Aggressive Lipid Lowering Controls Atherosclerosis Effe...

Aggressive Lipid Lowering Controls Atherosclerosis Effects

Aggressive Lipid Lowering Controls Atherosclerosis Effects
December 4, 2008
By Crystal Phend
MedPage Today

WASHINGTON, Dec. 4 -- Diabetic patients who reached aggressive lipid-lowering targets saw nearly identical vascular benefits whether on high-dose statins alone or statins with ezetimibe (Zetia), researchers found.

Mean carotid artery intima-media thickness regressed similarly in patients who required ezetimibe to reach cholesterol targets and those who needed only statins, whereas those in the standard treatment target group saw progression of plaque buildup (P<0.0001 for both comparisons), Wm. James Howard, M.D., of the Washington Hospital Center, and colleagues reported online in the Journal of the American College of Cardiology.

Their post hoc analysis of the randomized Stop Atherosclerosis in Native Diabetics Study (SANDS) vindicated ezetimibe as an effective treatment in reducing carotid artery intima-media thickness, Dr. Howard said.

Earlier this year, that assumption was challenged by the only other trial to look at ezetimibe's influence on atherosclerosis -- the highly controversial ENHANCE trial.

Despite a 17% greater reduction in LDL with ezetimibe in that trial, no significant difference in the primary endpoint -- mean change in carotid intima-media thickness -- appeared between patients randomized to ezetimibe/simvastatin (Vytorin) and those who received simvastatin alone (P=0.29).

Popular sentiment after discussions at the ACC meeting in March seemed to favor abandonment of the ezetimibe/simvastatin combination as first-line therapy. (See: ACC: ENHANCE Data on Ezetimibe/Simvastatin (Vytorin) Reveal Wavy Bottom Line)

However, Evan A. Stein, M.D., Ph.D., of the Metabolic and Atherosclerosis Research Center in Cincinnati and the only U.S. ENHANCE investigator, defended the use of ezetimibe both then and now.

In an editorial accompanying the SANDS post hoc analysis, he said ENHANCE likely failed because the population studied -- patients with heterozygous familial hypercholesterolemia -- had already had carotid atherosclerosis arrested by prior long-term effective treatment.

SANDS, he said, enrolled the right population to give the drug a chance --"treatment naive patients with significant atherosclerosis based on baseline CIMT."

Dr. Stein said the findings should be reassuring for continued use in patients who cannot achieve recommended goals on statins alone or cannot tolerate high-dose statins.

Although "still only a small post hoc substudy," he wrote, "it restores the balance doctors and patients need to make a decision as to ezetimibe's potential benefit, which ultimately will only be decided by the conclusion of an ongoing morbidity and mortality trial."

The SANDS trial was a randomized, open-label study but blinded to outcomes.

Over the course of three years, it compared two treatment targets in 427 American Indian patients with type 2 diabetes.

Among those treated to aggressive goals for LDL cholesterol (70 mg/dl or less), non-HDL cholesterol (100 mg/dl or less), and blood pressure (115/75 mm Hg or lower), about one-third needed ezetimibe as a statin adjunct after high-dose statin therapy failed to adequately reduce LDL or was limited by side effects.

Participants randomized to standard targets for LDL (100 mg/dl or less), non-HDL (130 mg/dl or less), and blood pressure (130/80 mm Hg or less) served as the control group.

As expected, aggressive treatment targets resulted in similar substantial reductions in cholesterol -- total, LDL, and non-HDL -- in both ezetimibe and non-ezetimibe groups compared with the standard therapy group.

The ezetimibe group averaged 10 mg/dl higher for LDL and non-HDL cholesterol compared with the statin-only group at the end of follow-up (P=0.02), "primarily reflecting higher baseline values."

But for the primary outcome, carotid intima-media thickness fell similarly from baseline to 36 months in the ezetimibe and non-ezetimibe groups compared with an increase in the standard therapy group (-0.025 [95% confidence interval -0.05 to 0.003] and -0.012 [-0.03 to 0.008] versus +0.039 [0.02 to 0.06] mm).

In the multivariate model, too, ezetimibe made no independent contribution to benefits of aggressive lipid lowering.

Although cardiovascular events tended, if anything, to be worse in the ezetimibe group compared with statin-only standard or aggressive therapy (5.8%, 3.5%, and 3.3%, respectively, P=0.62), the study was underpowered for clinical events, the researchers said.

The treatments appeared to be equally well tolerated. Notably, there was no signal of the cancer risk that stirred controversy at the European Cardiology Society meeting this year.

The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial likewise found no benefit of ezetimibe/simvastatin in reducing stenosis but a significantly higher risk of cancer (105 versus 70 with placebo, P=0.01). (See: ESC: SEAS Data Fail to Quiet Ezetimibe/Simvastatin Controversy)

In SANDS, the only cases of cancer were in the non-ezetimibe groups (three in the statin-only subgroup and two in the standard therapy group).

The study was funded by the National Heart, Lung, and Blood Institute. Medications were donated by First Horizon Pharmacy (Triglide), Merck and Co. (Cozaar/Hyzaar), and Pfizer (Lipitor).

Dr. Howard reported receiving research support from Pfizer, AstraZeneca, Merck, and Schering-Plough; serving as a consultant for Merck, Schering-Plough, Pfizer, and Reliant; and serving on the speakers' bureaus for Merck, Schering-Plough, Pfizer, AstraZeneca, Abbott, and Daiichi Sankyo.

His co-authors reported conflicts of interest for Merck, Schering-Plough, the Egg Nutrition Council, General Mills, Pfizer, AstraZeneca, Bayhill Therapeutics, Boehringer Ingelheim, GlaxoSmithKline, NovoNordisk, Takeda, Veraligh, Amylin, Eli Lilly, Lifescan, sanofi-aventis, Tethys Bioscience, Johnson & Johnson, Abbott, Merck Sharp & Dohme, Novartis, and Bristol-Myers Squibb.

Dr. Stein reported receiving consulting/speaker fees and funding for specific clinical trials from Abbott, AstraZeneca, Daiichi Sankyo, Sanofi, Schering-Plough, Roche, Isis, Takeda, Novartis, GlaxoSmithKline, and Merck.