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Fish Oil Improved Triglycerides
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"Randomized Study of the Safety and Efficacy of Fish Oil (Omega-3 Fatty Acid) Supplementation with Dietary and Exercise Counseling for the Treatment of Antiretroviral TherapyAssociated Hypertriglyceridemia""
Clinical Infectious Diseases Nov 15, 2005;41:1498-1504
"".....within-arm analyses demonstrate a significant triglyceride response among the fish oil recipients at weeks 4 and 16 and no such response in the subjects in the diet and exercise arm.... Omega-3 fatty acid supplementation was found in our study to be well tolerated; only 1 subject discontinued therapy (because of the development of nausea and vomiting).... Unexpectedly, increases in LDL cholesterol levels were consistently seen in patients assigned to the fish oil arm. Further study of the effect of omega-3 fatty acid supplementation on cholesterol subsets is warranted in light of the increases in LDL cholesterol we observed. Diet and exercise counseling alone did not lead to significant improvements in triglyceride levels or other lipid parameters...."
"..... Given the benefits of omega-3 fatty acid in reducing cardiovascular disease risk in HIV-uninfected populations and the increasing concern regarding cardiovascular complications of antiretroviral therapy, expanded study of omega-3 fatty acid supplementation in the treatment for HIV-infected individuals with hypertriglyceridemia is justified.....""
"Excerpts from The EDITORIAL by Carl Grunfeld:
Fasting triglyceride levels of >500 mg/dL are associated with risk of pancreatitis. Levels of >150 mg/dL may be associated with cardiovascular disease. It is difficult to reduce the triglyceride level when it is >500 mg/dL at baseline, as was the case in many of the patients in this study. The higher the starting level, the more difficult it is to reach the goal level, and the more likely the need for polypharmacy. Fish oil achieved a nice reduction in mean triglyceride levels, from 461 to 306 mg/dL at 4 weeks. At 16 weeks, the lower levels were sustained, but study dropouts and the usual fluctuations in triglyceride levels reduced the statistical significance of this finding. These triglyceride levels were still, unfortunately, above the level for cardiovascular risk.
However, the level of reduction achieved by fish oil supplementation is all we could have expected and is similar to that achieved by other agents, such as fibrates and niacin. In the HIV-uninfected population, very high triglyceride levels are treated first with dietary counseling, including recommendations to minimize the intake of fructose and alcohol, as well as to introduce a low-fat diet (as opposed to a lowsaturated fat diet, which is used to treat hypercholesterolemia)... Fish oils do cause nausea in some patients.... Low-density lipoprotein (LDL) levels rose by a mean of 22% in these patients.... Fish oil is not unique in increasing LDL levels in patients with hypertriglyceridemia; fibrates also raise LDL levels.... in this study of HIV-infected patients, fish oil therapy looks like it is as good as the other possible therapies. It potentially adds another powerful agent to our armamentarium. It will no doubt be used in combination with other therapies, as is often the case in HIV-uninfected subjects; however, the toxicities are complex, because fibrates and statins may synergize to cause rhabdomyolysis... I would also urge that larger studies be done, including studies of combination therapy.
Study authors: David A. Wohl,1 Hsiao-Chuan Tien,3 Marjorie Busby,4 Catherine Cunningham,1 Beth MacIntosh,4 Sonia Napravnik,1 Elisheva Danan,1 Kimberly Donovan,2 Mina Hossenipour,1 and Ross J. Simpson, Jr.2
Divisions of 1Infectious Diseases and 2Cardiology, 3Department of Biostatistics, and 4General Clinical Research Unit, University of North Carolina, Chapel Hill
(See the editorial commentary by Grunfeld below)
Background. Omega-3 fatty acids (fish oils) reduce fasting serum triglyceride levels and cardiovascular disease risk in individuals without HIV infection. Whether omega-3 fatty acid supplementation can reduce hypertriglyceridemia associated with antiretroviral therapy is not known.
Methods. We conducted an open-label, randomized trial that enrolled 52 patients receiving 3 active antiretrovirals who had fasting triglyceride levels of >200 mg/dL and were randomized to receive nutritionist-administered dietary and exercise counseling with or without fish oil supplementation for 16 weeks.
"Results."
Patients assigned to receive fish oil experienced a 25% mean decline in fasting triglyceride levels at week 4 (95% CI, -34.6% to -15.7% change), compared with a 2.8% mean increase among patients assigned to receive counseling alone (95% CI, -17.5% to +23.1% change) (P = .007).
By week 16, the mean reduction in triglyceride levels in the fish oil arm remained significant, at 19.5% (95% CI, -34.9% to -4.0% change), whereas the mean decrease in the diet and exercise only arm was 5.7% (95% CI, -24.6% to +13.2% change); however, the difference between study arms was no longer statistically significant (P = .12).
Low-density lipoprotein cholesterol levels had increased by 15.6% (95% CI, +4.8% to +26.4% change) at week 4 and by 22.4% (95% CI, +7.91% to +36.8% change) at week 16 in the fish oil arm but did not change in the diet and exercise only group.
Fish oil was well tolerated; only 1 patient experienced treatment-limiting toxicity.
"Conclusions."
Supplementation with omega-3 fatty acids in combination with dietary and exercise counseling was well tolerated and reduced fasting triglyceride levels in patients receiving antiretrovirals. To what extent the increase in low-density lipoprotein cholesterol levels observed in patients assigned this intervention is attributable to omega-3 fatty acid supplementation and whether this increase attenuates any benefit in lowering triglyceride levels is unclear. Given these results, further investigation of omega-3 fatty acid supplementation for the treatment of hypertriglyceridemia in HIV-infected patients is warranted.
"Lipid-level end points."
At week 4, there was a statistically significant mean decrease in fasting triglyceride levels in the fish oil arm, among whom the mean change was -25.1% (95% CI, -34.6% to -15.7%), compared with a mean change of +2.8% (95% CI, -17.5% to 23.1%) in the diet and exercise arm. The difference between the 2 arms in the mean change in triglyceride levels from entry was statistically significant (P = .0074). This difference remained significant when the data were logarithmically transformed into (P = .018). Likewise, we found a significant difference in the change in triglyceride levels remained after controlling for baseline levels (P = .001).
The mean absolute change in triglyceride levels also was significantly different between study arms: there was a mean change of -138.8 mg/dL in the fish oil arm, compared with a mean change of -25 mg/dL in the diet and exercise group (P = .03). At week 4, the mean triglyceride levels of the fish oil group were significantly lower than those of the diet and exercise group (mean ± SD, 306 ± 162 mg/dL vs. 503 ± 421 mg/dL; P = .03) (figure 1B). Further, the percentage of subjects who achieved a triglyceride level of <200 mg/dL at week 4 was 39.1% in the fish oil arm and 10.0% in the diet and exercise arm (P = .04).
At study week 16, there were 41 subjects remaining in the trial: 22 in the fish oil arm and 19 in the diet and exercise arm. Subjects in the fish oil group continued to have a statistically significant mean reduction in triglyceride levels since study entry (mean change, -19.5% [95% CI, -34.9% to -4.0%]). At this time the diet and exercise arm experienced a modest mean decline in triglyceride levels from baseline (mean change, -5.7% [95% CI, -24.6% to 13.2%]), which was not significantly different from the mean level at study entry; however, the difference between the study arms was no longer statistically significant (P = .12). There was a trend toward lower mean triglyceride levels in the fish oil arm compared with the diet and exercise arm (304 ± 219 mg/dL vs. 513 ± 626 mg/dL; P = .09) (figure 1B). Likewise, the difference between study arms in the percentage of subjects with triglyceride levels of <200 mg/dL became statistically insignificant at week 16 (31.8% for the fish oil arm versus 22.2% for the diet and exercise arm; P = .50).
During the study, total and high-density lipoprotein cholesterol levels, as well as lipoprotein A levels, did not change significantly from baseline in either arm. However, LDL cholesterol levels did significantly increase in the fish oil arm but not in the diet and exercise arm.
There were no reports of discontinuation or modification of HIV therapy by any subjects. In addition, none of the subjects initiated nonstudy lipid-lowering therapy and no subject in the diet and exercise arm reported taking fish oil supplementation during the study.
DISCUSSION
Among HIV-infected patients with elevated triglyceride levels who were receiving antiretroviral therapy, administration of omega-3 fatty acids in conjunction with a diet and exercise program based on AHA recommendations led to significant decreases from baseline in fasting triglyceride levels. At week 4, subjects randomized to receive omega-3 fatty acid had experienced a 25% mean reduction in triglyceride levels; at week 16, subjects assigned to the fish oil arm had maintained a mean decrease in triglyceride levels of >19%. At both points in time, the change from baseline was statistically significant. The magnitude of the hypotriglyceridemic effects of omega-3 fatty acid supplementation observed in this trial, which is the first published study of omega-3 fatty acid supplementation for the treatment of dyslipidemia in patients with HIV infection, is consistent with the results of studies performed among HIV-uninfected patients [1821] and is identical to the preliminary results of a trial of a higher dose of omega-3 fatty acid for the treatment of HIV-associated hypertriglyceridemia [36]. It is notable that fish oil supplementation was able to produce durable reductions in fasting triglyceride levels despite ongoing treatment with antiretroviral therapya finding that is similar to those from studies of omega-3 fatty acid for the treatment of isotretinoin- and etretinate-induced hypertriglyceridemia [29, 30]. In contrast to the subjects treated with fish oil, who demonstrated a reduction in mean triglyceride levels, the subjects who received the identical diet and exercise intervention alone did not experience a significant change from baseline in triglyceride levels during the study. Therefore, within-arm analyses demonstrate a significant triglyceride response among the fish oil recipients at weeks 4 and 16 and no such response in the subjects in the diet and exercise arm.
The difference between the 2 arms in the magnitude of the change in triglyceride levels was statistically significant at week 4 but not at week 16. There are several possible explanations for the lack of a significant difference between study arms at week 16. The most obvious is that the sample size available at week 16 of this pilot study resulted in vulnerability to a type I error. In addition, decreased adherence to fish oil therapy could explain this arm's slightly smaller decrease in triglyceride levels at week 16, despite their self-reported adherence. It is also possible that subjects in the diet and exercise arm were more adherent to the counseling they receivedthe only intervention this group receivedthan the subjects in the fish oil arm were; the latter may have relied more on the fish oil than on lifestyle modifications to treat hypertriglyceridemia. Importantly, there was no manipulation of antiretroviral therapy during the study, and no subject reported initiation of new lipid-lowering or fish oil therapies not provided by the study. Therefore, although fish oil supplementation produced a significant reduction in triglyceride levels throughout the study with the sample available, we were unable to demonstrate a sustained statistically significant difference between the study arms at week 16.
There was little effect of either intervention on other lipid markers, with the notable exception of LDL cholesterol. We observed significant mean increases from study entry in LDL cholesterol levels in the fish oil arm. Studies performed among a cohort of HIV-uninfected patients have also demonstrated an increase in LDL cholesterol levels during omega-3 fatty acid supplementation [1820]. However, increases in LDL cholesterol levels in these studies have generally been in the 5%10% range, whereas we observed increases of >20%. The basis for this increase is unclear. Whether the increase in the LDL cholesterol levels more than offset by the reduction in the level of atherogenic very lowdensity lipoprotein triglyceride is difficult to assess, and it should be noted that the potential to increase the LDL cholesterol level is not exclusive to omega-3 fatty acids. Fibrates may also increase the LDL cholesterol level in hypertriglyceridemic HIV-infected patients [37].
Omega-3 fatty acid supplementation was found in our study to be well tolerated; only 1 subject discontinued therapy (because of the development of nausea and vomiting). Mean insulin levels were significantly increased in the fish oil arm at week 4 but not at week 16. The significance of this finding is unclear and warrants further study. We did not detect a change in platelet function in the fish oil arm using a validated surrogate marker for bleeding time. Likewise, we observed no overt suggestion of increased immunosuppression due to fish oil supplementation during our study.
There are several limitations to this study. Foremost, the study was not blinded and, as a consequence, some subjects who were disappointed at being randomized to the diet and exercise arm withdrew from the study early. Another limitation was imbalance in the use of ritonavir between the study arms, despite the randomization to the interventions. However, the dosage of ritonavir never exceeded 100 mg twice per day, and the difference between arms did not achieve statistical significance. In addition, for this pilot investigation, we chose a daily dose of fish oil that was in line with that recommended by the AHA for patients with elevated triglyceride levels (24 g/day of eicosapentaenoic acid and docosahexaenoic acid), an amount that is considered generally safe by the US Food and Drug Administration, but that is lower than that used in several studies of HIV-uninfected patients. However, the daily dose of omega-3 fatty acids we studied was within the range of daily doses used in clinical studies that have demonstrated a benefit in patients with lipid disorders and/or cardiovascular disease [1820]. Lastly, data on pre-antiretroviral therapy lipid levels were not available, and whether hypertriglyceridemia among our subjects was the direct result of antiretroviral therapy is unclear.
BACKGROUND
Hypertriglyceridemia is the hallmark of HIV therapyassociated dyslipidemia [13]. With the enhanced survival HIV-infected patients have experienced and the publication of data supporting an association between receipt of combination antiretroviral therapy and cardiovascular disease, attention to therapeutic interventions to reduce cardiovascular disease risk, particularly elevations in lipid levels, is becoming a common component of the management of HIV disease [47]. Although dietary interventions, such as reduced dietary fat intake and regular exercise, have been found to improve dyslipidemia, these lifestyle modifications are often difficult for many patients to sustain and may have a modest effect in the treatment of drug-induced lipid disorders [8, 9]. Therefore, there has been increased use of lipid-lowering agents among patients with HIV infection [10, 11]. However, several considerations limit the options for drug treatment of lipid disorders in patients with HIV infection, including drug-drug interactions and the potential for overlapping toxicities between lipid-lowering agents and antiretrovirals [4, 1217].
Omega-3 fatty acids derived from marine sources, so-called fish oils, have been demonstrated to reduce fasting and postprandial triglyceride levels in individuals without HIV infection [1822]. Furthermore, epidemiological and clinical trials indicate omega-3 fatty acids can reduce the incidence of cardiovascular disease [2328]. Omega-3 fatty acid supplementation has also been effective in reducing drug-induced triglyceride level elevations [29, 30].
Whether omega-3 fatty acid supplementation can reduce hypertriglyceridemia accompanying antiretroviral therapy is not known. We conducted a pilot study to determine the safety, tolerability, and efficacy of omega-3 fatty acid supplementation in HIV-infected patients with hypertriglyceridemia who were receiving combination antiretroviral therapy.
METHODS
Patients. HIV-infected adults who had 8-h fasting serum triglyceride levels of >200 mg/dL and had been receiving at least 3 antiretrovirals for 3 months were recruited from the University of North Carolina Infectious Diseases Clinic. Subjects were excluded if they had diabetes mellitus or heart disease with an American Heart Association (AHA) classification of class I or greater. Patients receiving stable statin therapy were eligible; however, patients who had taken fibrates within 6 weeks prior to study entry were excluded.
Study design. The study, approved by the University of North Carolina School of Medicine Biomedical Institutional Review Board, was an open-label, randomized, controlled trial. Subjects were assigned to 1 of 2 intervention groups: the diet and exercise only arm (hereafter, "diet and exercise arm") or the fish oil arm. All subjects, regardless of treatment assignment, received diet and exercise counseling from a research assistant in accordance with AHA recommendations [31]. The nutritionist met one-on-one with all subjects at entry and at week 4 for 3045 min, during which time a diet and exercise plan was devised and reviewed. Specifically, subjects were provided with general information on strategies to reduce intake of overall dietary fat and transfatty acid, to increase intake of fiber, and how to adopt a daily aerobic exercise program. Increased intake of foods rich in omega-3 fatty acid was discussed only in general terms, in accordance with AHA guidelines. Target weight and exercise goals were tailored to the needs and capabilities of each subject. The fish oil arm received, in addition to this standard diet and exercise counseling program, a 16-week course of omega-3 fatty acid supplementation consisting of 1750 mg of eicosapentaenoic acid and 1150 mg of docosahexaenoic acid (Coromega, European Reference Botanical Laboratories) taken daily with food. This total dose is within the 24 g of eicosapentaenoic acid and docosahexaenoic acid per day recommended by the AHA for patients who need to lower triglyceride levels [32]. The formulation is a liquid that is relatively pleasant tasting. Data provided by the manufacturer support the conclusion that eicosapentaenoic acid and docosahexaenoic acid have high-level bioavailability (European Reference Botanical Laboratories, data on file).
Prior investigations of strategies for lowering lipid levels have typically demonstrated a maximum effect within the first 46 weeks after the initiation of the intervention. The National Cholesterol Education Program guidelines also suggest that response to lipid-lowering therapy be assessed after 4 weeks [8]. For these reasons, the primary efficacy outcome of the interventions was chosen to be the change in triglyceride levels at week 4 after randomization. An additional 8 weeks of study follow-up was included to permit fuller characterization of the tolerability and safety of omega-3 fatty acids, as well as the collection of additional efficacy data.
At study entry and at weeks 4 and 16 after enrollment, blood samples were collected to ascertain fasting triglyceride levels, total and high-density lipoprotein cholesterol levels, and direct low-density lipoprotein (LDL) cholesterol and lipoprotein A levels (cholesterol levels were determined with the VAP test; Atherotech). All subjects underwent 2-h oral glucose tolerance testing, platelet function analysis, and basic blood chemistry tests at each visit. Adverse clinical and laboratory events were graded according to the National Institutes of Health Division of AIDS toxicity grading table [33].
All subjects were asked to record all concomitant medications and supplements taken and to complete a 3-day food record at each study visit (or, when a record was not available, a 24-h food recall). Physical activity was self-assessed using the Lipid Research Clinics questionnaire [34]. Adherence to study medication was assessed using the AIDS Clinical Trials Group self-reported adherence measure [35].
Statistical considerations. The primary objective of this trial was to compare the mean change (defined as the week 4 value minus the entry value, divided by the entry value) in fasting triglyceride levels from baseline to week 4 within and between the study arms. Secondary outcomes included the comparison of the 2 study arms with respect to the mean triglyceride levels from baseline to week 16 and the change from study entry to weeks 4 and 8 in mean absolute change in triglyceride levels; change in weight; and change in the levels of total cholesterol, high-density lipoprotein cholesterol, LDL cholesterol, and lipoprotein A. The safety and tolerability of the study medication were also secondary outcomes. Paired Student's t tests were used for comparing the changes from baseline in lipid values, platelet function assay results, and weight. The Wilcoxon rank sum test was used to analyze the absolute change in triglyceride levels. SAS software, version 8.2 (SAS Institute) was used for the computations of all statistical tests and descriptive statistics.
RESULTS
Baseline characteristics and subject disposition.
Of the 52 subjects enrolled, 44 (85%) completed at least the week 4 study evaluation (for primary outcome) and 41 (79%) completed the week 16 study evaluation. Six subjects in the diet and exercise arm prematurely terminated study participation because of their disappointment at not being randomized to receive fish oil. One subject in the fish oil arm discontinued study participation because of the discomfort of phlebotomy, and another was lost to follow-up. After week 4, one additional subject in the diet and exercise arm withdrew before relocating to another state. In the fish oil arm, 1 subject withdrew because of toxicity, and another subject withdrew because of dislike of the liquid fish oil formulation. There were no major differences in demographic characteristics or laboratory values among the subjects who withdrew from the study prior to the week 4 visit and those who continued.
There were no statistically significant differences between the arms in any characteristic at baseline. More subjects in the diet and exercise arm were receiving ritonavir, but this difference did not achieve statistical significance. Likewise, the number of patients receiving stavudine was similar between the 2 arms (P > .5). The mean number of National Cholesterol Education Programdefined cardiovascular disease risk factors was 1.9 per subject.
Lipid-level end points.
At week 4, there was a statistically significant mean decrease in fasting triglyceride levels in the fish oil arm, among whom the mean change was -25.1% (95% CI, -34.6% to -15.7%), compared with a mean change of +2.8% (95% CI, -17.5% to 23.1%) in the diet and exercise arm. The difference between the 2 arms in the mean change in triglyceride levels from entry was statistically significant (P = .0074). This difference remained significant when the data were logarithmically transformed into (P = .018). Likewise, we found a significant difference in the change in triglyceride levels remained after controlling for baseline levels (P = .001).
The mean absolute change in triglyceride levels also was significantly different between study arms: there was a mean change of -138.8 mg/dL in the fish oil arm, compared with a mean change of -25 mg/dL in the diet and exercise group (P = .03). At week 4, the mean triglyceride levels of the fish oil group were significantly lower than those of the diet and exercise group (mean ± SD, 306 ± 162 mg/dL vs. 503 ± 421 mg/dL; P = .03) (figure 1B). Further, the percentage of subjects who achieved a triglyceride level of <200 mg/dL at week 4 was 39.1% in the fish oil arm and 10.0% in the diet and exercise arm (P = .04).
At study week 16, there were 41 subjects remaining in the trial: 22 in the fish oil arm and 19 in the diet and exercise arm. Subjects in the fish oil group continued to have a statistically significant mean reduction in triglyceride levels since study entry (mean change, -19.5% [95% CI, -34.9% to -4.0%]). At this time the diet and exercise arm experienced a modest mean decline in triglyceride levels from baseline (mean change, -5.7% [95% CI, -24.6% to 13.2%]), which was not significantly different from the mean level at study entry; however, the difference between the study arms was no longer statistically significant (P = .12). There was a trend toward lower mean triglyceride levels in the fish oil arm compared with the diet and exercise arm (304 ± 219 mg/dL vs. 513 ± 626 mg/dL; P = .09) (figure 1B). Likewise, the difference between study arms in the percentage of subjects with triglyceride levels of <200 mg/dL became statistically insignificant at week 16 (31.8% for the fish oil arm versus 22.2% for the diet and exercise arm; P = .50).
During the study, total and high-density lipoprotein cholesterol levels, as well as lipoprotein A levels, did not change significantly from baseline in either arm (table 2). However, LDL cholesterol levels did significantly increase in the fish oil arm but not in the diet and exercise arm.
There were no reports of discontinuation or modification of HIV therapy by any subjects. In addition, none of the subjects initiated nonstudy lipid-lowering therapy and no subject in the diet and exercise arm reported taking fish oil supplementation during the study.
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