Ezetimibe does not increase risk of new - onset diabetes : IMPROVE-IT substudy

Therefore, Nishant P. Shah, Duke University School of Medicine, Durham, NC, USA, and colleagues evaluated the risk of new‐onset diabetes with ezetimibe addition to simvastatin versus placebo added to simvastatin in IMPROVE‐IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

The findings of the study, published in the Journal of the American Heart Association, supported the safety and use of this medication as an adjunct to statins for further lowering of low‐density lipoprotein cholesterol (LDL cholesterol), which, combined with the PCSK9 inhibitor data and recent trials, could be important for national guidelines.

The analyses included patients without diabetes at baseline. New-onset diabetes was defined for the primary analysis as either initiating an antihyperglycemic medication or two consecutive blood glucose measurements of ≥126 mg/dL and was analyzed as a time‐to‐event outcome. Metabolic syndrome at randomization was defined as ≥3 of the criteria defined by the American Heart Association.

Patients were assessed for 30 days after randomization and then after every four months, with a minimum 2.5‐year and median 6‐year follow‐up. Of the 18 144 patients enrolled in IMPROVE‐IT, 8644 were excluded due to missing data (N=3360) or a history of diabetes (N=5284), leaving 9500 patients for the study population.

The authors reported the following findings:

• After randomization, 14.9% of patients met the criteria for NOD for an annualized incidence of approximately 2.7% per year.
• For those who developed NOD, there were no differences in baseline characteristics between those who received simvastatin/ezetimibe (n=720) and those who received simvastatin/placebo (n=694).
• Compared with patients who did not develop NOD (n=8086), those with NOD were more likely at baseline to have a higher body mass index (hazard ratio [HR], 1.27), higher systolic blood pressure (HR, 1.07), higher triglycerides (HR, 1.33), and ≥ three components of the metabolic syndrome (HR, 1.36).
• The groups had no significant differences between baseline medical therapies or low‐density lipoprotein cholesterol.
• Compared with the placebo/simvastatin arm, there was no difference in risk of NOD with the addition of ezetimibe to simvastatin (HR, 1.03).
• The addition of ezetimibe did not affect the risk of NOD in either statin‐naïve (not on a previous statin before trial qualifying event) or statin‐experienced (on a previous statin before trial qualifying event) patients (HR, 1.01 versus HR, 1.08, respectively).
• Furthermore, in an additional sensitivity analysis to assess the risk of NOD based on the presence of metabolic syndrome at baseline, the addition of ezetimibe did not affect risk in those with metabolic syndrome or in those without metabolic syndrome (HR, 1.06 versus HR, 0.98 respectively).

In the analysis of patients enrolled in IMPROVE‐IT, the researchers found no increase in NOD risk with ezetimibe's addition to statin therapy.

"Our data are consistent and supported by the findings from a recent trial that found a lower NOD risk with lower dose ezetimibe and rosuvastatin versus higher dose rosuvastatin," Dr Shah and colleagues wrote. "A similar lack of NOD has been seen with PCSK9 inhibitors."

"Given outcomes from IMPROVE‐IT, and the absence of any signal that ezetimibe increases NOD risk, our results support the use and safety of this medication as an adjunct to statins for further LDL cholesterol lowering, which, combined with recent trials and the PCSK9 inhibitor data, could be important for national guidelines," they concluded.

Reference:

Shah NP, McGuire DK, Cannon CP, Giugliano RP, Lokhnygina Y, Page CB, Tershakovec AM, Braunwald E, Blazing MA. Impact of Ezetimibe on New-Onset Diabetes: A Substudy of IMPROVE-IT. J Am Heart Assoc. 2023 Jun 22:e029593. doi: 10.1161/JAHA.122.029593. Epub ahead of print. PMID: 37345760.