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A randomized, double-blind study of gemfibrozil for the treatment of protease inhibitor-associated hypertriglyceridaemia

Miller, John; Brown, Dannae; Amin, Janaki; Kent-Hughes, Julia; Law, Matthew; Kaldor, John; Cooper, David A; Carr, Andrew

CLINICAL SCIENCE: CONCISE COMUNICATION
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Background: Hypertriglyceridaemia is common in patients with HIV, especially those taking protease inhibitors or with lipodystrophy, frequently observed at levels associated with accelerated cardiac disease. This study aimed to explore the efficacy and safety of gemfibrozil for hypertriglyceridemia in patients with HIV infection.

Methods: A 16-week, randomized, double-blind, comparative study of low saturated fat diet versus low saturated fat diet with gemfibrozil 600 mg twice daily in patients with triglycerides ≥ 3mmol/l receiving protease inhibitor therapy. Following a 4-week period of dietary intervention alone, patients were randomized to gemfibrozil or matching placebo. The primary outcome was the difference in mean change in fasting triglycerides at week 16 between the two groups.

Results: 37 men were randomized (17 gemfibrozil, 20 placebo) with median fasting triglycerides 5.6 mmol/l. Mean changes in triglycerides from week 4 to week 16 were –1.22 mmol/l and +0.35 mmol/l for the gemfibrozil and placebo groups respectively (between-group mean difference of 1.57 mmol/l; 95% confidence interval, –6.7 to 3.5; P = 0.08). Only one patient treated had triglycerides return to a desirable range (≤ 2.00 mmol/l). No significant changes in the other metabolic parameters were observed. Gemfibrozil was well tolerated, did not appear to induce additional protease inhibitor toxicity, and did not induce changes in CD4 lymphocyte counts or HIV RNA load.

Conclusions: Gemfibrozil is safe and demonstrated at most, modest efficacy for hypertriglyceridemia in HIV-infected patients receiving protease inhibitors. Given the level of response, however, it is unclear whether these reductions will confer clinical benefit, at least in the presence of continued protease inhibitor use.

From the From aSt. Vincent's Hospital, and the bNational Centre in HIV Epidemiology and Clinical Research University of New South Wales, Sydney, Australia.

Correspondence to J. Miller, HIV, Immunology and Infectious Diseases Clinical Services Unit, St. Vincent's Hospital, Sydney, 2010 Australia.

Received: 10 January 2002; revised: 5 July 2002; accepted: 29 July 2002.

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Introduction

Hypertriglyceridaemia is common in patients with HIV infection and has been associated with protease inhibitor therapy, lipodystrophy (peripheral lipoatrophy and central fat accumulation), higher total cholesterol, decreased high density lipoprotein (HDL) cholesterol, glucose intolerance and diabetes [1,2].

Elevated plasma triglycerides are a recognized risk factor for cardiovascular disease and the increased incidence of high lipids and insulin resistance associated with protease inhibitor use suggests that vascular disease may develop over the medium to long term if protease inhibitor containing regimens are continued [3–6].

While continued antiretroviral treatment is both desirable and essential for many patients with HIV disease, identification of treatment modalities that can either ameliorate or reverse lipid disturbances while allowing continued antiretroviral therapy are clearly required.

There are notably few randomized clinical trials in this patient group examining specific lipid lowering agents. An open-label study of atorvastatin and/or gemfibrozil by Henry et al., showed a 57% reduction in the gemfibrozil group and a study by Moyle et al. using pravastatin for hypercholesterolaemia showed a significant decrease in cholesterol but not triglycerides from baseline [7,8]. In switch studies where antiretroviral therapy is changed from a protease inhibitor-containing regimen to a non-protease inhibitor-containing regimen, the reductions in triglycerides are variable. Studies where protease inhibitors have been substituted with either efavirenz or nevirapine have demonstrated reductions in triglycerides of 31 and 57%, respectively [9,10]. A study by Carr et al. in which patients either continued their current protease inhibitor regimen or switched to a non-protease regimen demonstrated a significant reduction in triglycerides of 38% in the switch arm after 24 weeks off protease inhibitors [11]. Other studies using similar treatment approaches have, however, shown no effect on triglyceride levels [12,13]. No study has addressed changes in triglycerides as a primary endpoint within a randomized study with thorough evaluation of diet and other confounding variables.

Fibric acid derivatives (fibrates) such as gemfibrozil decrease triglyceride levels, probably through activation of the alpha-peroxisome proliferator-activated receptors and have been demonstrated to decrease cardiovascular events in some trials by between 28% (stroke), 40% (heart attacks) and 58% (transient ischaemic attacks) in patients with high triglycerides and low HDL cholesterol levels [14–20]. Gemfibrozil is generally well tolerated and has few potential drug interactions.

This study aimed to examine the triglyceride-lowering potential of gemfibrozil in the presence of a low cholesterol/low saturated fat diet in HIV-infected adults with elevated triglycerides receiving protease inhibitor therapy.

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Materials and methods

Participants

Thirty-eight adult males on stable (> 16 weeks) protease-inhibitor containing regimens with fasting triglycerides ≥ 3 mmol/l were enrolled through the HIV ambulatory care service of St. Vincent's Hospital, Sydney. Patients were excluded who had active AIDS-defining illnesses, were receiving lipid-lowering, hypoglycemic or anticoagulant drugs, had significant gastrointestinal disorders affecting absorption, or had had hepatitis or pancreatitis in the preceding 6 months.

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Study procedures

We conducted a 16-week, randomized, double-blind, parallel group study of gemfibrozil (600 mg/day) versus matching placebo. All patients underwent physical examinations and had fasting biochemical, lipid, glycaemic and haematological analyses measured plus an assessment of safety, dietary and medication adherence every 4 weeks. Lipodystrophy was diagnosed on clinical examination on the basis of peripheral lipoatrophy and/or central lipohypertrophy [6].

All venous blood sampling was done following a 12-h overnight fast. An oral glucose tolerance test, plasma HIV RNA and CD4 lymphocyte counts were performed at weeks 4 and 16.

Following screening for eligibility all patients received cholesterol and triglyceride lowering dietary advice from a dietitian at week 0. Three-day food diaries were completed at weeks 0, 4 and 16. Maintenance or achievement of ideal body weight and current exercise levels was recommended.

Following a 4-week run-in period with dietary instruction alone (week 0–4), participants were randomized 1 : 1 to gemfibrozil or matching placebo. The randomized treatment phase of the study continued for 12 weeks (weeks 4–16).

Patients who discontinued medication prematurely were followed according to the study schedule where possible. The study was reviewed and approved by the institutional Human Research Ethics Committee and all participants gave written, informed consent.

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Statistical analyses

The primary endpoint of this study was the mean difference between groups in changes in fasting serum triglycerides from week 4 to week 16.

A sample size of 36 subjects was chosen to have an 80% power to detect a 2.0 mmol/l difference in changes in triglycerides at week 16 from week 4 between the two groups.

All analyses of efficacy data were by intention-to-treat, including all available follow-up data on patients according to their initial randomized treatment regardless of treatment changes. Changes in metabolic parameters from baseline were summarized by randomized treatment. In summarizing changes from baseline by nominal study weeks, a last value carried forward approach was adopted. Formal statistical analyses compared the two randomized treatment groups in terms of changes from week 0 and week 4 to week 16, and were based on ANOVA methods or non-parametric equivalents as appropriate. Differences were declared statistically significant at P < 0.05 with no adjustments made for multiple comparisons.

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Results

Thirty-eight patients were recruited, one patient withdrew prior to randomization in order to enrol in another study that did not allow co-enrollment. Thirty-seven patients were randomized. One patient was lost to study after week 4 due to a motor vehicle accident in another state and one patient ceased randomized treatment at week 4 due to a transient ischaemic attack. All other randomized patients completed 12 weeks of randomized therapy and had complete follow-up. All 37 patients (17 gemfibrozil; 20 placebo) were included in efficacy analyses.

Baseline patient characteristics are summarized in Table 1. There was a baseline imbalance between the groups for triglycerides. This was driven largely by two patients in the gemfibrozil group who had triglyceride levels well above the group mean. All other lipid and glycaemic parameters were well matched.

Table 1

Table 1

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Efficacy

Table 2 summarizes the mean differences between groups in changes from baseline to week 16 and from week 4 to week 16. Patients in the gemfibrozil group had a 1.22 mmol/l reduction in triglycerides over 12 weeks of randomized therapy compared to a 0.35 mmol/l increase in the placebo group [95% confidence interval (CI), –3.37 to 0.23; P = 0.08] (Table 2). No significant effect was seen on the other study endpoints.

Table 2

Table 2

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Dietary intake

Patients randomized to gemfibrozil had significantly greater decreases in saturated fat intake (g/day) and total sugars than the placebo group (Table 2). No statistical differences in the percent of energy intake from saturated fats were seen between groups.

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Safety

Few adverse events were seen. Events in the gemfibrozil group were: mild indigestion (n = 1), transient nausea (n = 1), nephrolithiasis secondary to indinavir (n = 1) and motor vehicle accident (n = 1). In the placebo group recorded events were: transient ischaemic episode (n = 1), flu-like symptoms (n = 1), fever, headache and joint pain (n= 1) and infectious gastritis (n = 1). The patient with the transient ischaemic episode has a family history notable for cardiovascular disease; 4 weeks after commencing randomized study treatment he experienced a transient ischaemic episode lasting several hours. Following clinical investigation, the patient was commenced on gemfibrozil therapy by his neurologist. No laboratory grade 2, 3, or 4 events were seen and no patient required dose reduction. Medication adherence was > 85% for the duration of the study in both arms. No significant changes were observed in HIV RNA (−0.07, −0.06 log10 copies; 95% CI, −0.08 to 0.18; P = 0.46) or CD4 lymphocyte counts (−25, −21 × 106cells/l; 95% CI, –28 to −19; P = 0.76) in either the gemfibrozil or placebo groups, respectively.

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Discussion

Gemfibrozil in patients receiving protease inhibitors and with triglycerides > 3.0 mmol/l was safe, resulted in a modest (1.2 mmol/l) reduction in triglycerides and a non-significant increase in HDL cholesterol. These changes, however, appear less than those seen in non-HIV infected adults and for the most part did not result in optimization of lipid levels with only one patient having a return of triglyceride levels to < 2.0mmol/l which was the upper limit of normal for the laboratory used in this study [15]. Further, modest changes in both total and HDL cholesterol were seen in patients on the dietary intervention alone which is suggestive of a dietary effect. No significant effect on glycaemic parameters was seen. Patients in the gemfibrozil arm had greater reductions over 16 weeks in saturated and monosaturated fats, alcohol and sugar intake and total energy intake. As the study was not powered to discriminate between groups for dietary intake, these differences may reflect the relatively small patient numbers, evidenced by the wide confidence intervals for these variables.

The lower than expected reduction in triglycerides seen in this study therefore may be either a chance effect – which is unlikely given the consistency of the results across the group – or it may be that the drug is not addressing the cause of the hypertriglyceridaemia i.e., a direct effect of protease inhibitors, lipoatrophy, or insulin resistance. A less likely hypothesis is that HIV protease inhibitors may have an inhibitory effect on gemfibrozil's metabolism although there is no theoretical basis for this.

It would appear that gemfibrozil may not lower triglycerides optimally in this patient group, at least in the presence of protease inhibitor therapy, to be of sustained clinical benefit. However, given the independent associations between increased plasma triglycerides and coronary heart disease in non-HIV studies, long-term benefits may possibly be accrued by even modest reductions in triglycerides, particularly in those patients with other significant risk factors.

The mean percentage reduction in triglycerides in gemfibrozil treated patients in this study was 18%. This contrasts starkly with studies in HIV negative patients in whom reductions of up to 55% are obtained using fibric acid derivatives [21]. Of course direct comparisons between the two patient groups are not appropriate because of the confounding effects of HIV and antiretroviral therapy on lipid profiles.

One approach to optimizing therapeutic strategies for this patient group may be combination lipid lowering therapy although its safety and efficacy require thorough evaluation. The efficacy data (albeit limited) established from this study and the favourable safety profile would suggest that gemfibrozil may be a suitable candidate for further studies involving either higher doses or as a component of combination drug therapy for hyperlipidaemia. Combination therapy with a compound from the statin class of drugs such as pravastatin which has minimal interaction with the CYP3 system is worthy of further investigation. It is clear that adding another group of drugs into antiretroviral regimens that are frequently complex and onerous may have a deleterious impact on medication adherence and it is imperative that further work into non-drug approaches such as exercise also be considered.

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Keywords:

hypertriglyceridemia; gemfibrozil; HIV; antiretroviral

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