American Journal of Cardiology
Volume 102, Issue 10 , Pages 1341-1347, 15 November 2008

Comparison of Treatment of Severe High-Density Lipoprotein Cholesterol Deficiency in Men With Daily Atorvastatin (20 mg) Versus Fenofibrate (200 mg) Versus Extended-Release Niacin (2 g)

Cardiovascular Research Laboratories, McGill University Health Center/Royal Victoria Hospital, Montréal, Québec, Canada

Received 2 April 2008; received in revised form 13 July 2008; accepted 13 July 2008. published online 15 September 2008.

Article Outline

To determine whether available lipid-modifying medication can increase high-density lipoprotein (HDL) cholesterol in well-defined genetic or familial HDL-deficiency states, we studied 19 men with HDL deficiency (HDL cholesterol <5th percentile for age and gender) 55 ± 10 years of age. Concomitant risk factors included diabetes (n = 3) and hypertension (n = 7) and 8 patients had coronary artery disease. Molecular analysis revealed that 4 patients had a mutation in the ABCA1 gene. Patients were assigned to sequentially receive atorvastatin 20 mg/day, fenofibrate 200 mg/day, and extended-release niacin 2 g/day for 8 weeks, with a 4-week washout period between each treatment. Patients in whom a statin was required, according to current treatment guidelines, were kept on atorvastatin throughout the study. Baseline HDL cholesterol level was 0.63 ± 0.12 mmol/L (24 ± 5 mg/dl), triglycerides 2.01 ± 0.98 mmol/L (180 ± 86 mg/dl), and low-density lipoprotein (LDL) cholesterol 2.29 ± 0.95 mmol/L (94 ± 39 mg/dl). Mean percent changes in HDL cholesterol on atorvastatin, fenofibrate, and niacin were −6% (p = NS), +6% (p = NS), and +22% (p <0.05), respectively. Furthermore, niacin significantly increased the large α-1 apolipoprotein A-I–containing HDL subspecies (12 to 17 nm). In conclusion, niacin was the only effective drug to increase HDL cholesterol. The absolute increase in HDL cholesterol, ∼0.10 mmol/L (3.9 mg/dl), is of uncertain clinical significance. Biomarkers of HDL-mediated cellular cholesterol efflux were not changed by niacin therapy. Atorvastatin or fenofibrate had little effect on HDL cholesterol; atorvastatin decreased the total cholesterol/HDL cholesterol ratio by 26%. Fenofibrate did not change HDL cholesterol levels and caused an increase in LDL cholesterol. Aggressive LDL cholesterol lowering may be the strategy of choice in such patients.

 

The aim of this study was to identify potential pharmacologic approaches for the treatment of patients with severe high-density lipoprotein (HDL) deficiency. This pilot study aims to determine whether currently available medications, used in standard medical practice for the treatment of lipoprotein disorders, can substantially increase HDL cholesterol in patients with severe HDL deficiency. The primary end point of the study was the absolute (in millimoles per liter and in milligrams per deciliter) and percent changes in HDL cholesterol levels and the change in total cholesterol/HDL cholesterol ratio (TC/HDL cholesterol).

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Methods 

Only men were included in this pilot study. Estrogen status in premenopausal women and use of estrogens in postmenopausal women were considered to represent potential confounding biases. Patients were included in this study if they had an HDL cholesterol <5th percentile for age- and gender-matched subjects1 and an identified genetic cause of HDL deficiency or ≥1 first degree relative affected with HDL deficiency.2 Patients were excluded if ≥1 of the following criteria was present: triglyceride level >5 mmol/L, poorly controlled diabetes (hemoglobin A1c >7%), moderately severe obesity (body mass index >35 kg/m2), alcohol intake >21 drinks/week, hypothyroidism, or renal or hepatic failure. Patients were assigned to sequentially receive, in the following order, atorvastatin 20 mg/day, fenofibrate 200 mg/day, and niacin 2 g/day (Niaspan 1 g 2 times/day, Abbott Laboratories, Abbott Park, Illinois) for 8 weeks, with a 4-week washout period between each treatment period. Patients in whom a statin was required, according to current treatment guidelines,3, 4 were switched or maintained on atorvastatin 20 mg throughout the study. The protocol was approved by the institutional research ethics board. Figure 1 shows a summary of the study protocols. Serum from all study subjects was isolated in a glass tube after a 12-hour fast. Lipids and lipoproteins were measured using standardized techniques and low-density lipoprotein (LDL) cholesterol was calculated according to the Friedewald formula (LDL cholesterol [millimoles per liter] = TC − [triglycerides/2.19 + HDL cholesterol]), unless the triglyceride level was >4.5 mmol/L. Apolipoprotein (apo) A-I and apoB were measured using standardized rate-limiting nephelometry. Creatinine kinase and alanine aminotransferase were determined at each visit. A diet, corresponding to the American Heart Association diet, was recommended for all subjects and patients were encouraged to maintain their diet and level of exercise throughout the study. None of the patients changed his smoking habits during the study. Patients filled out a questionnaire for general health, cardiovascular symptoms, and medication side effects and underwent a general physical examination including weight, and blood pressure was measured at each visit.

HDL lipoprotein (Lp) subspecies were separated by 2-dimensional polyacrylamide gradient gel electrophoresis and were detected by human immunopurified polyclonal anti–apoA-I antibody as described previously.5 The HDL subfractions were separated into pre–β-LpA-I, α-1, α-2, and α-3 LpA-I particles on nondenaturing, 1-dimensional polyacrylamide gradient gel electrophoresis and quantified by densitometric scanning.

We studied the capacity of serum from patients to promote cellular cholesterol efflux from cells expressing the ABCA1 gene (the J744 macrophage cell line) or the scavenger receptor B1 (SR-B1; Fu5Ha cells) and a stably expressing ABCG1 cell line (baby hamster kidney cells). Baby hamster kidney cells express ABCG1 under the regulation of mifepristone and were a kind gift of Jack Oram, PhD (Seattle, Washington). Briefly, in the presence of mifepristone (10 μmol/L), the ACBG1 transporter is expressed in a dose-dependent fashion and cellular efflux studies can be carried out specifically addressing the role of this transporter. The cellular cholesterol efflux was carried out as previously described6 using human serum (25 μl/ml) as the cellular cholesterol acceptor. Cholesterol efflux was determined as percent total (media + cells) [3H] cholesterol measured in the medium. Values represent mean ± SD from triplicate wells. Student's t test was used to compare levels of serum lipids and lipoprotein lipids between baseline and treatment values. A p level <0.05 was considered statistically significant.

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Results 

We examined the effects of 3 conventional lipid-modifying agents, atorvastatin, fenofibrate, and niacin, on 19 men with severe, familial HDL deficiency. The primary end point of the study was absolute and percent changes in HDL cholesterol levels and the TC/HDL cholesterol ratio. Women were not included in this pilot study because of the possible confounding effects of estrogens on HDL cholesterol levels. All patients had a genetic or familial form of HDL deficiency. Table 1 lists the characteristics of the study subjects. Some patients with established atherosclerotic cardiovascular disease or at high risk of coronary heart disease death or nonfatal myocardial infarction according to the Canadian Lipid Guidelines4 were maintained on atorvastatin 20 mg/day or had their statin changed to atorvastatin 20 mg/day at the time of initiation of the study (Figure 1). If the patients were not at the recommended LDL cholesterol level according to the guidelines, the patient was excluded from the study. All patients were men, with an average age of 55 ± 10 years (range 44 to 71). Concomitant risk factors included diabetes (n = 3) and hypertension (n = 7) and 8 patients had documented coronary artery disease. Baseline lipid and lipoprotein lipid levels are listed in Table 2. Mean ± SD baseline HDL cholesterol level was 0.63 ± 0.12 mmol/L (24 ± 5 mg/dl), triglycerides 2.01 ± 0.98 mmol/L (171 ± 84 mg/dl), LDL cholesterol 2.29 ± 0.95 mmol/L (884 ± 36 mg/dl), TC/HDL cholesterol 6.06 ± 1.66, and non-HDL cholesterol 3.11 ± 1.00 mmol/L (120 ± 39 mg/dl). Molecular analysis revealed that 4 patients had a mutation in the ABCA1 gene.7 No patients had a mutation of the apoA-I or Lecithin: Cholesterol Acyl Transferase (LCAT) genes, known to cause monogenic severe HDL deficiency. In the remaining 15 subjects, study of the kindred confirmed the familial nature of the HDL deficiency. None of the patients was taking drugs known to alter HDL cholesterol levels (probucol, steroids, and retinoic acid derivatives).

Table 1. Characteristics of the patients under study
Patient No.Age (yrs)DMSHCADBMI (kg/m2)
161++028.9
2580+024.5
33800029.8
46400032.5
55000025.1
64400023.7
76500027.5
84800031.6
94400025.4
10630++31.3
11490++27.0
1255+0024.3
136600+26.0
147100+31.0
1571+++29.6
16520++26.1
176400+25.3
18450+029.2
194400+25.03
Average55±10 27.6±2.8

BMI = body mass index; CAD = coronary artery disease; DM = diabetes; SH = systemic hypertension.

Table 2. Baseline lipid profile, separated by protocol
Patient No.ProtocolGenetic CauseTC (mmol/L; mg/dl)TG (mmol/L; mg/dl)LDL Cholesterol (mmol/L; mg/dl)HDL Cholesterol (mmol/L; mg/dl)TC/HDL CholesterolNon-HDL Cholesterol (mmol/L; mg/dl)ApoA-I (g/L)ApoB (g/L)
11ABCA14.633.182.650.538.74.100.541.00
21ND5.111.263.840.77.34.410.971.27
31ABCA15.662.273.960.678.54.990.861.24
41ND3.082.561.560.368.62.720.690.92
51ND4.781.763.090.895.43.891.201.08
61ND2.592.11.10.544.82.050.970.69
71ND5.411.574.040.668.24.750.881.25
81ND4.550.863.510.6573.900.811.15
Mean ± SD 4.48±1.09;1.73±421.95±0.74;172±652.97±1.12;115±430.63±0.15;24±67.31±1.503.85±0.94;149±360.87±0.201.08±0.20
92ND3.682.891.840.536.93.150.720.84
102ND3.291.192.140.615.42.681.010.80
112ABCA13.551.442.360.546.63.010.630.87
122ND2.871.551.610.565.12.310.970.62
132ND2.921.51.630.614.82.310.971.21
142ND3.060.831.890.793.92.271.030.70
152ND4.072.612.240.646.43.400.950.84
162ND4.124.281.380.795.23.331.020.95
172ABCA12.263.811.740.583.91.680.820.90
182ND2.751.051.490.713.92.041.161.16
192ND2.71.531.40.64.52.10.910.63
Mean ± SD 3.21±0.59;124±232.06±1.16;182±1031.79±0.34;69±130.63±0.09;24±45.15±1.102.57±0.58;99±220.93±0.150.87±0.19
p Value⁎ 0.01570.77800.04090.96710.00570.00910.34180.0328

All patients on protocol 2 were on atorvastatin 20 mg/day at baseline.

ND = not determined; TG = triglyceride.

⁎T test between the 2 protocol groups.

Each patient was treated sequentially with atorvastatin 20 mg/day for 8 weeks, followed by a 4-week washout period, micronized fenofibrate 200 mg/day for 8 weeks, followed by a 4-week washout period, and with extended-releasecc niacin (Niaspan) 1 g 2 times/day. Baseline measurements (1 to 3) and on-treatment (1 to 3) measurements were taken in the fasted state before each intervention (Figure 1). Because patients on protocol 2 were on atorvastatin 20 mg/day, the results for each protocol were analyzed separately. As expected, patients on atorvastatin (protocol 2) had lower LDL cholesterol at baseline compared with those in protocol 1 (1.79 ± 0.34 vs 2.97 ± 1.12 mmol/L, 69 ± 13 vs 115 ± 43 mg/dl, p = 0.0409); similarly, TC, TC/HDL cholesterol, and non-HDL cholesterol were higher in patients on protocol 1 (Table 2). Table 3 presents absolute changes in HDL cholesterol levels in individual patients according to treatment given. Two patients were excluded from the study. Patient 8 developed high creatine kinase levels and patient 17 developed a myocardial infarction during the course of the study. Table 4 lists relative changes in HDL cholesterol, triglycerides, LDL cholesterol, TC/HDL cholesterol, and non-HDL cholesterol. It is noteworthy that only niacin increased HDL cholesterol by 22%, reflecting an absolute increase in HDL cholesterol of approximately 0.10 mmol/L (3.9 mg/dl, 95% confidence interval 0.023 to 0.18, p = 0.0192). HDL cholesterol levels were not affected by atorvastatin or fenofibrate (Table 4, Figure 2). Absolute changes in HDL cholesterol, LDL cholesterol, triglycerides, TC/HDL cholesterol, and non-HDL cholesterol for each treatment schedule are shown in Figure 2.

Table 3. Absolute changes in high-density lipoprotein cholesterol (millimoles per liter) for each patient, separated by study protocol
Patient No.Protocol 1Patient No.Protocol 2
Atorvastatin 20 mgFenofibrate 200 mgNiacin 2 g Atorvastatin 20 mg + Fenofibrate 200 mgAtorvastatin 20 mg + Niacin 2 g
BaselineTreatmentBaselineTreatmentBaselineTreatment BaselineTreatmentBaselineTreatment
10.530.440.440.460.560.5990.530.470.470.56
20.70.630.90.840.780.87100.610.720.730.57
30.670.540.640.660.660.68110.540.530.470.57
40.360.320.340.330.250.39120.560.630.650.74
50.890.750.670.930.740.77130.610.770.730.98
60.540.450.480.240.390.54140.790.60.570.85
70.660.720.791.20.730.98150.640.710.710.72
80.650.84NANANANA160.790.680.790.93
170.580.3NANA
180.710.790.760.82
190.60.570.540.72

To convert millimoles per liter, multiply by 38.67.

NA = not available.

Table 4. Percent change in lipid profile after each intervention
Protocol 1Protocol 2
Atorvastatin 20 mgFenofibrate 200 mgNiacin 2 gAtorvastatin 20 mg + Fenofibrate 200 mgAtorvastatin 20 mg + Niacin 2 g
%Δ HDL cholesterol−6%6%22%⁎−2%18%⁎
%Δ TG−34%†−8%−18%−16%⁎−24%†
%Δ LDL cholesterol−35%†19%−8%36%⁎−30%†
%Δ TC/HDL cholesterol−26%†19%−22%⁎32%−32%†
%Δ non-HDL cholesterol−35%†10%−11%22%−21%

ND = not determined; TG = triglyceride.

⁎p <0.05;

†p <0.01.

  • View full-size image.
  • Figure 2. 

    (A) Graphic representation of changes in lipid profile by protocol. (B) (Left) Two-dimensional polyacrylamide gradient gel electrophoresis of apoA-I–containing HDL particles at baseline (left) and on niacin (right) in 2 patients (Pts) with an increase in HDL cholesterol (HDL-C) of >20% on niacin. Note the increase in the large (12 to 17 nm) α-1 LpA-I particles after niacin treatment. (Right) Cellular cholesterol efflux from a patient's serum after niacin treatment. No significant ABCG1- or SR-B1–mediated efflux was observed, despite an increase in large HDL particles. BHK = baby hamster kidney cells; LDL-C = LDL cholesterol; TG = triglyceride.

  • *p<0.05; **p<0.01.

Serum (cell culture medium 25 μl/ml) from patients at baseline and treated with niacin was then tested for its ability to promote cellular cholesterol efflux from cells expressing the ABCA1 transporter (J774 macrophage cell line stimulated with cyclic adenosine monophosphate), SR-B1 (Fu5Ha cells), and AGCG1 (baby hamster kidney cells with mifepristone-inducible ABCG1 10 μmol/L). Figure 2 shows the results of efflux experiments for 2 representative patients (patients 13 and 14 in Table 3, with the highest increase in HDL cholesterol on niacin) in whom a >20% increase in HDL cholesterol was observed on niacin compared with baseline values. No significant cellular cholesterol efflux was observed for ABCA1-mediated cellular cholesterol efflux (data not shown). Similarly, SR-B1- and ABCG1-mediated cholesterol effluxes were not different at baseline or on niacin treatment (Figure 2). Results of 2-dimensional polyacrylamide gradient gel electrophoresis analysis revealed an increase in large HDL particles identified in Figure 2 as α-1 LpA-I. These particles have a size range of 12 to 17 nm and correspond to cholesterol-enriched, large HDL2 particles.

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Discussion 

In this pilot study, we treated 19 men with severe HDL deficiency with atorvastatin, fenofibrate, or niacin for 8 weeks. Niacin, but not atorvastatin or fenofibrate, increased HDL cholesterol significantly (Table 3). Interestingly, TC/HDL cholesterol was equally decreased by atorvastatin and niacin, by 26% and 22%, respectively. This effect is attributed to the marked LDL cholesterol-lowering effect of atorvastatin and, for niacin, to the combined effects on the increase in HDL cholesterol and further decrease in LDL cholesterol. Fenofibrate was not associated with an increase in HDL cholesterol, but caused a paradoxical increase in LDL cholesterol, a common observation with fibrates. Thus the use of fenofibrate in these patients was associated with an increase in LDL cholesterol, an increase in TC/HDL cholesterol, and no significant change in HDL cholesterol. Niacin use was associated with an increase in HDL cholesterol and an increase in the large, buoyant HDL2 (12- to 17-nm) particles. This increase in HDL cholesterol was not matched with 1 biomarker of HDL function, the ability to promote cellular cholesterol efflux with the ABCA1, SR-B1, or ABCG1 receptors.

Prospective longitudinal studies have demonstrated an inverse relation between HDL cholesterol and coronary artery disease risk. This observation is consistent across many populations studied.8, 9, 10, 11 Post hoc analysis of large-scale clinical trials of lipid-lowering agents revealed that HDL cholesterol continues to be a risk factor when LDL cholesterol is considered optimal (∼2.0 mmol/L, 80 mg/dl).12 Analysis from observational studies suggested that for every 1 mg/dl (0.026 mmol/L) increase in HDL cholesterol there is an associated 2% to 4% decrease in coronary artery disease risk.13 Despite a multitude of clinical trials of lipid-modifying drugs in the previous 3 decades, this observation has not been confirmed unequivocally. The standard of care for the treatment of a low level of HDL cholesterol is first lifestyle modifications that include exercise, smoking cessation, and weight control. The role of moderate alcohol intake and decreased dietary fat intake is of unknown clinical significance. Niacin is the most effective available medication, increasing HDL cholesterol by up to 15% to 35%.14 Niacin increases HDL cholesterol by several mechanisms, including inhibiting hepatic uptake of apoA-I, decreasing free fatty acid flux to the liver, and hepatic triglyceride secretion.14 The Coronary Drug Project, to this date the only large-scale placebo-controlled trial of niacin, demonstrated a significant decrease in the incidence of death and myocardial infarction after 5 years of niacin treatment in men with a history of myocardial infarction. A follow-up analysis of the data, 10 years after the trial was ended, showed an 11% decrease in mortality, although most participants were no longer on the drug.15 In the Stockholm Ischaemic Heart Disease Secondary Prevention Study, patients who received niacin and clofibrate had 26% fewer deaths from any cause and 36% fewer fatal and nonfatal myocardial infarctions.16 Several angiographic trials such as the Familial Atherosclerosis Treatment Study (FATS) and HDL Atherosclerosis Treatment Study (HATS) strongly suggest that niacin in combination with an LDL cholesterol-lowering drug decreases coronary artery disease events. However, these studies were not designed to examine clinical end points.17 The largest study of fenofibrate, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study in diabetics, proved to be neutral with respect to the prevention of ischemic heart disease.18 Surrogate end points, such as the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 and 3 studies, that study the effects of niacin on carotid intima–media thickness have provided convincing evidence that increasing HDL cholesterol with niacin adds to the coronary heart disease benefit achieved from lowering LDL cholesterol with a statin.19 The results of trials using fibric acid derivatives, potent activators, and peroxisome proliferator-activated receptor-α are more nuanced. Fibrates increase HDL cholesterol by 5% to 15%. In the Helsinki Heart Study, gemfibrozil 1,200 mg/day resulted in an increase in HDL cholesterol of 10%, a decrease in non-HDL cholesterol of 14%, and led to 34% fewer major coronary heart disease events after 5 years of treatment.20 In the Veterans Administration HDL Intervention Trial (VA-HIT), gemfibrozil 1,200 mg/day increased HDL cholesterol by 6%, decreased triglycerides by 31%, but did not change LDL cholesterol. Compared with placebo, the men randomized to gemfibrozil demonstrated a significant 22% decrease in major coronary artery disease events and a 29% decrease in strokes.21 Statins increase HDL cholesterol levels by 5% to 10% by increasing apoA-I synthesis through an indirect mechanism.22 New agents designed to increase HDL cholesterol include inhibitors of cholesteryl ester transfer protein that increase HDL cholesterol by up to 100%, but 1 such agent, torcetrapib, has apparent off-target toxicity, leading to an increase in overall mortality in a large-scale trial.23 It is also possible that the type of HDL particles generated with cholesteryl ester transfer protein inhibitors may lose some of their biological function and become proatherogenic.24 Small trials of intravenous injections of reconstituted nascent HDL particles have yielded interesting results with apoA-I Milano,25 but these results did not extend to wild-type apoA-I.26 Interestingly, Asztalos et al27 found that high-dose statins (atorvastatin 80 mg/day and rosuvastatin 40 mg/day) increase large α-1 and α-2 LpA-I particles, but cause a decrease in pre–β-1 LpA-I. This pilot study was designed to evaluate currently available therapies for treatment of severe HDL deficiency. Only men were included and all were Caucasians, reflecting the general population of our clinic. We selected patients with severe genetic or familial HDL deficiency, because these patients often present a clinically difficult and challenging problem and there is a paucity of studies addressing this group of patients. We used a relatively short treatment period (8 weeks). There are good data from clinical studies that statins and fibrates act rapidly (within the first 2 to 4 weeks). The effect of niacin is less well documented. The washout period was only 4 weeks and the possibility of a carryover effect, especially of niacin, cannot be ruled out. For this reason, we chose to test niacin last, because carryover effects are possible with this vitamin. We did not test a full range of “HDL biomarkers” that may provide more mechanistic insights on subtle changes in the quality of HDL produced with each treatment.28, 29

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Acknowledgment 

The authors thank Colette Rondeau, RN, for her expertise in carrying out this clinical trial.

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References 

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 Financial support for this trial was obtained from the research funds of Dr. Genest and Canadian Institutes of Health Research funds MOP 15042 and MOP 62834 at the McGill University Health Center Research Institute, Montréal, Québec, Canada.

PII: S0002-9149(08)01184-3

doi:10.1016/j.amjcard.2008.07.010

American Journal of Cardiology
Volume 102, Issue 10 , Pages 1341-1347, 15 November 2008

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