¹Physical Activity Sciences Laboratory, Division of Kinesiology, Department of Social and Preventive Medicine, Faculty of Medicine, Laval University, Québec, Canada

²Lipid Research Center, Laval University Medical Center, Québec, Canada

Correspondence to: D Prud'homme, School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, 125 University St. (224) CP 450 Suce A Ottawa, Ontario, KIN 6N5, Canada. E-mail: denisp@uottawa.ca

OBJECTIVE: The aim of the present study was to investigate the effects of a 6 month gemfibrozil treatment.

SUBJECTS: A sample of 64 visceral obese men (age 46±6 y; body mass index 31±3 kg/m²; waist circumference 104±7 cm; mean±s.d.) who received dietary recommendations.

METHODS: Subjects were randomly assigned to receive a placebo (n=32) or gemfibrozil (1200 mg/day) (n=32).

RESULTS: In both placebo and gemfibrozil treated groups, significant reductions were noted in body weight, fat mass, waist circumference and visceral adipose tissue area measured by computed tomography (0.0001<P<0.05). Plasma cholesterol (CHOL) and apolipoprotein B (apo B) levels were also decreased in both groups (P<0.01) whereas plasma high density lipoprotein (HDL) and HDL-3-CHOL levels were only significantly (P<0.01) increased in the gemfibrozil-treated group. After the 6 month treatment period, gemfibrozil-treated men displayed significantly lower plasma triglycerides (TG) levels, compared to those who received the placebo (P<0.01). Finally, both fasting plasma insulin concentration and insulin area measured during an oral glucose load were significantly decreased only in the placebo group (P<0.05). Taken together, these results suggest that the improvement in plasma lipid/lipoprotein profile observed in gemfibrozil treated visceral obese men seems to be independent from changes in adipose tissue mass and in visceral fat accumulation. Furthermore, improvements in the plasma lipoprotein profile produced by gemfibrozil therapy appear to be independent from changes in indices of plasma glucose-insulin homeostasis.

International Journal of Obesity (2001) 25, 1136-1143

visceral obesity; insulin sensitivity; lipids; gemfibrozil

Introduction

The measurement of plasma lipoprotein levels is a commonly used procedure to assess the risk of developing cardiovascular disease (CVD).^1,2 Although high plasma low-density lipoprotein-cholesterol (LDL-CHOL) and low high-density lipoprotein (HDL-CHOL) concentrations are independently associated with an increased CVD risk,³ the contribution of plasma triglycerides (TG) to coronary heart disease remains controversial. However, the lack of an unequivocal relationship between plasma TG levels and CVD could be partially attributed to the metabolic heterogeneity underlying hypertriglyceridemia. Indeed, there is more and more evidence indicating that a large subgroup of hypertriglyceridemic patients are abdominally obese and insulin resistant. In this regard, we have shown that abdominal obesity and hypertriglyceridemia are predictive of the presence of the atherogenic metabolic triad (hyperinsulinemia, elevated apo B and small, dense LDL) which is associated with a substantially increased risk of CVD.⁴

Abdominal obesity, especially in the presence of high levels of visceral adipose tissue, is considered as a major factor associated with insulin resistance^5,6,7,8 and related dyslipoproteinemias. Several groups,^{9,10,11,12,13} including ours,^14,15,16 have shown that visceral adipose tissue measured by computed tomography is a significant correlate of glucose intolerance, insulin resistance, and dyslipoproteinemic profile, in both genders. Furthermore, it has been suggested that the abnormal plasma lipoprotein changes observed in visceral obesity could be largely attributed to impaired insulin action.^17,18

Fibrates such as gemfibrozil are pharmacological agents which have been shown to reduce plasma TG levels and to increase HDL-CHOL concentrations, presumably by improving the catabolism of triglyceride-rich lipoproteins.¹⁹ These favorable metabolic changes are considered as important factors in the decrease of the incidence of CVD events that were reported first in the Helsinki Heart Study.²⁰ The Department of Veterans Affairs HDL Intervention Trial showed for the first time that lipid treatment, which had no effect on LDL-CHOL levels but produce favorable metabolic changes previously described, could substantially reduce major cardiac events.²¹ Furthermore, their data suggests that fibrates may be a particularly effective treatment for the dyslipidemia of the metabolic syndrome. However, we still don't know if gemfibrozil acts on all or only some of the risk factors of the metabolic syndrome to decrease major cardiac events. It is still unknown whether insulin sensitivity can be improved after gemfibrozil treatment. Indeed, to the best of our knowledge, only a few studies which were conducted on a limited number of subjects have reported some controversial findings related to this issue.^22,23

Therefore, it appears relevant to hypothesize that gemfibrozil may represent a valuable therapeutic approach for the management of metabolic alterations associated with an excess of visceral adipose tissue, especially when combined with dietary recommendations. Therefore, the objective of the present study was to investigate the effects of a 6 month gemfibrozil treatment (1200 mg/day) combined with dietary recommendations on both anthropometric and metabolic risk variables in a sample of 64 dyslipidemic visceral obese men.

Subjects and methods

Subjects

Sixty-four, viscerally obese men, aged 46±6 y (mean±s.d.) were recruited by solicitation through the media and volunteered to participate in this study. They gave their written consent, which had received the approval of the Medical Ethics Committee of Laval University. At the beginning of the study, a complete physical examination was performed by a physician, and men with history or evidence of cardiovascular disease, diabetes, endocrine disorders or who were taking any type of medication that could affect experimentation were excluded. After medical examination and baseline evaluation, men were randomly assigned to receive dietary recommendations and a placebo (n=32) or dietary recommendations and gemfibrozil (1200 mg/day; n=32). Drug safety was assessed every 4 weeks by the physician in charge of the project. Subjects met on an individual basis the study dietician at the beginning of the protocol and then upon the participant's demand. The dietary recommendations were based on the National Cholesterol Education Program step 1 dietary guidelines²⁴ with emphasis on lipid guideline and portions.

Anthropometry and body composition

Body weight and waist circumference were measured following the procedures recommended at the Airlie Conference.²⁵ The measurement of waist circumference was performed at the narrowest part of the torso while the subject was standing. Body density was measured by the hydrostatic weighing technique and percentage body fat was derived from body density using the equation of Siri.²⁶ Fat mass was determined by multiplying body weight by percentage body fat. Pulmonary residual volume was assessed with the helium dilution technique of Meneely and Kaltreider.²⁷ Regional adipose tissue (AT) distribution was assessed by measuring the abdominal AT area by computed tomography (CT) on a Siemens Somatom DRH scanner (Erlangen, Germany), using the procedure of Sjöström et al.²⁸ Briefly, subjects were examined in the supine position with both arms stretched above their head. CT scans were performed at the abdominal level (between L4 and L5 vertebrae), using a radiograph of the skeleton as a reference to establish the position of the scans to the nearest millimeter as previously described.²⁹ Total AT areas were calculated by delineating these areas with a graph pen and then computing the AT surfaces with an attenuation range of -190 to -30 Hounsfield units (HU). Abdominal visceral AT area was measured by drawing a line within the muscle wall surrounding the abdominal cavity. The abdominal subcutaneous AT area was calculated by subtracting the visceral AT area from the total abdominal AT area.

Oral glucose tolerance test

An oral glucose tolerance test (OGTT; 75 g glucose) was performed in the morning after a 12 h overnight fast. Blood samples were collected under EDTA and Trasylol (Miles, Rexdale, Ontario, Canada) through a venous catheter from an antecubital vein at -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 min for the determination of plasma glucose and insulin concentrations. Plasma glucose level was measured enzymically,³⁰ whereas plasma insulin and proinsulin levels were measured with specific commercial double-antibody radioimmunoassays (LINCO Research, St Louis, MO, USA). Plasma free fatty acids (FFA) were determined with a colorimetric method.³¹ The glucose, insulin and FFA areas under the curve assessed during the OGTT were determined with the trapezoid method.

Plasma lipids and lipoproteins

Blood samples were obtained in the morning after a 12 h fast from an antecubital vein. CHOL and TG levels in plasma and lipoprotein fractions, were measured enzymically on a RA-1000 automated analyzer (Technicon Instruments Corporation, Tarrytown, NY, USA). After an ultracentrifugation, the plasma HDL fraction was obtained after precipitation of LDL in the infranatant (d>1.006 g/ml) with heparin and MnCl₂.³² Plasma LDL-apolipoprotein (apo) B levels were measured by the rocket immunoelectrophoretic method of Laurell, as previously described.³³

Plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities

Blood was drawn from subjects who had fasted 12 h at 10 min after an intra-veinous injection of heparin (60 Ul/kg). Assays for enzyme activity were performed by a modification of the method of Nilsson-Ehle and Ekman,³⁴ as previously described.³⁵

Briefly, plasma LPL and HTGL activities were measured by using glycerol-tri[¹⁴C]-oleate as substrate in an artificial emulsion prepared in 0.2 M Tris-HCl buffer (pH 8.0). Aliquots in duplicate (0.2 ml) of the enzyme extract were incubated at 30°C for 20 min in the presence and absence of 3% protamin. Free fatty acids released during incubation were selectively extracted and aliquots were counted for ¹⁴C in aquasol (New England Nuclear, Lachine, Québec). LPL activity was calculated as the lipase activity sensitive to 3% protamin from the total lipase activity (without protamin).

Euglycemic insulin clamp

Basal and insulin stimulated glucose kinetics were measured by the euglycemic insulin clamp technique according to the original method described by DeFronzo et al.³⁶ All subjects were tested after a 12-h overnight fast. An intra-veinous (i.v.) catheter was placed in the right antecubital vein for a continuous infusion of regular insulin (Humulin-R, Lilly Co., Indianapolis, IN), at a rate of 40 mU/m² min, from time 0 to 120 min. Blood samples were taken prior to the test and during the 2 h of the infusion from an i.v. catheter placed in the left antecubital vein. Blood glucose was monitored every 5 min during the insulin infusion, and euglycemia was maintained throughout the clamp by infusing intravenously a 20% dextrose solution at a variable rate. The total M value was calculated from the mean glucose infusion rates of the five 10 min periods from 60 to 120 min of the euglycemic insulin clamp. All values were computed in dimensions of mg/(kg fat-free mass min). The M/I was calculated using the M value divided by the plasma insulin concentration at this time period.

Statistical analyses

Comparisons between groups, before and after treatment, were performed by an analysis of variance using the ANOVA. Intra-group changes for morphologic and metabolic variables were assessed, using a Student paired t-test, whereas changes between groups were evaluated with an unpaired t-test. All procedures were performed using StatView statistical software programs adapted for Macintosh.

Results

Physical characteristics of our sample of men studied before and after the treatment period are shown in Table 1. There was no difference in anthropometric and regional fat distribution variables between the placebo and the treatment group at the beginning of the study. As expected, the program induced a slight reduction in body weight, BMI, waist circumference and fat mass (P<0.01). Significant decreases in total, visceral and subcutaneous abdominal adipose tissue areas determined by computed tomography were also observed in both groups (P£0.01). Fat-free mass was slightly but significantly reduced in the treated group (P<0.001), exclusively.

As illustrated in Figure 1, the insulin/glucose profile assessed by OGTT did not change in the gemfibrozil treated group. Although both fasting plasma insulin levels and responses to an oral glucose load decreased significantly in the placebo group (P£0.01), no differences were observed in the glucose response profiles, in placebo and treated subjects. However, a decrease in plasma FFA concentrations was observed at 120 min in this group (P=0.05). Moreover, the fasting proinsulin levels were similar in both groups (data not shown). Two subgroups of subjects (treated, n=8; placebo, n=8) performed an euglycemic insulin clamp (Figure 2). In the placebo group, the glucose infusion rate was increased significantly (P<0.05) after the 6 month intervention period. On the other hand, glucose metabolism did not change in the gemfibrozil group. The amount of glucose metabolized (M value) assessed after the 6 month period was significantly different in the placebo, compared to the treated group (P<0.05). However, when the quantity of glucose metabolized was expressed per unit of plasma insulin concentration, a slight but not significant (P=0.07) increase was observed in the placebo group only (Table 2). In addition, FFA areas determined during OGTT did not significantly differ in both the placebo and gemfibrozil-treated groups (data not shown), a result which could be easily predicted from the dose-response curves presented in Figure 1.

On the other hand, plasma CHOL and Apo B levels were decreased in both groups at the end of the intervention period (P<0.01). However, plasma HDL and HDL-3 CHOL levels were increased only in the gemfibrozil treated group (P<0.01). Although this group shows a decrease in the CHOL/HDL-CHOL ratio, the placebo group displays an increase in the HDL-2/HDL-3 CHOL ratio. After the 6 month treatment-period, gemfibrozil-treated men were characterized by lower plasma TG levels, compared to those who received the placebo (P<0.01). However, we did not find any difference in LPL or HTGL activities between the two groups (Table 3).

Discussion

It is well established that gemfibrozil is an effective pharmacological agent to lower serum TG levels in patients with mild hypertriglyceridemia.^20,21 The aim of the present study was therefore to investigate the effects of a gemfibrozil treatment (1200 mg/day) combined with dietary recommendations on both anthropometric and metabolic risk variables in dyslipidemic viscerally obese men.

As expected, plasma TG levels were decreased in viscerally obese men under gemfibrozil treatment. Subjects displaying the greater initial TG levels were also those who had the higher decrease in TG concentrations after 6 months of treatment. The main effect was observed in men showing TG levels clustering at approximately 2.4 mmol/l or more, at the beginning of the study. In this regard, the mean decrease was approximatively 45%, compared to basal values. However, as we did not study men with severe hypertriglyceridemia, we can't speculate on the effect of gemfibrozil on this metabolic disorder. Our results are, however, consistent with previous observations reported by Shepherd,³⁷ who suggested an important role of fibrates in the management of the high TG-low HDL-C dyslipidemia.

Despite this decrease of 45% in plasma TG levels, we did not observe any improvement in the subjects' glucose response profile assessed by either an OGTT or an euglycemic insulin clamp, in gemfibrozil-treated subjects. However, an improved insulin sensitivity was found among men who received a placebo, although both groups showed similar changes in adiposity and regional fat distribution. To verify these results, we tried to estimate the insulin sensitivity/resistance of fasting insulin and glucose concentrations using the Homeostasis Model Assessment (HOMA).³⁸ The HOMA scores are known to agree with estimates of insulin sensitivity obtained by the euglycemic clamp. Our data suggested a tendency that corroborates with our clamp results. Indeed, the placebo group tends to increase its insulin sensitivity (P=0.09), unlike the gemfibrozil group. These results suggest that insulin resistance may be improved without major variation in neither plasma TG levels nor in body fatness and AT distribution.

On the other hand, Steiner²² has already reported an improved insulin sensitivity determined by OGTT in non-diabetic subjects treated with gemfibrozil. However, this improvement was only observed in subjects whose serum TG levels decreased more than a threshold value of 1.7 mmol/l. Our data do not thus exclude the possibility that correction of a severe hypertriglyceridemia may improve insulin sensitivity. At this time, it should be pointed out that our subjects who were classified as viscerally obese men were characterized by a slight deterioration of their lipid profile. This could explain our data, compared to results from other studies.

It is also well known that insulin resistance is closely associated with hypertriglyceridemia, but the mechanisms underlying this complex relationship are still not fully understood.^{39,40,41,42,43} Previous studies have shown that gemfibrozil decreases hepatic synthesis and secretion of TG-enriched lipoproteins and enhances their degradation by increasing LPL activity.^44,45 This observation could not be reproduced in the present sample of visceral obese men. Indeed, epidemiological data have suggested that insulin resistance precedes the development of hypertriglyceridemia.⁴⁶ However, the decrease in plasma TG levels that we observed in response to both gemfibrozil and dietary recommendations did not appear to be related to an increase in insulin sensitivity. It should be thus hypothesized that gemfibrozil decreases plasma TG levels through an unknown mechanism which excludes a regression of the insulin resistance syndrome or an improvement of insulin sensitivity. Concerning this issue, it has been put forward that Apo CIII should decrease TG catabolism by inhibiting lipoprotein lipase activity.⁴⁷ Thus, we can suppose that gemfibrozil can act on Apo CIII to lower its effect. Since, Apo CIII values are not available, we can't verify this hypothesis. It has already been reported that gemfibrozil may have an antilipolytic properties.⁴⁸ The resulting elevation in FFA levels has been thus proposed to be the consequence of a resistance to the antilipolytic action of insulin.⁴⁹ However, in the present study, gemfibrozil therapy did not substantially modify plasma FFA concentrations. Our data do not seem to hold up to the idea that gemfibrozil may lower TG levels via an antilipolytic effect. In our study, only plasma FFA concentrations were measured and we believe that further studies, including more precise methods of measurement, are necessary to resolve this question.

Finally, an increase in HDL-CHOL concentration was also found in the gemfibrozil treated group, a finding which has already been observed by others.^19,20,50 Since HTGL plays a role either in the catabolism of HDL₂^51,52 or in the conversion of HDL₂ to HDL₃⁵³ and that LPL activity is associated with plasma HDL level,^54,55 we needed to verify whether the increase of HDL₃ and of HDL-CHOL levels noted in the gemfibrozil-treated group was related to the HTGL or LPL activity. Since there was no change in either HTGL or LPL activity during the study, changes in HDL-CHOL concentration or their sub-fractions do not seem to be dependent upon these lipase activities. This may be due to the fact that the effect of gemfibrozil on LPL is partly mediated by its effect on adipose tissue.

In conclusion, gemfibrozil effectively reduces plasma TG levels in moderate hypertriglyceridemic viscerally obese men. However, it is devoid of effect on FFA metabolism. Furthermore, the improvements in the plasma lipiprotein profile observed in response to gemfibrozil treatment do not appear to involve changes in in vivo indices of insulin action.

Acknowledgements

The authors wish to express their gratitude to Dr André Nadeau, Linda Drolet, Lucie Allard, Suzanne Brulotte and Line Bargone for their excellent collaboration at various stages of the study. The subjects and the Physical Activity Sciences Laboratory staff are also gratefully acknowledged. Supported by Parke Davis. M Dumont is a fellow of the 'Formation de chercheurs et l'aide à la recherche et fonds de recherche en santé du Québec' (FRSQ-FCAR-SANTÉ).

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Figure 1 Effects of a 6 month-gemfibrozil treatment (n=32) or placebo (n=32) on plasma glucose (top panels), insulin (middle panels) and FFA (bottom panels) levels during an oral glucose tolerance test. Statistically different from baseline at P<0.05.

Figure 2 Effects of a 6 month-gemfibrozil treatment (n=8) or placebo (n=8) on steady-state plasma glucose concentrations, glucose infusion rates and plasma insulin responses during an euglycemic insulin clamp. Statistically different from baseline at P<0.05. Dark symbols stand for before treatment values and open symbols for after treatment values.

Table 1 Physical characteristics of men, before and after a 6 month-gemfibrozil or placebo treatment

Table 2 Plasma glucose and insulin levels of men measured by an euglycemic clamp, before and after gemfibrozil treatment or placebo

Table 3 Plasma lipid and lipoprotein concentrations of men, before and after gemfibrozil treatment or placebo