Ezetimibe Benefits Diabetics, and Does Not Increase Risk of New-Onset Diabetes

LONDON, England—Adding the cholesterol-absorption inhibitor ezetimibe to simvastatin and usual care is safe and can improve outcomes substantially, especially among diabetics, according to results of 2 studies presented at the European Society of Cardiology Congress. Additionally, ezetimibe is not responsible for causing new-onset diabetes.

Take Home: Ezetimibe Benefits Diabetics, and Does Not Increase Risk of New-Onset Diabetes

Diabetics Benefit

For the first study, Robert P. Giugliano, MD, MSc, of Brigham and Women's Hospital (Boston, MA), presented results of a prespecified subgroup analysis of the IMPROVE-IT trial, which enrolled 18,144 ACS patients with LDL levels between 1.3 and 3.2 mmol/L receiving standard medical therapy. They were randomized to a combination of 40 mg of simvastatin and 10 mg of ezetimibe (Vytorin; Merck) or simvastatin plus placebo.

Patients with diabetes (n = 4,933) tended to be older and female and to have higher BMIs than nondiabetics (n = 13,202). Diabetics also more often had prior MI and coronary revascularization, were more likely to be hypertensive, and were less likely to present with STEMI. Diabetes was linked with lower LDL and HDL cholesterol, but higher levels of triglycerides and high-sensitivity C-reactive protein (hs-CRP).

LDL cholesterol decreased from admission to 1 year by 0.46 mmol/L among nondiabetics and 0.51 mmol/L in diabetics. Moreover, the placebo-adjusted differences between the treatment groups in the changes from baseline through a time-weighted average during the trial seemed to indicate a greater benefit from adding ezetimibe in diabetics vs nondiabetics (table 1).

Table 1. Placebo-Adjusted Differences in Lipids and hs-CRP Between Ezetimibe and Placebo


Kaplan-Meier estimates at 7 years showed a 5.5% absolute risk reduction in the primary endpoint (cardiovascular death, hospital admission for unstable angina, MI, coronary revascularization day 30 or later, or stroke) for diabetics taking ezetimibe vs placebo (HR 0.86; 95% CI 0.78-0.94). This relationship was not seen among nondiabetics (HR 0.98; 95% CI 0.91-1.04). Results were consistent among the trial’s 3 specified composite secondary endpoints.

“For each of these we see a very consistent pattern: a greater benefit among diabetics for ezetimibe as compared with the nondiabetics,” Dr. Giugliano said.

There was no evidence of the interaction between diabetes and treatment for cardiovascular death, but diabetics derived greater benefit than nondiabetics from adding ezetimibe with respect to MI (P = .028) and ischemic stroke (P = .031).

As expected, “patients with diabetes were higher risk for cardiovascular events, but they also had greater relative and absolute benefit when ezetimibe was added to simvastatin as compared to nondiabetics,” Dr. Giugliano concluded. “We believe these findings are supportive of intensive lipid therapy in diabetics.”

But this analysis should not rule out ezetimibe for nondiabetics, he stressed. “I want to point out that this analysis was 1 of just over 20 prespecified subgroup analyses. We did also see some interesting signals in other high-risk subgroups,” including elderly patients, Dr. Giugliano reported.

“Please do not leave this auditorium thinking you should not give ezetimibe to nondiabetics,” he told the audience. “Nondiabetics are an inhomogeneous group. There are patients in there who are very high-risk because they are elderly or they have a history of stroke or both…. I would not conclude that you should withhold ezetimibe from nondiabetics.”

Dr. Giugliano’s team is in the process of developing a chronic CAD risk score to be presented at the American Heart Association Scientific Sessions in November, he said. “It’s a work in progress right now, but so far what I can say is that when we apply [it] to the IMPROVE-IT data, we see a powerful interaction between patient risk and benefit from ezetimibe.”

Ezetimibe Does Not Cause New-Onset Diabetes

In another analysis of IMPROVE-IT data, Michael A. Blazing, MD, of Duke University Medical Center (Durham, NC), and colleagues looked specifically at patients with new-onset diabetes.

Among patients in this subgroup (n = 1,414), there was no relationship between ezetimibe treatment and the primary endpoint (HR 1.04; 95% CI 0.94-1.15).

The criteria which led researchers to diagnose diabetes within the trial were either glucose (20.4%) or medication (51.6%), or a combination of the two (27.9%), and these were well balanced between treatment groups.

Researchers conducted sensitivity analyses reflecting 4 separate new-onset diabetes definitions, and also excluded prior diabetes and included 341 more high-risk patients with new-onset diabetes. Again, there were no differences by treatment with respect to the primary endpoint.

“The limitations of this study were that we did not have hemoglobin A1Cs and we did not do what is clinically done in an endocrine clinic for looking at new-onset diabetes,” Dr. Blazing reported. “But we did look at all of the available information that we had through sensitivity analyses and found no difference with any of these analyses or from our primary.

“The addition of ezetimibe to simvastatin vs simvastatin alone did not increase the risk of new-onset diabetes,” he continued. “The drug ezetimibe as we have studied it today has been found to be very safe in this trial. It’s the safety of the drug along with the efficacy that really has led to the outcomes we have seen.”

 


Sources: 
1. Giugliano RP. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with vs without diabetes: the IMPROVE-IT trial. Presented at: European Society of Cardiology Congress; August 30, 2015; London, England.
2. Blazing MA. Incidence of new-onset diabetes in the IMPROVE-IT trial: does adding ezetimibe to simvastatin increase risk compared to simvastatin alone? Presented at: European Society of Cardiology Congress; September 1, 2015; London, England.

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Disclosures
  • Dr. Giugliano reports holding research contracts and stocks in, owning, and receiving royalties and consulting fees from a healthcare company.
  • Dr. Blazing reports holding research contracts and stocks in, owning, and receiving royalties and consulting fees from a healthcare company.

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