Comparative Effectiveness Research in Evaluating Lipid-Modifying Therapies

San Francisco—Managed care professionals are increasingly utilizing comparative effectiveness research (CER) to determine the effectiveness, safety, and value of drugs. This detailed approach is particularly useful for patients with high cholesterol who can benefit greatly from taking statins and other medication classes such as cholesteryl ester transfer protein (CETP) inhibitors.

Still, challenges remain, most notably pertaining to the fact that only about half of the people at risk for coronary heart disease are receiving medications. During a satellite symposium at the AMCP meeting titled Evaluating Cost Effectiveness Beyond the Systematic Review Findings on Lipid-Modifying Therapies, pharmacists and doctors discussed the importance of comparing drugs and ensuring adherence to them.

Pete M. Penna, PharmD, principal and cofounder of Formulary Resources, LLC in Mercer Island, Washington, defined CER as a comparison of ≥2 drugs for the same disease, types of surgery, or other medical procedures and tests.

When conducting CER, Dr. Penna suggested seeking input from clinical experts, peers, and the public to draft research questions. The evaluators should then establish the criteria for their search, evaluate what studies meet the prespecified criteria, and conduct a meta-analysis of the available data. Results are usually included in a systematic review that summarizes, assesses, and evaluates clinical research studies.

According to Dr. Penna, formulary decision makers and pharmacy and therapeutic committees often use CER to analyze the safety, efficacy, and value of the drug under review in comparison to other options.

“Comparative effectiveness is all about answering these questions,” Dr. Penna said.

Current Medications

Richard E. Payne, MD, chief executive officer at the North Coast Family Medical Group in Encinitas, California, recommended that to detect, evaluate, and treat cholesterol in adults, healthcare professionals should consult the Adult Treatment Panel from the National Heart Lung and Blood Institute. These guidelines provide an integrated set of ways to reduce the risk of cardiovascular disease, according to Dr. Payne. The fourth edition is expected to be released later this year. Citing data from the Centers for Disease Control and Prevention’s National Health and Nutrition Examination Survey (NHANES), Dr. Payne said the mean serum total cholesterol level for people ≥20 years of age is 200 mg/dL, including 199 mg/dL for men and 201 mg/dL for women. He added that in the United States, 98.8 million people ≥20 years of age have a total cholesterol of ≥200 mg/dL, and 33.6 million have a total cholesterol of ≥240 mg/dL.

“This is a big deal,” Dr. Payne said.

Statins are the most common drugs used to treat high cholesterol, but Dr. Payne said that there was a need for additional therapies to address the residual risk for cardiovascular disease associated with statins. Dr. Payne said that studies have shown statins significantly lower low-density lipoprotein (LDL) and increase high-density lipoprotein (HDL). However, approximately 33% of patients may still be at risk of cardiovascular disease.

In February, the FDA made changes to statins’ safety labels, including removing the need for routine periodic monitoring of liver enzymes in patients. The FDA recommends that providers perform liver enzyme tests before patients start statin therapy and then when clinically indicated. Patients who take statins typically do not have serious liver injury, and periodic monitoring of liver enzymes is not effective at detecting or preventing serious liver injury.

The FDA also said that statins’ safety labels must contain information on the potential for generally non-serious and reversible cognitive side effects and increased blood sugar and hemoglobin A1c levels. Still, the FDA said statins remain the best option for treating high cholesterol.

“The bottom line is the cardiovascular benefit greatly outweighs the risks,” Dr. Payne said.

A major issue, according to Dr. Payne, is the low awareness and adherence rate in patients with high cholesterol. NHANES found that only 50.4% of people with a total cholesterol of ≥200 mg/dL were aware of their condition. Younger people were less likely to be aware, with only 28.3% in the 20 and 39 years of age category being aware of their high cholesterol, compared with 50.5% in the 40 to 59 years of age category, and 66.4% in the ≥60 years of age category.

Another study estimated ≤50% of people who qualify for lipid-modifying treatment for coronary heart disease (CHD) risk reduction receive the medications. Furthermore, approximately 33% receiving treatment achieve their goal LDL level, while 20% with CHD achieve their goal LDL level.

According to NHANES data from 2005 and 2006 of people with elevated LDL levels, 35.5% had not been screened previously, 24.9% had been screened but were not informed of their elevated cholesterol, and 39.6% received inadequate treatment.

Although high cholesterol is mostly found in older adults, younger people are also at risk. NHANES data from 1999 through 2006 showed 20.3% of people between 12 and 19 years of age had abnormal lipid levels.

“This is a shocking value,” Dr. Payne said.

CETP Inhibitor Overview

Mori J. Krantz, MD, director of cardiac rehabilitation at the Colorado Prevention Center in Denver, Colorado, said that to raise HDL, healthcare professionals generally recommend lifestyle changes such as better diet, aerobic exercise, weight loss, or smoking cessation. Pharmacologic therapies such as niacin, fibrates, and omega 3 fatty acids are also effective, to varying degrees, at increasing HDL.

Dr. Krantz said CETP inhibitors have been shown to markedly increase HDL, even more so than the traditional therapies. CETP inhibitors, a new drug class, inhibit the cholesteryl ester transfer protein and block the exchange of cholesteryl esters from HDL to apolipoprotein B, helping to increase HDL and leading to enlarged HDL particles.

Several companies are developing CETP inhibitors. Dr. Krantz said Pfizer spent $1 billion on torcetrapib, but, since the drug had adverse effects that were not related to CETP inhibition but led to increased mortality, major cardiovascular events, and high blood pressure, Pfizer terminated the trial due to safety concerns.

Other investigational CETP inhibitors included anacetrapib, dalcetrapib, and evacetrapib, which trials have shown to be safe and effective. In a phase 3 trial, anacetrapib improved HDL regardless of the baseline lipid profile of patients with diabetes or other high-risk characteristics as well as those taking statin therapy. In addition, a phase 3b study of healthy subjects with mild hyperlipidemia found that dalcetrapib significantly increased HDL and significantly lowered LDL. Finally, a phase 2 study of people with high LDL and low LDL found that evacetrapib significantly increased HDL and significantly lowered LDL compared with statin monotherapy.