Early and late effects of weight loss on lipoprotein metabolism in severe obesity

Atherosclerosis, 64 (1987) 125-130 Elsevier Scientific Publishers Ireland.

125 Ltd

ATH 03886

Early and late effects of weight loss on lipoprotein metabolism in severe obesity Stephan Riissner and Hjiirdis Bjiirvell Department

of Medicine, Karolinsku

Hospital and King

GurtufV Reseurch Institute, Stockholm

(Sweden)

(Received 29 April, 1986) (Revised, received 10 September, 1986) (Accepted 12 September, 1986)

Summary

In a group of grossly obese patients serum lipoproteins and the intravenous fat tolerance test were analysed before a weight reduction program (n = 98), after 6 weeks (n = 58) and 1 year (n = 15). At one year follow-up the mean weight had fallen from 120 to 105 to 100 kg, respectively. In spite of severe overweight, only a moderate hypertriglyceridaemia (males mean fasting concentration of plasma triglycerides (TG) 2.50 k 1.36, females 2.03 f 1.94 mmol/l) was found before treatment After 6 weeks significant reductions were found in VLDL-TG, -cholesterol, LDL-cholesterol and HDL-cholesterol (P < 0.05 at least). After one year VLDL-TG was still below pretreatment level, LDL-cholesterol had increased above pretreatment level, whereas HDL-cholesterol was significantly higher compared to pretreatment (P < 0.05). Some previous studies suggest that weight loss may lead to HDL-cholesterol reductions, which would be undesirable. The present study indicates that after sustained weight loss and at a stable lower body weight, HDL-cholesterol levels may increase above pretreatment levels after an initial drop during the catabolic weight reduction phase.

Key words: HDL-cholesterol; LDL-cholesterol; Intravenous fat tolerance test; Lipid metabolism; Obesity; Triglycerides; VLDL-cholesterol; VLDL-triglycerides

Introduction

Obesity is an independent risk factor for atherosclerotic manifestations and is associated with several metabolic alterations which accelerate the development of atherosclerosis [l]. The serum This study was supported by the Konung Gustaf V 80-year Foundation and the Swedish Medical Research Council B8619M-7457-OlA and 19X-204.

0021-9150/87/%03.50

0 1987 Elsevier Scientific

Publishers

Ireland,

lipoprotein abnormalities, found in obesity, constitute such a risk. Increased levels of serum triglycerides (TG) have generally been reported, caused by increased TG concentrations in the very low density lipoprotein fraction (VLDL) [2]. Concomitant reductions of cholesterol in high density lipoproteins (HDL) have also been found [2]. Weight reduction seems to affect lipoproteins in a way that is generally considered beneficial. TG levels fall rapidly. On the other hand the Ltd.

,126

effect of weight loss on HDL levels has been more variable. Both significant reductions as well as increases of HDL-cholesterol have been reported [3]. To some extent these different results can be explained by the fact that the studies have been varying in design. The degree of overweight, the phase of weight change (gain, maintenance or loss), the sex composition of the patient groups, the diet recommendations and the duration of the follow-up are examples of factors which might well explain discrepant results. At the Obesity Unit of the Karolinska Hospital a program has been developed for grossly obese subjects, which integrates behavioural modification and dietary advice [4]. In these subjects exercise has played a small role in the treatment program. The emphasis of the program has been on long-term treatment. As part of the evaluation of this program the effects of weight loss on lipoprotein metabolism were analysed after 6 weeks and after 1 year of therapy. Patients and Methods

Patients All patients had been screened and accepted for the so-called “Medicine 5” program [4]. In summary the patients were grossly overweight with severe somatic and/or psychiatric complications. They were admitted to a day care unit for an initial treatment period of 6 weeks. During this period they were given a 600 kcal diet (fat 24 energy%, protein 40% and carbohydrates 368, P/S ratio about 0.5). They were assisted in preparing their own meals by a dietitian. Behaviour modification treatment was given in repeated sessions and light exercise programs supervised by a pysiotherapist were included. Alcohol was prohibited, but smoking habits were not addressed. After 6 weeks the patients left the ward and were given the opportunity to come back to weekly weigh-in sessions including further behavioural modification training. At this time the recommended daily energy intake was increased to about 1000-1200 kcal/day. This weight maintenance program continued for several years. Physical activity was encouraged but in practice these patients carried out but little exercise. Baseline values for serum lipoproteins and the

intravenous fat tolerance were analysed in 98 patients entering the ‘Medicine 5’program. After the initial 6 weeks treatment when the patients were still in a catabolic state 58 patients were reexamined. A subsample of 18 female patients was studied after 12 weeks. The main follow-up was performed in 12 females and 3 males after about 1 year (52 + weeks). At this last follow-up patients were at a stable body weight. The mean (&SD) age of the 72 females was 47 * 11 years and of the 26 males 46 + 13 years at entry. The corresponding figures for height and weight were 166 + 6 cm and 110.8 k 18.1 kg in females and 179 k 8 cm and 136.8 * 27.5 kg in males. The body mass indices (BMI) at entry were 40.2 k 6.5 kg/m2 for females and 42.2 &-7.1 kg/m2 for males. The protocol was approved by the Ethical Committee of the Karolinska Hospital. Methods On admission before any dietary changes had been instituted several pretreatment laboratory tests were performed including an intravenous fat tolerance, serum lipoproteins and free fatty acids (FFA). Venous blood was sampled after an overnight fast for 12 h and lipoproteins analysed by an ultracentrifugal technique as described by [5]. After centrifugation at d = 1.006 kg/l, heparin-manganese was added to the infranatant, precipitating the apo-B containing low density lipoprotein (LDL) fraction. TG and cholesterol concentrations were determined by the Ultrolab system in the top (VLDL), the bottom fraction before (LDL + HDL) and after (HDL) precipitation [6,7]. TG and cholesterol concentrations in LDL were determined by subtraction. FFA were determined as described by [8]. Hyperlipoproteinaemias were classified according to [9]. Type IIB was defined as VLDL-TG > 1.25 mmol/l + LDL-cholesterol > 5.7 mmol/l. Type IV was defined as VLDL-TG > 1.25 mmol/l. The IVFTT was performed as described before [lo]. After a blank sample had been drawn, 1 ml/kg body weight of a 10% Intralipid emulsion was given as a pulse injection and venous blood was then drawn repeatedly during the ensuing 40 min. Light scattering of plasma was determined

127 by nephelometry and the slope of the Intralipid elimination curve was calculated by the method of least squares. Statistical methods

Data were processed on a Norsk data computer program, using conventional statistical methods. Relationships were analysed by linear regression, in some cases after logarithmic transformation of data. Student’s t-test or, when appropriate, Wilcoxon rank sum test were used to test statistical differences. Results Base line values

Mean serum lipoprotein lipid concentrations are shown in Table 1 for all patients. Before weight reduction elevated serum TG concentrations were found, whereas serum cholesterol was in the normal range. HDL-cholesterol was in the low range for both series. When the lipoprotein patterns were typed according to the Fredrickson classification, 2 patients were found to have a Type IIB pattern and 27 patients to have a Type IV pattern. Short-term effects

After 6 weeks significant reductions were found in VLDL-TG and -cholesterol, in LDL-cholesterol

and in HDL-cholesterol (P < 0.05 compared to pretreatment levels). After 12 weeks HDL-cholesterol was back in pretreatment range and after one year VLDL-TG and -cholesterol were still low but LDL- and HDL-cholesterol above pretreatment levels. The IVFTT k,-value increased significantly after the initial 6 weeks treatment period (P < 0.01). Long-term effects

In 15 patients complete analyses were available before therapy, after 6 and 52 + weeks. Paired comparisons performed in this group are shown for some lipids in Fig. 1. In this subgroup (including 3 males) the mean body weight before therapy was 119.6 f 24.0 kg. The corresponding weights after 6 and 52 weeks were 104.9 + 21.7 kg and 99.6 f 6.1 kg, respectively (P -C0.001 compared to pretreatment weight for both). In this group weight and lipoprotein changes were similar in both sexes and data were pooled. In this subgroup lipoprotein lipid concentrations were in principle similar to data in Table 1. After 6 weeks of therapy significant reductions (P at least < 0.05) were observed for VLDL-TG, VLDL-cholesterol (not shown in the figure), LDL-cholesterol and HDLcholesterol. At late follow-up the pattern was changed. Although VLDL-TG and cholesterol concentrations were still below entry values, the concentrations of LDL-cholesterol and HDL-

TABLE 1 SERUM LIPOPROTEINS

(mmol/l),

IVFTT k,-VALUES

AND FFA CONCENTRATIONS

The effects of a short-term weight reduction program are also shown ( X *SD). n

Femules Before

72

6 weeks

46

12 weeks

18

Mules Before 6 weeks

26 12

Weight

VLDL

(kg)

TG

LDL

IN GROSS OBESITY

Statistically significant differences. see text.

HDL

Total

Chol

TG

Chol

TG

Chol

TG

Chol

110.8 rfr18.1 102.0 f 18.2 88.1 * 13.0

1.36 i 1.74 0.78 +0.60 0.77 k 0.65

0.65 i 0.60 0.47 +0.34 0.43

0.42 &0.13 0.42 kO.13 0.37

4.14 + 1.05 3.73 +1.18 3.52

0.16 * 0.07 0.14 k 0.06 0.16

1.29 +0.31 1.13 k 0.26 1.30

2.03 i_ 1.94 1.33 +0.66 1.32

6.12 * 1.19 5.42 + 1.34 5.21

& 0.31

+0.14

10.86

i 0.07

* 0.25

i_ 0.76

* 0.78

137.8 + 27.5 119.3 * 21.9

1.73 + 1.19 1.05 i_ 0.57

0.82 f 0.47 0.57 & 0.27

0.50 *0.18 0.41 *0.16

4.24 + 0.84 3.49 _t 0.72

0.16 k 0.06 0.13 i 0.05

1.09 +0.27 1.04 kO.31

2.50 + 1.36 1.61 & 0.71

6.23 k1.17 5.20 kO.85

k, (%/min)

FFA (ymol/l)

4.0 * 1.7 5.4 + 1.7 -

855 2330 1104 5134 _

3.1 * 1.2 3.7 kO.8

891 +263 1100 * 446

128 Weight

w-

loss and

lipoproteins

TABLE

INTERCORRELATIONS BETWEEN SERUM LIPOPROTEIN LIPIDS AND THE IVFTT k,-VALUE BEFORE AND AFTER A 6 WEEKS WEIGHT REDUCTION PROGRAM

;k***

l

log VLDL-TG -log HDL-chol log VLDL TG -log HDL-chol

Ommol/l LDLcholesterol i:

w*

2lO-

4

6

120 kg

105 kg

Week

n

I

P

0

82

- 0.48

< 0.001

6

49

-0.52

< 0.001

log kz -log

VLDL-TG

0

56

-0.75

< 0.001

log kz -log

VLDL-TG

6

28

- 0.61

i 0.001

0 6

56 28

0.48 0.47

< 0.001 < 0.05

k2 - HDL-chol k2 - HDL-chol

mmol/l

Weight

2

Discussion

52+ weeks

100 kg

Fig. 1. Serum lipoprotein lipid concentrations in 15 obese patients before and after weight loss. Mean + SEM are shown. Significant differences are shown as * P < 0.05, (** = P c 0.01) and *** = P -c 0.001 for the O-52 + weeks comparison and 0 = P i 0.05 for the 6-52 + weeks comparison.

cholesterol had risen above pretreatment levels. LDL- and HDL-TG concentrations did not change significantly. Correlations

The only significant relationship between initial BMI and lipoprotein lipid concentrations was the weak negative correlation found for HDL-cholesterol and BMI (r = - 0.23, P < 0.05). The well established negative correlation between VLDL-TG and HDL-cholesterol was found both before and after 6 weeks of therapy (Table 2). The significant negative relation between k, and VLDL-TG as well as the positive relation between k, and HDL-cholesterol remained after initial weight reduction Table 2). There were no significant relations between weight loss in kg and serum concentrations changes for VLDL-TG, LDL-cholesterol and HDL-cholesterol at early or late follow-up.

Although it is wellknown that serum lipoprotein abnormalities are frequent in obese persons, this group of grossly obese subjects presents a rather uniform pattern of moderate hyperlipoprohypertriglyceridteinaemia. Before treatment, aemia was found in both sexes and about one fourth was classified as a Type IV pattern. On the other hand this group of patients did not exhibit an extreme degree of serum TG elevations in spite of massive obesity. This is further exemplified by the fact that within this subgroup of grossly obese individuals BMI did not correlate with VLDL and LDL lipid concentrations. Total cholesterol in this group was just slightly above control values. In Stockholm, the corresponding values for healthy males in the same age range was 5.39 + 1.28 mmol/l and for females 6.70 f 1.23 mmol/l ([ll], I&stein and Rbssner, unpublished). Obese subjects have been reported to have low HDL-cholesterol concentrations [2,12,13]. In this study the value for males 1.09 +- 0.27 mmol/l should be compared with the corresponding control values 1.37 f 0.40 (P -c 0.01). The HDLcholesterol concentration in obese females was significantly lower than in nonobese Stockholm controls of similar age, 1.29 _rt0.31 vs 1.79 f 0.42 mmol/l (P < 0.001). Although it was possible to control such factors as diet, drugs, alcohol and exercise to a reasonable

129 extent throughout the initial 6 weeks of therapy, this was clearly not possible during the ensuing year, when the obese patients were monitored on an out-patient basis. Repeated weekly interviews make it likely however, that the lipoprotein changes reported here mainly result from the pronounced weight loss, but other contributing factors cannot be ruled out. However, the long-term treated patients studied here represent a group with a documented good adherence to the weight reduction programme [4]. In a study of Zimmermann et al. [3] the effects of weight loss on lipoprotein metabolism were analysed in moderately obese patients. In that paper a helpful summary has been given of a number of studies on this topic. The most consistent finding is the reduction of serum TG. A reduction of serum cholesterol, mainly caused by a drop of LDL-cholesterol, has also been reported, but less consistently. The most controversial part relates to the changes of HDL-cholesterol. In some studies HDL has been found to increase [3,14-181, in others to fall [20-261. Sometimes these changes have differed between sexes [21]. Our 6-week data showing initial reductions of VLDL-TG and LDL-cholesterol concentrations during the initial catabolic phase are in agreement with most other studies [3]. The early fall in HDL-cholesterol of about 10% of initial values that we observed, is also in the same range as data from a number of papers. However, significant increases of HDL-cholesterol have been reported in studies of similar design, sex composition and duration. Sorbris et al. observed a 25% increase in HDL-cholesterol and Contaldo et al. a 56% increase, but in these studies the energy intake was only O-240 kcal/day [14,15]. With a diet of 1000 kcal, Avogaro et al. noted a 16% HDL-cholesterol increase [19]. In contrast to the report of Brownell and Stunkard [21] we did not observe any sexspecific pattern in lipoprotein changes. The mean IVFTT k, value was similar to values observed in several other studies at similar VLDL-TG concentrations and the k,-VLDL-TG relationship corresponds to previous findings in patients with a wide range of VLDL-TG concentrations [28]. It has been suggested that decreased synthesis

is responsible for the initial fall in TG concentrations after weight loss [17]. However, our results suggest that an increased elimination rate may at least contribute to the lower VLDL-TG concentrations, since we found higher k, values of the IVFTT after 6 weeks, indicating increased peripheral fractional elimination rates. This may not be at variance with the observation that lipoprotein lipase activity falls during caloric restriction. In several studies IVFTT k,-values and postheparin lipoprotein lipase activities have not been found to correlate well [29]. Few studies are available with a follow-up period exceeding 1 year. Our long-term data may therefore be of interest, since they demonstrate that TG-values remain in the low range, found already after 6 weeks, whereas there is an increase of LDL- and HDL-cholesterol in the normal range leading to concentrations above pretreatment levels (Table 1, Fig. 1). Clearly the weight loss achieved by these patients leads to an improved lipoprotein profile. The late LDL-cholesterol increase is balanced by a concomitant increase in HDL-cholesterol. The HDL-LDL cholesterol ratio in the whole group increases from about 0.31 at entry and after 6 weeks to 0.35 after 1 year. In this study we observed the well known negative VLDL-TG-HDL-cholesterol relationship also in the catabolic phase. The amount of weight lost was not important for the corresponding change in lipoprotein lipids here. There was no relationship between weight loss and the degree to which TG and cholesterol concentrations altered within the fractions. In summary, our data indicates that early and late findings in a weight reduction program may differ considerably. Thus it is important to keep in mind the study conditions when comparing results from different groups, since it could be expected that the lipoprotein metabolism will differ in a catabolic early stage compared to a later stable situation at lower body weight. Finally it should once again be emphasized that our data concern grossly obese individuals. However, the fact that atherosclerotic manifestations in this group are clearly important complications leads us to believe that a sustained weight reduction may have a beneficial effect also on this risk factor.

130

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