Mcpgoldberg

RANDOMIZED CONTROLLED TRIAL OF EZETIMIBE/SIMVASTATIN AND ATORVASTATIN IN DIABETES Ezetimibe/Simvastatin vs Atorvastatin in Patients With
Type 2 Diabetes Mellitus and Hypercholesterolemia:
The VYTAL Study
RONALD B. GOLDBERG, MD; JOHN R. GUYTON, MD; THEODORE MAZZONE, MD; RUTH S. WEINSTOCK, MD, PHD; ADAM POLIS, MA; PATRICIA EDWARDS RN, BSN; JOANNE E. TOMASSINI, PHD; AND ANDREW M. TERSHAKOVEC, MD OBJECTIVE: To compare the efficacy and safety of the recom- malities, typified by increased triglyceride levels, low mended usual starting and next highest doses of ezetimibe/ high-density lipoprotein cholesterol (HDL-C) levels, and simvastatin and atorvastatin in patients with type 2 diabetesmellitus and hypercholesterolemia.
increased numbers of small dense low-density lipoprotein PATIENTS AND METHODS: This double-blind, multicenter study (June 22 to December 7, 2005) consisted of adult patients random- Lipid management can reduce major CHD events asso- ized to the recommended usual starting (ezetimibe/simvastatin, ciated with type 2 diabetes as indicated by meta-analysis of 10/20 mg/d, vs atorvastatin, 10 or 20 mg/d) or next highest(ezetimibe/simvastatin, 10/40 mg/d, vs atorvastatin, 40 mg/d) several randomized clinical trials based on a composite of doses. Efficacy end points included percent changes from baseline major CHD events, including CHD death, nonfatal myo- in low-density lipoprotein cholesterol (LDL-C) levels (primary) and cardial infarction, or myocardial revascularization proce- proportion of patients attaining LDL-C levels less than 70 mg/dL(secondary).
dures.2,3,5 The American Diabetes Association (ADA), Na-tional Cholesterol Education Program Adult Treatment RESULTS: A total of 1229 patients participated in the study.
Significantly greater mean reductions were found in LDL-C levels Panel III (NCEP ATP III), and the American Heart Asso- with ezetimibe/simvastatin, 10/20 mg/d (–53.6%; 95% confi- ciation/American College of Cardiology consider aggres- dence interval [CI], –55.4% to –51.8%), than with atorvastatin, 10 sive lipid-lowering measures to be an integral aspect of the mg/d (–38.3%; 95% CI, –40.1% to –36.5%; P<.001))or 20 mg/d(–44.6%; 95% CI, –46.4% to –42.8%; P<.001), and with care of patients with type 2 diabetes.2,6,7 Lifestyle modifica- ezetimibe/simvastatin, 10/40 mg/d (–57.6%; 95% CI, –59.4% tion and glucose control can improve general lipid profiles to –55.8%), vs atorvastatin, 40 mg/d (–50.9%; 95% CI, –52.7% in these patients, but supplementary pharmacological inter- to –49.1%; P<.001). Ezetimibe/simvastatin was also superior toatorvastatin in attainment of LDL-C levels less than 70 mg/dL vention, primarily directed at LDL cholesterol (LDL-C), is (P<.001 for all dose comparisons). Significantly better improve- recommended for most patients. In particular, the impor- ments with ezetimibe/simvastatin than with atorvastatin (P≤.001) tance of statins in lowering plasma LDL-C levels to were observed for total cholesterol, high-density lipoprotein choles-terol, and non–high-density lipoprotein cholesterol. Ezetimibe/ achieve reductions in CVD events has been well demon- simvastatin, 10/20 mg/d, reduced high-sensitivity C-reactive pro- strated in patients with established CHD and CHD-equiva- tein and triglyceride levels significantly more than atorvastatin, 10 lent risk, including those with type 2 diabetes.5,8,9 mg/d (P=.02), with comparable reductions at other doses. Inci-dences of clinical adverse events, including serious drug-related The ADA and NCEP ATP III guidelines identify the and prespecified gastrointestinal-, gallbladder-, and hepatitis-re- primary goal of lipid-related therapy as an LDL-C level lated allergic reactions or rash events, and laboratory adverse less than 100 mg/dL for patients with type 2 diabetes. The events, including repeated elevation of hepatic transaminases orcreatine kinase levels, were similar for both treatments.
ADA further recommends that LDL-C levels should bereduced 30% to 40% from baseline through statin therapy CONCLUSION: Ezetimibe/simvastatin provided additional lipid-modifying benefits over atorvastatin monotherapy at the recom- in patients with type 2 diabetes older than 40 years or with mended usual starting and next highest doses in patients withtype 2 diabetes. Both treatments were generally well tolerated.
From the Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Fla (R.B.G.); Duke University, Durham, NC (J.R.G.); University ofIllinois, Chicago (T.M.); Division of Endocrinology, Diabetes and Metabolism, ADA = American Diabetes Association; CAE = clinical adverse event; SUNY Upstate Medical University and Veterans Affairs Medical Center, Syra- CHD = coronary heart disease; CI = confidence interval; CVD = cardiovas- cuse, NY (R.S.W.); and Merck & Co, Inc, West Point, Pa (A.P., P.E., J.E.T., cular disease; HDL-C = high-density lipoprotein cholesterol; hsCRP = high- A.M.T.). A complete list of the VYTAL Study investigators appears at the end of sensitivity C-reactive protein; LAE = laboratory adverse event; LDL = low- density lipoprotein; LDL-C = LDL cholesterol; NCEP ATP III = NationalCholesterol Education Program Adult Treatment Panel III; ULN = upper Funding was provided by Merck/Schering-Plough Pharmaceuticals, North Wales, Pa. Drs Goldberg, Guyton, Mazzone, and Weinstock have receivedspeaker honoraria from Merck/Schering-Plough. Drs Tomassini and Tersh-akovec, Mr Polis, and Ms Edwards are employees of Merck & Co, Inc, and ownstock in the company.
Address reprint requests and correspondence to Ronald B. Goldberg, MD, Individuals with type 2 diabetes mellitus are at increased risk for coronary heart disease (CHD).1,2 High rates of Diabetes Research Institute, Miller School of Medicine, University of Miami, cardiovascular disease (CVD)–related morbidity and mor- 1450 NW 10th Ave, Miami, FL 33136 (e-mail: rgoldber@med.miami.edu).
tality in this population are attributed in part to lipid abnor- 2006 Mayo Foundation for Medical Education and Research
Mayo Clin Proc. • December 2006;81(12):1579-1588 • www.mayoclinicproceedings.com RANDOMIZED CONTROLLED TRIAL OF EZETIMIBE/SIMVASTATIN AND ATORVASTATIN IN DIABETES overt CVD,2 and both the ADA and the NCEP ATP III After a 3- to 5-week washout period of current lipid- identify an LDL-C level of less than 70 mg/dL as an lowering medications, patients maintained their ADA or optional target for patients with type 2 diabetes who are at similar glucose- and cholesterol-lowering diets during a 4- high risk for CVD.2,6 Although LDL-C is the main target of week placebo run-in. Patients who had an LDL-C level lipid-modifying intervention in type 2 diabetes, raising greater than 100 mg/dL and a triglyceride level less than HDL-C levels to more than 40 mg/dL in men and more than 400 mg/dL in the third week of the run-in and who satisfied 50 mg/dL in women and lowering triglyceride levels to less other eligibility criteria were randomized via an interactive than 150 mg/dL have been proposed by the ADA for high- voice response system to the recommended usual starting risk patients.2 The NCEP ATP III6 also recommends target- doses of ezetimibe/simvastatin (10/20 mg/d) vs atorvastat- ing non–HDL-C in hypertriglyceridemic individuals after in (10 or 20 mg/d) or the next highest doses of ezetimibe/ achievement of LDL-C goal and then raising HDL-C levels simvastatin (10/40 mg/d) vs atorvastatin (40 mg/d). Treat- ment was administered daily for 6 weeks; the ADA-com- The challenge of attaining more stringent LDL-C targets patible diet was continued for the study duration. Patients has stimulated research into possible new combinations of were randomized according to LDL-C levels obtained after lipid-lowering drugs.10 Ezetimibe, a first-in-class inhibitor washout and placebo run-in periods (Table 1).18 Baseline of cholesterol absorption, has emerged as an effective efficacy parameters were the average of measurements agent for combined use with statins to achieve the recom- made 1 week before and on the day of the start of active mended levels of LDL-C.2,6 Specifically, ezetimibe in com- therapy. All lipid measurements were made after a fast of at bination with simvastatin, approved by the US Food and Drug Administration as a single-tablet formulation (Vy- Safety was assessed by monitoring clinical adverse torin, Merck/Schering-Plough Pharmaceuticals, West events (CAEs) and laboratory adverse events (LAEs).
Point, Pa), has proved highly effective in reducing LDL-C Prespecified clinical safety variables included gastrointes- levels through its dual inhibition of cholesterol absorption tinal-, gallbladder-, and hepatitis-related adverse events, plus allergic reactions and rash; laboratory safety variables Given the increasing prevalence of type 2 diabetes and included serum alanine aminotransferase, aspartate ami- projected growth in the numbers of patients expected to notransferase, and creatine kinase levels. Patients undergo- develop this disease in the next 20 years,17 the identification ing the same treatments were pooled across dose groups for of effective lipid-lowering therapy for these patients is im- assessment of safety and tolerability.
portant. Currently, most ezetimibe/simvastatin (84%) and Efficacy outcomes were assessed after 6 weeks of active atorvastatin (75%) prescriptions are accounted for by the treatment in the modified intent-to-treat population based recommended usual starting (ezetimibe/simvastatin, 10/20 on all randomized patients who had valid baseline mea- mg/d, or atorvastatin, 10 or 20 mg/d) and next highest surements and at least 1 valid postbaseline measurement.
(ezetimibe/simvastatin, 10/40 mg/d, or atorvastatin, 40 mg/d) The primary efficacy end point was the percent reduction doses (IMS Health, NPA Plus, NRXs, March 2006). The from baseline in LDL-C level. The secondary efficacy end current clinical trial (Vytorin vs Atorvastatin in Patients point was the proportion of patients who attained the NCEP With Type 2 Diabetes Mellitus and Hypercholesterolemia ATP III recommended LDL-C level of less than 70 mg/dL [VYTAL Study]) was undertaken to compare the lipid- for very high-risk patients. Other efficacy measures in- altering effects, LDL-C goal attainment, and safety profile cluded the proportion of patients who attained the NCEP of ezetimibe/simvastatin and atorvastatin at these doses in ATP III LDL-C target of less than 100 mg/dL; percent patients with type 2 diabetes and hypercholesterolemia.
change from baseline in total cholesterol, HDL-C, non–HDL-C, and triglyceride levels; and changes in high-sensi-tivity C-reactive protein (hsCRP).
Primary statistical hypotheses were the comparison of This randomized, double-blind, parallel-group study re- percent reductions in LDL-C levels at 6 weeks after treat- cruited patients with type 2 diabetes (aged 18-80 years) with ment at the recommended usual starting doses (ezetimibe/ hemoglobin A levels of 8.5% or less at 147 participating simvastatin, 10/20 mg/d, vs atorvastatin, 10 or 20 mg/d) or centers in the United States. Study conduct conformed to the next highest doses (ezetimibe/simvastatin, 10/40 mg/d, national and international standards regulating clinical stud- vs atorvastatin, 40 mg/d). Differences were tested using the ies in humans and was initiated on June 22, 2005, and Hochberg procedure19 with α=.05 for type I error. Treat- completed on December 7, 2005. The protocol (077) was ment comparisons were based on an analysis of variance approved by appropriate institutional review boards, and all model with terms for treatment and baseline LDL-C stra- patients provided informed written consent.
tum. This model was used to examine the percent change Mayo Clin Proc. • December 2006;81(12):1579-1588 • www.mayoclinicproceedings.com RANDOMIZED CONTROLLED TRIAL OF EZETIMIBE/SIMVASTATIN AND ATORVASTATIN IN DIABETES TABLE 1. Baseline Characteristics of the Patients* *Data derived from all patients randomized, including a patient in the ezetimibe/simvastatin, 10/40 mg/d, group who was inadvertently randomized and did not have CHD or a CHD risk equivalent, including diabetes at baseline. All atorvastatin = 10, 20, and 40 mg/d pooled across all doses; all ezetimibe/simvastatin = 10/20 and 10/40 mg/d pooled across all doses; BMI = body mass index; CHD = coronary heart disease; LDL = low-density lipoprotein;NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III.
†For patients who completed active treatment, BMI was determined at weeks –4, –1, 0, and 6.
‡Metabolic syndrome is defined as having ≥3 of the following 5 characteristics: (1) waist circumference >102 cm in males or >88 cm in females; (2) triglyceride level of >150 mg/dL; (3) high-density lipoprotein cholesterol level <40 mg/dL in males or <50 mg/dL in females; (4) blood pressure >130/85mm Hg or taking antihypertensive medication; and/or (5) fasting glucose level >100 mg/dL or diabetic.18 §Patients with CHD and CHD equivalent risk may be in more than 1 category of CHD, other forms of atherosclerosis, and diabetes (in which diabetes is defined as a baseline fasting glucose level ≥126 mg/dL on ≥2 occasions, a diagnosis of diabetes, or use of antidiabetic medications).
⁄⁄Other forms of atherosclerosis are peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease, transient ischemic attack, and stroke.
from baseline in other efficacy variables. The triglyceride Analysis of LAEs was based on all patients with at least 1 and hsCRP levels were assessed by nonparametric analysis postbaseline laboratory assessment. The Fisher exact test of variance of the ranks based on normal scores, and medi- was used for prespecified treatment group comparisons.
ans are reported rather than means. Patients who attainedan LDL-C level of less than 70 mg/dL and less than 100 mg/dL were analyzed by a logistic regression model withterms for treatment and baseline LDL-C stratum. A 2-tailed P≤.05 was specified for statistical significance.
Of 2299 patients screened, 1229 were randomized to treat- For the primary study hypothesis, more than 90% power ment. Baseline characteristics of the randomized patients was expected for 205 evaluable patients per treatment were similarly distributed among treatment groups (Table group, assuming treatment differences of 10% (ezetimibe/ 1). The LDL-C baseline values were comparable across the simvastatin, 10/20 mg/d, vs atorvastatin, 10 mg/d) and 5% prespecified strata, with a mean LDL-C level of 145 mg/dL (ezetimibe/simvastatin, 10/20 mg/d, vs atorvastatin, 20 mg/d, (Table 1). Metabolic syndrome was widely prevalent and ezetimibe/simvastatin, 10/40 mg/d, vs atorvastatin, (86.6%). All but 1 patient in the study (Table 1) had type 2 40 mg/d), 14% within-group SD, and an α of .05 (2-sided).
diabetes, 15.1% of the patients had prior CHD and type 2 The safety analysis of CAEs was based on all randomized diabetes, and 11.6% had other forms of atherosclerotic patients who received at least 1 dose of study medication.
vascular disease. Of the randomized patients, 1198 (97.5%) Mayo Clin Proc. • December 2006;81(12):1579-1588 • www.mayoclinicproceedings.com RANDOMIZED CONTROLLED TRIAL OF EZETIMIBE/SIMVASTATIN AND ATORVASTATIN IN DIABETES 3 Did not receive allocated inter vention 480 Analyzed ezetimibe/simvastatin (mITT cohor t) 718 Analyzed ator vastatin (mITT cohor t) FIGURE 1. Disposition of patients through the study. LDL-C = low-density lipoprotein cholesterol; mITT = modified intentto treat.
were included in the modified intent-to-treat population –40.1% to –36.5%; and –44.6%; 95% CI, –46.4% to –42.8%, (480 in the ezetimibe/simvastatin group and 718 in the respectively; P<.001) (Table 2 and Figure 2). At the next atorvastatin group) for efficacy analysis (Figure 1).
highest dose, the mean percent LDL reductions were –57.6%(95% CI, –59.4% to –55.8%) and –50.9% (95% CI, –52.7% to –49.1%) for ezetimibe/simvastatin, 10/40 mg/d, and ator- Mean percent reductions in LDL-C levels from baseline vastatin, 40 mg/d, respectively (P<.001).
were significantly greater with the recommended usual start- A significantly greater percentage of patients treated ing dose of ezetimibe/simvastatin, 10/20 mg/d (–53.6%; with ezetimibe/simvastatin, 10/20 mg/d (59.7%; 95% CI, 95% confidence interval [CI], –55.4% to –51.8%), com- 53.5% to 65.9%), attained levels of LDL-C less than 70 pared with atorvastatin, 10 and 20 mg/d (–38.3%; 95% CI, mg/dL compared with atorvastatin, 10 and 20 mg/d Mayo Clin Proc. • December 2006;81(12):1579-1588 • www.mayoclinicproceedings.com RANDOMIZED CONTROLLED TRIAL OF EZETIMIBE/SIMVASTATIN AND ATORVASTATIN IN DIABETES TABLE 2. Treatment Effects on Primary Efficacy and Exploratory Lipid or Lipoprotein Variables *Data derived from patients in the modified intent-to-treat population, which included all randomized patients who had a valid baseline and at least 1 valid postbaseline measurement. HDL-C = high-density lipoprotein cholesterol; LDL-C = low-densitylipoprotein cholesterol.
†Percent changes from baseline and between-treatment differences are least squares means and differences in least squares means from an analysis of variance model, including terms for treatment and pretreatment LDL-C stratum.
‡Treatment differences are ezetimibe/simvastatin, 10/20 mg/d, minus atorvastatin, 10 mg/d; ezetimibe/simvastatin, 10/20 mg/d, minus atorvastatin, 20 mg/d; and ezetimibe/simvastatin, 10/40 mg/d, minus atorvastatin, 40 mg/d.
§P<.001.
⁄⁄P=.001.
¶P=.02 for specified between-treatment difference.
(21.5%; 95% CI, 16.3% to 26.7%; and 35%; 95% CI, simvastatin, 10/40 mg (93.4%; 95% CI, 90.3% to 96.5%), 29.0% to 41.0%, respectively; P<.001) (Figure 3, top).
and atorvastatin, 40 mg/d (88.8%; 95% CI, 84.8% to Similarly, 74.4% (95% CI, 68.9% to 79.9%) of patients 92.8%), did not differ significantly (P=.07).
treated with ezetimibe/simvastatin, 10/40 mg/d, had at-tained LDL-C levels of less than 70 mg/dL compared with 55.2% (95% CI, 48.9% to 61.5%) with atorvastatin, 40 At all doses, the increases from baseline in HDL-C levels mg/d (P<.001). Consistent with the whole cohort, higher were significantly greater with ezetimibe/simvastatin com- proportions of patients in the CHD subgroup also attained pared with atorvastatin (P≤.001) (Table 2). Ezetimibe/ LDL-C levels less than 70 mg/dL with ezetimibe/simva- simvastatin was also superior to atorvastatin in lowering statin than atorvastatin (Figure 3, middle). The interaction plasma total cholesterol and non–HDL-C levels (P<.001) of treatment by CHD classification was not statistically at all prespecified comparisons. Ezetimibe/simvastatin, 10/ 20 mg/d, decreased levels of hsCRP and triglycerides sig- Similarly, the percentage of patients who attained a nificantly more than atorvastatin, 10 mg/d (P=.02). At the target LDL-C level of less than 100 mg/dL with ezetimibe/ other dose comparisons, reductions in hsCRP and triglycer- simvastatin, 10/20 mg/d (90.3%; 95% CI, 86.5% to 94.1%), was significantly greater than with atorvastatin, 10and 20 mg/d (70.0%; 95% CI, 64.2% to 75.8%; P<.001; and 82.1%; 95% CI, 77.2% to 87.0%; P=.007; respec- Clinical adverse events occurred in 98 patients (19.8%) in tively) (Figure 3, bottom). Attainment rates for ezetimibe/ the ezetimibe/simvastatin groups and 166 patients (22.7%) Mayo Clin Proc. • December 2006;81(12):1579-1588 • www.mayoclinicproceedings.com RANDOMIZED CONTROLLED TRIAL OF EZETIMIBE/SIMVASTATIN AND ATORVASTATIN IN DIABETES Atorvastatin (Ator)Ezetimibe/simvastatin (Eze/Sim) FIGURE 2. Effects of ezetimibe/simvastatin and atorvastatin on low-density lipoprotein cholesterolreduction. Error bars indicate SEs and 95% confidence intervals (CIs) as indicated.
in the atorvastatin groups (Table 3). No statistically signifi- patient at the randomization visit who then discontinued cant differences were found in the frequency of any participation in the study. None of the patients treated with prespecified CAEs between the treatment groups, includ- ezetimibe/simvastatin experienced similar elevations.
ing drug-related and/or serious CAEs, CAEs leading todiscontinuation, and CAEs related to the gastrointestinal tract, gallbladder, hepatitis, rash, or allergy. Eight patientsdiscontinued participation in the study because of drug- In this study, ezetimibe/simvastatin was consistently supe- related adverse events, and no patient discontinued par- rior to atorvastatin in reducing LDL-C levels at both the ticipation because of an adverse event that was both seri- recommended usual starting and next highest doses in pa- ous and drug related. One death occurred during the tients with type 2 diabetes and hypercholesterolemia.
study: a patient treated with atorvastatin, 20 mg/d, died of Ezetimibe/simvastatin reduced LDL-C levels by more than chronic obstructive pulmonary disease (not considered 50% from baseline at these doses, fulfilling the ADA rec- ommendation of a 30% to 40% reduction from baseline.2 Laboratory adverse events occurred in 8 patients (1.6%) This study also confirmed the superior attainment of LDL- in the ezetimibe/simvastatin group and 10 patients (1.4%) C levels of less than 70 mg/dL in high-risk patients with in the atorvastatin group. Drug-related LAEs occurred in 3 ezetimibe/simvastatin vs atorvastatin and did so across a patients in both treatment assignments. No serious LAEs wider range of dosages than previously reported.20 Thus, occurred, and no patients discontinued study participation these results add to the clinical experience with ezetimibe/ simvastatin, affirming its effectiveness in the management No patient had a creatine kinase elevation 10 or more of high LDL-C levels11-13,20,21 and extending that finding to times the upper limit of normal (ULN), with or without muscle symptoms. A creatine kinase elevation 5 or more to The baseline mean level of LDL-C in this study (145 less than 10 times the ULN occurred in 1 patient treated mg/dL) was similar to that reported elsewhere for patients with ezetimibe/simvastatin, 10/40 mg/d, and 1 treated with with type 2 diabetes (approximately 150 mg/dL)22 but was atorvastatin, 20 mg/d. Consecutive elevations of alanine lower than in many previous trials of lipid-lowering aminotransferase and/or aspartate aminotransferase to 3 or therapy for all patients (approximately 170 mg/dL). Given more times the ULN were observed in the atorvastatin this relatively low starting level, a high rate of attainment of treatment group in 2 patients at the end of the study and in 1 the LDL-C target of less than 100 mg/dL was anticipated Mayo Clin Proc. • December 2006;81(12):1579-1588 • www.mayoclinicproceedings.com RANDOMIZED CONTROLLED TRIAL OF EZETIMIBE/SIMVASTATIN AND ATORVASTATIN IN DIABETES and confirmed (Figure 3, bottom). A statistically greaterattainment of this goal occurred with ezetimibe/simvastatin compared with atorvastatin at the recommended usual starting doses. The proportion of patients reaching an LDL-C level of less than 100 mg/dL with ezetimibe/simvastat- in was near maximal at all doses (>90%); therefore, theintergroup difference diminished as the atorvastatin dose Achievement of large percent reductions in LDL-C was associated with significant reductions in major coronary events in the Heart Protection Study, which included 5963 patients with diabetes.8 In that study, intense treatment of patients with 40 mg of simvastatin resulted in improve-ments in major CHD events regardless of baseline LDL-C Patients (%) attaining LDL-C <70 mg/dL levels, and the investigators concluded that a threshold had Eze/Sim, 20 mg/d, Eze/Sim, 20 mg/d, Eze/Sim, 40 mg/d, not been identified below which a further reduction of LDL-C levels confers additional benefit.8 As such, theNCEP ATP III has recommended an optional target ofless than 70 mg/dL for very high-risk patients with CVD, including diabetic patients with CVD.6 Similarly, other studies of atorvastatin have demonstrated that aggressive treatment that lowers cholesterol levels to below currently recommended target thresholds is associated with addi-tional clinical benefits in patients with type 2 diabetes.22,23 Thus, given the very high levels of CVD risk confrontingpatients with type 2 diabetes, aggressive management of LDL-C to reach levels less than 70 mg/dL may be war- ranted in type 2 diabetes patients with CVD.
Our data indicate that the attainment of this more exact- ing LDL-C level of less than 70 mg/dL in patients with type Patients (%) attaining LDL-C <70 mg/dL 2 diabetes and hypercholesterolemia is substantially greater with ezetimibe/simvastatin than with atorvastatin monotherapy at the recommended usual starting or next Eze/Sim, 20 mg/d Eze/Sim, 20 mg/d Eze/Sim, 40 mg/d highest doses. Most patients attained LDL-C levels of less than 70 mg/dL at all doses of ezetimibe/simvastatin, in-cluding those with established CHD, who have been identi-fied as candidates for the most aggressive LDL-C lower- ing.2,6 The success in attainment of this level of LDL-C contrasts with reports of other therapies, in which achiev- ing an LDL-C level of less than 70 mg/dL was deemeddifficult.10,24,25 Diabetic dyslipidemia consists of increased numbers of small dense LDL particles, low HDL-C levels, and recip- rocally elevated triglyceride levels.3,18,26 In this study, sta-tistically greater increases in HDL-C were achieved with FIGURE 3. Proportion of patients attaining low-density lipoproteincholesterol (LDL-C) levels less than 70 mg/dL (top), LDL-C levelsless than 70 mg/dL in the coronary heart disease subgroup Patients (%) attaining LDL-C <100 mg/dL (middle), and LDL-C levels less than 100 mg/dL (bottom). *P<.001 for specified between-treatment difference. †P=.007. Error bars Eze/Sim, 20 mg/d Eze/Sim, 20 mg/d Eze/Sim, 40 mg/d Mayo Clin Proc. • December 2006;81(12):1579-1588 • www.mayoclinicproceedings.com RANDOMIZED CONTROLLED TRIAL OF EZETIMIBE/SIMVASTATIN AND ATORVASTATIN IN DIABETES *For the CAEs, the sample sizes were 732 for the all atorvastatin group and 494 for the all ezetimibe/ simvastatin group. For the LAEs, the sample sizes were 723 for the all atorvastatin group and 485 for the allezetimibe/simvastatin group. All atorvastatin = 10, 20, and 40 mg/d pooled across doses; all ezetimibe/simvastatin = 10/20 and 10/40 mg/d pooled across doses; ALT = alanine aminotransferase; AST =aspartate aminotransferase; CAEs = clinical adverse events; CI = confidence interval; CK = creatinekinase; LAEs = laboratory adverse events; ULN = upper limit of normal.
†Data derived from all patients randomized who had at least 1 dose of study drug.
‡Determined by investigators to be possibly, probably, or definitely drug related.
§Data derived from patients with at least 1 postbaseline laboratory assessment.
ezetimibe/simvastatin at all doses compared with ator- this is still debated.31 Previously, ezetimibe/simvastatin and vastatin. Although higher levels of HDL-C have been atorvastatin were shown to comparably reduce hsCRP at all shown to correlate with a lower risk of major coronary milligram-equivalent dose comparisons in patients with events, changes in HDL-C levels have not been demon- hypercholesterolemia.12 In that study, a significantly strated to predict risk.27 Similarly, ezetimibe/simvastatin greater proportion of patients also attained both LDL-C was significantly more effective at reducing non–HDL-C levels lower than 70 mg/dL and hsCRP levels lower than 2 levels than atorvastatin at all dose comparisons. A signifi- mg/L with ezetimibe/simvastatin (10, 20, 40, and 80 mg/d) cantly greater reduction in triglyceride levels was also ob- compared with atorvastatin (10, 20, 40, and 80 mg/d; tained with ezetimibe/simvastatin, 10/20 mg/d, compared P≤.01).32 Similarly, in this study, ezetimibe/simvastatin with atorvastatin, 10 mg/d (P=.02), and comparable reduc- and atorvastatin comparably reduced hsCRP levels at the tions were observed at other studied doses. Lipoprotein higher dose comparisons, although at the lowest dose com- ratios, including total cholesterol/HDL-C, LDL-C/HDL-C, parison, the reduction with ezetimibe/simvastatin was sig- apoB/apoA-1, and non-HDL/HDL-C, considered to be nificantly greater compared with that of atorvastatin. Of supplementary indicators of CVD risk, were also signifi- note, the prognostic value of lowering hsCRP levels has yet cantly improved by treatment with ezetimibe/simvastatin to be demonstrated in outcome trials.
compared with atorvastatin (data not shown; P<.001 for all The safety and tolerability elicited by both study drugs in this study are consistent with previous reports.8,9,13,15,16,33-35 Elevated levels of the inflammatory marker protein Overall rates of CAEs and discontinuations were low in hsCRP have been reported to predict the development of both groups, and none of the serious CAEs were attributed type 2 diabetes and risk of CVD in patients with (or with- to study treatment. A low incidence of elevated transami- out) type 2 diabetes,28-30 although the clinical importance of nase levels occurred in the atorvastatin group, but none Mayo Clin Proc. • December 2006;81(12):1579-1588 • www.mayoclinicproceedings.com RANDOMIZED CONTROLLED TRIAL OF EZETIMIBE/SIMVASTATIN AND ATORVASTATIN IN DIABETES were observed for ezetimibe/simvastatin. Although the in- Ronald M. Gilman, MD, East Providence, RI; Joseph A. Girgis, cidence of serious CAEs was low in this relatively large MD, Elyria, Ohio; Charles T. Givens, MD, Reading, Pa; Linda A.
study, it was neither powered nor of sufficient duration to Glaser, MD, PhD, Santa Monica, Calif; Donald M. Gleason, MD, accurately assess the prevalence of rare CAEs. Although Tucson, Ariz; Richard M. Glover II, MD, Newton, Kan; RonaldB. Goldberg, MD, Miami, Fla; Ronald J. Graf, MD, Tacoma, both drugs were well tolerated, use of the lowest effective Wash; Alan Graff, MD, Ft Lauderdale, Fla; Paul A. Hartley, MD, dose of a given product may be desirable to minimize the Uniontown, Pa; Alan M. Heller, MD, San Jose, Calif; David K.
Helton, MD, Chattanooga, Tenn; Bruce Henson, MD, KansasCity, Mo; Charles B. Herring, MD, Wilmington, NC; John N.
Herrod, MD, Sierra Vista, Ariz; Kenneth S. Hershon, MD, NewHyde Park, NY; Michael C. Hess, MD, Louisville, Ky; Robert K.
This study demonstrated that ezetimibe/simvastatin admin- Hippert, DO, Fleetwood, Pa; Jennifer Hone, MD, Denver, Colo; istered at its recommended usual starting and next highest Barry S. Horowitz, MD, West Palm Beach, Fla; Gary Ishkanian, doses was superior to the corresponding doses of ator- MD, Mount Vernon, NY; Rodney K. Ison, MD, Canal Fulton, vastatin in its effects on a range of lipid and lipoprotein Ohio; Rajeev K. Jain, MD, Milwaukee, Wis; Conigliaro Jones,MD, Columbia, SC; Dorothy Kahkonen, MD, Detroit, Mich; Zevi parameters. Thus, the dual cholesterol-lowering mecha- S. Kahn, MD, Everett, Wash; Joseph Kang, MD, Reading, Pa; nism of ezetimibe/simvastatin provides an effective and Roy A. Kaplan, MD, Concord, Calif; Stephen W. Kayota, MD, well-tolerated option as first-line lipid-modifying therapy Virginia Beach, Va; Robert J. Kirshbaum, MD, Rancho Cuca- for patients with type 2 diabetes and hypercholesterolemia.
monga, Calif; Eric J. Klein, MD, Olympia, Wash; Gary M. Knox,MD, Spokane, Wash; Walter B. Koppel, MD, Baltimore, Md; We acknowledge Peter Hughes, BS, and Martha Vollmer, MA, for Richard A. Krause, MD, Chattanooga, Tenn; Steven Landgarten, MD, Tulsa, Okla; Rick J. Lawson, MD, Louisville, Ky; KennethJ. Leopold, MD, Marietta, Ohio; Sam Lerman, MDCM, Holly-wood, Fla; Andrew Lewin, MD, Los Angeles, Calif; John E.
The VYTAL Study Investigators. Jay L. Adler, MD, Colorado
Liljenquist, MD, Idaho Falls, Idaho; Norman M. Lunde, MD, Springs, Colo; Luis E. Angles, MD, Shawnee Mission, Kan; Brooklyn Center, Minn; Peter G. Manolukas, DO, Beaver, Pa; Jonathan R. Anolik, MD, Moorestown, NJ; Stephen Arnold, MD, Richard N. Marple, MD, Tulsa, Okla; David W. McCarty, DO, Honolulu, Hawaii; Joseph E. Barrera, MD, Mission Viejo, Calif; Longmont, Colo; Dennis C. McCluskey, MD, Mogadore, Ohio; Darlene Bartilucci, MD, Jacksonville, Fla; Harold Bays, MD, Mary P. McGowan, MD, Concord, NH; Avishai Mendelson, MD, Louisville, Ky; Sabrina Benjamin, MD, Tacoma, Wash; Louis West Palm Beach, Fla; James H. Mersey, MD, Baltimore, Md; Bonavita, Jr, MD, East Syracuse, NY; Ronald L. Brazg, MD, Michael Miller, MD, Baltimore, Md; Stephen H. Miller, MD, Las Renton, Wash; Geoffrey M. Burgess, MD, Downingtown, Pa; Vegas, Nev; Leslie P. Moldauer, MD, Denver, Colo; David J.
Edward Busick, MD, Waltham, Mass; Dennis Buth, MD, Morin, MD, Bristol, Tenn; John Murray, Jr, MD, Pinellas Park, Wichita, Kan; Leroy J. Byrd, MD, Spokane, Wash; Albert A.
Fla; Derek D. Muse, MD, Salt Lake City, Utah; Daniel A.
Carr, MD, Augusta, Ga; Christopher M. Chappel, MD, Nadeau, MD, Hampton, NH; Brooke J. Nevins, MD, Bronxville, Kissimmee, Fla; Henryk Cioczek, MD, Brooklyn, NY; David A.
NY; Michael J. Noss, MD, Cincinnati, Ohio; Larry G. Padget, Claassen, MD, Ozark, Ala; James W. Clower III, MD, Jackson- MD, Georgetown, Tex; Edward B. Portnoy, MD, Westlake Vil- ville, Fla; Marco N. Diaz, MD, South Portland, Me; Gregory lage, Calif; Krishna K. Pudi, MD, Simpsonville, SC; James F.
Collins, MD, Charlotte, NC; Scott E. Conard, MD, Irving, Tex; Quigley, DO, Encinitas, Calif; George L. Raad, MD, Charlotte, Clinton N. Corder, MD, PhD, Oklahoma City, Okla; Adrian NC; Marina Raikhel, MD, Torrance, Calif; Seppo E. Rapo, MD, Dahdul, MD, Springfield, Mass; Michael H. Davidson, MD, Chi- West Yarmouth, Mass; Robert Ratner, MD, Washington, DC; cago, Ill; Mark A. Deeg, MD, PhD, Indianapolis, Ind; Paul S.
Ernie Riffer, MD, Phoenix, Ariz; Lon E. Roberts, MD, Lexington, Denker, MD, Clearwater, Fla; Richard DiMonte, DO, Philadel- Ky; Jane L. Rohlf, MD, Trenton, NJ; Jeffrey B. Rosen, MD, Coral phia, Pa; Daniel J. Dionne, MD, Spokane, Wash; Robert W.
Gables, Fla; Gary E. Ruoff, MD, Kalamazoo, Mich; David A.
Downs, MD, Richmond, Va; Joel D. Eade, MD, Campbellsville, Schmeidler, MD, Arkansas City, Kan; Douglas Schumacher, MD, Ky; Richard Eddy, MD, Medford, Ore; Richard H. Egelhof, MD, Columbus, Ohio; Nathan Segall, MD, Atlanta, Ga; Larry S.
Wichita, Kan; Andrew C. Eisenberg, MD, Madisonville, Tex; Seidman, DO, Philadelphia, Pa; Randall J. Severance, MD, Chan- Samuel S. Engel, MD, Norwalk, Conn; James I. Fidelholtz, MD, dler, Ariz; Jon Shapiro, MD, Philadelphia, Pa; Marc R. Shepard, Cincinnati, Ohio; Thomas Fiel, DO, Tempe, Ariz; Chester L.
MD, Riverdale, Md; Gerald Shockey, MD, Mesa, Ariz; Henry P.
Fisher, Jr, MD, Newport News, Va; David Fitz-Patrick, MD, Sideropoulos, MD, Pasadena, Calif; Henry J. Simon, MD, Toms Honolulu, Hawaii; John W. Foley, DO, Dover, NH; Steven D.
River, NJ; Michael J. Sinclair, MD, Loxahatchee, Fla; Timothy R.
Folkerth, MD, Las Vegas, Nev; Alan D. Forker, MD, Kansas Smith, MD, St Louis, Mo; Norman G. Soler, MD, PhD, Spring- City, Mo; Neil J. Fraser, MD, Troy, Mich; Ronald K. Garcia, MD, field, Mass; Joseph Soufer, MD, Waterbury, Conn; Phillip D.
San Antonio, Tex; Garo Garibian, MD, Philadelphia, Pa; Toth, MD, Indianapolis, Ind; Julio C. Ugarte, MD, Summerfield, Lawrence Gassner, MD, Phoenix, Ariz; David B. George, MD, Fla; James A. Underberg, MD, New York, NY; Martin Van Louisville, Ky; Larry I. Gilderman, DO, Pembroke Pines, Fla; Cleeff, MD, Cary, NC; Shalendra Varma, MD, Rocky Mount, Mayo Clin Proc. • December 2006;81(12):1579-1588 • www.mayoclinicproceedings.com RANDOMIZED CONTROLLED TRIAL OF EZETIMIBE/SIMVASTATIN AND ATORVASTATIN IN DIABETES 16. Catapano AL, Davidson MH, Ballantyne CM, et al. Lipid-altering effi-
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