Hollywood, Fla.—In 2011, the FDA issued new dosing limits on simvastatin that included a contraindication for concomitant use of the fibrate gemfibrozil due to concerns about an increased risk for rhabdomyolysis. But the reaction of some health systems to ban the use of all statin-fibrate combinations has come with its own set of dangers, according to new data presented at the annual meeting of the American College of Clinical Pharmacy.

The most troubling unintended consequence is an increased risk for cardiovascular events in patients who are taken off fibrates, according to a retrospective study of patients treated at the Portland Veterans Affairs Medical Center (PVAMC). The percentage of patients with triglycerides greater than 240 mg/dL, high-density lipoprotein (HDL) less than 34 mg/dL and diabetes more than doubled (18% vs. 39%) following a universal mandate to discontinue fibrates in patients who had been given the drugs with statins, reported Harleen Singh, PharmD, BCPS, an associate professor in the Department of Pharmacy Practice at the Oregon Health & Sciences University College of Pharmacy, in Portland.

An expert in cardiovascular medicine who was not affiliated with the study said the results should be seen as a warning not to apply fibrate-statin bans too aggressively. “I don’t think you can make a blanket statement for all patients,” said Robert DiDomenico, PharmD, a cardiovascular clinical pharmacist at the University of Illinois at Chicago (UIC) College of Pharmacy. “Some [patients] may have a real need to be on the fibrates to prevent the development of pancreatitis,” he said. Thus, issuing broad proscriptions without adequate investigation is “a little shortsighted.”

Policy’s Underpinnings

PVAMC’s policy came out of a Veterans Health Administration recommendation, which discouraged “the use of any statin–fibrate combination because of the known risks and yet to be proven incremental benefit of these combinations beyond statin therapy alone” (National PBM Bulletin, June 9, 2011; www.pbm.va.gov). To assess the impact of the PVAMC universal ban, Dr. Singh and her colleagues recorded lipid levels from the last test before discontinuation and the first test within eight to 20 weeks after. Of the 837 patients whose fibrates were discontinued, 398 have been screened to date and 348 met inclusion criteria. The majority had elevated triglycerides, 68% had diabetes, 32% had coronary artery disease, and 11% had a stroke before discontinuation.

The 51% of patients who had follow-up lipid tests had a significant increase in mean triglycerides (248 mg/dL before, 376 mg/dL after; P=0.0011), a decrease in mean HDL (38 mg/dL before, 36 mg/dL after; P=0.0013) and an increase in mean total cholesterol (171 mg/dL before, 188 mg/dL after; P<0.05). Low-density lipoprotein levels did not change significantly.

Part of the elevated cardiovascular risk may have been due to the fact that patients did not appear to be receiving alternatives to replace the benefits they may have been deriving from fibrates, Dr. Singh reported. Prescribing rates for adjunctive therapies such as niacin or omega-3 fatty acids, for example, did not significantly change, she noted.

The results suggest that patients such as those in the study may still benefit from statin–fibrate therapy in preventing major cardiovascular events, including nonfatal myocardial infarction and nonfatal strokes, Dr. Singh told Pharmacy Practice News. Those benefits already have been documented in a subgroup analysis of the ACCORD trial (N Engl J Med 2010;362:1563-1574), she noted.

Dr. Singh added that more diligent follow-up efforts are needed, including more frequent monitoring of lipid levels, which typically is required in patients with high triglycerides.

Dr. DiDomenico said that his own institution’s reaction to the FDA’s updated dosing guidelines on simvastatin may have been too broad. In response to the agency’s recommendations, he noted, clinical decision support on the electronic medical record at UIC no longer allows physicians to coprescribe gemfibrozil and simvastatin. “What you are essentially telling the docs in training is that you should never put a patient on both of these drugs together, and in some patients, there definitely could be a benefit” to such combination therapy.

—Susan Birk


Dr. DiDomenico reported that he has served on Roche’s advisory board. Dr. Singh reported no relevant financial conflicts of interest.