GRAPEVINE, TEX. — A combination of fibrates and statins to target different lipids may provide the best protection against cardiovascular events in diabetics and patients with metabolic syndrome, said Dr. Alistair I. Fyfe at the annual convention of the American College of Osteopathic Family Physicians.
The incidence of metabolic syndrome and type 2 diabetes is increasing because of the “fattening of America,” he said, noting that on average, Americans have gained 30 pounds since 1985.
Metabolic syndrome is a research term that refers to a combination of related health factors that together increase the risk for heart disease, including insulin resistance, obesity, unhealthy lipid levels, high blood pressure, and signs of kidney disease.
A hallmark of metabolic syndrome is the accumulation of visceral adipose fat, leading to disturbances in various cardiometabolic risk factors, which can increase insulin resistance and risk for both type 2 diabetes and heart attack.
The rationale for a combination treatment has evolved from a number of clinical trials that evaluated the efficacy of statins and fibrates in reducing cardiometabolic risk factors alone and together, said Dr. Fyfe, director of primary and secondary cardiac prevention at Medical City Hospital in Dallas.
“More patients achieve American Diabetes Association goals with combined drug therapy,” he said.
Diabetic subanalyses of four major placebo-controlled clinical trials that evaluated the efficacy of statins, a class of lipid-lowering drugs, to treat hypercholesterolemia, concluded that statins alone do not reduce cardiovascular risk in diabetic patients, said Dr. Fyfe. Cardiac risk in diabetics and people with metabolic syndrome is associated with elevated triglycerides and low HDL cholesterol, he explained.
Statins cured hypercholesterolemia in about one-third of study participants, but had no effect on the other 70%, he said. “Diabetic patients need to be treated differently [than other high-risk patients]. There is no doubt that statin therapy is here to stay; it is the right drug for 30% of people.”
Niacin and fibrates, another class of lipid-lowering drugs, improve triglycerides and increase HDL cholesterol. However, niacin is contraindicated for diabetics because it worsens insulin resistance. Fibrates have been used clinically since the 1970s to treat unhealthy lipids, but their mechanism of action was unclear until the 1990s, when researchers discovered that they activate peroxisome proliferator-activated receptors, which modulate carbohydrate and fat metabolism and adipose tissue differentiation.
By lowering triglycerides and raising HDL cholesterol levels, fibrates decrease the concentration of very-low-density lipoprotein (VLDL), resulting in a lower concentration of LDL cholesterol particles and increased particle size, which makes it easier for them to be eliminated from blood compared with small particles, Dr. Fyfe said, adding that elevated triglycerides are the result of an increase in VLDL.
Statins reduce hepatic cholesterol synthesis, which lowers intracellular cholesterol, which in turn stimulates upregulation of LDL cholesterol receptors and increases the uptake of non-HDL cholesterol particles from the blood. With the combined therapy, “the fibrate makes LDL available for the statin to clean out of the blood,” he said.
The results of several studies have verified the efficacy of combined therapy in diabetics. In one study, 120 patients were given 20 mg of atorvastatin or 200 mg of fenofibrate alone or a combination of the two drugs (Diabetes Care 2002;25:1198–202). The researchers recorded a 46% drop in LDL, a 50% reduction in triglycerides, and a 22% increase in HDL for participants who were given the combination therapy, compared with a 40% decline in LDL, a 30% drop in triglycerides, and a 9% increase in HDL for those who were given atorvastatin alone and a 15% decline in LDL, 41% reduction in triglycerides, and 15% increase in HDL in those who were given fenofibrate alone.
In another study, involving 618 participants, a combination of 20 mg of simvastatin and 160 mg of fenofibrate lowered LDL by 31%, VLDL by 48%, and triglycerides by 43% and raised HDL by 19%, compared with reductions of 26% in LDL, 24% in VLDL, and 20% in triglycerides and an increase of 10% in HDL in those who received 20 mg of simvastatin alone (Am. J. Cardiol. 2005;95:462–8).