Elsevier

Atherosclerosis

Volume 129, Issue 2, 21 March 1997, Pages 231-239
Atherosclerosis

A comparative study of the efficacy of simvastatin and gemfibrozil in combined hyperlipoproteinemia: prediction of response by baseline lipids, apo E genotype, lipoprotein(a) and insulin

https://doi.org/10.1016/S0021-9150(96)06031-5Get rights and content

Abstract

Combined hyperlipoproteinemia (CHL) can be difficult to treat because of the heterogeneous nature of the lipoprotein abnormalities. We compared the relative efficacies of simvastatin and gemfibrozil and sought predictors of responsiveness in terms of the baseline lipids and other potential metabolic determinants (plasma insulin, Lp(a) and apo E genotype). Sixty-six subjects entered a cross-over, randomized trial involving 12 weeks on each drug. Efficacy was assessed after 6 and 12 weeks on each treatment. Simvastatin lowered total cholesterol 24%, triglycerides 12%, LDL cholesterol 33%, raised HDL cholesterol 13% and substantially reduced the cholesterol:triglyceride ratio in VLDL and IDL. Gemfibrozil lowered total cholesterol 5%, triglycerides 44%, raised HDL 26% and reduced VLDL and IDL lipids more than simvastatin did. LDL size increased with both treatments and HDL size increased with simvastatin. Responsiveness (25% fall in cholesterol or 40% fall in triglycerides) was shown by 31/61 subjects when taking simvastatin (cholesterol-lowering) and by 44/60 taking gemfibrozil (triglyceride-lowering). Responsiveness was greatest in those with apo E2 genotype with both drugs (P<0.05). Unexpectedly, responders to simvastatin tended to have lower baseline total cholesterol but higher triglyceride levels than those whose cholesterol or triglyceride was lowered by gemfibrozil. Nevertheless, more hypercholesterolemic subjects responded to simvastatin and more hypertriglyceridemic subjects to gemfibrozil. Lp(a) (P=0.04) and plasma insulin concentrations (P=0.03) were negative predictors of percentage triglyceride-lowering with gemfibrozil. The difference between the two drugs in triglyceride-lowering lessened with rising insulin and falling HDL cholesterol. Thus, the responsiveness to the two major classes of lipid lowering drugs can be partly predicted from baseline lipids and related metabolic parameters.

Introduction

Combined hyperlipoproteinemia (CHL) is a heterogeneous lipid disorder which can be difficult to treat. Its familial expression is more common in our population than familial hypercholesterolemia (approximately 1 in 200) [1]. Excess dietary energy, saturated fat and alcohol frequently induce this lipoprotein phenotype, presumably on the basis of multiple minor abnormalities in lipoprotein regulation [2]. It occurs commonly in disorders that interfere with lipoprotein metabolism such as overweight, diabetes and the metabolic syndrome (insulin resistance) [3].

The need to treat stems from a strong association with coronary heart disease (CHD) [4]. CHL may be the most common abnormal lipoprotein phenotype in close relatives of men with premature CHD [4]. In Australia, its prevalence, albeit based on arbitrary cut-off points of cholesterol 6.5 mmol/l and triglyceride 2 mmol/l, was found in 1989 to be 6.3% for men and 4.1% for women [5].

Both cholesterol and triglyceride concentrations are raised while that of high density lipoprotein (HDL) cholesterol is usually low. More detailed analysis often shows abnormalities in the distribution of low density lipoprotein (LDL) subclasses, with smaller and potentially more atherogenic particles predominating [6]. The very low density lipoprotein (VLDL) species that transport most triglyceride may be enriched in cholesterol, indicating accumulation of VLDL remnants which may also be more atherogenic than normal VLDL [7]. The HDL particles may be smaller, tending to HDL3. Although these subspecies of the major lipoproteins are not routinely analysed, they may shed light on the predominant expression of the disorder, i.e. whether it reflects excess LDL (hypercholesterolemia) or excess VLDL (hypertriglyceridemia). This information may also provide clearer guidelines for initial selection of drug therapy.

The two classes of lipid-lowering drugs which are commonly used in CHL are HMGCoA reductase inhibitors and fibrates. In 1994 we undertook a cross-over study using two drugs, simvastatin and gemfibrozil, with the following objectives:

  • 1.

    to compare the relative efficacies of simvastatin and gemfibrozil in optimizing lipid and lipoprotein levels,

  • 2.

    to define the lipid and lipoprotein predictors of response to simvastatin and gemfibrozil, and

  • 3.

    to examine the predictive value of other metabolic parameters which are often disturbed in CHL.

Section snippets

Experimental design

This study was an open, multicentre, randomized, cross-over, comparative study of the efficacy of simvastatin versus gemfibrozil in combined hyperlipoproteinemia. Combined hyperlipoproteinemia was judged present on the basis of at least two pre-treatment lipid measurements, taken while patients were on a fat-restricted diet, in which calculated LDL cholesterol exceeded 4.5 mmol/l and plasma triglycerides were in the range 2.5–6.0 mmol/l (in the final recruitment several subjects did fall

Results

Seven patients discontinued during the study: one during treatment with simvastatin and six during treatment with gemfibrozil. Three had clinical adverse effects: gastrointestinal discomfort from gemfibrozil, leading to withdrawal. The remainder withdrew for reasons not related to the trial.

The changes from baseline in all lipid parameters for the subjects who remained in the study are shown in Fig. 1Fig. 2. These figures provide the percentage changes for all variables (Fig. 1) and an estimate

Discussion

The initial aim of the study was to compare the efficacy of the two commonly used drugs, simvastatin and gemfibrozil, in the treatment of combined hyperlipoproteinemia. It is not clear which drug might be used initially and this study attempted to provide some guidelines. Caution is advised in regard to combination therapy, although adverse effects on muscle function have not been reported to exceed substantially those from each drug used alone; a major review [14]reported only a small excess

Acknowledgements

This study was partly supported by a grant from Merck Sharp and Dohme (Australia) and we thank Ms Stella Axiak who coordinated the participating centres. Mr J Menten kindly carried out the statistical analyses, Professor D Thomas of the Institute of Medical and Veterinary Science, Adelaide performed apo E genotyping, and Amanda Patrick helped with the preparation of the manuscript.

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