Adding Ezetimibe Does Not Increase Fasting Glucose Levels More Than Statins Alone in Nondiabetic, Hypercholesterolemic Patients Peter P Toth MD, PhD 1 ; Alberico Catapano PhD 2 ; Michel Farnier MD, PhD 3 ; JoAnne Foody MD 4 ; Joanne E Tomassini PhD 4 ; Erin Jensen MS 4 ; Adam B Polis MA 4 ; Thomas A Musliner MD 4 ; Andrew M Tershakovec MD, MPH 4 1 CGH Medical Center, Sterling, IL, and University of Illinois, Peoria, IL, USA; 2 University of Milan, Milan, Italy; 3 Point Médical, Dijon, France; 4 Merck & Co., Inc., Kenilworth, NJ, USA
Disclosures The following relationships exist related to this presentation: • P Toth has served on speaker’s bureaus for Abbvie, Amarin, AstraZeneca, Merck, Kowa, and is a consultant to Amgen, AstraZeneca, Genzyme, Kowa and Merck. • A Catapano has received research grants from Merck, Schering-Plough and AstraZeneca, and received honoraria from Merck, Schering-Plough and AstraZeneca • M Farnier reports having received grants, consulting fees and/or honoraria and delivered lectures for Abbott, Amgen, AstraZeneca, Eli Lilly, Genzyme, Kowa, Merck, Novartis, Pfizer, Recordati, Roche and Sanofi-Regeneron. • J Foody, TA Musliner, AB Polis, AM Tershakovec, and JE Tomassini are current or former employees of Merck Sharp & Dohme and hold stock/stock options in the company. E Jensen is a contract employee of Merck. • Funding support: Merck & Co., Inc, Kenilworth, NJ 2
Introduction • Statins have been associated with an increased risk of diabetes mellitus and insulin resistance • The FDA added warnings to statin labels of increased HbA1c and fasting glucose (FSG) levels; the risk was considered small and cardiovascular benefits outweigh this risk • Prior analyses of data pooled from randomized clinical studies in statin-naïve, nondiabetic, hypercholesterolemic (HC), and heterozygous familial hypercholesterolemic (HeFH) patients showed that addition of ezetimibe (Eze) to statin therapy did not increase FSG more than statins alone during up to 96 weeks 3
FSG Changes Over Time in First-Line Statin-Naïve Cohorts (Short-Term Studies) * P <0.05 for FSG increase for statin and Eze+statin ** P <0.05 for FSG increase from week 2 to 4 for statin group *** P <0.05 for FSG decrease from week 8 to 12 for placebo and statin No significant between-treatment group differences except statin vs placebo 4
FSG Changes Over Time in First-Line Statin-Naïve Cohorts (Long-Term Studies) Long-Term Studies HC Patients HeFH Patients All P<0.05 for within-treatment group FSG increases; no significant between-treatment group differences † All Simva=10, 20, 40, 80 mg ‡ Eze/Simva= Eze 10 mg/Simva 10, 20, 40, 80 mg 5
Objectives • To assess FSG changes during Eze+statin and statin treatment of nondiabetic, HC patients already on statin (second-line) therapy • Data pooled from randomized, controlled, double-blind, second-line Eze add-on or uptitration studies in HC patients on stable statin therapy 6
Methods • Patient-level data pooled from randomized, controlled, second-line (on-statin) studies – HC patients, nondiabetic at baseline – Add-on: Eze (n=1506) vs placebo (n=851) added to stable statin therapy during 8 weeks – Uptitration: Eze added to stable statin therapy (n=645) vs statin dose doubling (n=650) during 6-12 weeks • Endpoints assessed (identical, separate analyses for both study types) – Mean FSG changes from baseline – Between-treatment-group differences – Proportion of patients with elevated FSG values ≥126 mg/ dL during treatment (baseline FSG <126, <100, and ≥100 - ≤126 mg/ dL) – Relationships between baseline covariates and FSG changes 7
Baseline Characteristics of Full Analysis Cohort Add-on Studies Uptitration Studies Statins Eze+Statins Atorva Eze+Atorva N=851 N=1506 N=650 N=645 Characteristic n (%) n (%) n (%) n (%) Age (yr) Mean (SD) 61.0 (12.0) 61.7 (11.6) 67.4 (8.5) 67.0 (9.1) Gender Female 393 (46.2) 669 (44.4) 305 (46.9) 298 (46.2) Race White 749 (88.0) 1318 (87.5) 580 (89.2) 581 (90.1) Black 52 (6.1) 93 (6.2) 29 (4.5) 22 (3.4) – – Hispanic 28 (3.3) 52 (3.5) Others 22 (2.6) 43 (2.9) 41 (6.3) 42 (6.5) CHD 399 (53.1) 630 (46.0) 163 (32.6) 141 (27.9) Metabolic Syndrome 314 (37.0) 619 (41.3) 305 (47.1) 298 (46.5) 8
Baseline BMI, FSG, and Lipids for Full Analysis Cohort Add-on Studies Uptitration Studies Statins Eze+Statins Atorva Eze+Atorva Characteristic N=851 N=1506 N=650 N=645 BMI (kg/m 2 ) 29.0 (5.2) 29.1 (5.6) 28.6 (4.6) 28.5 (4.4) FSG (mg/dL) 97.3 (12.1) 98.1 (12.1) 98.0 (12.1) 97.5 (11.8) Lipids (mg/dL) LDL-C 138.2 (36.5) 135.8 (33.5) 102.1 (20.6) 103.2 (27.2) HDL-C 50.2 (11.8) 49.3 (11.5) 52.9 (12.4) 53.0 (13.3) TG median (SD) 138.5 (82.8) 146.0 (84.7) 120.5 (64.7) 118.0 (61.9) 9
Mean FSG Values Pre- and Post-treatment: First- and Second-Line Studies Statin Eze+Statin 99.0 99.0 97.2 98.0 97.5 98.5 97.9 97.5 95.5 95.9 94.6 94.9 100 Mean FSG [mg/dL] ± SE Pre- and Post-treatment 80 60 40 20 0 Pre Post Pre Post Pre Post First-line † Second-line Second-line Add-on Uptitration † 1 st -line: 7 studies in statin-naïve/drug wash-out HC patients treated with Eze 10 mg+statin vs statin during 12 weeks. 10
Changes From Baseline in FSG in First- and Second-Line Studies Statin Eze+Statin 0.3 ns 1.4** 2 0.3 ns (n=645) 1.1** 1.1** (n=650) Baseline [mg/dL] ± SE FSG Change From 1.5 (n=1876) 0.3 ns 0.8** (n=1910) 0.5 ns 1 (n=1506) 0.2 ns (n=851) 0.5 0 First-Line † Second-Line Second-Line Add-on Uptitration ** P <0.05; ns=Not statistically significant at the 0.05 alpha level ( P >0.05). † First-line: 7 studies in statin-naïve/drug wash-out HC patients treated with Eze 10 mg + statin vs statin during 12 weeks. 11
Baseline Characteristics of Patients With Post-baseline FSG <126 vs ≥126 mg/ dL in Add-on Studies FSG ≥126 mg/dL FSG <126 mg/dL Statins Eze+Statins Statins Eze+Statins Characteristic N=779 N=1365 N=14 Nn=24 MetS % 35.1 39.2 64.3 87.0 BMI (kg/m 2 mean [SD]) 28.8 (4.9) 29.0 (5.6) 30.7 (5.5) 34.7 (8.1) FSG (mg/dL mean [SD]) 96.1 (9.7) 96.8 (9.6) 103.9 (15.5) 112.3 (19.5) Lipids (mg/dL mean [SD]) LDL-C 138.7 (36.7) 135.7 (33.6) 133.8 (52.1) 129.5 (32.4) HDL-C 50.5 (11.8) 49.4 (11.5) 47.0 (13.5) 42.2 (8.44) TG median (SD) 155.5 (75.1) 159.7 (72.5) 145.0 (52.6) 160.0 (82.5) 12
Baseline Characteristics of Patients With Post- baseline FSG <126 vs ≥126 mg/ dL in Uptitration Studies FSG ≥126 mg/dL FSG <126 mg/dL Atorva Eze+Atorva Atorva Eze+Atorva Characteristic N=613 N=604 N=12 N=23 MetS % 46.6 45.2 58.3 82.6 BMI (kg/m 2 mean [SD]) 28.5 (4.5) 28.3 (4.3) 28.6 (4.3) 31.6 (5.8) FSG (mg/dL mean [SD]) 97.0 (11.1) 96.6 (11.1) 108.1 (9.3) 111.7 (9.9) Lipids (mg/dL mean [SD]) LDL-C 101.6 (20.6) 103.5 (20.7) 95.9 (14.3) 97.4 (19.0) HDL-C 53.2 (12.5) 53.3 (13.5) 43.3 (10.1) 50.6 (11.5) TG median (SD) 119.5 (64.7) 117.3 (60.7) 116.3 (54.1) 130.5 (71.3) 13
Proportion of Patients With FSG ≥126 mg/ dL and Baseline FSG <126, <100, and ≥100 - ≤126 mg/dL 10 7.5 (n=19) Statin Eze+Statin 8 FSG ≥126 mg/ dL ± SE % of Patients With 6 4.0 4.0 (n=10) (n=21) 3.3 3.7 (n=9) (n=23) 4 1.9 1.8 (n=12) 1.7 (n=14) (n=24) 1.1 1.0 2 (n=4) (n=5) 0.5 0.3 (n=2) (n=3) 0 N = 793 1389 625 627 518 862 372 375 275 527 253 252 OR = 0.83 2.01 0.36 2.20 1.09 1.99 95% CI = (0.42, 1.65) (0.97, 4.19) (0.09, 1.55) (0.39,12.21) (0.48, 2.51) (0.89, 4.48) Add-on Uptitration Add-on Uptitration Add-on Uptitration ≥ 100- ≤126 <126 <100 Baseline FSG [mg/dL] 14
Associations Between FSG Changes and Baseline Covariates Were Small and Nonsignificant Add-on Studies Uptitration Studies SD of Estimate SD of Estimate Covariate Covariate mg/dL 95% CI Covariate mg/dL 95% CI Age 11.7 -0.067 (-0.16, 0.02) 8.7 -0.161 (-0.24, -0.08) – – Race 0.499 (-1.02, 2.02) 1.191 (-0.91, 3.29) – – Gender 0.160 (-0.82, 1.14) -0.021 (-1.28, 1.24) Baseline BMI 5.4 -0.090 (-0.18, -0.00) 4.5 -0.215 (-0.31, -0.12) Baseline FSG 12.2 0.025 (-0.04, 0.09) 12 -0.099 (-0.18, -0.02) Baseline HDL-C 11.6 -0.068 (-0.18, 0.04) 13 -0.279 (-0.43, -0.13) Baseline TG 74.1 -0.152 (-0.36, 0.05) 54.2 -0.473 (-0.71, -0.23) – – – Baseline ApoB 27.5 -0.090 (-0.19, 0.01) Treatment (Eze Add-on – – – – vs Atorva Uptitration) 0.463 (-0.79, 1.72) Treatment (Eze Add-on/ – – – – All Statin vs All Statin) 0.184 (-0.83, 1.20) 15
Correlations Between FSG Changes and Changes in Baseline BMI and Lipids and FSG Changes Statin Eze/Statin Variable N Correlation P -value N Correlation P -value Add-on LDL-C 792 -0.132 0.002 1402 -0.023 0.380 BMI 780 -0.053 0.139 1387 0.007 0.800 HDL-C 794 -0.107 0.003 1405 -0.001 0.964 Triglycerides 794 -0.058 0.102 1405 0.015 0.561 ApoB 775 -0.142 <0.001 1374 0.006 0.804 Uptitration LDL-C 629 0.158 <0.001 627 0.005 0.895 BMI 633 -0.074 0.060 628 -0.004 0.911 HDL-C 629 0.004 0.905 627 -0.047 0.238 Triglycerides 629 0.056 0.160 627 0.062 0.117 ApoB 625 0.158 <0.001 619 0.057 0.153 16
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