Impact of Ezetimibe on New-Onset Diabetes: A Substudy of IMPROVE-IT.

HomeJournal of the American Heart AssociationAhead of PrintImpact of Ezetimibe on New‐Onset Diabetes: A Substudy of IMPROVE‐IT Open AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessLetterPDF/EPUBImpact of Ezetimibe on New‐Onset Diabetes: A Substudy of IMPROVE‐IT Nishant P. Shah, Darren K. McGuire, Christopher P. Cannon, Robert P. Giugliano, Yuliya Lokhnygina, Courtney B. Page, Andrew M. Tershakovec, Eugene Braunwald and Michael A. Blazing Nishant P. ShahNishant P. Shah *Correspondence to: Nishant P. Shah, MD, Duke Hospital North, 2301 Erwin Road, Suite 7400, Cubicle 13, Durham, NC 27710. Email: E-mail Address: [email protected] https://orcid.org/0000-0002-2666-7132 , Duke University School of Medicine, , Durham, , NC, , USA, , Duke Clinical Research Institute, , NC, , Durham, , USA, Search for more papers by this author , Darren K. McGuireDarren K. McGuire https://orcid.org/0000-0002-6412-7989 , University of Texas Southwestern Medical Center, , Dallas, , TX, , USA, , Parkland Health and Hospital System, , Dallas, , TX, , USA, Search for more papers by this author , Christopher P. CannonChristopher P. Cannon https://orcid.org/0000-0003-4596-2791 , TIMI Study Group, Brigham and Women’s Hospital, , Boston, , MA, , USA, Search for more papers by this author , Robert P. GiuglianoRobert P. Giugliano https://orcid.org/0000-0003-4110-7675 , TIMI Study Group, Brigham and Women’s Hospital, , Boston, , MA, , USA, Search for more papers by this author , Yuliya LokhnyginaYuliya Lokhnygina , Duke University School of Medicine, , Durham, , NC, , USA, , Duke Clinical Research Institute, , NC, , Durham, , USA, Search for more papers by this author , Courtney B. PageCourtney B. Page https://orcid.org/0000-0001-7671-3355 , Duke Clinical Research Institute, , NC, , Durham, , USA, Search for more papers by this author , Andrew M. TershakovecAndrew M. Tershakovec , Merck & Co., Inc., , Kenilworth, , NJ, , USA, Search for more papers by this author , Eugene BraunwaldEugene Braunwald https://orcid.org/0000-0002-3472-626X , TIMI Study Group, Brigham and Women’s Hospital, , Boston, , MA, , USA, Search for more papers by this author and Michael A. BlazingMichael A. Blazing , Duke University School of Medicine, , Durham, , NC, , USA, , Duke Clinical Research Institute, , NC, , Durham, , USA, Search for more papers by this author Originally published22 Jun 2023https://doi.org/10.1161/JAHA.122.029593Journal of the American Heart Association. 2023;0:e029593Statins have been associated with an increased risk for new‐onset diabetes (NOD).1 However, it is unclear if the addition of the nonstatin therapy ezetimibe to a statin would affect the incidence of NOD. We therefore evaluated the risk of NOD with ezetimibe added to simvastatin versus placebo added to simvastatin in IMPROVE‐IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).2These analyses were carried out in patients without diabetes at baseline (no prior diagnosis of diabetes, no antihyperglycemic medication, and no elevated blood glucose [≥126 mg/dL fasting or ≥200 nonfasting] at randomization). Because glycosylated hemoglobin was not measured systematically during the trial, NOD was defined for the primary analysis as either the initiation of an antihyperglycemic medication or 2 consecutive blood glucose measurements of ≥126 mg/dL and was analyzed as time‐to‐event outcome. Sensitivity analyses using other potential indicators to define NOD were also performed (Table). To account for interval censored data due to medications and blood glucose recorded only at the study visits, parametric Weibull regression univariable and multivariable models were used to determine predictors of NOD.Table 1. Sensitivity Analyses for the Development of New‐Onset Diabetes in IMPROVE‐ITDefinitionSimvastatinSimvastatin/ezetimibeHR (95% CI)P valuePrimary definition of new‐onset diabetes694/4740720/47601.03 (0.93–1.15)0.549Sensitivity analysesS1: Initiation of diabetic medication post randomization547/6084578/60421.06 (0.95–1.21)0.300S2: Two consecutive post. baseline glucose ≥126 mg/dL335/4650348/46751.03 (0.9–1.22)0.655S3: Diabetes‐related AE or SAE defined from clinical review of Medical Dictionary for Regulatory Activities codes501/6141510/61131.03 (0.91–1.17)0.692S4: Diabetes‐related AE/SAE or diabetic medication post randomization671/6084690/60421.02 (0.93–1.13)0.718S5: Diabetes‐related AE/SAE or diabetic medication post randomization or 2 consecutive postbaseline fasting glucose ≥126 mg/dL786/4746804/47631.03 (0.93–1.16)0.530Sensitivity analyses with respective hazard ratios (HRs), 95% CIs, and P values for the simvastatin vs simvastatin/ezetimibe arms of IMPROVE‐IT. AE indicates adverse event; IMPROVE‐IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; and SAE, serious adverse event.Baseline characteristics included age, sex, self‐identified race, current smoking, hypertension, waist circumference, metabolic syndrome, body mass index, systolic and diastolic blood pressure, total cholesterol, low‐ and high‐density lipoprotein cholesterol, triglycerides, glucose at randomization, use of prior statin, beta blocker, and angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker. Metabolic syndrome at randomization was defined as ≥3 of the criteria defined by the American Heart Association.3 Reported P values are 2‐sided, with <0.05 considered statistically significant. Analyses were completed using SAS version 9.4.The data that support the findings of this study are available from the corresponding author upon reasonable request. Institutional review board approval or informed consent was not needed because this was a prespecified analysis of a clinical trial already conducted and published.Patients were evaluated at 30 days after randomization and then every 4 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 a history of diabetes (N=5284), or missing data (N=3360), leaving 9500 patients for the study population. After randomization, 1414 patients (14.9%) met 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 [95% CI, 1.20–1.35]), higher systolic blood pressure (HR, 1.07 [95% CI, 1.00–1.14]), higher triglycerides (HR, 1.33 [95% CI, 1.17–1.53]), and ≥3 components of the metabolic syndrome (HR, 1.36 [95% CI, 1.17–1.61]). There were no major differences in baseline medical therapies or low‐density lipoprotein cholesterol between any of the groups. Compared with the placebo/simvastatin arm, there was no difference in risk of NOD with the addition of ezetimibe to simvastatin (HR, 1.03 [95% CI, 0.93–1.15]). This relationship remained qualitatively consistent across sensitivity analyses using various NOD definitions including the following: initiation of a diabetes medication (HR, 1.06 [95% CI, 0.95–1.21]), 2 glucose measurements ≥126 mg/dL (HR, 1.03 [95% CI, 0.90–1.22]), diabetes‐related adverse event (HR, 1.03 [95% CI, 0.91–1.17]), diabetes‐related adverse event or initiation of diabetes medication (HR, 1.02 [95% CI, 0.93–1.13]), and diabetes‐related adverse event or initiation of diabetes medication or 2 glucose readings ≥126 mg/dL (HR, 1.01 [95% CI, 0.93–1.16]); Table). The addition of ezetimibe did not affect risk of NOD in either statin‐naïve (not on previous statin before trial qualifying event) or statin‐experienced (on previous statin before trial qualifying event) patients (HR, 1.01 [95% CI, 0.89–1.15] versus HR, 1.08 [95% CI, 0.87–1.36], respectively; Pinteraction = 0.50). Furthermore, in an additional sensitivity analysis to assess the risk of NOD based on 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 [95% CI, 0.94–1.21] versus HR, 0.98 [95% CI, 0.81–1.18], respectively, Pinteraction = 0.46).In this analysis of patients enrolled in IMPROVE‐IT, we found no increase in the risk of NOD with addition of ezetimibe to statin therapy. Our data are consistent and supported by the findings from a recent trial that found a lower risk of NOD with lower dose rosuvastatin and ezetimibe versus higher dose rosuvastatin.4 Similar lack of NOD has been seen with PCSK9 inhibitors.5 Limitations of the present study include not having glycosylated hemoglobin measurements or glucose tolerance tests and use of only simvastatin as the background statin therapy. However, sensitivity analyses were performed for validation, and the results are further strengthened by being obtained in the context of a large randomized clinical trial with 6 years follow‐up. Therefore, given outcomes from IMPROVE‐IT, and absence of any signal that ezetimibe increases risk of NOD, our results support the use and safety of this medication as an adjunct to statins for further low‐density lipoprotein cholesterol lowering, which, combined with recent trials and the PCSK9 inhibitor data, could be important for national guidelines.Sources of FundingThis study was funded by Merck and Co. The sponsor had no role in the development of the analytic plan, data analysis, or data interpretation. No additional external sources of funding was obtained.DisclosuresN.P.S. reports the following research grants: Amgen, Janssen, National Institutes of Health; consultant/advisor: Esperion, Amgen, Norvartis. D.K.M.: honoraria for trial leadership from Boehringer Ingelheim, Sanofi, Merck & Co, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, Lexicon, CSL Behring, and honoraria for consultancy from Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Applied Therapeutics, Sanofi, CSL Behring, Bayer, Altimmune, Intercept, and GSK. C.P.C. reports research grants from Amgen, Better Therapeutics, Boehringer‐Ingelheim (BI), Bristol‐Myers Squibb (BMS), Daiichi Sankyo, Merck, Novo Nordisk, Pfizer; consulting fees from Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, BI, BMS, Eli Lilly, Janssen, Lexicon, Merck, Pfizer, Rhoshan, Sanofi; serves on data and safety monitoring board for Applied Therapeutics and NovoNordisk. R.P.G. reports research grants: Amgen, Anthos Therapeutics: Ionis; consulting fees: Amarin, Amgen, Artivion, Bayer, Boston Scientific, Daiichi Sankyo, Gilead, Inari, Inventiva, Labcorp, Medpace, Paratek, Pfizer, PhaseBio Pharmaceuticals, St. Lukes Hospital System, Samsung, Sanofi Aventis. Y.L.: institutional grant to DCRI from Merck during the conduct of the study and institutional grants to DCRI from Amylin Pharmaceuticals Inc (a wholly owned subsidiary of AstraZeneca). A.M.T. is employed by Merck. E.B.: research support: AstraZeneca, Daiichi Sankyo, Merck, and Novartis; consultancies with Amgen, Cardurion, MyoKardia, Novo Nordisk, and Verve. The remaining authors have no disclosures to report.Footnotes*Correspondence to: Nishant P. Shah, MD, Duke Hospital North, 2301 Erwin Road, Suite 7400, Cubicle 13, Durham, NC 27710. Email: nishant.[email protected]eduThis article was sent to Mahasin S. Mujahid, PhD, MS, FAHA, Associate Editor, for review by expert referees, editorial decision, and final disposition.For Disclosures and Sources of Funding, see page 2.References1 Preiss D. Risk of incident diabetes with intensive‐dose compared with moderate‐dose statin therapy. JAMA. 2011; 305:2556–2564. doi: 10.1001/jama.2011.860CrossrefMedlineGoogle Scholar2 Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015; 372:2387–2397. doi: 10.1056/NEJMoa1410489CrossrefMedlineGoogle Scholar3 Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC, et al. Diagnosis and management of the metabolic syndrome. Circulation. 2005; 112:2735–2752. doi: 10.1161/CIRCULATIONAHA.105.169404LinkGoogle Scholar4 Kim BK, Hong SJ, Lee YJ, Hong SJ, Yun KH, Hong BK, Heo JH, Rha SW, Cho YH, Lee SJ, et al. Long‐term efficacy and safety of moderate‐intensity statin with ezetimibe combination therapy versus high‐intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): a randomised, open‐label, non‐inferiority trial. Lancet. 2022; 400:380–390. doi: 10.1016/S0140-6736(22)00916-3CrossrefMedlineGoogle Scholar5 Sabatine MS, Leiter LA, Wiviott SD, Giugliano RP, Deedwania P, De Ferrari GM, Murphy SA, Kuder JF, Gouni‐Berthold I, Lewis BS, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new‐onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017; 5:941–950. doi: 10.1016/S2213-8587(17)30313-3CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. 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Published on behalf of the American Heart Association, Inc., by Wiley BlackwellThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.https://doi.org/10.1161/JAHA.122.029593PMID: 37345760 Originally publishedJune 22, 2023 KeywordsdiabetespreventionlipidsLDL‐CezetimibePDF download SubjectsCardiovascular DiseaseLipids and Cholesterol