are delivered through portal circulation to the liver and serve as substrates for the production and release of very low-density lipoprotein (VLDL) particles into the bloodstream. The longer these particles remain in circulation, the greater the opportunity for them to be acted on by cholesteryl ester transport protein, which transfers cholesterol from LDL and HDL particles to VLDL particles in exchange for triglycerides. This cholesterol transfer results in large VLDL particles that are enriched in cholesterol and small LDL and HDL particles that are cholesterol-depleted.

In addition, triglyceride-enriched HDL particles are more easily cleared by the kidneys, which reduces the number of HDL particles in the bloodstream. It is no wonder that three key components of the metabolic syndrome are obesity, low HDL-C levels, and hypertriglyceridemia. Atherogenic dyslipidemia results in increased atherosclerotic plaque formation because of an imbalance between an increased number of small, dense LDL particles (which carry cholesterol to the vascular endothelium) and a decreased number of HDL particles (which remove cholesterol from atherosclerotic vessels).

The role of statins

As Dr Rosenson explains in his article, statin therapy provides at least as much cardiovascular risk reduction in diabetic patients as in patients without diabetes. Although statin therapy uniformly lowers cardiovascular risk in diabetic patients regardless of their baseline LDL-C level, diabetic patients treated with statins remain at the same or higher absolute risk of a cardiovascular event as similar patients without diabetes who do not take statins.

For example, in the Scandinavian Simvastatin Survival Study (4S) (1), patients with coronary artery disease and very high LDL-C levels (mean value at baseline, 190 mg/dL [4.92 mmol/L]) were randomly assigned to receive either simvastatin or placebo. Total mortality was reduced by 43% among diabetic patients compared to 29% in patients without diabetes; however, survival in untreated patients without diabetes was superior to that in treated diabetic patients (figure 1).

In the Cholesterol and Recurrent Events (CARE) trial (2), patients with known coronary artery disease and average cholesterol levels (mean LDL-C, 140 mg/dL [3.62 mmol/L]) were randomly assigned to receive either pravastatin sodium or placebo. Diabetic patients had a 27% reduction in coronary events with treatment, compared to a 22% reduction in patients without diabetes. Risk of a cardiovascular event was again comparable between diabetic patients who received statin therapy and patients without diabetes who did not receive treatment.

The heightened residual risk of cardiovascular disease seen in diabetic patients treated with statins cannot be ameliorated by controlling blood glucose. In the UK Prospective Diabetes Study (UKPDS) (3), lowering subjects' blood glucose from an average hemoglobin A_1c level of 8% to 7% with use of sulfonylureas or insulin resulted in a 30% reduction in microvascular complications but had no significant impact on macrovascular events. In this study of more than 4,000 persons in whom type 2 diabetes was newly diagnosed, the strongest predictor of macrovascular events was their LDL-C level. The second best predictor was their HDL-C level (4).

Niacin and HDL-C

Primary care physicians seldom make HDL-C a target of diabetes therapy. However, I believe raising HDL-C levels in statin-treated patients will be the next major advance in the treatment of atherogenic dyslipidemia. For this reason, I asked Dr McGovern to review present treatment options to raise HDL-C concentration and to preview future therapies being studied to increase HDL-C levels.

Fibric acid derivatives and niacin are currently used to raise HDL-C levels. We have known for years that both classes of drugs can reduce cardiovascular events when used as monotherapy. In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (5), 2,531 patients with low levels of HDL-C were randomly assigned to receive either gemfibrozil or placebo. Diabetic patients in the study had a 32% reduction in cardiovascular events, compared to an 18% reduction in patients without diabetes (6). Similarly, in the Coronary Drug Project, therapy with niacin reduced nonfatal myocardial infarction by about 30% (7). The project was a randomized, double-blind, placebo-controlled trial, conducted from 1966 to 1974, that evaluated five lipid-modifying agents in 8,341 male patients who had a previous myocardial infarction. A recent analysis of the Coronary Drug Project (8) showed that diabetic patients treated with niacin had the same or greater reduction in coronary events as nondiabetic patients (figure 2).

One of the concerns about niacin therapy for diabetic patients is that it increases their blood glucose level. Although treatment produces a modest increase in glucose of about 10 mg/dL and an increase in hemoglobin A_1c of about 0.2%, the reduction in cardiovascular risk far outweighs the negative impact of this small increase in hemoglobin A_1c. Therefore, I prescribe niacin therapy for my diabetic patients who have low levels of HDL-C.

The combined effect of niacin and statin therapy was examined by Brown and colleagues (9). After 3 years, patients treated with a statin and niacin showed an amazing 90% reduction in cardiovascular events compared with patients treated with placebo. However, until recently, the incremental effect of adding a drug to raise HDL-C levels in patients already being treated with a statin had not been studied.

In the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 trial (10), 1,000 mg of extended-release niacin was added to background statin therapy in 167 patients with known coronary artery disease. Levels of HDL-C increased 21% in the treated group, while LDL-C was unchanged. The primary end point was change in carotid intima-media thickness. Although patients who received statin-only therapy showed progression of carotid atherosclerosis, no progression was seen in patients treated with the combination of statins and niacin. Clinical cardiovascular events occurred in three patients treated with combination therapy and in seven patients treated with statins alone (P=.20). Thus, adding niacin to background statin therapy slowed the progression of atherosclerosis in patients with known coronary artery disease.

Conclusion

It seems clear that atherogenic dyslipidemia represents an imbalance in cholesterol transport, resulting in more cholesterol being delivered to the blood vessel wall and less being removed. Statin therapy can decrease diabetic patients' coronary event risk to a level comparable to that of untreated persons without diabetes. Combining treatments aimed at raising HDL-C with use of a statin is necessary to achieve a favorable outcome for our insulin-resistant patients with atherogenic dyslipidemia.

References

1. Pyorala K, Pedersen TR, Kjekshus J, et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997;20(4):614-20 [Erratum, Diabetes Care 1997;20(6):1048]
2. Goldberg RB, Mellies MJ, Sacks FM, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The CARE Investigators. Circulation 1998;98(23):2513-9
3. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):837-53 [Erratum, Lancet 1999;354(9178):602]
4. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998;316(7134):823-8
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. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341(6):410-8
6. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch Intern Med 2002;162(22):2597-604
7. Clofibrate and niacin in coronary heart disease. JAMA 1975;231(4):360-81
8. Canner PL, Furberg CD, Terrin ML, et al. Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol 2005;95(2):254-7
9. 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(22):1583-92
10. Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004;110(23):3512-7

Dr Reasner, coordinator of this symposium, is professor of medicine, University of Texas Medical School at San Antonio, and medical director, Texas Diabetes Institute, San Antonio. Correspondence: Charles A. Reasner, MD, 701 S Zarzamora St, San Antonio, TX 78207. E-mail: charles.reasner@uhs-sa.com.

Symposium Index

• Commentary: A NEW APPROACH TO ATHEROGENIC DYSLIPIDEMIA. By Charles A. Reasner, MD
• CHOLESTEROL LOWERING IN DIABETES: New evidence supports aggressive LDL-C targets. By Robert S. Rosenson, MD
• TAKING AIM AT HDL-C: Raising levels to reduce cardiovascular risk. By Mark E. McGovern, MD

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