- Email: [email protected]
Simvastatin Plus Extended-Release Niacin in Patients With Hyperlipidemia
Long-Term Safety and Efficacy of Triple Combination Ezetimibe/Simvastatin Plus Extended-Release Niacin in Patients With Hyperlipidemia Sergio Fazio, MD, PhDa,*, John R. Guyton, MDb, Adam B. Polis, MAc, Adeniyi J. Adewale, PhDc, Joanne E. Tomassini, PhDc, Nicholas W. Ryan, PharmDc, and Andrew M. Tershakovec, MD, MPHc The safety and efficacy of combination ezetimibe/simvastatin (E/S) plus extended-release niacin was assessed in 942 patients with type IIa/IIb hyperlipidemia for 64 weeks in a randomized, double-blind study. Patients received E/S (10/20 mg) plus niacin (to 2 g) or E/S (10/20 mg) for 64 weeks, or niacin (to 2 g) for 24 weeks and then E/S (10/20 mg) plus niacin (2 g) or E/S (10/20 mg) for an additional 40 weeks. The primary end point, the safety of E/S plus niacin, included prespecified adverse events (ie, liver, muscle, discontinuations due to flushing, gallbladder-related, cholecystectomy, fasting glucose changes, new-onset diabetes). The secondary end points included the percentage of change from baseline in highdensity lipoprotein (HDL) cholesterol, triglycerides, non-HDL cholesterol, and low-density lipoprotein cholesterol, other lipids, lipoprotein ratios and high-sensitivity C-reactive protein. The anticipated niacin-associated flushing led to a greater rate of study discontinuations with the E/S plus niacin regimen than with E/S alone (0.7%, p <0.001). The rate of liver and muscle adverse events was low (<1%) in both groups. Four patients had gallbladder-related adverse events; 1 patient in the E/S and 1 in the E/S plus niacin group underwent cholecystectomy. The occurrence of new-onset diabetes was 3.1% for the E/S and 4.9% for the E/S plus niacin group. The fasting glucose levels increased to greater than baseline during the first 12 weeks (E/S, 3.2 mg/dl; E/S plus niacin, 7.7 mg/dl) and gradually decreased to pretreatment levels by 64 weeks in both groups. E/S plus niacin significantly improved HDL cholesterol, triglycerides, non-HDL cholesterol, low-density lipoprotein cholesterol, apolipoprotein B and A-I, and lipoprotein ratios compared with E/S (p <0.004). The changes in high-sensitivity C-reactive protein were comparable for both groups. In conclusion, the combination of E/S plus niacin was generally well tolerated, aside from niacin-associated flushing, and was significantly superior to E/S alone in improving several lipoprotein parameters during a 64-week trial in patients with hyperlipidemia. E/S plus niacin provided a broad, lipid-altering therapeutic option for these patients, even in the presence of diabetes with glucose monitoring. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:487– 494)
a
Division of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee; bDuke University, Durham, North Carolina; and cMerck and Co., Inc., North Wales, Pennsylvania. Manuscript received September 11, 2009; revised manuscript received and accepted October 9, 2009. This study was funded by Merck/Schering-Plough Pharmaceuticals, Inc., North Wales, Pennsylvania. Drs. Fazio and Guyton have received honoraria from Merck/Schering-Plough Pharmaceuticals, Inc. (North Wales, Pennsylvania). Dr. Fazio has also received honoraria from Abbott Laboratories (North Chicago, Illinois), GlaxoSmithKline (Philadelphia, Pennsylvania), and research support from ISIS (Carlsbad, California)/ Genzyme (Cambridge, Massachusetts) and Takeda (Osaka, Japan). Dr. Guyton has also received educational and research grants from Merck and Co., Inc. (Whitehouse Station, New Jersey) and consulting fees and honoraria from Abbott Laboratories (North Chicago, Illinois). Drs. Tershakovec, Tomassini, and Adewale and Mr. Polis and Mr. Ryan are employees of Merck and Co., Inc. (Whitehouse Station, New Jersey) and own stock and stock options in the company. *Corresponding author: Tel: (615) 936-1450; fax: (615) 936-3486. E-mail address: [email protected] (S. Fazio). 0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.10.001
A combination of low-density lipoprotein (LDL) cholesterol lowering and high-density lipoprotein (HDL) cholesterol increasing therapies might provide a broad, lipid-altering treatment for patients with combined dyslipidemia.1–3 Niacin, currently the most effective HDL cholesterol increasing therapy, also improves other lipid parameters, reduces cardiovascular disease-related morbidity and mortality, and slows the progression and/or induces the regression of coronary atherosclerosis.4 –10 Although niacin-associated flushing can limit its use, this effect can be mitigated through patient counseling and proper administration.11 Niacin can also be associated with increases in blood glucose levels, which require monitoring and possibly therapeutic changes, particularly in patients with diabetes.11 Ezetimibe/ simvastatin (E/S) is an effective and generally well-tolerated LDL cholesterol lowering agent that also reduces the levels of triglycerides, non-HDL cholesterol, and apolipoprotein B and modestly increases HDL cholesterol.12–15 The complementary lipid-altering benefits and safety of E/S co-administered with extended-release niacin (Niaspan, Abbott Laboratories, North Chicago, Illinois) were www.AJConline.org
488
The American Journal of Cardiology (www.AJConline.org)
Figure 1. Patient disposition. During first 24 weeks, 1,214 patients received E/S (n ⫽ 272), niacin (n ⫽ 272), or E/S plus niacin (n ⫽ 670).16 Primary safety and efficacy populations included 942 patients who received E/S and E/S plus niacin during first 24 weeks, who were scheduled to continue these therapies through 64 weeks. Secondary safety and efficacy populations included those patients treated with niacin during first 24 weeks who then switched to and continued with E/S (⬃1/3) and E/S plus niacin (⬃2/3) through 64 weeks.
demonstrated compared to E/S and niacin in patients with type IIa/IIb hyperlipidemia during the initial 24-week phase of this 64-week study.16 Patients taking E/S and E/S plus niacin continued these therapies and those taking niacin alone were switched to E/S or E/S plus niacin for an additional 40 weeks. In the present report, the 64-week safety and lipid-modifying efficacy of E/S plus niacin versus E/S is presented from the largest, long-term randomized clinical trial of niacin (2 g) to date since the Coronary Drug Project.9 Methods This was a multicenter, randomized, double-blind, 64week study of patients with type IIa and IIb hyperlipidemia. Protocol 091 (Clinicaltrials.gov number NCT00271817) was approved by the appropriate institutional review boards, and all patients provided informed written consent. Men and women (18 to 79 years old) with LDL cholesterol levels of 130 to 190 mg/dl, triglyceride levels ⱕ500 mg/dl, creatinine ⬍2 mg/dl, creatine kinase ⱕ2⫻ the upper limit of normal (ULN), transaminases ⱕ1.5⫻ ULN, and hemoglobin A1c ⱕ8% were enrolled at 107 United States centers. During the first 24 weeks of the study, after a 4-week washout period, the eligible patients were randomized (5: 2:2) and treated with E/S (10/20 mg) plus niacin (to 2 g),
niacin (to 2 g), or E/S (10/20 mg).16 Niacin was increased by 500 mg every 4 weeks to 2 g/day within 12 weeks from a 500 mg/day starting dose. At the end of 24 weeks, patients taking E/S and E/S plus niacin continued these therapies. Of those in the niacin arm, 1/3 were preassigned to E/S and 2/3 to E/S plus niacin for an additional 40 weeks. Patients were counseled to take niacin at bedtime with a low-fat snack, aspirin (325 mg) or ibuprofen (200 mg) 30 minutes before taking niacin, and to avoid alcoholic and hot beverages near this time. Patients were preassigned by central allocation to 1 of 4 treatment arms (arm 1, E/S plus niacin for 24 weeks and then E/S plus niacin for weeks 24 to 64; arm 2, E/S for 24 weeks and then E/S for weeks 24 to 64; arm 3, niacin for 24 weeks and then E/S plus niacin for weeks 24 to 64; and arm 4, niacin for 24 weeks and then E/S for weeks 24 to 64) in a 15:6:4:2 ratio, using a computer-generated, interactive voice response system schedule with block sizes of 27 for each of the 4 baseline strata (LDL cholesterol 130 to 159 or 160 to 190 mg/dl and triglycerides ⬍200 mg/dl; LDL cholesterol 130 to 159 or 160 to 190 mg/dl and triglyceride 201 to 500 mg/dl). None of the clinical team involved with trial conduct were aware of the patient-level data during the analysis of the 24-week data, and the study remained double blinded for the entire duration of the 64-week study.
Preventive Cardiology/Niacin and Ezetimibe/Simvastatin in Hyperlipidemia Table 1 Baseline characteristics Characteristic
Age (years) Women Race Asian Black Hispanic Other White Body mass index (kg/m2) Fasting glucose (mg/dl) NCEP-ATP III CHD/CHD risk equivalent* High risk with atherosclerotic vascular disease CHD Other forms of atherosclerosis† High risk without atherosclerotic vascular disease Diabetes mellitus‡ ⱖ2 CHD (10 years ⬎20%) risk factors Metabolic syndrome§ Lipid parameters (mg/dl)¶ HDL cholesterol Triglycerides Non-HDL cholesterol LDL cholesterol Total cholesterol Total cholesterol/HDL cholesterol LDL cholesterol/HDL cholesterol Non-HDL cholesterol/HDL cholesterol ApoB储 Apo A-I储 ApoB/apoA-I储 hs-CRP (mg/L)#
489
Table 2 Clinical and laboratory adverse events E/S (n ⫽ 272)
E/S Plus Niacin (n ⫽ 676)
Adverse Events
57.5 ⫾ 10.3 120 (44%)
56.9 ⫾ 10.9 352 (52%)
4 (2%) 17 (6%) 11 (6%) 0 240 (88%) 30.3 ⫾ 6.0 101.6 ⫾ 14.1
11 (2%) 38 (6%) 49 (6%) 2 (⬍1%) 576 (85%) 29.8 ⫾ 5.5 101.6 ⫾ 18.1
Clinical ⱖ1 Event 208 (76.5%) 552 (82.4%) Drug-related* 61 (22.4%) 377 (56.3%) Serious 18 (6.6%) 37 (5.5%) Serious drug-related* 1 (0.4%) 0 Deaths 0 0 Discontinuations† 36 (13.2%) 177 (26.4%) Drug-related* 19 (7.0%) 136 (20.3%) Serious 8 (2.9%) 13 (1.9%) Serious drug-related* 0 0 Laboratory‡ n ⫽ 272 n ⫽ 669 ⱖ1 Event 29 (10.7%) 51 (7.6%) Drug-related* 13 (4.8%) 37 (5.5%) Serious 0 0 Serious drug-related* 0 0 Deaths 0 0 Discontinuations 3 (1.1%) 8 (1.2%) Drug-related* 3 (1.1%) 6 (0.9%) Serious 0 0 Serious drug-related* 0 0
84 (31%) 36 (13%)
183 (27%) 77 (11%)
22 (8%) 18 (7%) 48 (18%)
60 (9%) 34 (5%) 106 (16%)
43 (16%) 22 (8%)
105 (16%) 42 (6%)
156 (57%) n ⫽ 207 49.9 ⫾ 13.9 158.0 ⫾ 100.5 191.0 ⫾ 28.3 155.6 ⫾ 21.8 240.9 ⫾ 28.7 5.1 ⫾ 1.3 3.3 ⫾ 0.9 4.1 ⫾ 1.3 151.3 ⫾ 22.2 165.8 ⫾ 29.2 0.9 ⫾ 0.2 2.1 ⫾ 3.5
319 (47%) n ⫽ 369 50.4 ⫾ 13.1 159.0 ⫾ 91.2 191.2 ⫾ 26.1 157.1 ⫾ 23.1 241.6 ⫾ 27.6 5.0 ⫾ 1.1 3.3 ⫾ 0.8 4.0 ⫾ 1.1 151.7 ⫾ 21.3 165.2 ⫾ 28.0 0.9 ⫾ 0.2 2.4 ⫾ 3.4
Data are presented as mean ⫾ SD or numbers (%). * Patients with coronary heart disease and CHD risk equivalents might be in ⬎1 category of CHD, other forms of atherosclerosis, and diabetes (with diabetes defined as baseline fasting glucose ⱖ126 mg/dl on ⱖ2 occasions, or a diagnosis of diabetes, or use of antidiabetic medications). † Other forms of atherosclerosis include peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease, transient ischemic attack, and stroke. ‡ Patients with diabetes had hemoglobin A1c levels of ⱕ8%, and 91 of these patients (9.7%) had previous antidiabetic medication use at enrollment. § Defined as having ⱖ3 of following characteristics: (1) waist circumference ⬎102 cm for men or ⬎88 cm for women; (2) triglycerides ⱖ150 mg/dl; (3) HDL cholesterol ⬍40 mg/dl for men or ⬍50 mg/dl for women; (4) blood pressure ⬎130/85 mm Hg or taking antihypertensive medication; and (5) fasting glucose ⬎100 mg/dl or diagnosis of diabetes. ¶ Primary efficacy population. 储 n ⫽ 182 for E/S, n ⫽ 321 for E/S plus niacin. # n ⫽ 187 for E/S; n ⫽ 324 for E/S plus niacin. Apo ⫽ apolipoprotein; E/S ⫽ ezetimibe/simvastatin 10/20 mg; CHD ⫽ coronary heart disease; hs-CRP ⫽ high-sensitivity C-reactive protein; NCEP-ATP III ⫽ National Cholesterol Education Program, Adult Treatment Panel III; niacin ⫽ extended-release niacin (titrated to 2 g); E/S plus niacin ⫽ ezetimibe/simvastatin 10/20 mg plus niacin (titrated to 2 g).
E/S (n ⫽ 272)
E/S Plus Niacin (n ⫽ 670)
E/S Plus Niacin vs E/S Difference (95% CI) 5.9 (0.3, 11.9) 33.8 (27.3, 39.7) ⫺1.1 (⫺5.0, 2.0) — — 13.2 (7.6, 18.1) 13.3 (8.7, 17.4) ⫺1.0 (⫺3.9, 1.0) — ⫺3.0 (⫺7.6, 0.8) 0.8 (⫺2.8, 3.6) — — — 0.1 (⫺2.1, 1.5) ⫺0.2 (⫺2.4, 1.1) — —
* Determined by investigator to be possibly, probably, or definitely drug related. † Most common reasons for discontinuations from clinical AEs for E/S plus niacin were flushing/hot flush (n ⫽ 69), pruritis/pruritis generalized (n ⫽ 21), rash/rash papular/rash erythematous (n ⫽ 10), myalgia (n ⫽ 9), and nausea (n ⫽ 5) and for E/S were myalgia (n ⫽ 7), rash/rash pruritic (n ⫽ 3), flushing (n ⫽ 2), fatigue (n ⫽ 2), and nausea (n ⫽ 2). ‡ Patients with ⱖ1 postbaseline laboratory test measurement. CI ⫽ confidence interval.
The primary end point of the 64-week study was the safety and tolerability of E/S plus niacin. Prespecified adverse events (AEs) included alanine aminotransferase and aspartate aminotransferase ⱖ3⫻ ULN, creatine kinase ⱖ10⫻ ULN with and without muscle symptoms, discontinuation due to flushing, gallbladder-related AEs, cholecystectomy, change from baseline in fasting glucose, and new onset of diabetes (patients with an AE related to a diagnosis of diabetes [from clinical AE reports using a predefined set of Medical Dictionary for Regulatory Activities terms], 2 consecutive fasting glucose measurements ⱖ126 mg/dl, or the initiation of antidiabetic medication during the study). The secondary end points were changes from baseline in HDL cholesterol, triglycerides, non-HDL cholesterol, LDL cholesterol, other lipids, lipoprotein ratios, and high-sensitivity C-reactive protein. The 64-week primary hypothesis, the safety and tolerability of E/S plus niacin, was assessed by clinical and/or statistical review of all safety parameters in the primary safety analysis population, which included patients originally randomized to E/S plus niacin or E/S who had received ⱖ1 dose of study medication. For the analysis of changes from baseline in the safety parameters, patients were also required to have baseline and ⱖ1 on-treatment measurements. The incidence of prespecified AEs was compared by Fisher’s exact test. The primary safety analysis
490
The American Journal of Cardiology (www.AJConline.org)
Table 3 Safety end points Safety End Point
Alanine aminotransferase ⱖ3⫻ upper limit of normal, consecutive* Aspartate aminotransferase ⱖ3⫻ upper limit of normal, consecutive* Aspartate aminotransferase and/or alanine aminotransferase ⱖ3⫻ upper limit of normal, consecutive* Creatine kinase ⱖ10⫻ upper limit of normal ⱖ10⫻ upper limit of normal with muscle symptoms ⱖ10⫻ upper limit of normal with drug-related muscle symptoms Patients (n) Discontinuation due to flushing‡ Gallbladder-related Cholecystectomy Patients (n) New-onset diabetes§ Initiated use of antidiabetic medications Consecutive fasting glucose elevations ⱖ126 mg/dl Diagnosis of type 2 diabetes mellitus储 Patients (n) Worsening of diabetes# Initiated use of antidiabetic medications Diagnosis of type 2 diabetes mellitus**
E/S (n ⫽ 260)
E/S Plus Niacin (n ⫽ 605)
2 (0.8%) 1 (0.4%)
E/S Plus Niacin vs E/S Difference (95% CI)
p Value
2 (0.3%) 2 (0.3%)
⫺0.4 (⫺2.4, 0.6) ⫺0.1 (⫺1.8, 0.9)
0.587 ⬎0.999
2 (0.8%)
2 (0.3%)
⫺0.4 (⫺2.4, 0.6)
0.587
2 (0.8%) 0 0 272 2 (0.7%) 1 (0.4%) 1 (0.4%) 229 7 (3.1%)¶ 3 (1.3%) 5 (2.2%) 2 (0.9%) n ⫽ 43 6 (14.0%) 5 (11.6%) 2 (4.7%)
4 (0.7%) 1 (0.2%)† 0 670 69 (10.3%) 3 (0.4%) 1 (0.1%) 569 28 (4.9%)¶ 5 (0.9%) 25 (4.4%) 6 (1.1%) N ⫽ 101 15 (14.9%) 14 (13.9%) 3 (3.0%)
⫺0.1 (⫺2.1, 1.1) 0.2 (⫺1.3, 0.9) —
⬎0.999 ⬎0.999 —
9.6 (6.7, 12.2) 0.1 (⫺1.6, 1.0) ⫺0.2 (⫺1.9, 0.5)
⬍0.001 ⬎0.999 0.494
1.9 (⫺1.6, 4.5) ⫺0.4 (⫺3.0, 1.0) 2.2 (⫺0.9, 4.6) 0.2 (⫺2.1, 1.6)
0.338 — — —
0.9 (⫺13.6, 12.0) 2.2 (⫺11.7, 12.6) ⫺1.7 (⫺12.8, 4.7)
⬎0.999 — —
* Patients with 2 consecutive measurements ⱖ3⫻ ULN, a single, last measurement ⱖ3⫻ ULN, or measurement of ⱖ3⫻ ULN followed by measurement ⬍3⫻ ULN taken 2 days after the last dose of study medication. † CK elevation in this patient was accompanied by clinical AE of myalgia considered by investigator to be related to strenuous exercise and not the study drug; the patient recovered from the event. ‡ Flushing-related discontinuation rate reported at 24 weeks was 0.4% for E/S and 9.9% for E/S plus niacin.16 § AE related to elevation of fasting glucose from ⬍100 mg/dl at baseline (no history of diabetes) to ⬎100 mg/dl during treatment, or clinical AE report using broad set of Medical Dictionary for Regulatory Activities terms for blood glucose increase under System Organ Class (SOC) of Investigations or glucose tolerance impaired under SOC of Metabolism and Nutrition. ¶ Two patients taking E/S and 25 taking E/S plus niacin were diagnosed with new-onset diabetes at 24 weeks.23 储 During first 24 weeks of study, 1 patient diagnosed with type 2 diabetes taking E/S and 1 taking E/S plus niacin were given metformin and 1 patient taking E/S plus niacin was treated with diet only; during 24 – 64 weeks, 1 additional patient was diagnosed with type 2 diabetes taking E/S and 1 taking E/S plus niacin, neither was given antidiabetic medications. # Clinical AE related to worsening of diabetes (using Medical Dictionary for Regulatory Activities terms) or required a change in antidiabetic medication (up titrated existing medication/changed to new medication or added medication to existing regimen). ** Considered to have diabetes according to study criteria but did not have actual diagnosis at study entry and were diagnosed with AE of diabetes by investigator during study period. Abbreviations as in Table 1.
was cumulative and included the 24-week and 24- to 64week data. A secondary, supportive, safety analysis included the patients originally assigned to niacin, who were preassigned to switch at 24 weeks and continue with E/S or E/S plus niacin for an additional 40 weeks. Only the safety data reported during the 24 to 64 weeks for these patients were included in the secondary analysis. An incidence of 1% for a particular AE among 256 patients in the E/S group would give 90% power to detect an increase to 5.3% among 640 patients assigned to E/S plus niacin. The efficacy end points, categorized as hypothesized and nonhypothesized, were assessed in the primary efficacy population composed of those patients originally randomized to E/S plus niacin or E/S. A secondary, supportive efficacy analysis was performed on those patients originally assigned to niacin for 24 weeks who continued with E/S plus niacin or E/S, and included only the 24- to 64-week data. The hypothesized end points were assessed in the order of HDL cholesterol, triglyc-
erides, non-HDL cholesterol, and LDL cholesterol using a step-down procedure to control the overall error rate at ␣ ⫽ 0.05. A modified intention-to-treat approach was used for these efficacy analyses (patients with baseline and ⱖ1 measurements after week 24). For any missing week-64 data, the last observed value was carried forward and imputed as the week-64 value. An analysis of covariance model with terms for treatment, baseline LDL cholesterol and triglycerides, and gender was used to assess the percentage of change from baseline. For high-sensitivity C-reactive protein, the same model was used, except the dependent variable was the logarithm of the postbaseline/baseline value ratio. Triglycerides were assessed using a nonparametric analysis of variance model. Assuming a within-group standard deviation for the percentage of change in LDL cholesterol of 15%, 628 subjects (n ⫽ 410, E/S plus niacin; n ⫽ 218, E/S) would be sufficient to detect a 4.1% point difference in LDL cholesterol between the treatment groups with 90% power (␣ ⫽ 0.05, 2-tailed).
Preventive Cardiology/Niacin and Ezetimibe/Simvastatin in Hyperlipidemia
Figure 2. Time and dose effects on fasting glucose. Change from baseline in fasting glucose during 64 weeks in modified intent-to-treat population (24-week phase)16 and primary safety population (24- to 64-week phase).
Results During the initial 24-week phase of the present study, 1,214 patients received niacin (n ⫽ 272), E/S (n ⫽ 272), or E/S plus niacin (n ⫽ 670).16 The 942 patients originally assigned to, and treated with, E/S (n ⫽ 272) and E/S plus niacin (n ⫽ 670) for 24 weeks who continued with these therapies for an additional 40 weeks constituted the primary safety population, in which the cumulative 64-week data were assessed (Figure 1). The most frequent reason for discontinuation was clinical AEs related to niacin-associated flushing in the E/S plus niacin group (0.7% for E/S; 10.3% for E/S plus niacin). A significant number of patients in the E/S plus niacin group discontinued because of low LDL cholesterol levels ⬍50 mg/dl (1.5% for E/S; 7.1% for E/S plus niacin). The primary efficacy population (modified intention-to-treat group) of the 64-week study included 576 patients (E/S ⫽ 207; E/S plus niacin ⫽ 369). The 272 patients taking niacin who completed 24 weeks of treatment and then continued with E/S or E/S plus niacin were included in the secondary safety and efficacy population. The baseline characteristics and levels of the efficacy parameters in both treatment groups were generally balanced (Table 1). During the first 24 weeks of the study, self-reported treatment compliance was ⬎85% for most patients across the E/S, niacin, and E/S plus niacin groups; during the 24- to 64-week period, compliance was ⬎90% in ⱖ49% of patients for both E/S and E/S plus niacin groups. The overall incidence of clinical AEs was slightly greater for E/S plus niacin than for E/S treatment during the 64 weeks (Table 2) owing to the greater number of patients who experienced drug-related clinical AEs and drug-related discontinuations in the E/S plus niacin group, mainly attributed to niacin-associated flushing and pruritus. The incidence of laboratory AEs was generally similar. The percentage of patients with consecutive ⱖ3⫻ ULN elevations in alanine aminotransferase or aspartate aminotransferase and creatine kinase levels ⱖ10⫻ ULN were low and comparable in both treatment groups (Table 3). One patient with
491
creatine kinase ⱖ10⫻ ULN had muscle symptoms taking E/S plus niacin that were considered not to be study drug related by the investigator. Significantly greater numbers of patients taking E/S plus niacin discontinued the study because of flushing AEs compared to those taking E/S and was a slight increase from the flushing-related discontinuations observed at 24 weeks.16 Four patients had gallbladder-related AEs; 1 patient in each treatment group underwent cholecystectomy. A total of 19 patients had AEs of increased fasting glucose levels, with 8 patients (2.9%) in the E/S group (4 considered drug related; none discontinued) and 11 patients (1.6%) in the E/S plus niacin group (10 considered drug related; 1 discontinued). The fasting glucose levels increased during niacin titration to a maximum of 3.2 mg/dl greater than baseline for E/S at 4 weeks and 7.7 mg/dl for E/S plus niacin at 12 weeks (Figure 2) and decreased to pretreatment levels at 64 weeks for both treatments. The number of patients who met the study criteria for new-onset diabetes during the 24 to 64 weeks increased slightly compared to that in the first 24 weeks of the study (5 additional patients for E/S; 3 additional for E/S plus niacin; Table 3).16 Most patients with new-onset diabetes were classified as having diabetes because of 2 consecutive increases in fasting glucose (ⱖ126 mg/dl). Similar numbers of patients in both groups had a worsening of diabetes, mainly inferred from a change in antidiabetic medications. E/S plus niacin significantly improved the changes from baseline in HDL cholesterol, triglycerides, non-HDL cholesterol, LDL cholesterol, apolipoprotein B, apolipoprotein A-I, and lipoprotein ratios compared to E/S (p ⱕ0.004) at week 64 (Table 4). The changes from baseline in total cholesterol were comparable. The reduction in high-sensitivity C-reactive protein was numerically, but not significantly, greater with E/S plus niacin than with E/S. In the E/S plus niacin group, the HDL cholesterol increased considerably during the 16-week niacin titration to 2 g and at a lower, but significant, rate from 16 to 24 weeks, and then remained constant through 64 weeks (Figure 3). The HDL cholesterol change was significantly larger in the E/S plus niacin versus E/S group throughout the 64-week study (p ⬍0.001). Both treatments substantially reduced the levels of LDL cholesterol, non-HDL cholesterol, and triglycerides from baseline (⬃53%, ⬃49%, ⬃29%, respectively) at week 4. In the E/S plus niacin group, these levels continued to decrease during the 16-week niacin dose titration (⫺60%, ⫺57%, ⫺43%, respectively) and then were maintained at relatively constant levels throughout the 64 weeks. In contrast, the levels remained relatively stable from 4 to 64 weeks for the E/S group. Between-treatment differences in triglycerides were approximately twofold greater with E/S plus niacin than with E/S through the 64 weeks (p ⬍0.001) and became significant for non-HDL cholesterol after 8 weeks (p ⫽ 0.002) and LDL cholesterol after 12 weeks (p ⬍0.001). Discussion During this 64 week study, the triple combination of E/S plus niacin was generally well tolerated and significantly improved several lipid/lipoprotein measures compared to
492
The American Journal of Cardiology (www.AJConline.org)
Table 4 Percentage of change from baseline in efficacy parameters Efficacy Variable
Key end points† High-density lipoprotein cholesterol‡ Triglycerides Non-high-density lipoprotein cholesterol‡ Low-density lipoprotein cholesterol‡ Other end points Total cholesterol‡ Total cholesterol/high-density lipoprotein cholesterol‡ Low-density lipoprotein cholesterol/high-density lipoprotein cholesterol‡ Non-high-density lipoprotein cholesterol/high-density lipoprotein cholesterol‡ Apolipoprotein‡§ Apolipoprotein-I‡§ ApolipoproteinB/apolipoproteinA-I‡§ High-sensitivity C-reactive protein‡¶
Change from Baseline (%)
Treatment difference*
E/S (n ⫽ 207)
E/S Plus Niacin (n ⫽ 369)
E/S Plus Niacin vs E/S (95% CI)
p Value
9.0 ⫺26.8 ⫺45.1 ⫺49.3
30.5 ⫺44.5 ⫺52.4 ⫺54.0
21.5 (18.0, 25.0) ⫺17.6 (⫺21.8,⫺13.6) ⫺7.3 (⫺10.4, ⫺4.2) ⫺4.8 (⫺8.0, ⫺1.5)
⬍0.001 ⬍0.001 ⬍0.001 0.004
⫺34.0 ⫺38.1 ⫺52.0 ⫺47.9 ⫺40.6 ⫺0.5 ⫺39.5 ⫺30.9
⫺35.4 ⫺48.4 ⫺62.5 ⫺61.1 ⫺47.6 7.6 ⫺50.1 ⫺38.8
⫺1.4 (⫺3.6, 0.9) ⫺10.3 (⫺13.1, ⫺7.6) ⫺10.5 (⫺14.0, ⫺7.0) ⫺13.2 (⫺16.7, ⫺9.7) ⫺7.0 (⫺10.0, ⫺4.0) 8.1 (5.5, 10.7) ⫺10.6 (⫺14.1, ⫺7.1) ⫺7.9 (⫺19.3, 3.5)
0.229 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.165
* Least squares means determined from analysis of covariance, except triglyceride median treatment difference was determined from Hodges-Lehmann estimates of shift. † Hypothesized end points, tested in order given in table. ‡ Least squares mean. § n ⫽ 182 for E/S, n ⫽ 321 for E/S plus niacin. ¶ n ⫽ 187 for E/S; n ⫽ 324 for E/S plus niacin. Abbreviations as in Tables 1 and 2.
Figure 3. Time and dose effects on lipids. Percentage of change from baseline in HDL cholesterol, triglycerides (TG), non-HDL cholesterol, and LDL cholesterol during 64 weeks in completers (24-week phase)16 and primary efficacy population (24- to 64-week phase).
E/S in patients with type IIa and IIb hyperlipidemia. These results expand on those reported for the initial 24-week phase of the present study, which demonstrated the compa-
rable safety and complementary lipid-altering benefits of E/S plus niacin compared to E/S and niacin.16 Importantly, the present study has provided long-term data for combina-
Preventive Cardiology/Niacin and Ezetimibe/Simvastatin in Hyperlipidemia
tion niacin (2 g) therapy in the largest, randomized clinical trial reported since the Coronary Drug Project trial.9 The safety profile of E/S plus niacin at 64 weeks was similar to those of E/S and niacin alone or in combination.4,11,12,17-20 The incidence of laboratory and clinical AEs was low and rare, with the exception of niacin-associated flushing, which was, as anticipated, the most common reason significantly more patients taking E/S plus niacin discontinued the study compared to patients taking E/S.4,11 The cumulative discontinuation rates due to flushing in the E/S plus niacin group increased only slightly (0.4%) during the 24 to 64 weeks from the initial 24-week phase (9.9%)16 and were similar to those of other longer term extended-release niacin therapy studies.4,11 These results also indicate that niacin tolerability improved over time, consistent with the finding from previous studies.4,11 Future strategies currently in development to reduce niacin-related vasodilatory effects might enable more patients to use niacin therapy at higher doses.21,22 The potential for liver toxicity increases with co-administered statins and niacin, although at moderate doses these toxic effects are of less concern.4,11 Earlier case reports suggested that rhabdomyolysis might be associated with statin-niacin co-administration; however, the rates of muscle AEs reported in controlled clinical trials of niacin combination therapy have been low and not greater than would be expected from statin monotherapy.11 In the present study, the numbers of patients with muscle and liver AEs were low and similar for the E/S and E/S plus niacin groups within the 64 weeks. These results suggest that co-administration of E/S plus niacin is relatively safe with regard to liver and muscle AEs, consistent with previous clinical experience for the individual drug components.4,11,12 Niacin can substantially improve the lipid abnormalities associated with dyslipidemia and is an important therapeutic approach, particularly for patients with diabetes, obesity, and the metabolic syndrome.1,23–25 However, the American Diabetes Association currently recommends the use of niacin ⱕ2 g/day with frequent glucose monitoring in patients with diabetes at coronary heart disease risk, owing to concerns of increased blood glucose levels with high-dose niacin therapy.11,23 In the present study, the fasting glucose changes were generally mild and diminished over time. The fasting glucose increases reached a maximum greater than baseline in the E/S plus niacin group during the 16-week escalation to niacin 2 g and gradually decreased to pretreatment levels by 64 weeks, similar to the effect of niacin therapy in other long-term studies, including in patients with diabetes.8,11,17,18,25 The incidence of new-onset diabetes, attributed mainly to consecutive increases in fasting glucose levels (ⱖ126 mg/dl), was also greater in both niacin-treatment groups compared to E/S during the first 24 weeks of the study and increased only slightly, with 3 additional occurrences during the 24 to 64 weeks of E/S plus niacin therapy. During 64 weeks, similar numbers of patients with diabetes in both treatment groups experienced a worsening of diabetes, ascertained mainly from a change in antidiabetic medications. Overall, these findings indicate that most patients who experience niacin-associated increases in fasting glucose levels do so during the first 6 months of therapy and that the initial glucose effects abate
493
with time. However, it should be noted that these observations are limited to a relatively small number of events that occurred in these patient subsets. Co-administered E/S plus niacin resulted in complementary lipid-altering effects beyond that of E/S at 64 weeks. E/S plus niacin reduced LDL cholesterol, non-HDL cholesterol, and triglyceride levels significantly more than either agent during the first 24 weeks16 and more than E/S at 64 weeks. By week 4, these end points were substantially reduced by E/S plus niacin and continued to decrease through the 16-week niacin titration period and then persisted through the 64 weeks. Moreover, the decreases in triglycerides were almost twofold greater, and those in nonHDL cholesterol and LDL cholesterol were slightly better with E/S plus niacin than with E/S. The sustained improvements in these end points, attributed to the combined lipidaltering actions of E/S plus niacin, was more effective or comparable to those of previously studied niacin combination therapies.8,20,26 –28 Increases in HDL cholesterol were significantly greater with E/S plus niacin compared to E/S throughout the 64week study and slightly greater than niacin during 24 weeks, likely due both to increasing niacin doses and the additional effect of E/S on HDL cholesterol.16 During the first 16 weeks, the HDL cholesterol levels increased substantially as niacin was escalated to 2 g and subsequently increased further at a significant, albeit lower, rate from 16 to 24 weeks as the patients continued to take niacin 2 g. The effect of E/S plus niacin on increasing HDL cholesterol remained generally consistent and significantly greater than E/S through the remainder of the study. The magnitude and timing of increasing HDL cholesterol achieved by E/S plus niacin (30.5%) were similar to those of combination extended-release niacin and lovastatin during long-term treatment.20,27 The combination of E/S plus niacin was also more effective than E/S in reducing the levels of apolipoprotein B and lipoprotein ratios at 64 weeks and compared to niacin and E/S during the first 24 weeks of the study.16 The improvements in lipoprotein ratios were greater than the individual lipid components, reflecting the simultaneous, beneficial effects of E/S plus niacin on atherogenic and antiatherogenic lipoproteins. The reductions in high-sensitivity C-reactive protein were slightly greater with E/S plus niacin versus E/S at 64 weeks and significantly greater than niacin at 24 weeks,16 consistent with previous studies in which niacin monotherapy had a minimal effect on highsensitivity C-reactive protein and the combination of niacin and lovastatin significantly reduced high-sensitivity C-reactive protein.20,29 In conclusion, E/S co-administered with niacin ⱕ2 g/day offers a generally well-tolerated, broad lipid-altering option for patients with type IIa/IIb hyperlipidemia, including those with diabetes, although glucose monitoring is required. The ultimate benefit of this triple therapy awaits additional study in large, randomized outcome trials.21,30 1. Grundy SM, Cleeman JI, Merz CNB, Brewer HB, Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Stone NJ. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227–239.
494
The American Journal of Cardiology (www.AJConline.org)
2. Smith SC Jr, Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC, Grundy SM, Hiratzka L, Jones D, Krumholz HM, Mosca L, Pasternak RC, Pearson T, Pfeffer MA, Taubert KA. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006;113:2363–2372. 3. Sanyal S, Karas RH, Kuvin JT. Present-day uses of niacin: effects on lipid and non-lipid parameters. Expert Opin Pharmacother 2007: 1711–1717. 4. Niaspan [product insert]. North Chicago, Illinois: Abbott Pharmaceuticals, 2008. 5. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ, Serafini L, Huss-Frechette E, Wang S, DeAngelis D, Dodek A. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583– 1592. 6. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, Zhao XQ, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronaryartery disease as a result of intensive lipid-lowering therapy in men with high-levels of apolipoprotein-B. N Engl J Med 1990;323:1289 – 1298. 7. Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA 1990;264: 3007–3012. 8. Whitney EJ, Krasuski RA, Personius BE, Michalek JE, Maranian AM, Kolasa MW, Monick E, Brown BG, Gotto AM. A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events. Ann Intern Med 2005;142:95–104. 9. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360 –381. 10. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial biology for the investigation of the treatment effects of reducing cholesterol (ARBITER) 2—a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004;110:3512– 3517. 11. Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol 2007;99:22C–31C. 12. Vytorin [Product Insert]. North Wales, Pennsylvania: Merck ScheringPlough, 2009. 13. Bays HE, Ose L, Fraser N, Tribble DL, Quinto K, Reyes R, JohnsonLevonas AO, Sapre A, Donahue SR. A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther 2004;26:1758 – 1773. 14. Ballantyne CM, Abate N, Yuan Z, King TR, Palmisano J. Dosecomparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin versus atorvastatin (VYVA) study. Am Heart J 2005;149: 464 – 473. 15. Catapano AL, Davidson MH, Ballantyne CM, Brady WE, Gazzara RA, Tomassini JE, Tershakovec AM. Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus Rosuvastatin in hypercholesterolemic patients. Curr Med Res Opin 2006;22:2041–2053. 16. Guyton JR, Brown BG, Fazio S, Polis A, Tomassini JE, Tershakovec AM. Lipid-altering efficacy and safety of ezetimibe/simvastatin coad-
17.
18.
19.
20.
21.
22.
23. 24.
25.
26.
27.
28.
29.
30.
ministered with extended-release niacin in patients with type IIa or type IIb hyperlipidemia. J Am Coll Cardiol 2008;51:1564 –1572. Zhao XQ, Morse JS, Dowdy AA, Heise N, DeAngelis D, Frohlich J, Chait A, Albers JJ, Brown BG. Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low highdensity lipoprotein cholesterol (the HDL Atherosclerosis Treatment Study). Am J Cardiol 2004;93:307–312. Elam MB, Hunninghake DB, Davis KB, Garg R, Johnson C, Egan D, Kostis JB, Sheps DS, Brinton EA. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease—the ADMIT study: a randomized trial. JAMA 2000;284:1263–1270. Goldberg A, Alagona P, Capuzzi DM, Guyton J, Morgan JM, Rodgers J, Sachson R, Samuel P. Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia. Am J Cardiol 2000;85:1100 –1105. Kashyap ML, McGovern ME, Berra K, Guyton JR, Kwiterovich PO, Harper WL, Toth PD, Favrot LK, Kerzner B, Nash SD, Bays HE, Simmons PD. Long-term safety and efficacy of a once-daily niacin/ lovastatin formulation for patients with dyslipidemia. Am J Cardiol 2002;89:672– 678. University of Oxford. Treatment of HDL to reduce the incidence of vascular events HPS2-THRIVE. Available from: www.clinicaltrials. gov/ct2/show/NCT00461630. Accessed August 21, 2009. Cefali EA, Simmons PD, Stanek EJ, Shamp TR. Improved control of niacin-induced flushing using an optimized once-daily, extended-release niacin formulation. Int J Clin Pharmacol Ther 2006;44:633– 640. American Diabetes Association. Standards of medical care in diabetes2009. Diabetes Care 2009;32:S13–S61. Shepherd J, Betteridge J, Van Gaal L. Nicotinic acid in the management of dyslipidaemia associated with diabetes and metabolic syndrome: a position paper developed by a European Consensus Panel. Curr Med Res Opin 2005;21:665– 682. Grundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall DM, Fitz-Patrick D, Ganda OP, Rosenson RS, Buse JB, Robertson DD, Sheehan JP. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes—results of the assessment of diabetes control and evaluation of the efficacy of Niaspan trial. Arch Intern Med 2000;162:1568 –1576. McKenney JM, Jones PH, Bays HE, Knopp RH, Kashyap ML, Ruoff GE, McGovern ME. Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). Atheroscleorsis 2007; 192:432– 437. Bays HE, Dujovne CA, McGovern ME, White TE, Kashyap ML, Hutcheson AG, Crouse JR. Comparison of once-daily, niacin extended/release/lovastatin with standard doses of atorvastatin and simvastatin (the Advicor Versus Other Cholesterol-Modulating Agents Trial Evaluation [ADVOCATE]). Am J Cardiol 2003;91:667– 672. Guyton JR, Goldberg AC, Kreisberg RA, Sprecher DL, Superko HR, O’Connor CM. Effectiveness of once-nightly dosing of extendedrelease niacin alone and in combination for hypercholesterolemia. Am J Cardiol 1998;82:737–743. Taylor AJ, Hyun JL, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima– media thickness: ARBITER3*. Curr Med Res Opin 2006;22:2243– 2250. National Heart LaBI. Niacin plus statin to prevent vascular events. Available from: www.clinicaltrials.gov/show/NCT00120289. Accessed August 12, 2009.
a
Division of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee; bDuke University, Durham, North Carolina; and cMerck and Co., Inc., North Wales, Pennsylvania. Manuscript received September 11, 2009; revised manuscript received and accepted October 9, 2009. This study was funded by Merck/Schering-Plough Pharmaceuticals, Inc., North Wales, Pennsylvania. Drs. Fazio and Guyton have received honoraria from Merck/Schering-Plough Pharmaceuticals, Inc. (North Wales, Pennsylvania). Dr. Fazio has also received honoraria from Abbott Laboratories (North Chicago, Illinois), GlaxoSmithKline (Philadelphia, Pennsylvania), and research support from ISIS (Carlsbad, California)/ Genzyme (Cambridge, Massachusetts) and Takeda (Osaka, Japan). Dr. Guyton has also received educational and research grants from Merck and Co., Inc. (Whitehouse Station, New Jersey) and consulting fees and honoraria from Abbott Laboratories (North Chicago, Illinois). Drs. Tershakovec, Tomassini, and Adewale and Mr. Polis and Mr. Ryan are employees of Merck and Co., Inc. (Whitehouse Station, New Jersey) and own stock and stock options in the company. *Corresponding author: Tel: (615) 936-1450; fax: (615) 936-3486. E-mail address: [email protected] (S. Fazio). 0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.10.001
A combination of low-density lipoprotein (LDL) cholesterol lowering and high-density lipoprotein (HDL) cholesterol increasing therapies might provide a broad, lipid-altering treatment for patients with combined dyslipidemia.1–3 Niacin, currently the most effective HDL cholesterol increasing therapy, also improves other lipid parameters, reduces cardiovascular disease-related morbidity and mortality, and slows the progression and/or induces the regression of coronary atherosclerosis.4 –10 Although niacin-associated flushing can limit its use, this effect can be mitigated through patient counseling and proper administration.11 Niacin can also be associated with increases in blood glucose levels, which require monitoring and possibly therapeutic changes, particularly in patients with diabetes.11 Ezetimibe/ simvastatin (E/S) is an effective and generally well-tolerated LDL cholesterol lowering agent that also reduces the levels of triglycerides, non-HDL cholesterol, and apolipoprotein B and modestly increases HDL cholesterol.12–15 The complementary lipid-altering benefits and safety of E/S co-administered with extended-release niacin (Niaspan, Abbott Laboratories, North Chicago, Illinois) were www.AJConline.org
488
The American Journal of Cardiology (www.AJConline.org)
Figure 1. Patient disposition. During first 24 weeks, 1,214 patients received E/S (n ⫽ 272), niacin (n ⫽ 272), or E/S plus niacin (n ⫽ 670).16 Primary safety and efficacy populations included 942 patients who received E/S and E/S plus niacin during first 24 weeks, who were scheduled to continue these therapies through 64 weeks. Secondary safety and efficacy populations included those patients treated with niacin during first 24 weeks who then switched to and continued with E/S (⬃1/3) and E/S plus niacin (⬃2/3) through 64 weeks.
demonstrated compared to E/S and niacin in patients with type IIa/IIb hyperlipidemia during the initial 24-week phase of this 64-week study.16 Patients taking E/S and E/S plus niacin continued these therapies and those taking niacin alone were switched to E/S or E/S plus niacin for an additional 40 weeks. In the present report, the 64-week safety and lipid-modifying efficacy of E/S plus niacin versus E/S is presented from the largest, long-term randomized clinical trial of niacin (2 g) to date since the Coronary Drug Project.9 Methods This was a multicenter, randomized, double-blind, 64week study of patients with type IIa and IIb hyperlipidemia. Protocol 091 (Clinicaltrials.gov number NCT00271817) was approved by the appropriate institutional review boards, and all patients provided informed written consent. Men and women (18 to 79 years old) with LDL cholesterol levels of 130 to 190 mg/dl, triglyceride levels ⱕ500 mg/dl, creatinine ⬍2 mg/dl, creatine kinase ⱕ2⫻ the upper limit of normal (ULN), transaminases ⱕ1.5⫻ ULN, and hemoglobin A1c ⱕ8% were enrolled at 107 United States centers. During the first 24 weeks of the study, after a 4-week washout period, the eligible patients were randomized (5: 2:2) and treated with E/S (10/20 mg) plus niacin (to 2 g),
niacin (to 2 g), or E/S (10/20 mg).16 Niacin was increased by 500 mg every 4 weeks to 2 g/day within 12 weeks from a 500 mg/day starting dose. At the end of 24 weeks, patients taking E/S and E/S plus niacin continued these therapies. Of those in the niacin arm, 1/3 were preassigned to E/S and 2/3 to E/S plus niacin for an additional 40 weeks. Patients were counseled to take niacin at bedtime with a low-fat snack, aspirin (325 mg) or ibuprofen (200 mg) 30 minutes before taking niacin, and to avoid alcoholic and hot beverages near this time. Patients were preassigned by central allocation to 1 of 4 treatment arms (arm 1, E/S plus niacin for 24 weeks and then E/S plus niacin for weeks 24 to 64; arm 2, E/S for 24 weeks and then E/S for weeks 24 to 64; arm 3, niacin for 24 weeks and then E/S plus niacin for weeks 24 to 64; and arm 4, niacin for 24 weeks and then E/S for weeks 24 to 64) in a 15:6:4:2 ratio, using a computer-generated, interactive voice response system schedule with block sizes of 27 for each of the 4 baseline strata (LDL cholesterol 130 to 159 or 160 to 190 mg/dl and triglycerides ⬍200 mg/dl; LDL cholesterol 130 to 159 or 160 to 190 mg/dl and triglyceride 201 to 500 mg/dl). None of the clinical team involved with trial conduct were aware of the patient-level data during the analysis of the 24-week data, and the study remained double blinded for the entire duration of the 64-week study.
Preventive Cardiology/Niacin and Ezetimibe/Simvastatin in Hyperlipidemia Table 1 Baseline characteristics Characteristic
Age (years) Women Race Asian Black Hispanic Other White Body mass index (kg/m2) Fasting glucose (mg/dl) NCEP-ATP III CHD/CHD risk equivalent* High risk with atherosclerotic vascular disease CHD Other forms of atherosclerosis† High risk without atherosclerotic vascular disease Diabetes mellitus‡ ⱖ2 CHD (10 years ⬎20%) risk factors Metabolic syndrome§ Lipid parameters (mg/dl)¶ HDL cholesterol Triglycerides Non-HDL cholesterol LDL cholesterol Total cholesterol Total cholesterol/HDL cholesterol LDL cholesterol/HDL cholesterol Non-HDL cholesterol/HDL cholesterol ApoB储 Apo A-I储 ApoB/apoA-I储 hs-CRP (mg/L)#
489
Table 2 Clinical and laboratory adverse events E/S (n ⫽ 272)
E/S Plus Niacin (n ⫽ 676)
Adverse Events
57.5 ⫾ 10.3 120 (44%)
56.9 ⫾ 10.9 352 (52%)
4 (2%) 17 (6%) 11 (6%) 0 240 (88%) 30.3 ⫾ 6.0 101.6 ⫾ 14.1
11 (2%) 38 (6%) 49 (6%) 2 (⬍1%) 576 (85%) 29.8 ⫾ 5.5 101.6 ⫾ 18.1
Clinical ⱖ1 Event 208 (76.5%) 552 (82.4%) Drug-related* 61 (22.4%) 377 (56.3%) Serious 18 (6.6%) 37 (5.5%) Serious drug-related* 1 (0.4%) 0 Deaths 0 0 Discontinuations† 36 (13.2%) 177 (26.4%) Drug-related* 19 (7.0%) 136 (20.3%) Serious 8 (2.9%) 13 (1.9%) Serious drug-related* 0 0 Laboratory‡ n ⫽ 272 n ⫽ 669 ⱖ1 Event 29 (10.7%) 51 (7.6%) Drug-related* 13 (4.8%) 37 (5.5%) Serious 0 0 Serious drug-related* 0 0 Deaths 0 0 Discontinuations 3 (1.1%) 8 (1.2%) Drug-related* 3 (1.1%) 6 (0.9%) Serious 0 0 Serious drug-related* 0 0
84 (31%) 36 (13%)
183 (27%) 77 (11%)
22 (8%) 18 (7%) 48 (18%)
60 (9%) 34 (5%) 106 (16%)
43 (16%) 22 (8%)
105 (16%) 42 (6%)
156 (57%) n ⫽ 207 49.9 ⫾ 13.9 158.0 ⫾ 100.5 191.0 ⫾ 28.3 155.6 ⫾ 21.8 240.9 ⫾ 28.7 5.1 ⫾ 1.3 3.3 ⫾ 0.9 4.1 ⫾ 1.3 151.3 ⫾ 22.2 165.8 ⫾ 29.2 0.9 ⫾ 0.2 2.1 ⫾ 3.5
319 (47%) n ⫽ 369 50.4 ⫾ 13.1 159.0 ⫾ 91.2 191.2 ⫾ 26.1 157.1 ⫾ 23.1 241.6 ⫾ 27.6 5.0 ⫾ 1.1 3.3 ⫾ 0.8 4.0 ⫾ 1.1 151.7 ⫾ 21.3 165.2 ⫾ 28.0 0.9 ⫾ 0.2 2.4 ⫾ 3.4
Data are presented as mean ⫾ SD or numbers (%). * Patients with coronary heart disease and CHD risk equivalents might be in ⬎1 category of CHD, other forms of atherosclerosis, and diabetes (with diabetes defined as baseline fasting glucose ⱖ126 mg/dl on ⱖ2 occasions, or a diagnosis of diabetes, or use of antidiabetic medications). † Other forms of atherosclerosis include peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease, transient ischemic attack, and stroke. ‡ Patients with diabetes had hemoglobin A1c levels of ⱕ8%, and 91 of these patients (9.7%) had previous antidiabetic medication use at enrollment. § Defined as having ⱖ3 of following characteristics: (1) waist circumference ⬎102 cm for men or ⬎88 cm for women; (2) triglycerides ⱖ150 mg/dl; (3) HDL cholesterol ⬍40 mg/dl for men or ⬍50 mg/dl for women; (4) blood pressure ⬎130/85 mm Hg or taking antihypertensive medication; and (5) fasting glucose ⬎100 mg/dl or diagnosis of diabetes. ¶ Primary efficacy population. 储 n ⫽ 182 for E/S, n ⫽ 321 for E/S plus niacin. # n ⫽ 187 for E/S; n ⫽ 324 for E/S plus niacin. Apo ⫽ apolipoprotein; E/S ⫽ ezetimibe/simvastatin 10/20 mg; CHD ⫽ coronary heart disease; hs-CRP ⫽ high-sensitivity C-reactive protein; NCEP-ATP III ⫽ National Cholesterol Education Program, Adult Treatment Panel III; niacin ⫽ extended-release niacin (titrated to 2 g); E/S plus niacin ⫽ ezetimibe/simvastatin 10/20 mg plus niacin (titrated to 2 g).
E/S (n ⫽ 272)
E/S Plus Niacin (n ⫽ 670)
E/S Plus Niacin vs E/S Difference (95% CI) 5.9 (0.3, 11.9) 33.8 (27.3, 39.7) ⫺1.1 (⫺5.0, 2.0) — — 13.2 (7.6, 18.1) 13.3 (8.7, 17.4) ⫺1.0 (⫺3.9, 1.0) — ⫺3.0 (⫺7.6, 0.8) 0.8 (⫺2.8, 3.6) — — — 0.1 (⫺2.1, 1.5) ⫺0.2 (⫺2.4, 1.1) — —
* Determined by investigator to be possibly, probably, or definitely drug related. † Most common reasons for discontinuations from clinical AEs for E/S plus niacin were flushing/hot flush (n ⫽ 69), pruritis/pruritis generalized (n ⫽ 21), rash/rash papular/rash erythematous (n ⫽ 10), myalgia (n ⫽ 9), and nausea (n ⫽ 5) and for E/S were myalgia (n ⫽ 7), rash/rash pruritic (n ⫽ 3), flushing (n ⫽ 2), fatigue (n ⫽ 2), and nausea (n ⫽ 2). ‡ Patients with ⱖ1 postbaseline laboratory test measurement. CI ⫽ confidence interval.
The primary end point of the 64-week study was the safety and tolerability of E/S plus niacin. Prespecified adverse events (AEs) included alanine aminotransferase and aspartate aminotransferase ⱖ3⫻ ULN, creatine kinase ⱖ10⫻ ULN with and without muscle symptoms, discontinuation due to flushing, gallbladder-related AEs, cholecystectomy, change from baseline in fasting glucose, and new onset of diabetes (patients with an AE related to a diagnosis of diabetes [from clinical AE reports using a predefined set of Medical Dictionary for Regulatory Activities terms], 2 consecutive fasting glucose measurements ⱖ126 mg/dl, or the initiation of antidiabetic medication during the study). The secondary end points were changes from baseline in HDL cholesterol, triglycerides, non-HDL cholesterol, LDL cholesterol, other lipids, lipoprotein ratios, and high-sensitivity C-reactive protein. The 64-week primary hypothesis, the safety and tolerability of E/S plus niacin, was assessed by clinical and/or statistical review of all safety parameters in the primary safety analysis population, which included patients originally randomized to E/S plus niacin or E/S who had received ⱖ1 dose of study medication. For the analysis of changes from baseline in the safety parameters, patients were also required to have baseline and ⱖ1 on-treatment measurements. The incidence of prespecified AEs was compared by Fisher’s exact test. The primary safety analysis
490
The American Journal of Cardiology (www.AJConline.org)
Table 3 Safety end points Safety End Point
Alanine aminotransferase ⱖ3⫻ upper limit of normal, consecutive* Aspartate aminotransferase ⱖ3⫻ upper limit of normal, consecutive* Aspartate aminotransferase and/or alanine aminotransferase ⱖ3⫻ upper limit of normal, consecutive* Creatine kinase ⱖ10⫻ upper limit of normal ⱖ10⫻ upper limit of normal with muscle symptoms ⱖ10⫻ upper limit of normal with drug-related muscle symptoms Patients (n) Discontinuation due to flushing‡ Gallbladder-related Cholecystectomy Patients (n) New-onset diabetes§ Initiated use of antidiabetic medications Consecutive fasting glucose elevations ⱖ126 mg/dl Diagnosis of type 2 diabetes mellitus储 Patients (n) Worsening of diabetes# Initiated use of antidiabetic medications Diagnosis of type 2 diabetes mellitus**
E/S (n ⫽ 260)
E/S Plus Niacin (n ⫽ 605)
2 (0.8%) 1 (0.4%)
E/S Plus Niacin vs E/S Difference (95% CI)
p Value
2 (0.3%) 2 (0.3%)
⫺0.4 (⫺2.4, 0.6) ⫺0.1 (⫺1.8, 0.9)
0.587 ⬎0.999
2 (0.8%)
2 (0.3%)
⫺0.4 (⫺2.4, 0.6)
0.587
2 (0.8%) 0 0 272 2 (0.7%) 1 (0.4%) 1 (0.4%) 229 7 (3.1%)¶ 3 (1.3%) 5 (2.2%) 2 (0.9%) n ⫽ 43 6 (14.0%) 5 (11.6%) 2 (4.7%)
4 (0.7%) 1 (0.2%)† 0 670 69 (10.3%) 3 (0.4%) 1 (0.1%) 569 28 (4.9%)¶ 5 (0.9%) 25 (4.4%) 6 (1.1%) N ⫽ 101 15 (14.9%) 14 (13.9%) 3 (3.0%)
⫺0.1 (⫺2.1, 1.1) 0.2 (⫺1.3, 0.9) —
⬎0.999 ⬎0.999 —
9.6 (6.7, 12.2) 0.1 (⫺1.6, 1.0) ⫺0.2 (⫺1.9, 0.5)
⬍0.001 ⬎0.999 0.494
1.9 (⫺1.6, 4.5) ⫺0.4 (⫺3.0, 1.0) 2.2 (⫺0.9, 4.6) 0.2 (⫺2.1, 1.6)
0.338 — — —
0.9 (⫺13.6, 12.0) 2.2 (⫺11.7, 12.6) ⫺1.7 (⫺12.8, 4.7)
⬎0.999 — —
* Patients with 2 consecutive measurements ⱖ3⫻ ULN, a single, last measurement ⱖ3⫻ ULN, or measurement of ⱖ3⫻ ULN followed by measurement ⬍3⫻ ULN taken 2 days after the last dose of study medication. † CK elevation in this patient was accompanied by clinical AE of myalgia considered by investigator to be related to strenuous exercise and not the study drug; the patient recovered from the event. ‡ Flushing-related discontinuation rate reported at 24 weeks was 0.4% for E/S and 9.9% for E/S plus niacin.16 § AE related to elevation of fasting glucose from ⬍100 mg/dl at baseline (no history of diabetes) to ⬎100 mg/dl during treatment, or clinical AE report using broad set of Medical Dictionary for Regulatory Activities terms for blood glucose increase under System Organ Class (SOC) of Investigations or glucose tolerance impaired under SOC of Metabolism and Nutrition. ¶ Two patients taking E/S and 25 taking E/S plus niacin were diagnosed with new-onset diabetes at 24 weeks.23 储 During first 24 weeks of study, 1 patient diagnosed with type 2 diabetes taking E/S and 1 taking E/S plus niacin were given metformin and 1 patient taking E/S plus niacin was treated with diet only; during 24 – 64 weeks, 1 additional patient was diagnosed with type 2 diabetes taking E/S and 1 taking E/S plus niacin, neither was given antidiabetic medications. # Clinical AE related to worsening of diabetes (using Medical Dictionary for Regulatory Activities terms) or required a change in antidiabetic medication (up titrated existing medication/changed to new medication or added medication to existing regimen). ** Considered to have diabetes according to study criteria but did not have actual diagnosis at study entry and were diagnosed with AE of diabetes by investigator during study period. Abbreviations as in Table 1.
was cumulative and included the 24-week and 24- to 64week data. A secondary, supportive, safety analysis included the patients originally assigned to niacin, who were preassigned to switch at 24 weeks and continue with E/S or E/S plus niacin for an additional 40 weeks. Only the safety data reported during the 24 to 64 weeks for these patients were included in the secondary analysis. An incidence of 1% for a particular AE among 256 patients in the E/S group would give 90% power to detect an increase to 5.3% among 640 patients assigned to E/S plus niacin. The efficacy end points, categorized as hypothesized and nonhypothesized, were assessed in the primary efficacy population composed of those patients originally randomized to E/S plus niacin or E/S. A secondary, supportive efficacy analysis was performed on those patients originally assigned to niacin for 24 weeks who continued with E/S plus niacin or E/S, and included only the 24- to 64-week data. The hypothesized end points were assessed in the order of HDL cholesterol, triglyc-
erides, non-HDL cholesterol, and LDL cholesterol using a step-down procedure to control the overall error rate at ␣ ⫽ 0.05. A modified intention-to-treat approach was used for these efficacy analyses (patients with baseline and ⱖ1 measurements after week 24). For any missing week-64 data, the last observed value was carried forward and imputed as the week-64 value. An analysis of covariance model with terms for treatment, baseline LDL cholesterol and triglycerides, and gender was used to assess the percentage of change from baseline. For high-sensitivity C-reactive protein, the same model was used, except the dependent variable was the logarithm of the postbaseline/baseline value ratio. Triglycerides were assessed using a nonparametric analysis of variance model. Assuming a within-group standard deviation for the percentage of change in LDL cholesterol of 15%, 628 subjects (n ⫽ 410, E/S plus niacin; n ⫽ 218, E/S) would be sufficient to detect a 4.1% point difference in LDL cholesterol between the treatment groups with 90% power (␣ ⫽ 0.05, 2-tailed).
Preventive Cardiology/Niacin and Ezetimibe/Simvastatin in Hyperlipidemia
Figure 2. Time and dose effects on fasting glucose. Change from baseline in fasting glucose during 64 weeks in modified intent-to-treat population (24-week phase)16 and primary safety population (24- to 64-week phase).
Results During the initial 24-week phase of the present study, 1,214 patients received niacin (n ⫽ 272), E/S (n ⫽ 272), or E/S plus niacin (n ⫽ 670).16 The 942 patients originally assigned to, and treated with, E/S (n ⫽ 272) and E/S plus niacin (n ⫽ 670) for 24 weeks who continued with these therapies for an additional 40 weeks constituted the primary safety population, in which the cumulative 64-week data were assessed (Figure 1). The most frequent reason for discontinuation was clinical AEs related to niacin-associated flushing in the E/S plus niacin group (0.7% for E/S; 10.3% for E/S plus niacin). A significant number of patients in the E/S plus niacin group discontinued because of low LDL cholesterol levels ⬍50 mg/dl (1.5% for E/S; 7.1% for E/S plus niacin). The primary efficacy population (modified intention-to-treat group) of the 64-week study included 576 patients (E/S ⫽ 207; E/S plus niacin ⫽ 369). The 272 patients taking niacin who completed 24 weeks of treatment and then continued with E/S or E/S plus niacin were included in the secondary safety and efficacy population. The baseline characteristics and levels of the efficacy parameters in both treatment groups were generally balanced (Table 1). During the first 24 weeks of the study, self-reported treatment compliance was ⬎85% for most patients across the E/S, niacin, and E/S plus niacin groups; during the 24- to 64-week period, compliance was ⬎90% in ⱖ49% of patients for both E/S and E/S plus niacin groups. The overall incidence of clinical AEs was slightly greater for E/S plus niacin than for E/S treatment during the 64 weeks (Table 2) owing to the greater number of patients who experienced drug-related clinical AEs and drug-related discontinuations in the E/S plus niacin group, mainly attributed to niacin-associated flushing and pruritus. The incidence of laboratory AEs was generally similar. The percentage of patients with consecutive ⱖ3⫻ ULN elevations in alanine aminotransferase or aspartate aminotransferase and creatine kinase levels ⱖ10⫻ ULN were low and comparable in both treatment groups (Table 3). One patient with
491
creatine kinase ⱖ10⫻ ULN had muscle symptoms taking E/S plus niacin that were considered not to be study drug related by the investigator. Significantly greater numbers of patients taking E/S plus niacin discontinued the study because of flushing AEs compared to those taking E/S and was a slight increase from the flushing-related discontinuations observed at 24 weeks.16 Four patients had gallbladder-related AEs; 1 patient in each treatment group underwent cholecystectomy. A total of 19 patients had AEs of increased fasting glucose levels, with 8 patients (2.9%) in the E/S group (4 considered drug related; none discontinued) and 11 patients (1.6%) in the E/S plus niacin group (10 considered drug related; 1 discontinued). The fasting glucose levels increased during niacin titration to a maximum of 3.2 mg/dl greater than baseline for E/S at 4 weeks and 7.7 mg/dl for E/S plus niacin at 12 weeks (Figure 2) and decreased to pretreatment levels at 64 weeks for both treatments. The number of patients who met the study criteria for new-onset diabetes during the 24 to 64 weeks increased slightly compared to that in the first 24 weeks of the study (5 additional patients for E/S; 3 additional for E/S plus niacin; Table 3).16 Most patients with new-onset diabetes were classified as having diabetes because of 2 consecutive increases in fasting glucose (ⱖ126 mg/dl). Similar numbers of patients in both groups had a worsening of diabetes, mainly inferred from a change in antidiabetic medications. E/S plus niacin significantly improved the changes from baseline in HDL cholesterol, triglycerides, non-HDL cholesterol, LDL cholesterol, apolipoprotein B, apolipoprotein A-I, and lipoprotein ratios compared to E/S (p ⱕ0.004) at week 64 (Table 4). The changes from baseline in total cholesterol were comparable. The reduction in high-sensitivity C-reactive protein was numerically, but not significantly, greater with E/S plus niacin than with E/S. In the E/S plus niacin group, the HDL cholesterol increased considerably during the 16-week niacin titration to 2 g and at a lower, but significant, rate from 16 to 24 weeks, and then remained constant through 64 weeks (Figure 3). The HDL cholesterol change was significantly larger in the E/S plus niacin versus E/S group throughout the 64-week study (p ⬍0.001). Both treatments substantially reduced the levels of LDL cholesterol, non-HDL cholesterol, and triglycerides from baseline (⬃53%, ⬃49%, ⬃29%, respectively) at week 4. In the E/S plus niacin group, these levels continued to decrease during the 16-week niacin dose titration (⫺60%, ⫺57%, ⫺43%, respectively) and then were maintained at relatively constant levels throughout the 64 weeks. In contrast, the levels remained relatively stable from 4 to 64 weeks for the E/S group. Between-treatment differences in triglycerides were approximately twofold greater with E/S plus niacin than with E/S through the 64 weeks (p ⬍0.001) and became significant for non-HDL cholesterol after 8 weeks (p ⫽ 0.002) and LDL cholesterol after 12 weeks (p ⬍0.001). Discussion During this 64 week study, the triple combination of E/S plus niacin was generally well tolerated and significantly improved several lipid/lipoprotein measures compared to
492
The American Journal of Cardiology (www.AJConline.org)
Table 4 Percentage of change from baseline in efficacy parameters Efficacy Variable
Key end points† High-density lipoprotein cholesterol‡ Triglycerides Non-high-density lipoprotein cholesterol‡ Low-density lipoprotein cholesterol‡ Other end points Total cholesterol‡ Total cholesterol/high-density lipoprotein cholesterol‡ Low-density lipoprotein cholesterol/high-density lipoprotein cholesterol‡ Non-high-density lipoprotein cholesterol/high-density lipoprotein cholesterol‡ Apolipoprotein‡§ Apolipoprotein-I‡§ ApolipoproteinB/apolipoproteinA-I‡§ High-sensitivity C-reactive protein‡¶
Change from Baseline (%)
Treatment difference*
E/S (n ⫽ 207)
E/S Plus Niacin (n ⫽ 369)
E/S Plus Niacin vs E/S (95% CI)
p Value
9.0 ⫺26.8 ⫺45.1 ⫺49.3
30.5 ⫺44.5 ⫺52.4 ⫺54.0
21.5 (18.0, 25.0) ⫺17.6 (⫺21.8,⫺13.6) ⫺7.3 (⫺10.4, ⫺4.2) ⫺4.8 (⫺8.0, ⫺1.5)
⬍0.001 ⬍0.001 ⬍0.001 0.004
⫺34.0 ⫺38.1 ⫺52.0 ⫺47.9 ⫺40.6 ⫺0.5 ⫺39.5 ⫺30.9
⫺35.4 ⫺48.4 ⫺62.5 ⫺61.1 ⫺47.6 7.6 ⫺50.1 ⫺38.8
⫺1.4 (⫺3.6, 0.9) ⫺10.3 (⫺13.1, ⫺7.6) ⫺10.5 (⫺14.0, ⫺7.0) ⫺13.2 (⫺16.7, ⫺9.7) ⫺7.0 (⫺10.0, ⫺4.0) 8.1 (5.5, 10.7) ⫺10.6 (⫺14.1, ⫺7.1) ⫺7.9 (⫺19.3, 3.5)
0.229 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.165
* Least squares means determined from analysis of covariance, except triglyceride median treatment difference was determined from Hodges-Lehmann estimates of shift. † Hypothesized end points, tested in order given in table. ‡ Least squares mean. § n ⫽ 182 for E/S, n ⫽ 321 for E/S plus niacin. ¶ n ⫽ 187 for E/S; n ⫽ 324 for E/S plus niacin. Abbreviations as in Tables 1 and 2.
Figure 3. Time and dose effects on lipids. Percentage of change from baseline in HDL cholesterol, triglycerides (TG), non-HDL cholesterol, and LDL cholesterol during 64 weeks in completers (24-week phase)16 and primary efficacy population (24- to 64-week phase).
E/S in patients with type IIa and IIb hyperlipidemia. These results expand on those reported for the initial 24-week phase of the present study, which demonstrated the compa-
rable safety and complementary lipid-altering benefits of E/S plus niacin compared to E/S and niacin.16 Importantly, the present study has provided long-term data for combina-
Preventive Cardiology/Niacin and Ezetimibe/Simvastatin in Hyperlipidemia
tion niacin (2 g) therapy in the largest, randomized clinical trial reported since the Coronary Drug Project trial.9 The safety profile of E/S plus niacin at 64 weeks was similar to those of E/S and niacin alone or in combination.4,11,12,17-20 The incidence of laboratory and clinical AEs was low and rare, with the exception of niacin-associated flushing, which was, as anticipated, the most common reason significantly more patients taking E/S plus niacin discontinued the study compared to patients taking E/S.4,11 The cumulative discontinuation rates due to flushing in the E/S plus niacin group increased only slightly (0.4%) during the 24 to 64 weeks from the initial 24-week phase (9.9%)16 and were similar to those of other longer term extended-release niacin therapy studies.4,11 These results also indicate that niacin tolerability improved over time, consistent with the finding from previous studies.4,11 Future strategies currently in development to reduce niacin-related vasodilatory effects might enable more patients to use niacin therapy at higher doses.21,22 The potential for liver toxicity increases with co-administered statins and niacin, although at moderate doses these toxic effects are of less concern.4,11 Earlier case reports suggested that rhabdomyolysis might be associated with statin-niacin co-administration; however, the rates of muscle AEs reported in controlled clinical trials of niacin combination therapy have been low and not greater than would be expected from statin monotherapy.11 In the present study, the numbers of patients with muscle and liver AEs were low and similar for the E/S and E/S plus niacin groups within the 64 weeks. These results suggest that co-administration of E/S plus niacin is relatively safe with regard to liver and muscle AEs, consistent with previous clinical experience for the individual drug components.4,11,12 Niacin can substantially improve the lipid abnormalities associated with dyslipidemia and is an important therapeutic approach, particularly for patients with diabetes, obesity, and the metabolic syndrome.1,23–25 However, the American Diabetes Association currently recommends the use of niacin ⱕ2 g/day with frequent glucose monitoring in patients with diabetes at coronary heart disease risk, owing to concerns of increased blood glucose levels with high-dose niacin therapy.11,23 In the present study, the fasting glucose changes were generally mild and diminished over time. The fasting glucose increases reached a maximum greater than baseline in the E/S plus niacin group during the 16-week escalation to niacin 2 g and gradually decreased to pretreatment levels by 64 weeks, similar to the effect of niacin therapy in other long-term studies, including in patients with diabetes.8,11,17,18,25 The incidence of new-onset diabetes, attributed mainly to consecutive increases in fasting glucose levels (ⱖ126 mg/dl), was also greater in both niacin-treatment groups compared to E/S during the first 24 weeks of the study and increased only slightly, with 3 additional occurrences during the 24 to 64 weeks of E/S plus niacin therapy. During 64 weeks, similar numbers of patients with diabetes in both treatment groups experienced a worsening of diabetes, ascertained mainly from a change in antidiabetic medications. Overall, these findings indicate that most patients who experience niacin-associated increases in fasting glucose levels do so during the first 6 months of therapy and that the initial glucose effects abate
493
with time. However, it should be noted that these observations are limited to a relatively small number of events that occurred in these patient subsets. Co-administered E/S plus niacin resulted in complementary lipid-altering effects beyond that of E/S at 64 weeks. E/S plus niacin reduced LDL cholesterol, non-HDL cholesterol, and triglyceride levels significantly more than either agent during the first 24 weeks16 and more than E/S at 64 weeks. By week 4, these end points were substantially reduced by E/S plus niacin and continued to decrease through the 16-week niacin titration period and then persisted through the 64 weeks. Moreover, the decreases in triglycerides were almost twofold greater, and those in nonHDL cholesterol and LDL cholesterol were slightly better with E/S plus niacin than with E/S. The sustained improvements in these end points, attributed to the combined lipidaltering actions of E/S plus niacin, was more effective or comparable to those of previously studied niacin combination therapies.8,20,26 –28 Increases in HDL cholesterol were significantly greater with E/S plus niacin compared to E/S throughout the 64week study and slightly greater than niacin during 24 weeks, likely due both to increasing niacin doses and the additional effect of E/S on HDL cholesterol.16 During the first 16 weeks, the HDL cholesterol levels increased substantially as niacin was escalated to 2 g and subsequently increased further at a significant, albeit lower, rate from 16 to 24 weeks as the patients continued to take niacin 2 g. The effect of E/S plus niacin on increasing HDL cholesterol remained generally consistent and significantly greater than E/S through the remainder of the study. The magnitude and timing of increasing HDL cholesterol achieved by E/S plus niacin (30.5%) were similar to those of combination extended-release niacin and lovastatin during long-term treatment.20,27 The combination of E/S plus niacin was also more effective than E/S in reducing the levels of apolipoprotein B and lipoprotein ratios at 64 weeks and compared to niacin and E/S during the first 24 weeks of the study.16 The improvements in lipoprotein ratios were greater than the individual lipid components, reflecting the simultaneous, beneficial effects of E/S plus niacin on atherogenic and antiatherogenic lipoproteins. The reductions in high-sensitivity C-reactive protein were slightly greater with E/S plus niacin versus E/S at 64 weeks and significantly greater than niacin at 24 weeks,16 consistent with previous studies in which niacin monotherapy had a minimal effect on highsensitivity C-reactive protein and the combination of niacin and lovastatin significantly reduced high-sensitivity C-reactive protein.20,29 In conclusion, E/S co-administered with niacin ⱕ2 g/day offers a generally well-tolerated, broad lipid-altering option for patients with type IIa/IIb hyperlipidemia, including those with diabetes, although glucose monitoring is required. The ultimate benefit of this triple therapy awaits additional study in large, randomized outcome trials.21,30 1. Grundy SM, Cleeman JI, Merz CNB, Brewer HB, Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Stone NJ. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227–239.
494
The American Journal of Cardiology (www.AJConline.org)
2. Smith SC Jr, Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC, Grundy SM, Hiratzka L, Jones D, Krumholz HM, Mosca L, Pasternak RC, Pearson T, Pfeffer MA, Taubert KA. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006;113:2363–2372. 3. Sanyal S, Karas RH, Kuvin JT. Present-day uses of niacin: effects on lipid and non-lipid parameters. Expert Opin Pharmacother 2007: 1711–1717. 4. Niaspan [product insert]. North Chicago, Illinois: Abbott Pharmaceuticals, 2008. 5. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ, Serafini L, Huss-Frechette E, Wang S, DeAngelis D, Dodek A. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583– 1592. 6. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, Zhao XQ, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronaryartery disease as a result of intensive lipid-lowering therapy in men with high-levels of apolipoprotein-B. N Engl J Med 1990;323:1289 – 1298. 7. Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA 1990;264: 3007–3012. 8. Whitney EJ, Krasuski RA, Personius BE, Michalek JE, Maranian AM, Kolasa MW, Monick E, Brown BG, Gotto AM. A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events. Ann Intern Med 2005;142:95–104. 9. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360 –381. 10. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial biology for the investigation of the treatment effects of reducing cholesterol (ARBITER) 2—a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004;110:3512– 3517. 11. Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol 2007;99:22C–31C. 12. Vytorin [Product Insert]. North Wales, Pennsylvania: Merck ScheringPlough, 2009. 13. Bays HE, Ose L, Fraser N, Tribble DL, Quinto K, Reyes R, JohnsonLevonas AO, Sapre A, Donahue SR. A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther 2004;26:1758 – 1773. 14. Ballantyne CM, Abate N, Yuan Z, King TR, Palmisano J. Dosecomparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin versus atorvastatin (VYVA) study. Am Heart J 2005;149: 464 – 473. 15. Catapano AL, Davidson MH, Ballantyne CM, Brady WE, Gazzara RA, Tomassini JE, Tershakovec AM. Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus Rosuvastatin in hypercholesterolemic patients. Curr Med Res Opin 2006;22:2041–2053. 16. Guyton JR, Brown BG, Fazio S, Polis A, Tomassini JE, Tershakovec AM. Lipid-altering efficacy and safety of ezetimibe/simvastatin coad-
17.
18.
19.
20.
21.
22.
23. 24.
25.
26.
27.
28.
29.
30.
ministered with extended-release niacin in patients with type IIa or type IIb hyperlipidemia. J Am Coll Cardiol 2008;51:1564 –1572. Zhao XQ, Morse JS, Dowdy AA, Heise N, DeAngelis D, Frohlich J, Chait A, Albers JJ, Brown BG. Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low highdensity lipoprotein cholesterol (the HDL Atherosclerosis Treatment Study). Am J Cardiol 2004;93:307–312. Elam MB, Hunninghake DB, Davis KB, Garg R, Johnson C, Egan D, Kostis JB, Sheps DS, Brinton EA. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease—the ADMIT study: a randomized trial. JAMA 2000;284:1263–1270. Goldberg A, Alagona P, Capuzzi DM, Guyton J, Morgan JM, Rodgers J, Sachson R, Samuel P. Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia. Am J Cardiol 2000;85:1100 –1105. Kashyap ML, McGovern ME, Berra K, Guyton JR, Kwiterovich PO, Harper WL, Toth PD, Favrot LK, Kerzner B, Nash SD, Bays HE, Simmons PD. Long-term safety and efficacy of a once-daily niacin/ lovastatin formulation for patients with dyslipidemia. Am J Cardiol 2002;89:672– 678. University of Oxford. Treatment of HDL to reduce the incidence of vascular events HPS2-THRIVE. Available from: www.clinicaltrials. gov/ct2/show/NCT00461630. Accessed August 21, 2009. Cefali EA, Simmons PD, Stanek EJ, Shamp TR. Improved control of niacin-induced flushing using an optimized once-daily, extended-release niacin formulation. Int J Clin Pharmacol Ther 2006;44:633– 640. American Diabetes Association. Standards of medical care in diabetes2009. Diabetes Care 2009;32:S13–S61. Shepherd J, Betteridge J, Van Gaal L. Nicotinic acid in the management of dyslipidaemia associated with diabetes and metabolic syndrome: a position paper developed by a European Consensus Panel. Curr Med Res Opin 2005;21:665– 682. Grundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall DM, Fitz-Patrick D, Ganda OP, Rosenson RS, Buse JB, Robertson DD, Sheehan JP. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes—results of the assessment of diabetes control and evaluation of the efficacy of Niaspan trial. Arch Intern Med 2000;162:1568 –1576. McKenney JM, Jones PH, Bays HE, Knopp RH, Kashyap ML, Ruoff GE, McGovern ME. Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). Atheroscleorsis 2007; 192:432– 437. Bays HE, Dujovne CA, McGovern ME, White TE, Kashyap ML, Hutcheson AG, Crouse JR. Comparison of once-daily, niacin extended/release/lovastatin with standard doses of atorvastatin and simvastatin (the Advicor Versus Other Cholesterol-Modulating Agents Trial Evaluation [ADVOCATE]). Am J Cardiol 2003;91:667– 672. Guyton JR, Goldberg AC, Kreisberg RA, Sprecher DL, Superko HR, O’Connor CM. Effectiveness of once-nightly dosing of extendedrelease niacin alone and in combination for hypercholesterolemia. Am J Cardiol 1998;82:737–743. Taylor AJ, Hyun JL, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima– media thickness: ARBITER3*. Curr Med Res Opin 2006;22:2243– 2250. National Heart LaBI. Niacin plus statin to prevent vascular events. Available from: www.clinicaltrials.gov/show/NCT00120289. Accessed August 12, 2009.