NATAP: Fish Oil Supplements Reduce Triglycerides

[Guest guest]

http://www.natap.org

Fish Oil Reduces Triglycerides 25% in HIV+ in French Study

Reduction in Triglyceride Level With N-3 Polyunsaturated Fatty Acids in HIV-Infected Patients Taking Potent Antiretroviral Therapy: A Randomized Prospective Study

JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 44(3) 1 March 2007 pp 278-285

De Truchis, Pierre MD*; Kirstetter, Myriam MD†; Perier, Antoine MPhil‡; Meunier, §; Zucman, MD‖; Force, Gilles MD¶; Doll, Jacques MD#; Katlama, MD, PhD**; Rozenbaum, Willy MD††; Masson, Hélène MD‡‡; Gardette, MD§; Melchior, Jean-Claude MD, PhD*; and the Maxepa-HIV Group

*Hôpital Poincaré, Garches, France, University Paris-Ile-de-France-Ouest-Versailles; †Hôpital Saint-Antoine, Paris, France; ‡Cardinal Systems, Paris, France; §Innovation Développement Pierre Fabre, Ramonville, France; ‖Hôpital Foch, Suresnes, France; ¶Hôpital Perpétuel Secours, Levallois-Perret, France; #Hôpital A. Mignot, Versailles, France; **Hôpital Pitié-Salpétrière, Paris, France; ††Hôpital Tenon, Paris, France; and ‡‡Hôpital de Poissy-St. Germain, Poissy, France.

The study performed here included one of the largest populations followed for lipid-lowering drug efficacy and safety testing. Our results suggest that N-3 PUFAs (N-3 polyunsaturated fatty acids) have a sustained effect on HAART-linked hypertriglyceridemia, without any specific safety concerns. The beneficial effects of PUFAs are of importance regarding the absence of drug interaction recognized with these compounds, even if only 22.4% of the patients presented with complete normalization of their hypertriglyceridemia. The efficacy of N-3 PUFAs is recognized as secondary prevention in patients with myocardial infarction.44 Because of the high benefit/risk ratio of the product, N-3 PUFAs could be proposed as a possible treatment in patients with isolated or predominant hypertriglyceridemia in the context of HAART to decrease the higher level of TGs. The place of PUFAs in the armamentarium of treatment of metabolic disorders in HIV-infected patients (eg, statins, fibrates, glitazones) needs to be further investigated with future prospective studies, however. No general recommendations can be proposed, despite the positive results of the present study. Therapies to reduce or prevent cardiovascular risk factors (eg, hypertriglyceridemia)45 in these patients are useful, however

“….The median change in TG level was a decrease of 25.5% in the PUFA group compared with an increase of 1.0% in the placebo group…. TG levels had returned to normal at the end of the double-blind period for 22.4% of patients in the PUFA group versus only 6.5% of patients in the placebo group, with a relative risk of success of 3.5 with N-3 PUFAs (P = 0.0126). Furthermore, a significantly higher percentage of patients achieved a 20% decrease on N-3 PUFAs compared with placebo (58.6% vs. 33.9%; P = 0.007)….. A total of 111 patients (55 PUFA patients and 56 placebo patients) continued on to the 8-week open period on PUFAs after the double-blind treatment period. In the PUFA group, the TG level remained almost stable at the end the open phase (4.2%). Conversely, the TG level that had remained almost unchanged in the placebo arm during the randomized period decreased after the switch to open PUFAs to a similar extent compared with that obtained in the randomized PUFA arm (-21.2%)….. For the 10 patients with a baseline TG level >10 g/L included in the open PUFA arm, an important decrease in TG level was achieved during the first 8 weeks of treatment: a median (Q1, Q3) percent change of -43.6% (95%CI: -66.5% to -4.6%; mean TG change of -35.6%). The efficacy was sustained in the next 8 weeks, with a global decrease over the 16-week period of -38.7% (95%CI: -62.1% to +2.1%) for 9 patients….. For the 10 patients with a baseline TG level >10 g/L included in the open PUFA arm, an important decrease in TG level was achieved during the first 8 weeks of treatment: a median (Q1, Q3) percent change of -43.6% (95%CI: -66.5% to -4.6%; mean TG change of -35.6%). The efficacy was sustained in the next 8 weeks, with a global decrease over the 16-week period of -38.7% (95%CI: -62.1% to +2.1%) for 9 patients….. HDL-C (see Table 2) was comparable between groups as well at baseline (0.98 ± 0.23 mmol/L [PUFA group] vs. 0.98 ± 0.25 mmol/L [placebo group]; difference NS) and at week 8 (1.06 ± 0.26 mmol/L [PUFA group] vs. 1.05 ± 0.27 mmol/L [placebo group]; difference NS). A slight but nonsignificant increase in HDL-C was noted in both groups (6.57% and 8.97%, respectively, in the PUFA and placebo groups), with no significant difference between groups…

….. The efficacy of N-3 PUFAs was reported in hyperlipidemic HIV-negative patients receiving the same dose as in the present study (6 g/d).30 The decrease in TG levels was 28% in patients with type IIb hyperlipemia and 41% in patients with type IV hyperlipemia….

…. The fasting glucose level was normal for all patients at the time of randomization (<6.6 mmol/L) and remained unchanged at 8 weeks, except for 1 patient in the placebo group who exhibited a slight increase in fasting glycemia (7.2 mmol/L) without other metabolic abnormalities. Measurement of insulin was not assessed in the present study….â€

Summary: To assess the evolution of triglyceride (TG) levels in HIV-infected patients receiving stable potent antiretroviral therapy treated with N-3 polyunsaturated fatty acids (PUFAs), a prospective double-blind randomized design for a reliable assessment of TG evolution was performed.

One hundred twenty-two patients with TG levels >2 g/L and ≤10 g/L after a 4-week diet (baseline TG: 4.5 ± 1.9 g/L) were randomized for 8 weeks to N-3 PUFAs (2 capsules containing 1 g of fish oil 3 times daily, n = 60), or placebo (1 g of paraffin oil capsules, n = 62). An 8-week open-label phase of N-3 PUFAs followed.

Evaluation criteria were TG percent change at week 8, percentage of responders (normalization or ≥20% TG decrease), and safety issues. Ten patients with baseline TG levels >10 g/L were not randomized and received N-3 PUFAs as open treatment.

The difference (PUFA - placebo) in TG percent change at week 8 was -24.6% (range: -40.9% to -8.4%; P = 0.0033), the median was -25.5% in the PUFA group versus 1% in the placebo group, and mean TG levels at week 8 were 3.4 ± 1.8 g/L and 4.8 ± 3.1 g/L, respectively.

TG levels were normalized in 22.4% (PUFA) versus 6.5% (placebo) of patients (P = 0.013) with a ≥20% reduction in 58.6% (PUFA) versus 33.9% (placebo) of patients (P = 0.007).

Under the open-label phase of N-3 PUFAs, the decrease in TG levels was sustained at week 16 for patients in the PUFA group (mean TG: 3.4 ± 1.7 g/L), whereas a 21.2% decrease in TG levels occurred for patients in the placebo group (mean TG: 3.3 ± 1.4 g/L). No significant differences were observed between groups in the occurrence of adverse events.

The median TG change at week 8 was -43.6% (range: Q1-Q3; 95% CI: -66.5% to -4.6%) for patients with baseline TG levels >10 g/L. The difference in mean total cholesterol between groups (PUFA - placebo) at week 8 was -8.5% (P = 0.0117).

This study demonstrated the efficacy of PUFAs to lower elevated TG levels in treated HIV-infected hypertriglyceridemic patients. N-3 PUFAs have a good safety profile.

Patients

Inclusion Criteria

Ambulatory patients of either gender, aged at least 18 years, and presenting with HIV infection treated with stable multiple antiretroviral therapy for at least 2 months were included in the study if the following criteria were fulfilled: (1) known and documented hypertriglyceridemia (≥3 g/L [3.43 mmol/L]) within 6 months before selection and remaining at least at the same level at the selection visit and (2) baseline TG level >2 g/L and <10 g/L after a 4-week TG-lowering diet. Included patients were randomized to 2 treatment groups (placebo + diet or N-3 PUFAs + diet). Patients with a TG level >10 g/L were not randomized for ethical consideration (because hypertriglyceridemia can lead to acute pancreatitis at such a level). It was proposed that they be treated with N-3 PUFAs plus diet on an open basis and separately analyzed.

This was a double-blind, phase 4, randomized, 2-arm, parallel-group study. After a 4-week screening period on the basis of diet alone, eligible patients were randomized to N-3 PUFAs (2 1-g capsules 3 times daily) plus diet or placebo plus diet during an 8-week period (placebo was presented as ochre gelatin capsules similar to PUFA capsules containing 1 g of paraffin oil). This period of treatment was chosen because previous studies have indicated that after 2 months of treatment, no further effects on TG blood levels could be obtained.34

A combination of nucleoside reverse transcriptase inhibitors and PIs was the most common antiretroviral therapy (46.6% of patients in the PUFA group and 53.2% in the placebo group). Nucleoside reverse transcriptase inhibitors plus nonnucleoside reverse transcriptase inhibitors were taken by 25.9% and 22.6% of patients, respectively, whereas 17.2% and 17.7% of patients were taking nucleoside transcriptase inhibitors plus nonnucleoside reverse transcriptase inhibitors plus PIs. Ritonavir-boosted PIs were used in all cases of PI regimens.

Safety Results

The incidence of treatment-emergent adverse events during the randomized double-blind study period was not more frequent in the PUFA group: 19 (32.2%) of 59 patients versus 27 (43.5%) of 62 of patients in the placebo group (NS). The most common adverse events were minor gastrointestinal disorders without vomiting, which did not lead to stopping the treatment, except for 1 patient in the placebo group (11.9% of patients on PUFA compared with 14.5% patients in the placebo group; P = 0.790), and infections and/or infestations (11.9% of patients on N-3 PUFAs compared with 16.1% of patients in the placebo group; P = 0.604). The proportion of patients experiencing events that were thought by the investigator to be possibly or probably related to study drug was not significantly different between groups (11.9% in the PUFA group vs. 14.5% in the placebo group; P = 0.790). Two patients experienced serious adverse events on N-3 PUFAs (renal colic and urinary calculus, which were considered to be related to indinavir), and 3 patients in the placebo group experienced serious adverse events (diarrhea, an episode of acute alcohol abuse, and surgical treatment of condylomas, which were not considered to be related to the study treatment).

No relevant variation was observed in either group for vital signs during the study. Transaminases rose to at least twice the upper limit of normal (ULN) for 2 patients from each group at the end of the double-blind period. No clinically significant change was otherwise observed for laboratory parameters. The CD4+ cell count, CD8+ cell count, and viral load remained stable throughout the study.

DISCUSSION

The present study is the first randomized double-blind study assessing the effect of N-3 PUFAs on hypertriglyceridemia of HAART-treated patients.

The primary efficacy analysis testing a difference of at least 20% between treatment groups was significant for the ITT and PP populations (PUFA - placebo: -24.6% [95% CI: -40.9% to -8.4%]; P = 0.0033 for ITT, and PUFA - placebo: -24.7% [95% CI: -42.5% to -7%]; P = 0.0068 for PP). Nevertheless, the primary model (which included baseline TG levels) gave a good estimate of the difference between treatment groups (PUFA - placebo). Furthermore, this estimate was well supported by all the preplanned sensitivity analyses, which gave similar P values for the log ratio, raw differences analyses, and the nonparametric analysis of covariance for the difference between treatment groups.

The median percent change in TG level over the 8-week double-blind period was -25.5% (95% CI: -44% to +1%; range: Q1-Q3) for N-3 PUFAs and 1.0% (95% CI: -30% to +31%; range: Q1-Q3) for placebo in the ITT population. Because the distribution of the percent change in TG level is asymmetric (right-skewed) by nature, the median percent change more accurately represents the central distribution of the evolution of TG levels in each group.

The secondary criteria based on percentages of responders were also significantly different in favor of N-3 PUFAs. A further indication of the efficacy of N-3 PUFAs can be clearly seen in the second phase of the trial (the open phase, where all patients were assigned to N-3 PUFAs). In this phase, there was a marked decrease in TG level in patients who were assigned placebo at the time of randomization and a sustained TG level at week 16 in patients who had been assigned N-3 PUFAs. Despite comparable levels in total cholesterol at entry and week 8 between groups, the difference in mean total cholesterol variation (-5.8%) indicates that the use of N-3 PUFAs was associated with a decrease in total cholesterol. Conversely, although HDL-C was comparable between groups, a slight (NS) increase was observed at week 8. These results ruled out a hypothetic elevation of low-density lipoprotein cholesterol (LDL-C) on N-3 PUFAs, as also demonstrated by others.34,37 The slight increase in HDL-C was not significant and could not be considered or analyzed. From a metabolic point of view, a decrease in very low-density lipoprotein (VLDL) TG is usually associated with an increase in HDL-C. This effect may contribute to the cardiovascular benefit of lowering TG levels reported in the literature.28 The present study was not designed to test this hypothesis in the particular situation of HIV-infected patients. In light of the results of the present study, the effect of decreasing TG levels with PUFAs is clear in HIV-infected patients. The results should not be overinterpreted, however, and the cardiovascular hypothetic benefit of this result in this situation remains unknown and needs further long-term studies.

For the 10 patients with a baseline TG level >10 g/L included in the open PUFA arm, the important decrease in TG level achieved at week 8 and sustained at week 16 further demonstrated the high activity of N-3 PUFAs on hypertriglyceridemia. Even if the TG level was not normalized for all patients, the possible risks (eg, acute pancreatitis) related to extremely high levels of TG >10 g/L were probably reduced by the treatment. Overall, the study showed good clinical and biologic tolerability of N-3 PUFAs. The most common adverse events were minor gastrointestinal disorders, particularly moderate diarrhea, which could be related, in part, to the toxicity of the HIV treatment. The paraffin oil used in the placebo group could also have played a role in this kind of adverse event, however.

The CD4+ cell count, CD8+ cell count, and viral load measurements were stable throughout the study, suggesting the lack of effect of N-3 PUFAs on HIV disease itself in patients without any change in their HIV treatment during the study.

The efficacy of N-3 PUFAs was reported in hyperlipidemic HIV-negative patients receiving the same dose as in the present study (6 g/d).30 The decrease in TG levels was 28% in patients with type IIb hyperlipemia and 41% in patients with type IV hyperlipemia.

Only a few studies have investigated the efficacy of fish oil in HIV-infected patients. A short open study on moderate hypertriglyceridemia (2-5 g/L) in HIV-infected patients was reported by Manfredi et al,33 comparing 1 group of patients with diet and exercise, 1 group receiving treatment with fibrate, and 1 group receiving ω-3 fatty acids (2 g of fish oil per day). The decreases in mean triglyceridemia were only 5.6% and 15.8% at 3 and 6 months, respectively, but the initial level was only 3 g/L and the dose administrated was only 2 g/d. Another open-label randomized study was conducted in 52 patients by Wohl et al.34 The mean decrease in triglyceridemia was 25% at week 4, which represents results comparable with ours. The results of our study are emphasized by the efficacy of the treatment in the second open period in both groups. Moreover, the efficacy of the treatment in the group with severe hypertriglyceridemia >10 g/L is a positive and notable result of our study.

Thus, the prescription of N-3 PUFAs in the treatment of HAART-related hypertriglyceridemia showed a favorable safety profile, and no issues regarding the control of the viral disease or the hepatic tolerance appeared during the study.

The results of this study are comparable to the results obtained with other lipid-lowering drugs on TG levels and confirm the retrospective data obtained previously.38-40 Decreases of 17%, 25%, and 27% were obtained by different treatments with fibrates at 3, 6, and 9 months, respectively.33 Among the other drugs tested in this specific field, rosiglitazone unexpectedly caused significant increases in serum TG and cholesterol concentrations.41,42 Metformin seems to have some beneficial impact on the insulin-resistance syndrome existing in these patients.43 The results of the present study cannot emphasize a direct beneficial effect on the metabolic syndrome often associated with HIV infection.

The study performed here included one of the largest populations followed for lipid-lowering drug efficacy and safety testing. Our results suggest that N-3 PUFAs have a sustained effect on HAART-linked hypertriglyceridemia, without any specific safety concerns. The beneficial effects of PUFAs are of importance regarding the absence of drug interaction recognized with these compounds, even if only 22.4% of the patients presented with complete normalization of their hypertriglyceridemia. The efficacy of N-3 PUFAs is recognized as secondary prevention in patients with myocardial infarction.44 Because of the high benefit/risk ratio of the product, N-3 PUFAs could be proposed as a possible treatment in patients with isolated or predominant hypertriglyceridemia in the context of HAART to decrease the higher level of TGs. The place of PUFAs in the armamentarium of treatment of metabolic disorders in HIV-infected patients (eg, statins, fibrates, glitazones) needs to be further investigated with future prospective studies, however. No general recommendations can be proposed, despite the positive results of the present study. Therapies to reduce or prevent cardiovascular risk factors (eg, hypertriglyceridemia)45 in these patients are useful, however.46,47

Treatment with PUFAs is a good way to reduce some risks of hypertriglyceridemia such as sudden death in patients with known or unknown coronary artery disease,44,48 even if a recent study suggests that this may not necessarily be the case in patients with high risk of ventricular tachyarrhythmia.49 Improvement of TG levels in the context of a metabolic syndrome and reducing the risk of acute pancreatitis in case of a high level of hypertriglyceridemia (>10 g/L) may be considered as beneficial effects in the context of HIV infection. Recent studies have shown that the beneficial effect on cardiovascular disease occurs not only by reducing the rate of sudden death in secondary prevention but by reducing cardiovascular ischemic events by 30%.44 Further studies should be useful to assess the beneficial effects of PUFAs that might be expected in the HIV population, which is at high risk of cardiac ischemic disease.46,47

************************************** See what's free at http://www.aol.com.