Levels More Than Statins Alone in Nondiabetic, Hypercholesterolemic - - PowerPoint PPT Presentation

Peter P Toth MD, PhD1; Alberico Catapano PhD2; Michel Farnier MD, PhD3; JoAnne Foody MD4; Joanne E Tomassini PhD4; Erin Jensen MS4; Adam B Polis MA4; Thomas A Musliner MD4; Andrew M Tershakovec MD, MPH4

1CGH Medical Center, Sterling, IL, and University of Illinois, Peoria, IL, USA; 2University of Milan, Milan, Italy; 3Point Médical, Dijon, France; 4Merck & Co., Inc., Kenilworth, NJ, USA

Adding Ezetimibe Does Not Increase Fasting Glucose Levels More Than Statins Alone in Nondiabetic, Hypercholesterolemic Patients

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

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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

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FSG Changes Over Time in First-Line Statin-Naïve Cohorts (Short-Term Studies)

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*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

FSG Changes Over Time in First-Line Statin-Naïve Cohorts (Long-Term Studies)

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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

HeFH Patients HC Patients

Long-Term Studies

Objectives

• To assess FSG changes during Eze+statin and statin treatment
• f 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

• n stable statin therapy

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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

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Baseline Characteristics of Full Analysis Cohort

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Add-on Studies Uptitration Studies Characteristic Statins N=851 n (%) Eze+Statins N=1506 n (%) Atorva N=650 n (%) Eze+Atorva N=645 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)

Baseline BMI, FSG, and Lipids for Full Analysis Cohort

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Add-on Studies Uptitration Studies Characteristic Statins N=851 Eze+Statins N=1506 Atorva N=650 Eze+Atorva N=645 BMI (kg/m2) 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)

Mean FSG Values Pre- and Post-treatment: First- and Second-Line Studies

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†1st-line: 7 studies in statin-naïve/drug wash-out HC patients treated with Eze 10 mg+statin vs

statin during 12 weeks. 20 40 60 80 100 Pre Post Pre Post Pre Post

94.6 95.5 97.5 99.0 97.2 97.9 94.9 95.9 98.5 99.0 98.0 97.5

Mean FSG [mg/dL] ± SE Pre- and Post-treatment First-line† Second-line Add-on Second-line Uptitration Statin Eze+Statin

Changes From Baseline in FSG in First- and Second-Line Studies

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**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. 0.5 1 1.5 2

0.8** (n=1910) 1.1** (n=1876)

FSG Change From Baseline [mg/dL] ± SE

0.2ns (n=851) 0.5ns (n=1506) 0.3ns 1.1** (n=650) 1.4** (n=645) 0.3ns 0.3ns

First-Line† Second-Line Add-on Second-Line Uptitration Statin Eze+Statin

Baseline Characteristics of Patients With Post-baseline FSG <126 vs ≥126 mg/dL in Add-on Studies

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Characteristic FSG <126 mg/dL FSG ≥126 mg/dL Statins N=779 Eze+Statins N=1365 Statins N=14 Eze+Statins Nn=24 MetS % 35.1 39.2 64.3 87.0 BMI (kg/m2 mean [SD]) 28.8 (4.9) 29.0 (5.6) 34.7 (8.1) 30.7 (5.5) 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)

Baseline Characteristics of Patients With Post-baseline FSG <126 vs ≥126 mg/dL in Uptitration Studies

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Characteristic FSG <126 mg/dL FSG ≥126 mg/dL Atorva N=613 Eze+Atorva N=604 Atorva N=12 Eze+Atorva N=23 MetS % 46.6 45.2 58.3 82.6 BMI (kg/m2 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)

Proportion of Patients With FSG ≥126 mg/dL and Baseline FSG <126, <100, and ≥100-≤126 mg/dL

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2 4 6 8 10

1.9 (n=12) 1.8 (n=14) 0.5 (n=2) 1.0 (n=5) 4.0 (n=10) 3.3 (n=9) 3.7 (n=23) 1.7 (n=24) 1.1 (n=4) 0.3 (n=3) 7.5 (n=19) 4.0 (n=21)

% of Patients With FSG ≥126 mg/dL ± SE

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)

Baseline FSG [mg/dL] Add-on Uptitration Add-on Uptitration Add-on Uptitration <126 <100 ≥100-≤126

N = 793 1389 625 627 518 862 372 375 275 527 253 252

Statin Eze+Statin

Associations Between FSG Changes and Baseline Covariates Were Small and Nonsignificant

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Covariate Add-on Studies Uptitration Studies SD of Covariate Estimate mg/dL 95% CI SD of Covariate Estimate 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) – – –

Correlations Between FSG Changes and Changes in Baseline BMI and Lipids and FSG Changes

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Variable Statin Eze/Statin 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

Conclusions

• The addition of Eze did not increase FSG levels more than statin

monotherapy in HC patients on stable statin therapy

• FSG elevations ≥126 mg/dL were overall infrequent for both

treatments, with no significant differences between groups

• Patients with post-baseline FSG ≥126 mg/dL had higher baseline

BMI, FSG, and TG levels, and numerically lower baseline HDL-C levels, than those with FSG <126 mg/dL; these factors were not related to increased FSG changes

• Changes from baseline in LDL-C, BMI, HDL-C, TG, and ApoB were

not related to changes in FSG

• These data indicate that the addition of Eze therapy does not further

increase FSG levels beyond those with statin treatment

• These results are further consistent with lack of glucose excursion

with: 1) Eze monotherapy and 2) Eze+statin therapy in statin-naïve HC and HeFH patients during 12 to 96 weeks of treatment

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