New cholestorol treatment guidelines — reaching even lower LDL levels

Physicians debate drug combination or aggressive statin therapy

Now that the National Cholesterol Education Program has updated its clinical practice guidelines on cholesterol management, one of the questions is how health care providers can reach the lower treatment goals for low-density lipoprotein (LDL) cholesterol for patients at high and moderately high risk of a heart attack. The guidelines, for example, offer a new therapeutic option to treat very high-risk patients to levels below 70 mg/dL.

Peter H. Jones, MD, associate professor of medicine and co-director of the Lipid Metabolism and Atherosclerosis Clinic at Baylor College of Medicine in Houston, recently gave a presentation about how to achieve the LDL goals in high-risk patients. He made this presentation at the National Lipid Association meeting in Orlando, FL, in August.

High-dose therapy: Is more really better?

Clinical trial evidence shows that in those very high-risk individuals, a more intense LDL-lowering treatment program is in their best interest, certainly better than a less intensive LDL-lowering program, Jones says. "Most of those trials have tended to focus on monotherapy and they tend to be higher-dose statins, at least the more efficacious statins like high-dose atorvastatin [Lipitor], for instance."

The average LDL of the patient at risk for coronary disease is around 130 to 140 mg/dL, he explains. Getting this patient to 70 mg/dL, therefore, is a 50% reduction.

That might be possible with a high-dose atorvastatin or a high-dose rosuvastatin (Crestor), but a lot of physicians aren’t comfortable using those kinds of doses, Jones says. Instead, he advocates using statins in combination with other drugs. "I think combinations of treatments are accessible and tolerable and reasonable for physicians to use with good safety so that more moderate doses of statins along with a bile acid resin like Welchol [colesevelam], or a moderate-dose statin plus the cholesterol-absorption inhibitor Zetia [ezetimibe] can get you 50% LDL lowering easily."

Lifestyle changes can add extra LDL lowering on top of what is possible with the drugs, he notes. "This 50% of more LDL-lowering range is now feasible in routine clinical practice without doctors having to feel that they are using maximum doses or possibly doses that may have higher adverse events," Jones says.

Combination therapy

In some situations, patients have other lipid problems, such as low HDL or high triglycerides. Combinations that include niacin and possibly the fibrates may help these patients, he says. "Pharmacists and the FDA have always been a little skittish about using fibrates in combination with statins, but the data support that fenofibrate, which is both branded and generic, is a safer combination to use than gemfibrozil. In selective patients, the benefits of those kinds of combinations would outweigh the risks."

Other cardiologists aren’t as supportive of the idea of using combination therapies to lower LDL levels. Steven E. Nissen, MD, medical director of the Cardiovascular Coordinating Center in the department of cardiovascular medicine at the Cleveland Clinic, is an advocate of more aggressive statin therapy instead.

"There are no data whatsoever on combination therapy having any incremental benefits on events. I am particularly opposed to the use of ezetimibe in combination with statins unless absolutely necessary. The reason is that I am concerned that LDL lowering with agents like ezetimibe will have little or no effect on morbidity and mortality," he says.

In fact, Nissen spoke of this concern in his editorial in the Sept. 15 issue of the Journal of the American Medical Association (full text available at: http://jama.ama-assn.org/cgi/content/full/292.11.1365v1). The editorial addressed the A to Z statin trial.

In this editorial, Nissen says that each statin requires careful testing in clinical trials to establish the extent of benefit and risk. This is even more important with regard to nonstatin LDL-cholesterol-lowering therapies, he continues. "Because these agents, such as ezetimibe, have not demonstrated anti-inflammatory effects in the absence of concomitant statin administration, their value in reducing events cannot be assumed and must be tested in well-designed clinical outcome trials."

Nissen also is not a big advocate of bile acid resins because he says they are not well tolerated and their efficacy is limited. He does use fibric acid derivatives and niacin, however. "Niacin is very effective in raising HDL and further lowering of LDL, but there is not a lot of outcome data for niacin either."

Jones and Nissen do agree on this: Statins are going to be the core central treatment.

"The statin is going to be a standard of care in high-risk individuals," Jones says. "Although there are known adverse problems, they are manageable, they are reversible, they are low-incidence, and the benefits do outweigh those risks."