Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

15th Annual Meeting of the American Association of Clinical Endocrinologists

Chicago, Illinois / April 26-30, 2006

Current National Cholesterol Education Program (NCEP) guidelines for cholesterol reduction focus primarily on lowering LDL-C, with statins considered the most effective pharmacological agents. However, statins have limited therapeutic effect on HDL-C and triglycerides (TG) (NCEP Adult Treatment Panel [ATPIII] Circulation 2002;106(25):3143-421).

According to Dr. David G. Robertson, Division of Endocrinology and Metabolism, Emory University School of Medicine, Atlanta, Georgia, “LDL-C is not necessarily the best predictor of who will have a cardiovascular [CV] event. CV disease is what we want to impact, and there is strong opportunity for intervention and for diabetes patients to alter risk.”

Mixed dyslipidemia (moderately elevated LDL-C, low levels of HDL-C and high levels of TG) is highly atherogenic and commonly diagnosed in patients with diabetes and the metabolic syndrome. Therapy with fibrates may offer greater therapeutic intervention for CV disease risk reduction in this patient population as these compounds tend to raise HDL-C, lower TG and lower LDL-C to a modest extent.

Increasing HDL-C in the Diabetic Patient

Even though the focus of CV treatment is LDL-C, epidemiological studies, in particular, the Framingham Heart Study, document that the lower the HDL-C level, the greater the risk of coronary heart disease (CHD). Risk reduction is associated with increased levels of HDL-C; HDL-C is inversely correlated by TG (Gordon et al. Am J Med 1977;62(5):707-14).

According to Dr. George Steiner, Director, Lipid Research Clinic, Toronto General Hospital, and Professor of Medicine and Physiology, University of Toronto, Ontario, “It’s unclear as to whether low HDL-C or high TG puts patients at greater [CV] risk,” adding that “if two tightly related variables change, it’s difficult to determine which is more important.”

Among other functions, HDL-C is essential in transporting cholesterol to the liver from peripheral tissues, resulting in the removal of cholesterol from the body, known as reverse cholesterol transport. “Reverse cholesterol transport could deplete the body of cholesterol,” commented Dr. Steiner.

Fibrates increase HDL-C, especially in hypertriglyceridemic patients, and both niacin and fibrates are used to treat patients with low HDL-C. However, Dr. Steiner explained that using niacin to increase HDL-C in diabetic patients presents a problem, as its side effects include flushing, gastric irritation, liver enzyme changes, hyperuricemia and induction of insulin resistance. Insulin resistance is the most worrisome, he noted, as it can bring on or exacerbate diabetes and is associated with increased coronary risk. Although extended-release niacin likely produces less hyperglycemia than does the immediate-release formulation, no studies on insulin resistance have been undertaken. On the other hand, it may be considered in patients with impaired renal function.

FIELD Study: Macrovascular Results and Primary Prevention Benefits

The role of fibrates in type 2 diabetes has been evaluated in the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study. The study randomized type 2 diabetes patients to receive micronized fenofibrate 200 mg/day (n=4895) or placebo (n=4900). “The FIELD study demonstrates the long-term safety of fibrates, which have an important role to play in further reducing CV events for type 2 [diabetes] patients,” Dr. Robertson told delegates. He noted that although statins remain the primary intervention, “many patients are still at high [CV] risk, despite the use of statins. FIELD revealed that fibrates are particularly effective in reducing CV disease risk in patients with type 2 diabetes.”

Results demonstrated that actively treated type 2 diabetes patients (for five years) had significant reductions in total CV disease events, in particular nonfatal myocardial infarction (MI) and coronary revascularization (24%, P=0.01 and 21%, P=0.003, respectively). In patients with no history of CV disease, the total CV events were reduced by 19% (P=0.004). Although major coronary events, the primary end point of the study, were not significantly reduced, the researchers determined that the higher rate of initiating statin therapy in the placebo group might have obscured a greater benefit (Keech et al. Lancet 2005;366(9500):1849-61).

Microvascular Benefits

Although the mechanisms involved are unknown, in the FIELD study, active treatment was associated with a beneficial effect on the microvasculature and associated complications were reduced.

A significant reduction in the rate of progression to albuminuria and a significant increase in the rate of regression of microalbuminuria were observed in the active treatment cohort (P=0.002). In addition, fenofibrate significantly reduced laser treatment for retinopathy by 30% (P=0.0003). In a subgroup of patients without retinopathy at baseline, the effect in reducing laser therapy was similar (P=0.001). During the study, the number of patients requiring dialysis was 16 in the fibrate group and 21 in the placebo group.

Combination Strategy

Combining fibrates with statins is a pharmacologic strategy that strives to comprehensively target all lipoproteins to reduce CV risk in mixed dyslipidemia patients and may offer greater risk reduction than can be achieved with LDL-C lowering alone.

According to Dr. Peter H. Jones, Associate Professor of Medicine, Section of Atherosclerosis and Lipid Research, Baylor College of Medicine, Houston, Texas, high doses of statins are not the optimal choice for raising HDL-C in comparison with niacin and fibrates, especially in mixed dylipidemia. “Prescribing high-dose statin therapy must also be balanced with the risk for side effects, which include increased hepatic transaminases and muscle symptoms,” he noted.

“The NCEP ATP III’s focus on LDL-C has led us to be statin-centric in our therapies,” Dr. Jones commented, adding that NCEP ATP III guidelines do recommend adding a fibrate or nicotinic acid to LDL-C-lowering therapy in high-risk patients and combination treatments help clinicians achieve cholesterol goals as delineated by the American Diabetes Association.

When using a fibrate/statin combination, clinicians fear increased adverse effects in the form of myositis and rhabdomyolysis. This may be due in part to negative experience with the gemfibrozil/cerivastatin combination. Dr. Jones noted that part of the problem with gemfibrozil is its interaction with statins, while fenofibrate and bezafibrate are less likely to produce deleterious muscle side effects (such as rhabdomyolysis) when used in combination with statins.

In managing patients with muscle complaints, experts recommended caution and careful regulation of dosing. According to Dr. Robertson, “The message is we don’t give up. We keep trying other things, knowing that not treating the lipids leaves the patient at intolerable risk.”

Dr. Jones reiterated, “Statins are the cornerstone of treatment, but not the only treatment. The vast majority of diabetes patients should be on another [lipid] therapy. Combination drug treatment in high-risk patients with dyslipidemia will be the wave of the future.”

Summary

While the five-year results of the FIELD study have demonstrated the good safety and tolerability profile of fenofibrate in patients with type 2 diabetes and the significant mortality reduction in patients without a history of CV disease, the safety and efficacy of combination therapy with a statin in this population warrants continued study. Finding the optimal combination treatment strategy in the patient with type 2 diabetes may be the next step in reducing CV outcomes. The ACCORD (Action to Control Cardiovascular Risk in Diabetes) study in 10,000 patients analyzing a fibrate/statin combination is one study aimed at answering this question.