SANDS: nearly identical regression in LDL, carotid intima-media thickness with statins alone, statins plus ezetimibe

Patients with type 2 diabetes experienced increases in carotid intima-media thickness with standard treatment.

Aggressive lowering of LDL was accompanied by a similar regression of carotid artery intima-media thickness in patients with type 2 diabetes assigned to statins alone or statins plus ezetimibe during 36 months of follow-up, according to study findings.

Researchers of this secondary analysis of the Stop Atherosclerosis in Native Diabetes Study (SANDS) examined the effect of LDL lowering with statins alone compared with statins plus ezetimibe (Zetia, Merck/Schering-Plough) on common carotid artery intima-media thickness in patients with type 2 diabetes and no history of cardiovascular events. Researchers enrolled 499 American Indian men and women aged 40 years and older with type 2 diabetes (LDL >100 mg/dL; systolic blood pressure >130 mm Hg).

Patients were randomly assigned to an aggressive treatment group (n=252; target LDL ≤70 mg/dL; non-HDL ≤100 mg/dL; systolic BP ≤115 mm Hg) or a standard treatment group (n=247; target LDL ≤100 mg/dL; non-HDL ≤130 mg/dL; systolic BP ≤130 mm Hg). In the aggressive treatment group, patients received statins if lifestyle modification did not lower LDL to the prescribed goals within three months; if the goals were not reached with statins alone, ezetimibe was added.

“For a similar extent of LDL and non-HDL lowering to respective targets of ≤70 mg/dL and ≤100 mg/dL, a nearly identical regression in carotid intima-media thickness occurs in patients with type 2 diabetes who achieve similar reductions in these lipid levels from a statin alone vs. statin plus ezetimibe; in contrast, carotid intima-media thickness increased in patients titrated to a conventional LDL target of ≤100 mg/dL,” the researchers wrote. The results were published in the Journal of the American College of Cardiology.

At 36 months, LDL was reduced by 32 mg/dL among patients assigned to statins alone and 31 mg/dL among patients assigned to statins plus ezetimibe compared with 1 mg/dL among patients assigned to standard treatment (P<.0001).

A 0.025-mm reduction in carotid intima-media thickness was observed with statins plus ezetimibe compared with a 0.012-mm reduction with statins alone; however, carotid intima-media thickness progressed by 0.039 mm in the standard group.

Mean change in blood pressure, lipids and carotid artery measures at 36 months

Statins alone Statins + ezetimibe Standard group Carotid intima-media thickness –0.012 mm –0.025 mm 0.039 mm LDL –32.3 mg/dL –31.1 mg/dL 0.9 mg/dL Non-HDL –36.6 mg/dL –34 mg/dL –0.7 mg/dL Systolic BP –13 mm Hg –9 mm Hg –2.4 mm Hg

Multivariate analysis revealed that greater decreases in carotid intima-media thickness correlated with greater reductions in LDL and non-HDL, higher baseline carotid intima-media thickness and younger age. The researchers reported no independent contribution when comparing statins alone with statins plus ezetimibe.

“Thus, comparable LDL and non-HDL lowering accomplished with statins plus ezetimibe vs. statins alone resulted in similar benefit on carotid intima-media thickness,” the researchers wrote.

BMI and HbA1c remained unchanged despite aggressive vs. standard treatment, according to the researchers. No serious adverse events were reported with the lipid drugs used in the SANDS trial. – by Katie Kalvaitis

J Am Coll Cardiol. 2008;doi:10.1016/j.jacc.2008.10.031.

These results are reassuring in the sense that a modest decrease in carotid intima-media thickness was seen in the group that had been treated with ezetimibe plus a statin for approximately three years while no significant change in carotid intima-media thickness was seen in the much larger ENHANCE study over the course of two years. However, this article is a secondary analysis from the larger SANDS trial and it has a number of limitations that the authors addressed. For now, most clinicians will aim to get to lipid targets first with a huge dose of a potent statin. If the LDL and non-HDL targets are not reached using this approach, then the options are to consider niacin, fenofibrate, a resin or ezetimibe. Unfortunately, it will be several more years before we have the results of the randomized, placebo-controlled IMPROVE-IT study that will tell us once and for all whether ezetimibe provides clinical benefit on top of 40 mg simvastatin.

– Roger S. Blumenthal, MD

Director, Johns Hopkins Ciccarone Center for the Prevention of Heart Disease

This result is reassuring as it parallels real-life treatment of patients using successive agents to predefined treatment goals. The evidence favors the initial use of statin, titrated as needed to target LDL and non-HDL goals. Most physicians will choose to add a second agent such as ezetimibe if primarily further LDL lowering is needed after statin titration. So while this is not a trial of statin vs. statin plus ezetimibe, it shows us that essentially identical carotid intima-media thickness outcomes can be achieved with the two treatment strategies to achieve a common lipid goal. It is very notable that the standard treatment goals were associated with progression of atherosclerosis at 36 months while the aggressive goals yielded regression, supporting the wider use of the optional Adult Treatment Panel-III intensive goals in patients with diabetes.

The SANDS study comes at an important time given the intense controversy raised by the publication of the ENHANCE trial. The two trials are not really comparable as they study two very different patient populations with very different lipid disorders using entirely different study designs. At the minimum, one major difference is the on-treatment LDL and non-HDL levels achieved with the statin vs. statin plus ezetimibe regimens. Along with other potentially confounding factors, the ENHANCE patients had on-treatment non-HDL levels well above any currently accepted secondary prevention guideline treatment goals: 220 mg/dL with simvastatin alone; 166 mg/dL with combined simvastatin plus ezetimibe. Based on prior trials, high non-HDL levels in this range would be expected to result in progression of atherosclerosis or increasing carotid intima-media thickness in both groups. In contrast, the two drug treatment strategies in SANDS were compared at low secondary prevention non-HDL levels of approximately 100 mg/dL, the range where at least carotid intima-media thickness stabilization or more likely regression should occur.

As Dr. Blumenthal remarked in his commentary, we all eagerly await the results of IMPROVE-IT which will compare simvastatin 40 mg per day with and without added ezetimibe therapy in a large randomized trial using hard events as a primary endpoint. Until we have the results of IMPROVE-IT, the SANDS results provide support for the ongoing judicious use of ezetimibe as a second-line, add-on agent for use after optimized high-dose statin therapy to achieve intensive lipid-lowering goals.

– Steven R. Jones, MD

Assistant Professor of Medicine, Johns Hopkins Hospital