December 4, 2008 (Bethesda, Maryland) — Reducing LDL and non-HDL cholesterol to very low levels in patients with diabetes results in a regression of carotid intima-media thickness (CIMT) over a three-year period, a new study has shown [1]. Interestingly, the regression of CIMT occurs in aggressively treated patients who reach treatment goals with statins alone and in those treated with statins and ezetimibe combination therapy.
"It's a unique study design because it compares two different targets rather than comparing two different drug-treatment regimens," senior investigator Dr Wm James Howard (Washington Hospital Center, Washington, DC) told heartwire . "Our feeling is that it doesn't make a lot of difference how you get there, it's getting to the low LDL and non-HDL levels that counts."
The study, an analysis of the Stop Atherosclerosis in Native Diabetics Study (SANDS), is published online December 3, 2008 in the Journal of the American College of Cardiology. In addition to the SANDS trial, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) investigators also published a CIMT study online in the same journal. In this study, however, treatment with fenofibrate was not associated with positive changes in CIMT and other markers, including the augmentation index [2].
SANDS vs ENHANCE: Two Studies With Different Results
The SANDS study looked exclusively at American Indian men and women with type 2 diabetes, hypertension, and dyslipidemia. Patients were randomized to drug treatment to reach the standard targets of 100 mg/dL or lower for LDL cholesterol, 130 mg/dL or lower for non-HDL cholesterol, and 130 mm Hg or lower for systolic blood pressure (SBP). Comparatively, others were randomized to a more aggressive target of 70 mg/dL or lower for LDL cholesterol, 100 mg/dL or lower for non-HDL cholesterol, and 115 mm Hg or lower for SBP.
To achieve the aggressive lipid targets, patients were treated first with a statin, and if they failed to reach the treatment goal, ezetimibe was added. In total, 154 subjects were treated with a statin alone and 69 received a statin and ezetimibe, for a total of 223 in the aggressive-target arm. In the standard target group, 204 individuals were randomized to treatment.
After three years, there was a regression in CIMT in the aggressively treated patients compared with an increase in CIMT in those randomized to standard treatment targets. The regression in CIMT in those randomized to aggressive targets occurred in patients who received ezetimibe/statin therapy and in those who received only a statin.
SANDS: Follow-Up Carotid IMT Measures
| CIMT measure | Standard group | Aggressive target: statin and ezetimibe group | Aggressive target: statin alone | Group difference between ezetimibe/statin and statin alone (p) | Group difference between ezetimibe/statin and standard therapy (p) | Group difference between statin alone and standard therapy (p) |
| Mean change, 36 mo | 0.039 | -0.025 | -0.012 | 0.01 (0.999) | 0.06 (0.001) | 0.05 (0.001) |
Howard told heartwire that, to be included in the study, patients were required to have a readable CIMT at baseline, which helped avoid some of the pitfalls of the ENHANCE study. Compared with that study, where baseline IMT was low (some believe too low to detect to any meaningful change as a result of treatment), baseline IMT in SANDS was 0.81 mm. In addition, Howard noted this trial was three years, not two like ENHANCE, an important distinction, as the benefit of treatment emerged within the last 18 months.
Asked about recent criticisms of ezetimibe in light of ENHANCE, particularly the possibility that ezetimibe provides no clinical benefit when added to statin therapy, Howard said the carotid regression observed in SANDS is at least as good with ezetimibe and a statin as with the statin alone when patients get LDL and non-HDL cholesterol levels down to low targets.
"People have misinterpreted this because the two treatments were equal, saying well, there's no difference, that ezetimibe didn't add anything," said Howard. "But the design of the study is a comparison of two different treatment goals. Ezetimibe is needed to get to that treatment goal."
Howard added that while there exist hard clinical end-point data for the statins and none for ezetimibe, getting patients to goal without an add-on therapy is difficult. Treating these patients to LDL cholesterol of less than 100 mg/dL still leaves a high amount of residual risk, he said.
"I'm one of the few clinical lipidologists in DC, and most of the patients I see are statin intolerant," he told heartwire . "If they could get to goal by statin alone, we'd get them there. But what happens is that we get them on a low-dose statin, we don't get them to goal, and so we have to add an adjunct drug. Ezetimibe is proven to be the easiest and most effective adjunct to get them to goal."
Howard pointed out that the study is small and used surrogate end points, but the findings emphasize the importance of reducing risk by treating to more aggressive targets. Importantly, the group observed no cancer signal, although it was underpowered to detect such events. There have been concerns raised with ezetimibe and cancer, notably in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, although later analyses suggest the finding is an outlier.
The FIELD Study
In an editorial accompanying the published study [3], Dr Evan Stein (Metabolic and Atherosclerosis Research Center, Cincinnati, OH) defended the use the of ezetimibe and noted many of the flaws of ENHANCE, including baseline CIMT levels, the duration of the study, and patient population, a group of familial hypercholesterolemia patients who were well-treated with statin therapy since childhood.
Like Howard, Stein believes the drug is useful in patients who need additional LDL-cholesterol lowering but who cannot tolerate higher doses of statins. "The evidence shows that, even with the design flaws in one trial that was neutral and the latest trial in which it showed a benefit, the continued use of the drug is consistent with the well-proven LDL-cholesterol hypothesis."
Based on the FIELD analysis, however, a study led by Dr Anne Hiukka (University of Helsinki, Finland), "the news for fenofibrate may not be as good," adds Stein. In this most recent study of 170 patients with type 2 diabetes, the addition of 200 mg/day of fenofibrate was not associated with beneficial changes in CIMT, the augmentation index, or biomarkers of inflammation and endothelial function.
Stein notes the drug missed the primary end point in the larger FIELD study, despite reducing nonfatal MI and coronary revascularizations, and this should give clinicians pause about the cardiovascular benefits of the drug, particularly when added to proven statin therapy.
According to Stein, the evidence for CVD event reduction when adding a fibrate to statin therapy in patients with moderate triglyceride elevations and elevated LDL and non-HDL cholesterol does not exist. "Until such evidence is produced, its routine addition to beautify triglycerides or HDL cholesterol should be avoided," he writes.
The complete benefit of fenofibrate when added to statin therapy won't be known until the Action to Control Cardiovascular Risk in Diabetes is completed in a few years, he comments.
The National Heart, Lung, and Blood Institute sponsored the SANDS study. Howard reports consulting and speakers' fees and research support from Pfizer, AstraZeneca, Merck, Schering-Plough, Reliant, Abbott, and Daiichi-Sankyo. Stein reports consulting and speakers' fees and research support from Abbott, AstraZeneca, Daiichi-Sankyo, Sanofi, Schering-Plough, Roche, Isis, Takeda, Novartis, GlaxoSmithKline, and Merck.
Fleg JL, Mete M, Howard BV, et al. Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes. J Am Coll Cardiol 2008; DOI:10.1016/j.jacc.2008.10.031. Available at: https://content.onlinejacc.org.
Hiukka A, Westerbacka J, Leinonen ES, et al. Long-term effects of fenofibrate on carotid intima-media thickness and augmentation index in subjects with type 2 diabetes mellitus. J Am Coll Cardiol 2008; DOI:10.1016/j.jacc.2008.09.049. Available at: https://content.onlinejacc.org.
Stein EA. Additional lipid lowering trials using surrogate measurements of atherosclerosis by carotid intima-media thickness. J Am Coll Cardiol 2008; DOI:10.1016/j.jacc.2008.11.002. Available at: https://content.onlinejacc.org.
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Cite this: Michael O'Riordan. Treating Diabetic Patients to Very Low Lipid Targets Regresses CIMT - Medscape - Dec 04, 2008.
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