¹Department of Endocrinology, Metabolism and Nutrition, University Hospital, Gasthuisberg, Leuven, Belgium

²University Hospital St Luc, Brussels, Belgium

³Département de Médecine, Centre Hospitalier Universitaire Sart Tilman, Liége, Belgium

⁴Department of Endocrinology, Metabolism and Clinical Nutrition, University Hospital Antwerp, Edegem-Antwerp, Belgium

Correspondence to: E Muls, Department of Endocrinology, Metabolism and Nutrition, Herestraat 49, B-3000 Leuven, Belgium. E-mail: Erik.Muls@uz.kuleuven.ac.be

^aObesity Linked with Hypercholesterolemia treated with Xenical.

OBJECTIVE: Assessment of the effects of orlistat 120 mg three times daily vs placebo on weight loss and serum lipids in obese hypercholesterolemic patients.

DESIGN: A 24 week multicentre, double-blind, randomized, placebo-controlled trial. After a 2-week single-blind run-in period (placebo+diet (-600 kcal/day; £30% of calories as fat)), 294 patients were submitted to the hypocaloric diet and randomly assigned to either orlistat 120 mg or placebo three times daily. Patients who completed the double-blind study (n=255) were eligible for participation in a subsequent 24 week open-label orlistat extension phase.

SUBJECTS: Patients with body mass index (BMI) 27-40 kg/m² and hypercholesterolemia (low-density-lipoprotein cholesterol, LDL-C, 4.1-6.7 mmol/l).

MEASUREMENTS: Efficacy assessments included weight loss, lipid levels, other cardiovascular risk factors and anthropometric parameters. Safety assessments.

RESULTS: Weight loss during run-in was similar in both groups. After randomization, orlistat-treated patients lost significantly more weight than placebo recipients: mean percentage weight loss from start of run-in to week 24 was-6.8% in the orlistat group and -3.8% in the placebo group (P<0.001). Moreover, more patients in the orlistat group than in the placebo group achieved clinically meaningful weight loss of 5% (64 vs 39%) or 10% (23 vs 13%) at week 24. Treatment with orlistat was associated with significantly greater changes in total cholesterol (-11.9% vs -4.0%; P<0.001) and LDL-C (-17.6 vs -7.6%; P<0.001). For any category of weight loss during the double-blind treatment period, change in LDL-C was more pronounced in orlistat-treated patients than in placebo recipients, indicating that orlistat had a direct cholesterol-lowering effect that was independent of weight reduction (P<0.001). Adjunction of orlistat during the extension phase in patients who initially received placebo induced a further decrease in weight, total cholesterol and LDL-C. Orlistat was generally well tolerated with a safety profile comparable to placebo, with the exception of a higher incidence of gastrointestinal events (1 event in 64 vs 38% of patients).

CONCLUSION: Orlistat as an adjunct to dietary intervention promotes weight loss and reduces LDL-C beyond the effect of weight loss in overweight or obese patients with concomitant hypercholesterolemia.

International Journal of Obesity (2001) 25, 1713-1721

obesity; orlistat; lipase inhibition; lipids; cardiovascular risk factors

Introduction

Dyslipidemia is a frequent co-morbidity of obesity and a major risk factor for coronary heart disease. Increases in body fat mass and/or in visceral fat are associated with elevated total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels, and with a decrease in high-density-lipoprotein cholesterol (HDL-C).¹ Weight loss produced by lifestyle modifications, including diet and increased physical activity, reduces serum TG and increases HDL-C, and generally produces some reductions in serum TC and LDL-C.^2,3 Unfortunately, long-term¾even modest¾weight loss is difficult to achieve.⁴ Accordingly, there is a need for pharmacological agents as adjuncts to lifestyle changes aimed at promoting and maintaining weight loss.^5,6,7,8 Orlistat (Xenical) is a non-systemically acting agent for the long-term management of obesity, that partially blocks dietary fat absorption by inhibiting gastrointestinal lipases.⁹ Orlistat in combination with a mildly hypocaloric diet promotes weight loss, enhances long-term weight maintenance after weight loss and improves serum lipid profiles.^{10,11,12,13,14,15} The majority of patients in previous long-term studies of orlistat had normal or only mildly elevated cholesterol levels. The lipid-lowering effect of the drug may thus have been underestimated. A 6 month, multicentre, randomized, placebo-controlled study was therefore conducted to assess the effects of orlistat on body weight and serum lipids in obese patients with hypercholesterolemia (LDL-C 160-260 mg/dl; 4.1-6.7 mmol/l). Patients who completed the double-blind study without protocol violation were eligible for participation in a subsequent 6 month open-label orlistat extension.

Materials and methods

Patients

Obese (body mass index (BMI) 27-40 kg/m²) men and women, aged 18-70 y, with fasting serum LDL-C 4.1-6.7 mmol/l and TG<4.5 mmol/l (<400 mg/dl) were eligible for inclusion. Patients with serious diseases, diabetes or uncontrolled hypertension, and women of childbearing potential without adequate contraception were excluded. Other exclusion criteria were: previous bariatric surgery; use of appetite suppressants or lipid-lowering agents; evidence of alcohol or substance abuse. The study conformed with the Declaration of Helsinki. The study protocol was approved by the ethics committee of all centres, and all patients gave written informed consent.

Study design

This 50 week multicentre trial was conducted in 19 centres in Belgium. A 2 week, single-blind, placebo three times daily run-in period was followed by a 24 week, double-blind, randomized, parallel-group, placebo-controlled phase. All patients who completed the double-blind phase without protocol violations were subsequently offered the option of entering a 24 week open-label orlistat extension phase.

Eligible patients (>75% compliance with therapy calculated from the number of placebo capsules returned; and <1.0 kg weight gain during run-in) were randomly assigned to either orlistat 120 mg or placebo three times daily after being stratified according to study center and to weight loss during run-in (£2.0 vs >2.0 kg). Clinic visits occurred at the start and end of run-in, monthly during the double-blind phase, and at weeks 28, 36 and 48 during open-label extension.

Diet

Patients were instructed on a nutritionally balanced low-energy diet containing 30% of energy as fat at the start of placebo run-in. The energy content of the diet of individual patients was calculated from estimated total daily energy expenditure minus 600 kcal/day (1 kcal=4.2 kJ). Total daily energy expenditure was estimated by multiplying the basal metabolic rate, calculated from weight, age and sex according to World Health Organization formulas, by 1.3 or 1.5 according to level of daily physical activity.¹⁶ The lowest energy intake allowed was 1200 kcal/day. Patients were encouraged to take three main meals per day. The patients met a dietician to assess dietary compliance at randomization, and at weeks 4, 12 and 24. The initially prescribed diet was to be maintained during the open-label extension period.

Assessments

Patients were weighed using calibrated scales at each clinic visit. Patients wore light indoor clothing and no shoes. Other efficacy parameters, which were determined after the patients had fasted overnight at weeks -2, 0, 12, 24 and 48, included lipid and lipoprotein levels (TC, LDL-C, HDL-C, TG, lipoprotein(a)), other cardiovascular risk factors (plasma glucose and insulin, fibrinogen, blood pressure), and waist-to-hip ratio. Waist and hip circumferences were measured while the patients were standing with their weight balanced over both feet, and while they were in mid-exhalation. The waist circumference was measured at the level midway between the lateral lower rib margin and the iliac crest. The hip circumference was measured at the level of the trochanters, through the pubic symphysis.

All clinical chemistry tests of outcome measures were analysed centrally (Barc Laboratories, Ghent, Belgium), using standard methods. LDL-C was calculated using the Friedewald formula. Standard hematological, clinical chemistry and urinalysis assessments were performed at weeks 0, 12, 24 and 48. Adverse events were coded using the WHO-ART dictionary.

Sample size

Sample size was determined on the basis of on-treatment percentage weight change. The s.d. of this variable was anticipated to be 6.5%. A 2.6% difference between placebo and orlistat would be judged to be clinically relevant. With 100 evaluable patients in each treatment group, there would be a 80% probability of showing such a 2.6% difference (an effect size of 0.4) at the 0.05 significance level (two-sided). Assuming that approximately 30% of patients would not be fully evaluable, the total number of patients to be randomized was estimated to be 284. The planned sample size of 350 patients for entry into the run-in phase was based on the assumption of withdrawal rates of 20% during the placebo lead-in period.

Statistical analysis

The statistical analysis was performed using the SAS software package. Statistical tests were performed two-tailed at the 0.05 level of significance, and interaction was tested at the 10% level of significance. No correction for multiplicity was applied since the statistical analysis plan, agreed upon before database lock, made a clear distinction between the primary efficacy parameter (percentage weight change from week 0 to week 24) and supportive efficacy variables. The statistical analysis was primarily based on the intention-to-treat (ITT) population, ie all patients who were randomized and for whom any follow-up information was available. The ITT data set included observed data and data from the last observation carried forward. The data recorded at randomization were defined as baseline. The statistical testing of efficacy data considers the evolution from baseline to week 24, ie during the double-blind phase of the study. The evaluation of the percentage change in weight and lipids was performed using two-way analysis of variance, controlling for treatment weight change during run-in (£2.0 vs >2.0 kg). Least square estimates of treatment effect were made after removal of non-significant terms from the ANOVA model. The relationship between variables was quantified by means of the Pearson correlation coefficient. The ² test was used to compare the frequencies of patients with adverse events among treatment groups. Changes of variables from week -2 onwards, and from week 24 to 48 (open-label phase) are given for descriptive purposes only.

Results

A total of 441 patients entered the 2 week placebo run-in period (Figure 1). One-hundred and forty-seven subjects (33%) were not eligible for entry in the double-blind treatment phase, of whom 129 had LDL-C levels at week-2 outside the 4.1-6.7 mmol/l inclusion criterion range. Two-hundred and ninety-four subjects were randomized to placebo or orlistat 120 mg three times daily. Four early withdrawals, all assigned to placebo, reduced the ITT population to 290 patients (placebo, n=143; orlistat, n=147). Patient characteristics at randomization were similar in the placebo and orlistat ITT populations (Tables 1 and 2). In the ITT population, of 216 patients with £2.0 kg weight loss during run-in, 106 received placebo and 110 received orlistat, while of 74 subjects with run-in weight loss>2.0 kg, 37 were allocated to placebo and 37 to orlistat. The double-blind phase was completed by 255 subjects (placebo, n=127, 89%; orlistat, n=128, 87%). Among 35 non-completers, 16 withdrew due to adverse events (placebo, n=4; orlistat, n=12), five dropped out because of insufficient therapeutic response (placebo, n=4; orlistat, n=1), and 14 patients were lost to follow-up or did not cooperate (placebo, n=8; orlistat, n=6).

A total of 248 completers of the double-blind phase were subsequently enrolled in the orlistat open-label extension study. Six subjects, of whom two had previously received orlistat and four placebo, were lost to follow-up immediately after entry into the extension period. Data at week 48 were available in 242 patients, of whom 121 (50%) had previously received orlistat.

Weight loss

Initial mean percentage weight loss during run-in was -1.6 and -1.5% in the future placebo and orlistat groups, respectively (Figure 2). After randomization, orlistat-treated patients achieved a more rapid and significantly greater weight loss than placebo recipients: at week 24, additional mean percentage weight change was -2.3% in the placebo group, and -5.3% in the orlistat group (P<0.001) (Table 2). Thus, mean percentage weight loss from the start of run-in to week 24 was -3.8% in placebo recipients, and -6.8% in orlistat-treated subjects. More patients in the orlistat group than in the placebo group had lost 5% of initial body weight at week 24 (64% vs 39%), and, similarly, more patients on orlistat than on placebo had lost 10% of initial body weight (23% vs 13%).

The difference in percentage weight change at week 24 between treatment groups was comparable for subjects having lost less and for those having lost more than 2.0 kg during run-in: -1.1% for placebo, and -4.2% for orlistat if £2.0 kg weight loss during run-in; and -5.5% for placebo, and -8.4% for orlistat if >2.0 kg weight loss during run-in. Similarly, weight loss during the first 4 weeks after randomization was correlated with weight loss at week 24 in both the placebo (r=0.330, P<0.001) and the orlistat group (r=0.343, P<0.001). Changes from baseline to week 24 in waist to hip ratio were not statistically significant, but waist circumference tended to decrease in the orlistat group (P=0.08).

During open-label extension, a further decrease in weight was observed, as expected, in the former placebo group, whereas in patients who continued orlistat treatment, weight-loss was maintained. At week 48, mean percentage weight-loss from baseline and start of run-in, respectively, was -5.6% and -7.2% in the former placebo group, and -5.3% and -6.9% in the group receiving orlistat throughout 48 weeks (Figure 2).

Lipids and lipoproteins

In both groups, a 6% decrease in TC levels was observed during run-in. After randomization, TC concentrations continued to decline in orlistat-treated subjects, but started to increase in the placebo group. At week 24, orlistat treatment was associated with significantly greater additional changes in TC (-5.5% from baseline with orlistat vs +2.8% with placebo; P<0.001; Table 2), corresponding to a 0.42 mmol/l decrease in the orlistat group vs a 0.14 mmol/l increase in the placebo group. TC levels were similar at the end of open-label extension (week 48) in both groups (placebo, 6.47±0.93 mmol/l; orlistat, 6.47±0.97 mmol/l).

LDL-C declined in both groups during the lead-in period and continued to decrease in the orlistat group during double-blind therapy (Table 2; Figure 3). In the placebo group, LDL-C remained largely unchanged during double-blind treatment despite further weight loss. Thus, after 24 weeks, mean percentage change in LDL-C from baseline was significantly greater in the orlistat group than in the placebo group (-10.7% vs -0.7%, respectively; P<0.001). The percentages of randomized patients achieving 10% or 20% LDL-C decreases from baseline were 25.2 and 12.6% in the placebo group, and 54.4 and 23.8% in the orlistat group. Mean percentage changes in LDL-C from start of run-in were -17.6% and -7.6% in the orlistat and placebo groups, respectively. Mean percentage change in LDL-C from baseline to week 24 was not related to average percentage weight change in the placebo group (r=0.067; P=0.46), nor in the orlistat group (r=0.130; P=0.14). For any category of weight loss during double-blind treatment, ie from actual weight gain to >10% weight loss, change in LDL-C was more pronounced in orlistat-treated patients than in placebo-treated subjects, indicating that orlistat had a direct cholesterol-lowering effect that was independent of weight reduction (Figure 4). LDL-C values after open-label use of orlistat were similar in both groups (Figure 3).

Acute weight loss during the run-in phase resulted in decreases in HDL-C levels in both groups. The extent of the subsequent increase in HDL-C concentrations in both treatment arms during the double-blind phase was more pronounced in the placebo group (P<0.001; Table 2). HDL-C concentrations were comparable at the end of the extension phase (placebo, 1.59±0.38 mmol/l; orlistat, 1.52±0.37 mmol/l). No significant differences were observed between treatments in LDL-C/HDL-C ratio, TG, or Lp(a) (Table 2). Small decreases in glucose, insulin, diastolic blood pressure, and systolic blood pressure were not statistically significant.

Adverse events

Adverse events were more frequently reported in the orlistat group (80%) than in the placebo group (67%; P=0.016), due to a higher incidence of gastrointestinal events in the orlistat group (64 vs 38%). The most frequently reported adverse events were liquid stools (orlistat, 23%; placebo, 8%), increased defecation (orlistat, 22%; placebo, 5%), loose stools (orlistat, 16%; placebo, 3%), decreased defecation (orlistat, 3%; placebo, 12%), and bronchitis (orlistat, 11%; placebo, 6%). During open-label extension, adverse events were more frequently reported in the former placebo group (81%) than in the former orlistat group (59%).

Discussion

The present study was designed to evaluate the effects of orlistat on weight loss and on cardiovascular risk factors, in particular on serum lipids, in obese patients with hypercholesterolemia. The main findings were that orlistat promotes clinically significant weight loss, and that it reduces LDL-C beyond the effect of weight loss in obese patients with elevated cholesterol levels. Our data support the conclusions of previous controlled trials: partial inhibition of dietary fat absorption with the gastrointestinal lipase inhibitor orlistat, in conjunction with a hypocaloric diet, promotes weight loss of 6-10% and improves long-term weight maintenance in obese individuals.^{10,11,12,13,14,17,18} Such a degree of modest, intentional weight loss followed by weight maintenance, rather than a target of ideal weight, is in keeping with current guidelines for the management of obesity.^2,6,19 In addition, orlistat has an acceptable tolerability profile and a lack of systemic adverse effects.¹⁸

In the present study, run-in weight loss and weight loss during the first 4 weeks of double-blind treatment were predictors of longer-term weight loss at week 24 in both the orlistat and the placebo group. This observation is important for clinical practice since previous analyses of weight loss intervention studies have shown that a greater initial weight loss as the first step of a weight management program is associated with a better long-term outcome, ie a sustained weight loss 1-5 y later.²⁰

The improvements in lipid profiles that were observed during the diet-placebo lead-in period of this study are in agreement with a meta-analysis, conducted by Datillo and Kris-Etherton,²¹ on the effects of weight loss on plasma lipids and lipoproteins. It was estimated that for every 1 kg reduction in body weight there is 0.05, 0.02 and 0.015 mmol/l decrease in TC, LDL-C and TG, respectively. In addition, for every 1 kg decrease in body weight, a 0.007 mmol/l decrease in HDL-C occurred in subjects actively losing weight, and a 0.009 mmol/l increase in subjects at stabilized, reduced weight.²¹ Baseline risk factors, the magnitude of weight lost, and exercise can influence the degree of change in lipid profile.^1,3,22 Weight loss and dietary fat modification appear to have independent and additive effects on the reduction in serum lipids: the net favourable effect of weight loss seems to be greater than that of dietary fat modification, as weight loss per se is responsible for about 60 and 70% of the fall in LDL-C and TG, respectively.²³

Orlistat has been shown previously to have a positive effect on obesity-associated cardiovascular risk factors and type 2 diabetes.^15,17 The present study extends these beneficial effects of orlistat on cardiovascular risk as it demonstrates, compared with placebo, an additional 10% LDL-C lowering in obese subjects with elevated LDL-C levels (Table 3). For comparison, Table 3 also provides mean percentage changes in LDL-C at week 24 of double-blind treatment in three previous 2 y controlled trials, where the majority of patients were normocholesterolemic at baseline.^10,11,12,24 These data indicate that the difference in mean percentage change in LDL-C between orlistat and placebo is roughly 10% in all studies, whether this difference is computed as change from the start of the single-blind placebo dietary run-in or from the start of double-blind treatment. It is noteworthy that LDL-C levels continued to decline after the start of double-blind treatment in orlistat-treated subjects in all trials, but that LDL-C either remained largely unchanged or increased during double-blind therapy in placebo recipients, despite further weight loss (Table 3). In addition, our data are in agreement with the 10% LDL-C decrease previously seen with orlistat 120 mg three times daily in non-obese patients with primary hyperlipidemia, who were kept on a weight maintenance diet.²⁵ This independent cholesterol-lowering effect is likely to reflect the ability of orlistat to reduce intestinal energy uptake from fat.^10,26 Since lipase inhibition by orlistat prevents the absorption of approximately 30% of dietary fat intake, the prescribed diet of 30% of energy from fat would thus become in effect a 20-24% fat diet when associated with orlistat treatment.^9,11 It has been hypothesized that inhibition of gastrointestinal lipase activity may lower the solubility of cholesterol through a reduction in the amounts of fatty acids and monoglycerides present in the gut, and/or may lead to sequestration of cholesterol within a more persistent oil-phase in the intestine.¹⁵ Partial inhibition of intestinal fat and cholesterol absorption probably leads to decreased hepatic cholesterol and saturated fatty acid concentrations, upregulation of hepatic LDL receptors, and decreased LDL-C levels. The decrease in LDL-C observed in the present study is comparable to the 14% LDL-C reduction that was previously achieved with a plant stanol ester-containing margarine²⁷ but of a lesser magnitude than the LDL-C lowering effects that are commonly observed with fibrate²⁸ or statin²⁹ drugs.

Conclusion

Orlistat as an adjunct of dietary intervention promotes weight loss and reduces LDL-C beyond the effect of weight loss in overweight or obese patients with concomitant hypercholesterolemia.

Acknowledgements

This study was financially supported by NV Roche SA, Belgium. The authors acknowledge and thank the research nurses and dieticians, as well as J Masure, MD, A Lefever, MD, and P Ysebaert (NV Roche SA, Belgium) for logistical support, and Derde MP (DICE) for statistical analysis.

1 Hecker KD, Kris-Etherton PM, Zhao G, Coval S, Jeor SS. Impact of body weight and weight loss on cardiovascular risk factors. Curr Atheroscler Rep 1999; 1: 236-242, MEDLINE

2 NHLBI Obesity Education Initiative Expert Panel. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults¾the Evidence Report. Obes Res 1998; 6: (Suppl 2): 51S-209S,

3 Van Gaal LF, Wauters MA, De Leeuw IH. The beneficial effects of modest weight loss on cardiovascular risk factors. Int J Obes Relat Metab Disord 1997; 21(Suppl 1): S5-S9, MEDLINE

4 Hyman FN, Sempos E, Saltsman J, Glinsmann WH. Evidence for success of caloric restriction in weight loss and control. Summary of data from industry. Ann Intern Med 1993; 119: 681-687, MEDLINE

5 Goldstein DJ, Parvin JH. Long-term weight loss: the effect of pharmacologic agents. Am J Clin Nutr 1994; 60: 647-657, MEDLINE

6 A Report by the Royal College of Physicians. Clinical management of overweight and obese patients with particular reference to the use of drugs. London: Royal College of Physicians, 1998,

7 Kolanowski J. A risk-benefit assessment of anti-obesity drugs. Drug Safety 1999; 20: 119-131, MEDLINE

8 Scheen AJ, Lefèbvre PJ. Pharmacological treatment of obesity: present status. Int J Obes Relat Metab Disord 1999; 23: (Suppl 1): S47-S53, MEDLINE

9 Guerciolini R. Mode of action of orlistat. Int J Obes Relat Metab Disord 1997; 21: (Suppl 3): S12-S23, MEDLINE

10 Davidson MH, Hauptman J, DiGirolamo M, Foreyt JP, Halsted CH, Heber D, Heimburger DC, Lucas CP, Robbins DC, Chung J, Heymsfield SB. Weight control and risk factor reduction in obese subjects treated for 2 y with orlistat. A randomized controlled trial. JAMA 1999; 281: 235-242, MEDLINE

11 Sjöström L, Rissanen A, Andersen T, Boldrin M, Golay A, Koppeschaar HPF, Krempf M for the European Multicentre Orlistat Study Group. Randomized placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet 1998; 352: 167-172, Article MEDLINE

12 Rössner S, Sjöstrom L, Noack R, Meinders E, Noseda G on behalf of the European Orlistat Study Group. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 y treatment with orlistat for obesity. Obes Res 2000; 8: 49-61, MEDLINE

13 Finer N, James WPT, Kopelman PG, Lean MEJ, Williams G. One-year treatment of obesity: a randomized, double-blind, placebo-controlled, multicentre study of orlistat, a gastrointestinal lipase inhibitor. Int J Obes Relat Metab Disord 2000; 24: 306-313, MEDLINE

14 Hill JO, Hauptman J, Anderson JW, Fujioka K, O'Neil PM, Smith DK, Zavoral JH, Aronne LJ. Orlistat, a lipase inhibitor, for weight maintenance after conventional dieting: a 1-y study. Am J Clin Nutr 1999; 69: 1108-1116, MEDLINE

15 Zavoral JH. Treatment with orlistat reduces cardiovascular risk in obese patients. J Hypertens 1998; 16: 2013-2017, MEDLINE

16 World Health Organization. Energy and protein requirement. Report of a joint FAO/WHO/UNU Expert Consultation. Technical Report Series no. 724. WHO: Geneva, 1985,

17 Hollander PA, Elbein SC, Hirsch IB, Kelley D, McGill J, Taylor T, Weiss SR, Crockett SE, Kaplan RY, Comstock J, Lucas CP, Lodewick PA, Canovatchel W, Chung J, Hauptman J. Role of orlistat in the treatment of obese patients with type 2 diabetes. Diabetes Care 1998; 21: 1288-1294, MEDLINE

18 Hvizdos KM, Markham A. Orlistat. A review of its use in the management of obesity. Drugs 1999; 58: 743-760, MEDLINE

19 World Health Organization. Obesity: preventing and managing the global epidemic. WHO: Geneva, 1998,

20 Astrup A, Rössner S. Lessons from obesity management programmes: greater initial weight loss improves long-term maintenance. Obes Rev 2000; 1: 17-19, MEDLINE

21 Datillo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr 1992; 56: 320-328, MEDLINE

22 Muls E, Kempen K, Vansant G, Cobbaert C, Saris W. The effects of weight loss and apoprotein E polymorphism on serum lipids, apolipoproteins A-I and B, and lipoprotein(a). Int J Obes Relat Metab Disord 1993; 17: 711-716, MEDLINE

23 Leenen R, van der Kooy K, Meyboom S, Seidell JC, Deurenberg P, Westrate JA. Relative effects of weight loss and dietary fat modification on serum lipid levels in the dietary treatment of obesity. J Lip Res 1993; 34: 2183-2191,

24 Hoffman-La. Roche Laboratories, Nutley, New Jersey, Data on file.

25 Tonstad S, Pometta D, Erkelens DW, Ose L, Moccetti T, Schouten JA, Golay A, Del Bufalo A, Pasotti E, van der Wal P. The effect of the gastrointestinal lipase inhibitor, orlistat, on serum lipids and lipoproteins in patients with primary hyperlipidaemia. Eur J Clin Pharmac 1994; 46: 405-410,

26 Zhi J, Melia AT, Guerciolini R, Chung J, Kinberg J, Hauptman JB, Patel IH. Retrospective population-based analysis of the dose-response (fecal fat excretion) relationship of orlistat in normal and obese volunteers. Clin Pharmac Ther 1994; 56: 82-85,

27 Miettinen TA, Puska P, Gylling H, Vanhanen H, Vartiainen E. Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population. New Engl J Med 1995; 333: 1308-1312, MEDLINE

28 Linton MF, Fazio S. Re-emergence of fibrates in the management of dyslipidemia and cardiovascular risk. Curr Atheroscler Rep 2000; 2: 29-35, MEDLINE

29 Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 2000; 101: 207-213, MEDLINE

Figure 1 Flow and dispositions of subjects entered into the study (ITT=intention to treat).

Figure 2 Mean percentage change in body weight (orlistat 120 mg three times daily vs placebo).

Figure 3 Mean percentage change in low density-lipoprotein (LDL cholesterol) (orlistat 120 mg three times daily vs placebo).

Figure 4 Change in LDL cholesterol (%) according to weight change category during the double-blind treatment period (intention-to-treat population; orlistat 120 mg three times daily vs placebo).

Table 1 Characteristics (mean±s.d.) of intention-to-treat opulation at randomization

Table 2 Body weight, serum lipids and lipoproteins at the start of run-in, at randomization and the mean change from start of double-blind treatment at 24 weeks (intent-to-treat population)

Table 3 Comparison with previous randomized, double-blind, placebo-controlled studies of mean percentage change in low-density-lipoprotein cholesterol (LDL-C) at week 24 of double-blind treatment