CHICAGO — Lowering LDL cholesterol using statins will remain the main focus of cardiovascular prevention in the next generation of clinical practice guidelines, according to one expert.
“Lately, because of controversies concerning new medications we've had, some people say maybe LDL shouldn't be the focus of the clinical guidelines. There are four strong reasons why that's not true: the breadth and depth of the supporting genetic, epidemiologic, experimental, and clinical trial evidence,” Dr. Neil J. Stone said at the annual meeting of the American Thyroid Association. Dr. Stone is a cochair of the National Heart, Lung, and Blood Institute's Adult Treatment Panel (ATP) IV, along with Dr. Scott M. Grundy, chairman of the department of clinical nutrition at the University of Texas at Dallas.
Dr. Stone, who also served on ATP I and III, provided a glimpse into the future of the dyslipidemia guidelines and the thinking of those who fashion them, and also fielded audience criticism that the guidelines are too LDL centric and described the high bar that's been set for acceptance of new therapies, including the novel thyroid hormone analogues many endocrinologists are interested in using to lower LDL.
He stressed that statins, the drugs of choice for lowering LDL cholesterol, are among only three therapies with well-established safety and efficacy in lowering LDL while reducing cardiovascular events. The others are bile acid sequestrants and partial ileal bypass, which surgically excludes the last 100 cm of terminal ileum.
“Any new therapy that's going to rival statins would have to lower LDL by at least 30%–50%, as can be attained by statins now available,” said Dr. Stone, professor of clinical medicine at Northwestern University, Chicago.
Moreover, before any new therapy can win large-scale acceptance, it will need to demonstrate both safety and efficacy in a large-scale randomized clinical trial, conducted over a period of at least several years, with hard cardiovascular outcomes such as acute MI and mortality, not just surrogate imaging or biomarker end points, the cardiologist added.
This point was brought home for him by the defining experience of serving on the independent data safety monitoring board of the landmark Heart and Estrogen Replacement Study (HERS), a double-blind randomized clinical trial that some prominent physicians dismissed during the organizing stages as a waste of time. After all, the critics noted, hormone therapy had already been shown to reduce LDL and slow carotid intimal medial thickening, and ATP II recommended it for cardiovascular risk reduction.
Yet HERS ultimately demonstrated an increased cardiovascular event rate in hormone-treated patients, leading to a strong recommendation against giving such therapy to women with coronary heart disease. A similarly unexpected negative finding resulted from the first large randomized trial of torcetrapib, the once highly promising but now abandoned HDL-boosting/LDL-lowering cholesterol esterase transport protein inhibitor.
The best bet in the near future for important new advances in lipid-lowering therapy to arrive on the scene, in Dr. Stone's view, will be in agents piggybacked on top of statin therapy to reduce the residual cardiovascular risk remaining in statin-treated patients.
Expected to report results within this time frame are the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial evaluating a simvastatin/fenofibrate combination in 10,000 patients with type 2 diabetes, as well as the 3,300-subject Atherothrombosis Intervention in Metabolic Syndrome with Low HDL\High Triglycerides and Impact on Global Health Outcomes (AIM HIGH), featuring a long-acting niacin (Niaspan)\simvastatin combination. Both double-blind randomized trials are sponsored by the National Heart, Lung, and Blood Institute.
Audience members asked what they should do about the growing number of statin-intolerant patients they're encountering as the drugs become more widely prescribed. “People who can't tolerate statins are filling our schedules and are very frustrating,” Dr. Stone agreed, while noting they constitute only a small percentage of all patients prescribed the drugs. In the setting of statin intolerance he urged greater use of bile acid sequestrants, as well as an emphasis on plant-based diets, which reduce LDL in adherent individuals to an extent comparable to starting doses of statins. It's also important to identify and treat hypothyroidism in statin-intolerant patients because it makes treatment of their myositis much easier.
As for the newer investigational thyroid hormone analogues turning heads with their statin-sized LDL lowering and evidence of additive LDL lowering when combined with statins, Dr. Stone said preliminary studies look promising—just as they once did for estrogen replacement and torcetrapib—and he reiterated the need for large definitive, double-blind, randomized trials with hard end points. He noted that d-thyroxine was recommended for lipid lowering in the late 1960s and early 1970s but was dropped because of arrhythmic problems in the Coronary Drug Project.