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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Study design
  7. Statistical analysis
  8. Results
  9. Cardiovascular risk factors
  10. Weight loss
  11. Lipids
  12. Discussion
  13. Acknowledgements
  14. References

Background : Orlistat reduces energy uptake by the impairment of fat digestion and some evidence indicates it also lowers plasma cholesterol.

Aim : To examine total, low-density lipoprotein- and high-density lipoprotein cholesterol during a weight reducing regimen, and assess the effect of orlistat in lowering cholesterol levels independent of its weight reducing efficacy.

Methods : A total of 448 patients with elevated cholesterol according to cardiovascular risk factors entered a 2 week single-blind run-in period on a hypocaloric diet. Of 384 patients were subsequently assigned double-blind treatment with orlistat (3 × 120 mg/day) or placebo for 6 months in conjunction with the hypocaloric diet.

Results : Weight loss in the orlistat group was 7.4 kg vs. 4.9 kg with placebo. Total and low-density lipoprotein cholesterol decreased by 25–30 mg/dL vs. 10–15 mg/dL with placebo. Reduction of cholesterol with orlistat was significantly greater than anticipated from weight loss alone. In patients with cardiovascular risk factors entering the study with lower cholesterol values orlistat was also superior to placebo. On the contrary, reduction of cholesterol concentrations never exceeded 20%.

Conclusion : Orlistat has a cholesterol lowering efficacy independent of its weight reducing effect. Because of the limited therapeutic effectiveness, patients at high cardiovascular risk should receive rather early additional cholesterol lowering medication during weight loss programmes.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Study design
  7. Statistical analysis
  8. Results
  9. Cardiovascular risk factors
  10. Weight loss
  11. Lipids
  12. Discussion
  13. Acknowledgements
  14. References

Elevated plasma cholesterol levels are causally related to increased cardiovascular morbidity and mortality.1 Several intervention trials have demonstrated the clinical benefit of pharmacological inhibition of cholesterol synthesis.2–7 On the contrary, it must be kept in mind that the intake of inhibitors of cholesterol synthesis can be associated with various in part deleterious side-effects.8

As obesity is an important determinant of elevated plasma cholesterol the primary goal of treatment should be weight reduction and indeed the treatment of over-weight and obesity has been shown to reduce plasma cholesterol and other blood lipids as summarized in a recently published meta-analysis of 70 studies.9

Orlistat, a lipase inhibitor, has been shown to be effective in the treatment of obesity.10–16 Due to its mechanism of action orlistat prevents the digestion of approximately 30% of the ingested fat load. Accordingly, this pharmacologically induced fat malassimilation could have a lowering effect on cholesterol absorption resulting finally in a greater decrease of plasma cholesterol levels than anticipated from weight reduction alone.

Supportive evidence for this notion has been obtained in a short-term study in 18 normal weight hyperlipidaemic subjects who had a significant decrease of total and low-density lipoprotein (LDL)-cholesterol and apolipoprotein B (apo-B) levels by 7–10% without any change of body weight.17

Furthermore, a recent study of Muls et al.18 has strongly suggested that orlistat can lower plasma cholesterol beyond its effect on weight loss. Due to fairly long intervals between cholesterol measurements a direct comparison of the plasma cholesterol values at an identical degree of weight loss in the respective groups was not possible from those data.

The present study was performed between October 1998 and December 1999 more or less in parallel with the recently published work of the Belgian group. It was designed to assess the effect of orlistat (3 × 120 mg daily) on serum lipids in obese patients with hypercholesterolaemia considering the cardiovascular risk profile. Accordingly, for inclusion of patients the upper limit of LDL-cholesterol was adjusted according to risk factors as suggested by the European and United States expert commissions,19, 20 which permits to define more precisely the potential benefit but also its limitations in the therapeutic effort to lower plasma cholesterol adequately.

Patients

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Study design
  7. Statistical analysis
  8. Results
  9. Cardiovascular risk factors
  10. Weight loss
  11. Lipids
  12. Discussion
  13. Acknowledgements
  14. References

Obese men and women, aged 18–70 years with a body mass index (BMI) of 28–40 kg/m2 and no evidence of coronary heart disease (CHD) were eligible for inclusion when the following criteria were met:

  • 1
    LDL-cholesterol ≥ 180 mg/dL (4.5 mm) and ≤210 mg/dL (5.3 mm) and no cardiovascular risk factors.
  • 2
    LDL-cholesterol ≥ 160 mg/dL (4.0 mm) and < 180 mg/dL (4.5 mm) and one cardiovascular risk factor.
  • 3
    LDL-cholesterol ≥ 130 mg/dL (3.3 mm) and < 160 mg/dL (4 mm) and two or more cardiovascular risk factors.

Cardiovascular risk factors were: diabetes mellitus, hypertension, smoking cigarettes and peripheral artery occlusive disease: coronary heart disease was defined as no history of angina pectoris but an abnormal electrocardiogram at rest.19, 20

Women of child-bearing potential were included if they were using adequate contraception. The study conferred with the Declaration of Helsinki. The ethics committees of all 42 centres approved the study, and all participants gave written informed consent.

Patients were excluded if they were pregnant, lactating or of child-bearing potential and not taking adequate contraceptive measures, or if they had any clinically relevant condition that might affect the outcome of the study (e.g. psychiatric disorders, substance abuse, pancreatic, hepatic or gastrointestinal disease, uncontrolled hypertension, newly diagnosed endocrine diseases).

Patients were also excluded if they had plasma triglyceride levels of ≥ 400 mg/dL (4.56 mm), weight loss > 4 kg during the previous 3 months, a history of gastrointestinal surgery for weight reducing purposes, bulimia, laxative abuse, treatment with diuretics, β-blockers, anorectics, antidepressants and other drugs with a known impact on body weight and/or lipid metabolism.

Study design

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Study design
  7. Statistical analysis
  8. Results
  9. Cardiovascular risk factors
  10. Weight loss
  11. Lipids
  12. Discussion
  13. Acknowledgements
  14. References

This multicentre trial had a double-blind, randomized, parallel group, placebo-controlled design. After a single-blind 2-weeks run-in period during which patients received placebo three times a day with meals eligible patients (> 75% compliance with therapy calculated from the number of capsules returned) were randomized to receive either 120 mg orlistat or placebo t.d.s. in a double-blind fashion.

Patients were assigned to treatment using a central minimization algorithm which used the stratification factors – centre, cardiovascular risk factors, LDL-cholesterol and reduction in weight during the run-in period (≥ 2 kg vs. < 2 kg). Study treatment was taken with main meals for a maximum of 24 weeks.

Patients were instructed to consume a hypocaloric diet (−600 kcal deficit) with maximally 30% of energy as fat.

During the treatment period patients were seen at the study centres at 4-week intervals. At all visits during the entire study period the following parameters were assessed: body weight, blood pressure, heart rate, total cholesterol, low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol, triglycerides, LDL–HDL ratio, apo-B, apo-A1. All blood samples were drawn after an overnight 12-h fast.

Laboratory safety tests and determination of blood glucose and vitamins were performed at weeks 0, 12 and 24; ECG and urine analysis were undergone at screening visits and at week 24; thyroid-stimulating hormone (TSH) was determined at screening visit only. All laboratory measurements were carried out by a central laboratory (Schottdorf, Augsburg).

Statistical analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Study design
  7. Statistical analysis
  8. Results
  9. Cardiovascular risk factors
  10. Weight loss
  11. Lipids
  12. Discussion
  13. Acknowledgements
  14. References

The primary efficacy parameters, change in weight and in LDL-cholesterol between week 0 and 24 were analysed by a two sample Wilcoxon–Mann–Whitney test on the intent-to-treat population. The analysis of secondary efficacy parameters was also tested by the Wilcoxon–Mann–Whitney test at a 5%α-level.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Study design
  7. Statistical analysis
  8. Results
  9. Cardiovascular risk factors
  10. Weight loss
  11. Lipids
  12. Discussion
  13. Acknowledgements
  14. References

A total of 448 patients entered the 2-week placebo run-in period, 384 patients who completed the run-in were randomized to double-blind treatment with orlistat 120 mg (n = 192) or placebo (n = 192) three times a day.

At the end of the 24 weeks period 302 patients (79% of randomized) had completed treatment.

The demographic characteristics of the patient population at study entry, shown in Table 1 did not differ between treatment groups.

Table 1.  Demographic data of patient population at study entry; data are mean ± s.d.
ParameterPlaceboOrlistat
n192192
Sex (M/F)57/13550/142
Age (years)
 Mean45.8 ± 12.246.3 ± 11.2
 Range18–6919–69
Weight (kg)98.0 ± 14.995.2 ± 15.3
Height (cm)169 ± 0.09168 ± 0.09
BMI (kg/m2)34.2 ± 3.733.5 ± 3.6

Cardiovascular risk factors

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Study design
  7. Statistical analysis
  8. Results
  9. Cardiovascular risk factors
  10. Weight loss
  11. Lipids
  12. Discussion
  13. Acknowledgements
  14. References

The proportion of cardiovascular risk factors and the distribution within treatment groups is shown in Table 2. Most patients had one or two risk factors. The proportion was similar within treatment groups.

Table 2.  Cardiovascular risk factors of patient population at study entry
 Placebo n = 192 [n (%)]Orlistat n = 192 [n (%)]
Number of risk factors
 026 (13.5)30 (15.6)
 163 (32.8)61 (31.8)
 286 (44.8)81 (42.2)
 316 (8.3)17 (8.9)
 41 (0.5)3 (1.6)
Type of risk factor
 Hypertension69 (35.9)67 (34.9)
 Smoker84 (43.8)82 (42.7)
 Diabetes mellitus19 (9.9)15 (7.8)
 Peripheral arterial occlusive disease3 (1.6)1 (0.5)

Weight loss

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Study design
  7. Statistical analysis
  8. Results
  9. Cardiovascular risk factors
  10. Weight loss
  11. Lipids
  12. Discussion
  13. Acknowledgements
  14. References

In the placebo group body weight decreased from 98 ± 14.9 kg (week-2; mean ± s.d.) to 93.1 ± 14.6 kg. In the orlistat group weight decreased from 95.2 ± 15.3 kg to 87.8 ± 14.9 kg.

The total decrease of 7.4 kg was significantly greater compared with 4.9 kg with placebo (P < 0.01). The first statistically significant difference of body weight between the placebo and orlistat-treated subjects was observed at week 4. The maximal reduction of body weight in the placebo group (−4.9 kg) was accomplished in the orlistat group already at week 8 (−5.1 kg) (Figure 1 and Table 3).

image

Figure 1. Effect of orlistat (3 × 120 mg/day, n = 192) or placebo (n = 192) on body weight, total cholesterol. Low-density lipoprotein (LDL)-A high-density lipoprotein (HDL)-A and LDL/HDL-A ratio during a 6 months treatment period.

Download figure to PowerPoint

Table 3.  Body weight, serum lipids and lipoproteins at the start of run-in, at randomization and at week 24 (intent-to-treat population, mean ± s.d.) with orlistat (3 × 120 mg) or placebo; *P < 0.05 or less compared with placebo
 Initial valueRandomizationWeek 24
  1. LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; Apo, apolipoprotein.

Weight (kg)
 Placebo98.0 ± 14.996.4 ± 14.693.1 ± 14.6
 Orlistat95.2 ± 15.393.7 ± 15.087.1 ± 14.9*
Total cholesterol (mg/dL)
 Placebo230.4 ± 24.9218.4 ± 35.1222.5 ± 36.9
 Orlistat231.0 ± 25.6219.9 ± 35.0210.9 ± 34.3*
LDL-C (mg/dL)
 Placebo160.3 ± 20.1149.1 ± 33.3145.4 ± 34.4
 Orlistat161.1 ± 20.9150.5 ± 31.3134.9 ± 32.3
HDL-C (mg/dL)
 Placebo50.9 ± 11.448.9 ± 11.152.1 ± 12.2
 Orlistat51.1 ± 11.848.9 ± 11.650.7 ± 12.0*
LDL-/HDL-C
 Placebo3.3 ± 0.83.2 ± 0.92.9 ± 0.9
 Orlistat3.3 ± 0.93.2 ± 0.92.8 ± 0.9
Apo-B (mg/dL)
 Placebo118.2 ± 20.8111.7 ± 23.9112.0 ± 25.3
 Orlistat119.5 ± 18.1113.2 ± 22.5107.9 ± 21.6*
Apo-A1 (mg/dL)
 Placebo154.5 ± 26.2145.2 ± 25.7157.7 ± 26.1
 Orlistat155.2 ± 28.0146.7 ± 27.3155.5 ± 27.9

Lipids

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Study design
  7. Statistical analysis
  8. Results
  9. Cardiovascular risk factors
  10. Weight loss
  11. Lipids
  12. Discussion
  13. Acknowledgements
  14. References

Table 3 summarizes the changes of serum lipid levels during the study period. Total, LDL- and HDL-cholesterol levels were comparable in both treatment groups at the start of the run-in period and so was the decrease during the first 2 weeks of placebo treatment. After randomization orlistat-treated patients showed a significantly greater decrease of total, LDL- and HDL-cholesterol compared with the placebo-treated group where total and LDL-cholesterol remained fairly constant after the initial 4 weeks of the study period while HDL-cholesterol rose more rapidly and to a greater extent (Figure 1). The LDL/HDL ratio decreased similarly in both groups. Apo-B was significantly lower in the orlistat group for the entire period after randomization while apo-A1 remained unchanged.

Plasma triglyceride levels at the start of the run-in period were 166 mg/dL (placebo) and 165 mg/dL (orlistat) and decreased similarly by 10.4 and 11.4 mg/dL during the study period, respectively.

The LDL-cholesterol was lower in those patients who had an increased number of cardiovascular risk factors according to the inclusion criteria at study entry (Table 4). Since the efficiency of orlistat could be different in the presence of only moderate elevations of cholesterol a separate subgroup analysis was performed. Despite lower levels at the beginning orlistat had a significantly greater effect compared with placebo in the group with one risk factor (148 ± 35 vs. 136 ± 31 mg/dL, P < 0.01) and also in the group with two and more risk factors (135 ± 28 vs. 125 ± 31, P < 0.01). In the group with no risk factor the difference was not statistically significant most likely due to the smaller number of patients in this group (Table 4).

Table 4.  Effect of orlistat on low-density lipoprotein (LDL)-cholesterol (mg/dL) in three subgroups according to cardiovascular risk factors (intent-to-treat population, mean ± s.d.); *P < 0.05 or less vs. placebo
 RandomizationWeek 24
No risk factor
 Placebo (n = 26)178.1 ± 33.6176.8 ± 33.7
 Orlistat (n = 30)177.9 ± 21.8160.1 ± 21.8
One risk factor
 Placebo (n = 63)156.1 ± 29.6148.2 ± 35.4
 Orlistat (n = 61)157.2 ± 30.9136.2 ± 31.4*
Two or more risk factors
 Placebo (n = 103)137.3 ± 29.6135.6 ± 28.6
 Orlistat (n = 101)138.8 ± 27.5125.2 ± 31.4*

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Study design
  7. Statistical analysis
  8. Results
  9. Cardiovascular risk factors
  10. Weight loss
  11. Lipids
  12. Discussion
  13. Acknowledgements
  14. References

Orlistat is an inhibitor of pancreatic lipase resulting in a reduction of intestinal fat digestion and absorption which accounts for a faecal fat excretion of 30% of the ingested fat load at the doses employed in the present study. The substance has been shown to contribute significantly to the reduction of body weight in combination with a hypocaloric diet in obese subjects.10–16 Furthermore, it improves body weight and glycaemic control in overweight and obese type 2 diabetic patients.11, 12

Increased body weight and diabetes mellitus are important components of the metabolic syndrome which has to be considered as an important risk factor for cardiovascular morbidity and mortality.21

Serum cholesterol is another extremely relevant factor in this context. Evidence from epidemiological studies and more important from large intervention trials has shown that cholesterol is indeed an important risk factor for cardiovascular morbidity and mortality.1–7 Consequently, guidelines have been developed and constantly up dated for the evaluation and treatment of high-blood cholesterol.19, 20, 22

Previous studies have suggested that orlistat could have a cholesterol reducing effect which is independent of its weight reducing action. Reitsma et al.17 showed in a small group of normal weight hyperlipidaemic subjects that 8 weeks of orlistat treatment led to a decrease of fasting cholesterol, LDL-cholesterol and apo-B by 8–10% while fasting triglyceride and HDL-cholesterol remained unchanged.

In a 12 week trial Drent et al.23 showed that orlistat treatment of overweight and obese subjects resulted in a weight loss of approximately 4 kg paralleled by a small but significant change of approximately 8 mg/dL for total- and LDL-cholesterol, respectively. It must be noted, although that basal lipid levels were completely normal in these subjects.

Similarly, in the large European multicentre trial10 a small decrease of cholesterol and LDL-cholesterol was observed during orlistat in comparison with placebo. Basal levels were also normal in both groups (cholesterol approximately 220 mg/dL, LDL-cholesterol 140–150 mg/dL). In patients with type 2 diabetes cholesterol and LDL-cholesterol were significantly lower compared with placebo by 20 mg/dL and 14 mg/dL, respectively, while HDL-cholesterol and triglycerides remained unchanged.12 In this study, basal levels are not mentioned, which makes the interpretation difficult.

The present data clearly demonstrate that in overweight and obese patients weight reduction per se leads to a decrease of elevated serum cholesterol which is in agreement with a large number of earlier studies.9 Concomitant treatment with orlistat 3 × 120 mg augments the lipid lowering effect of weight loss significantly as the respective cholesterol and LDL-cholesterol levels were significantly lower at a comparable degree of reduced body weight (orlistat week 8, placebo week 24). This is in good agreement with the previously reported effect of orlistat on LDL-cholesterol.18

Despite the fact that in the present study only patients with hypercholesterolaemia were included mean basal levels of the lipid parameters of the entire study population were not substantially higher in comparison with previous trials. It must be considered, however, that the definition of elevated cholesterol is relative to the cardiovascular risk profile so that patients with fairly low absolute cholesterol levels were included in the study population.19, 20 Nevertheless, a significantly greater decrease of LDL-cholesterol was also observed in patients with relative hypercholesterolaemia. In patients with one risk factor orlistat reduced LDL by 13.4% compared with 0.05% with placebo and in the group with two and more risk factors there was still a 9.8% reduction with orlistat compared with 0.01% under placebo.

The exact mechanism of action of orlistat for this more rapid and sustained decrease of serum cholesterol with orlistat remains to be determined. The most likely explanation is that orlistat prevents 30% of ingested fat from being digested and absorbed.24 Together with the undigested fat cholesterol could be excreted in the faeces. The average caloric intake recommended at week-2 was 1570 kcal/day. Patients were advised to consume not more than 30% of total energy as fat, which is equivalent to a daily fat intake of 53 g. As 30% of the ingested fat remains unavailable for assimilation in the presence of orlistat the final amount of fat available for digestion was 35 g. This means that total energy available for assimilation in the intestine is 1410 kcal/day with 22% of the energy as fat.

Despite the advantageous effect of orlistat during weight reduction on LDL-cholesterol it should be kept in mind, however, that the simultaneous decrease of HDL-cholesterol counterbalances this benefit at least during the 6 months of this intervention. The subsequent increase of HDL-cholesterol can finally result in an improvement of the LDL-/HDL-cholesterol ratio as shown in a recent study over a 2 year period.25

The present data demonstrate the efficacy of orlistat to lower LDL-cholesterol even when pre-treatment levels are already fairly low. On the contrary, this study also demonstrates the limitations of orlistat in conjunction with a dietary regimen to shift plasma cholesterol down to adequate target values.

Thus, in patients with a high cardiovascular risk profile who start on rather high pre-treatment levels but require a substantial reduction of LDL-cholesterol according to the most recent recommendations22 the decrease of 14–20% that can be accomplished by weight reduction and orlistat is certainly not sufficient. Accordingly, a simultaneous therapy with statins with or without specific inhibition of cholesterol absorption26 should accompany weight reducing strategies rather early in the course of treatment.

In conclusion, orlistat therapy augments weight loss-induced reduction of plasma cholesterol levels. Such a combined therapeutic effort might be sufficient when an only small further decrease from already low basal levels is required depending on the underlying cardiovascular risk factors. Otherwise, additional cholesterol lowering strategies should be considered rather early in the course of obesity treatment.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Study design
  7. Statistical analysis
  8. Results
  9. Cardiovascular risk factors
  10. Weight loss
  11. Lipids
  12. Discussion
  13. Acknowledgements
  14. References
  • 1
    Gotto AM Jr, LaRosa JC, Hunninghake D, et al. The cholesterol facts. A summary of the evidence relating dietary fats, serum cholesterol and coronary heart disease. Circulation 1990; 81: 172133.
  • 2
    Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4.444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 13839.
  • 3
    The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with prava-statin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 134957.
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    Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 13017.
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    Brown L, Warnica JW, Arnold JMO, Wun C, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 10019.
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    Down JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. JAMA 1998; 279: 161522.
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    Gould AL, Rossouw JE, Santanello NC, Heyse JF, Furberg CD. Cholesterol reduction yields clinical benefit. Impact of statin trials. Circulation 1998; 97: 94652.
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    Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JJ, Lenfant C. ACC/AHA/NHL BI clinical advisory on the use and safety of statins. Circulation 2002; 106: 10248.
  • 9
    Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr 1992; 56: 3208.
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    Sjöström L, Rissanen A, Andersen T, et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet 1998; 352: 16772.
  • 11
    Heymsfield StB, Segal KR, Hauptman J, et al. Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults. Arch Intern Med 2000; 160: 132126.
  • 12
    Hollander PA, Elbein StC, Hirsch IB, et al. Role of orlistat in the treatment of obese patients with type 2 diabetes-a1-year randomized double-blind study. Diabetes Care 1998; 21: 128894.
  • 13
    Davidson MH, Hauptmann J, DiGirolamo M, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat – a randomized controlled trial. JAMA 1998; 281: 23542.
  • 14
    Finer N, James WPT, Kopelman PG, Lean MEJ, Williams G. One-year treatment of obesity: a randomized, double-blind, placebo-controlled, multicenter study of orlistat, a gastrointestinal lipase inhibitor. Int J Obesity 2000; 24: 30613.
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    Hauptman J, Lucas CH, Boldrin MS, Collins H, Segal KR. Orlistat in the long-term treatment of obesity in primary care settings. Arch Fam Med 2000; 9: 1607.
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    Hill JO, Hauptman J, Anderson JW, et al. Orlistat, a lipase inhibitor, for weight maintenance after conventional dieting: a 1-y-study. Am J Clin Nutr 1999; 69: 110816.
  • 17
    Reitsma JB, Cabezas MC, de Bruin TWA, Erkelens DW. Relationship between improved postprandial lipidemia and low-density lipoprotein metabolism during treatment with tetrahydrolipstatin, a pancreatic lipase inhibitor. Metabolism 1994; 43: 29398.
  • 18
    Muls E, Kolanowski J, Scheen A, VanGaal L. The effects of orlistat on weight and on serum lipids in obese patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled multicentre study. Int J Obesity 2001; 25: 171321.
  • 19
    Study Group, European Atherosclerosis Society. Strategies for the prevention of coronary heart disease: a policy statement of the European Atherosclerosis Society. Eur Heart J 1987; 8: 7788.
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    Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II). JAMA 1993; 269: 301523.
  • 21
    Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Health CW Jr. Body mass index and mortality in a prospective cohort of US Adults. N Engl J Med 1999; 341: 1097104.
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    Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001; 285: 248697.
  • 23
    Drent ML, Larsson I, William-Olssen T, et al. Orlistat (RO 18-0647), a lipase inhibitor, in the treatment of human obesity: a multiple dose study. Int J Obesity 1995; 19: 2216.
  • 24
    Zhi J, Melia AT, Guerciolini R, et al. Retrospective population-based analysis of the dose-response (fecal fat excretion) relationship of orlistat in normal and obese volunteers. Clin Pharmacol Ther 1994; 56: 825.
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    Rossner St, Sjöström L, Noack R, Meinders E, Noseda G. Weight loss, weight maintenance and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. Obes Res 2000; 8: 4961.
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    Ballantyne CM. Ezetimibe: efficacy and safety in clinical trials. Eur Heart J 2002; 4(Suppl. J.): 918.