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 high-density 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.
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. 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. Although niacin-associated flushing can limit its use, this effect can be mitigated through patient counseling and proper administration. Niacin can also be associated with increases in blood glucose levels, which require monitoring and possibly therapeutic changes, particularly in patients with diabetes. 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. The complementary lipid-altering benefits and safety of E/S co-administered with extended-release niacin (Niaspan, Abbott Laboratories, North Chicago, Illinois) were 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. 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.
Methods
This was a multicenter, randomized, double-blind, 64-week 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 ≤500 mg/dl, creatinine <2 mg/dl, creatine kinase ≤2× the upper limit of normal (ULN), transaminases ≤1.5× ULN, and hemoglobin A1c ≤8% 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). 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.
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 ≥3× ULN, creatine kinase ≥10× 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 ≥126 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 ≥1 dose of study medication. For the analysis of changes from baseline in the safety parameters, patients were also required to have baseline and ≥1 on-treatment measurements. The incidence of prespecified AEs was compared by Fisher’s exact test. The primary safety analysis was cumulative and included the 24-week and 24- to 64-week 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, triglycerides, non-HDL cholesterol, and LDL cholesterol using a step-down procedure to control the overall error rate at α = 0.05. A modified intention-to-treat approach was used for these efficacy analyses (patients with baseline and ≥1 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 (α = 0.05, 2-tailed).
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). 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 ≥49% of patients for both E/S and E/S plus niacin groups.
| Characteristic | E/S (n = 272) | E/S Plus Niacin (n = 676) |
|---|---|---|
| Age (years) | 57.5 ± 10.3 | 56.9 ± 10.9 |
| Women | 120 (44%) | 352 (52%) |
| Race | ||
| Asian | 4 (2%) | 11 (2%) |
| Black | 17 (6%) | 38 (6%) |
| Hispanic | 11 (6%) | 49 (6%) |
| Other | 0 | 2 (<1%) |
| White | 240 (88%) | 576 (85%) |
| Body mass index (kg/m 2 ) | 30.3 ± 6.0 | 29.8 ± 5.5 |
| Fasting glucose (mg/dl) | 101.6 ± 14.1 | 101.6 ± 18.1 |
| NCEP-ATP III | ||
| CHD/CHD risk equivalent ⁎ | 84 (31%) | 183 (27%) |
| High risk with atherosclerotic vascular disease | 36 (13%) | 77 (11%) |
| CHD | 22 (8%) | 60 (9%) |
| Other forms of atherosclerosis † | 18 (7%) | 34 (5%) |
| High risk without atherosclerotic vascular disease | 48 (18%) | 106 (16%) |
| Diabetes mellitus ‡ | 43 (16%) | 105 (16%) |
| ≥2 CHD (10 years >20%) risk factors | 22 (8%) | 42 (6%) |
| Metabolic syndrome § | 156 (57%) | 319 (47%) |
| Lipid parameters (mg/dl) ¶ | n = 207 | n = 369 |
| HDL cholesterol | 49.9 ± 13.9 | 50.4 ± 13.1 |
| Triglycerides | 158.0 ± 100.5 | 159.0 ± 91.2 |
| Non-HDL cholesterol | 191.0 ± 28.3 | 191.2 ± 26.1 |
| LDL cholesterol | 155.6 ± 21.8 | 157.1 ± 23.1 |
| Total cholesterol | 240.9 ± 28.7 | 241.6 ± 27.6 |
| Total cholesterol/HDL cholesterol | 5.1 ± 1.3 | 5.0 ± 1.1 |
| LDL cholesterol/HDL cholesterol | 3.3 ± 0.9 | 3.3 ± 0.8 |
| Non-HDL cholesterol/HDL cholesterol | 4.1 ± 1.3 | 4.0 ± 1.1 |
| ApoB ∥ | 151.3 ± 22.2 | 151.7 ± 21.3 |
| Apo A-I ∥ | 165.8 ± 29.2 | 165.2 ± 28.0 |
| ApoB/apoA-I ∥ | 0.9 ± 0.2 | 0.9 ± 0.2 |
| hs-CRP (mg/L) # | 2.1 ± 3.5 | 2.4 ± 3.4 |
⁎ 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 ≥126 mg/dl on ≥2 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 ≤8%, and 91 of these patients (9.7%) had previous antidiabetic medication use at enrollment.
§ Defined as having ≥3 of following characteristics: (1) waist circumference >102 cm for men or >88 cm for women; (2) triglycerides ≥150 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.
∥ n = 182 for E/S, n = 321 for E/S plus niacin.
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 ≥3× ULN elevations in alanine aminotransferase or aspartate aminotransferase and creatine kinase levels ≥10× ULN were low and comparable in both treatment groups ( Table 3 ). One patient with creatine kinase ≥10× 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. Four patients had gallbladder-related AEs; 1 patient in each treatment group underwent cholecystectomy.
| Adverse Events | E/S (n = 272) | E/S Plus Niacin (n = 670) | E/S Plus Niacin vs E/S Difference (95% CI) |
|---|---|---|---|
| Clinical | |||
| ≥1 Event | 208 (76.5%) | 552 (82.4%) | 5.9 (0.3, 11.9) |
| Drug-related ⁎ | 61 (22.4%) | 377 (56.3%) | 33.8 (27.3, 39.7) |
| Serious | 18 (6.6%) | 37 (5.5%) | −1.1 (−5.0, 2.0) |
| Serious drug-related ⁎ | 1 (0.4%) | 0 | — |
| Deaths | 0 | 0 | — |
| Discontinuations † | 36 (13.2%) | 177 (26.4%) | 13.2 (7.6, 18.1) |
| Drug-related ⁎ | 19 (7.0%) | 136 (20.3%) | 13.3 (8.7, 17.4) |
| Serious | 8 (2.9%) | 13 (1.9%) | −1.0 (−3.9, 1.0) |
| Serious drug-related ⁎ | 0 | 0 | — |
| Laboratory ‡ | n = 272 | n = 669 | |
| ≥1 Event | 29 (10.7%) | 51 (7.6%) | −3.0 (−7.6, 0.8) |
| Drug-related ⁎ | 13 (4.8%) | 37 (5.5%) | 0.8 (−2.8, 3.6) |
| Serious | 0 | 0 | — |
| Serious drug-related ⁎ | 0 | 0 | — |
| Deaths | 0 | 0 | — |
| Discontinuations | 3 (1.1%) | 8 (1.2%) | 0.1 (−2.1, 1.5) |
| Drug-related ⁎ | 3 (1.1%) | 6 (0.9%) | −0.2 (−2.4, 1.1) |
| Serious | 0 | 0 | — |
| Serious drug-related ⁎ | 0 | 0 | — |
⁎ 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 ≥1 postbaseline laboratory test measurement.
| Safety End Point | E/S (n = 260) | E/S Plus Niacin (n = 605) | E/S Plus Niacin vs E/S | |
|---|---|---|---|---|
| Difference (95% CI) | p Value | |||
| Alanine aminotransferase ≥3× upper limit of normal, consecutive ⁎ | 2 (0.8%) | 2 (0.3%) | −0.4 (−2.4, 0.6) | 0.587 |
| Aspartate aminotransferase ≥3× upper limit of normal, consecutive ⁎ | 1 (0.4%) | 2 (0.3%) | −0.1 (−1.8, 0.9) | >0.999 |
| Aspartate aminotransferase and/or alanine aminotransferase ≥3× upper limit of normal, consecutive ⁎ | 2 (0.8%) | 2 (0.3%) | −0.4 (−2.4, 0.6) | 0.587 |
| Creatine kinase | ||||
| ≥10× upper limit of normal | 2 (0.8%) | 4 (0.7%) | −0.1 (−2.1, 1.1) | >0.999 |
| ≥10× upper limit of normal with muscle symptoms | 0 | 1 (0.2%) † | 0.2 (−1.3, 0.9) | >0.999 |
| ≥10× upper limit of normal with drug-related muscle symptoms | 0 | 0 | — | — |
| Patients (n) | 272 | 670 | ||
| Discontinuation due to flushing ‡ | 2 (0.7%) | 69 (10.3%) | 9.6 (6.7, 12.2) | <0.001 |
| Gallbladder-related | 1 (0.4%) | 3 (0.4%) | 0.1 (−1.6, 1.0) | >0.999 |
| Cholecystectomy | 1 (0.4%) | 1 (0.1%) | −0.2 (−1.9, 0.5) | 0.494 |
| Patients (n) | 229 | 569 | ||
| New-onset diabetes § | 7 (3.1%) ¶ | 28 (4.9%) ¶ | 1.9 (−1.6, 4.5) | 0.338 |
| Initiated use of antidiabetic medications | 3 (1.3%) | 5 (0.9%) | −0.4 (−3.0, 1.0) | — |
| Consecutive fasting glucose elevations ≥126 mg/dl | 5 (2.2%) | 25 (4.4%) | 2.2 (−0.9, 4.6) | — |
| Diagnosis of type 2 diabetes mellitus ∥ | 2 (0.9%) | 6 (1.1%) | 0.2 (−2.1, 1.6) | — |
| Patients (n) | n = 43 | N = 101 | ||
| Worsening of diabetes # | 6 (14.0%) | 15 (14.9%) | 0.9 (−13.6, 12.0) | >0.999 |
| Initiated use of antidiabetic medications | 5 (11.6%) | 14 (13.9%) | 2.2 (−11.7, 12.6) | — |
| Diagnosis of type 2 diabetes mellitus ⁎⁎ | 2 (4.7%) | 3 (3.0%) | −1.7 (−12.8, 4.7) | — |
⁎ Patients with 2 consecutive measurements ≥3× ULN, a single, last measurement ≥3× ULN, or measurement of ≥3× 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.
§ 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.
∥ 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.
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