IMPROVE-IT: Diabetics Benefit With Ezetimibe, but Is It Enough?

August 31, 2015

LONDON — A new analysis of the IMPROVE-IT trial indicates that the nonstatin, cholesterol-lowering drug ezetimibe (Zetia, Merck) is of specific benefit in patients with acute coronary syndrome who also have diabetes.

But in an interesting twist, the analysis showed that nondiabetics in fact saw little benefit with this agent, although there are high-risk subgroups among this population that could gain, argued Robert Giugliano, MD, a cardiologist at Brigham and Women's Hospital, Boston, Massachusetts, who presented the findings in a clinical-trial update at the European Society of Cardiology 2015 Congress.

"In this particular [prespecified] analysis, we focused on the 4933 patients (27%) enrolled [in IMPROVE-IT] with diabetes. We know from prior work among diabetics that ezetimibe not only reduces LDL cholesterol but also reduces triglycerides and other atherogenic lipoproteins and also reduces insulin resistance," he told the meeting.

Now, "we see a very consistent pattern of a greater benefit with ezetimibe for diabetic patients vs nondiabetics [in IMPROVE-IT], with a 24% reduction in myocardial infarction and a 39% reduction in ischemic stroke, and no safety signals," Dr Giugliano reported.

"We believe these findings are supportive of intensive lipid therapy in diabetics," he added.

But cochair of the session, Maarten L Simoons, MD, PhD, professor emeritus of cardiology at Erasmus University Medical Center, Rotterdam, the Netherlands, told Medscape Medical News he is still not convinced about the benefits of ezetimibe.

"I am somewhat worried. First of all, the effect that they show in IMPROVE-IT overall is very small, and that required a very long-term follow-up. If you calculate it, you need to treat about 200 patients to avoid one event. And in most European countries, it's quite expensive — that means you are going to spend €200,000 or more to avoid one event, without any effect on mortality."

Dr Robert Giugliano

And even the reduction in events shown in diabetics in this new analysis is not enough to convince Dr Simoons to use ezetimibe. "I would be reluctant to use it and really look forward to [further] risk assessment because if, in the very high-risk patients, those figures change, then it becomes important."

Dr Giugliano said that other high-risk subgroups are emerging, including those age 75 and greater and those with a history of stroke. "In an ongoing effort, we are developing a chronic risk score, which we will present at [the American Heart Association Scientific Sessions]."

Therefore, "you must have a very high-risk group to find a benefit — an elderly diabetic with high blood pressure who is smoking," Dr Simoons commented to Medscape Medical News.

14% Reduction in Primary End Point Among Diabetics Taking Ezetimibe

IMPROVE-IT was the large-scale, long-delayed, and controversial study of ezetimibe in post–acute-coronary-syndrome (ACS) patients and showed a "modest" benefit in reducing cardiovascular events when ezetimibe was added to simvastatin.

Patients in IMPROVE-IT were hospitalized with an ACS, on standard medical therapy, and were seen at day 30 and then every 4 months thereafter until around 2 years. They were randomized to ezetimibe 10 mg plus simvastatin 40 mg or to placebo plus simvastatin and were followed up for 7 years.

In his new presentation, Dr Giugliano detailed the outcomes for the 4933 patients with diabetes compared with the 13,202 who did not have diabetes.

Those with diabetes taking ezetimibe plus simvastatin vs placebo/simvastatin saw bigger drops in LDL-C from admission to year 1 — ezetimibe added to simvastatin reduced LDL cholesterol by 43 mg/dL after 1 year compared with 23 mg/dL with simvastatin alone.

And the primary composite end point of cardiovascular death, myocardial infarction, documented unstable angina requiring rehospitalization, coronary revascularization (within 30 days), or stroke occurred in 40% of those diabetics taking ezetimibe/simvastatin, compared with 45.5% of those taking placebo/simvastatin (hazard ratio [HR], 0.86; P = .023).

"We conclude, with all the caveats of a subgroup analysis — although this subgroup is larger than the PROVE-IT and 4S studies," Dr Giugliano commented, "that these patients with diabetes, as expected, were higher risk for cardiovascular events. But they also had greater relative and absolute benefit when ezetimibe was added to simvastatin, as compared with nondiabetics."

"Our study findings represent particularly good news for patients with diabetes who have coronary artery disease," added Dr Giugliano in a statement from Brigham and Women's Hospital. "We believe that patients who suffer a heart attack and cannot get to a very low level of LDL-C with a statin should be considered for ezetimibe, particularly if they have diabetes."

No Benefit of Adding Ezetimibe in Nondiabetics

In contrast, there was no difference in the primary end point in the new analysis between those nondiabetics who received ezetimibe and those who got placebo (30.2% had an event vs 30.8%). Nor were there any differences in any of the prespecified secondary end points.

Individual CV End Points and CVD/MI/Stroke

End point

Group by diabetes status


Placebo/Simvastatin (%) Ezetimibe/Simvastatin (%) P for interaction
CV death No DM 1.03 5.3 5.3 0.57
DM 0.96 11.2 11.7
MI No DM 0.93 12.7 12.0


DM 0.76 20.8 16.4
Ischemic stroke No DM 0.91 3.4 3.2 0.031
DM 0.61 6.5


CV death, MI, or ischemic stroke No DM 0.96 17.7 17.0 0.016
DM 0.80 29.9 24.9

"There was no effect at all in nondiabetics," Dr Simoons said. "You showed no effect on mortality, no effect on MI, and no effect on stroke in the nondiabetic population — in fact, they all went slightly in the wrong direction," he commented to Dr Giugliano.

One audience member asked whether this therefore means that "if you do not have diabetes, ezetimibe may not be the best choice."

Dr Giugliano said it did not.

"Please do not leave this auditorium thinking you should withhold ezetimibe from nondiabetics. The nondiabetics are not a homogeneous group — there are patients in there who are very high risk, because they are elderly or they have a high risk of stroke or both, and those patients derive benefit from ezetimibe."

"So your plea is, in fact, to restrict the use of ezetimibe to a limited subgroup of high-risk patients, which needs to be perhaps better defined, which includes diabetics, the very elderly, or extensive vascular disease, but not in the run-of-the-mill disease," Dr Simoons said Dr Giugliano.

"You'll get more benefit from the higher the risk of the patient, and we'll have more data [in future] on which patients have lesser benefit or even perhaps no benefit," Dr Giugliano replied.

Robert Giugliano reports research contracts to his institution from Amgen, Merck, and Daiichi-Sankyo; honoraria for CME from Daiichi-Sankyo and Merck; and consulting for Amgen, Bristol-Myers Squibb/Pfizer, CVS Caremark, Daiichi-Sankyo, and Merck. Dr Simoons reports no relevant financial relationships.

European Society of Cardiology 2015 Congress. Presented August 30, 2015. Abstract 1947.


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