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Comparison of the effect of orlistat vs orlistat plus metformin on weight loss and insulin resistance in obese women

Abstract

BACKGROUND AND AIM: Orlistat and metformin are the currently used drugs for weight loss. We aimed to compare the effect of orlistat and orlistat plus metformin combination therapy on weight loss and insulin resistance in obese women.

PATIENTS AND METHODS: In all, 57 obese women (body mass index ≥30 kg/m2 and normal glucose tolerance) were included. All subjects took the same content and caloric diet therapy during the study. After a month of diet period, each individual was randomly assigned to receive 360 mg orlistat per day (group 1; n=30) or 360 mg orlistat plus 1700 mg metformin per day (group 2; n=27) during the next 3 months. Body weight and insulin resistance by the homeostasis model assessment model (HOMA-IR) was measured at baseline, first month and fourth month.

RESULTS: The mean weight loss in groups 1 and 2 was 1.36±0.8 kg (1.4±0.7%) and 1.11±0.7 kg (1.1±0.7%) from baseline to first month; 4.8±2.9 kg (5.28±3.0%) and 5.77±2.5 kg (6.17±2.9%) from first month to fourth month. Body weight was decreased in groups 1 (P< 0.001) and 2 (P< 0.001), but there was no statistically significant difference between groups. Change of HOMA-IR in groups 1 and 2 was 0.41±0.4 (14.9±10.1%) and 0.23±0.7 (8.16±12.3%) from baseline to first month; 0.49±0.77 (22.0±26%) and 0.95±0.88 (34.8±29.1%) from first month to fourth month. HOMA-IR value was decreased in groups 1 (P< 0.001) and 2 (P< 0.001) but was not different between groups during the study period.

CONCLUSIONS: Combination of orlistat with metformin did not result in an additional effect on weight loss and insulin resistance when compared to orlistat alone in our study. However, new studies which have more sample sizes and the longer study period are necessary for this purpose.

Introduction

Obesity is associated with diabetes, insulin resistance, cardiovascular disease, hypertension, and dyslipidemia. Obese women are five times more probable to die from cardiovascular disease than women in the general population, and cardiovascular risk increases by 3.1% for each kilogram of weight gain.1, 2 Weight loss is important in reducing morbidity and mortality in obese individuals.3, 4, 5 Hyperinsulinemia and insulin resistance are common features of obesity in humans and experimental animals. Despite a modest weight reduction of 3–5%, this was associated with disproportionate improvement in most of the cardiovascular risk factors, including insulin sensitivity in both diabetic and nondiabetic obese subjects.5, 6, 7

Diet restriction and exercise remain the most common methods of weight loss; however, these usually do not achieve the necessary results.8, 9, 10 Moreover, obese individuals usually want to lose two to three times more weight than is typically possible in real life.11 Apart from dietary restriction and lifestyle modification, pharmacological agents are often used in weight reduction programs. Orlistat is an inhibitor of the gastrointestinal lipase that reduces the absorption of dietary fat by about 30%.12 Previous studies have confirmed the efficacy of orlistat in weight reduction, with improvement in cardiovascular risk factors among obese subjects.12, 13, 14 Generally, orlistat treatment is associated with significant improvement in the insulin sensitivity.14, 15 On the other hand, it has been demonstrated that metformin, an antihyperglycemic agent, decreases hyperinsulinemia and insulin resistance, leading to decreased adiposity in obese and non-insulin-dependent diabetes mellitus.16, 17, 18

Some investigators have suggested that greater weight loss might be achieved by combining the above-mentioned anti-obesity drugs,11, 19, 20 as they have different mechanisms of action. There are no studies in the obese, normal glucose tolerance subjects that have investigated the probably additional effect of metformin plus orlistat combination therapy on weight loss and insulin resistance. In a prospective, randomized trial, we assessed the effects of 3 months of metformin plus orlistat treatment on weight loss and insulin sensitivity and compared this treatment with orlistat alone in obese women.

Patients and methods

We conducted a prospective and randomized study. The study population consisted of 57 obese women having a body mass index (BMI) ≥30 kg/m2 and normal glucose tolerance. Approval was obtained from the Ethical Committee of the Akdeniz University Medical Faculty. Informed consent was obtained from the subjects. Eligible subjects underwent a comprehensive assessment including documentation of medical history, physical examination, anthropometric indices, and measurement of laboratory variables. Body weight (kg) and height (m) were measured with the patient in light clothes and without shoes. Body weight, insulin resistance, and serum lipid levels were measured at baseline, first month, and fourth month. Fasting plasma insulin level was measured by the immunometric assay method (IMMULITE 2000 Analyzer, USA), fasting plasma glucose level was measured by the enzymatic colorimetric assay method (GLU, Roche Diagnostics GmbH, Mannheim, Germany), and fasting cholesterol and triglyceride levels were measured by the enzymatic colorimetric assay method (Roche Diagnostics GmbH, Mannheim, Germany). Insulin resistance was estimated using the homeostasis model assessment (HOMA-IR) derived from the equation HOMA-IR=(Fasting plasma glucose level × fasting plasma insulin level)/22.5.

Exclusion criteria included impaired glucose tolerance (confirmed with oral glucose tolerance test), diabetes, hyperlipidemia, hypertension, pregnancy, lactation, childbearing potential with inadequate contraceptive measures, psychiatric or neurological disorders, alcohol or other substance abuse, a history of recurrent nephrolithiasis or symptomatic cholelithiasis, previous gastrointestinal tract surgery for weight reduction, a history or the presence of malignancy, a significant history of cardiovascular complications, and renal impairment with a plasma creatinine level of greater than 1.3 mg/dl.

All subjects took the same content and caloric diet therapy during the study. Diet therapy was based partially on the National Heart, Lung, and Blood Institute suggestion.21 Energy requirements of patients were calculated, and they were instructed to consume a diet of 1200–1600 kcal/day ((25 kcal/kg) ideal body weight), representing a deficit of approximately 600–850 kcal/day. A balanced diet with approximately 50% of calories from carbohydrate, 20% from protein, and ≤30% from fat was recommended.

At the first month of diet therapy, each individual was assigned randomly to receive 120 mg orlistat three times daily (Xenical, Roche Ltd), (group 1; n=30; mean age 46.2±7.7, mean BMI 37.5±3.4 kg/m2), or orlistat 120 mg three times daily (Xenical, Roche Ltd) plus 850 mg metformin twice daily (Glucophage, Merck Ltd) (group 2; n=27; mean age 45.7±13.6, mean BMI 38.2±2.6 kg/m2). All subjects took the medications for 3 months.

At the baseline, first and fourth months of therapy dietary, drug compliance of the subjects was evaluated by a dietitian and physician.

Statistical analysis

Statistical analysis was done by the SPSS statistical software (SPSS 10.0. for Windows, standard version). The results were presented as mean±s.d. Kruskal–Wallis test was performed to compare the groups. Friedman and Wilcoxon signed ranks tests were performed to compare the baseline values with the first and fourth month results. A P-value <0.05 was considered statistically significant. The estimated power for two-sample comparison of weight loss was 28% in our study.

Results

Body weight, total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglyceride levels at baseline, first and fourth months were similar in the two groups (P>0.05). There was no statistically significant change of serum lipid levels during the study in the groups. The changes in body weight, HOMA-IR, and lipid levels during the study period are shown in Table 1. There was a significant weight loss from baseline to the first month (P<0.001 for group 1; P<0.001 for group 2), from the first month to fourth month (P<0.001 for group 1; P<0.001 for group 2) both in groups 1 and 2, respectively. There was a significant decrease of HOMA-IR from baseline to the first month (P<0.001) and from the first month to fourth month (P=0.003) in group 1. There was no significant difference of HOMA-IR values from the baseline and first month in group 2 (P=0.136). However, HOMA-IR was decreased from the first month to fourth month in group 2 (P<0.001). Body weight and HOMA-IR values at baseline, first and fourth months were not different between the two groups.

Table 1 Body weight, HOMA-IR, lipid levels during the study

The mean weight losses in groups 1 and 2 were 1.36±0.8 kg (1.4±0.7%) and 1.11±0.7 kg (1.1±0.7%) from the baseline to first month; 4.8±2.9 kg (5.28±3.0%) and 5.77±2.5 kg (6.17±2.9%) from the first month to fourth month. Weight loss was not different between the two groups from baseline to the first month (P=0.29) and from the first month to fourth month (P=0.18). Change of HOMA-IR from baseline to the first month (0.41±0.4 (14.9±10.1%) and 0.23±0.7 (8.16±12.3%); P=0.279) and from the first month to fourth month (0.49±0.77 (22.0±26%) and 0.95±0.88 (34.8±29.1%); P=0.169) was not different between groups 1 and 2 (Figures 1 and 2).

Figure 1
figure1

Change of body weight (%) in groups during the study.

Figure 2
figure2

Change of HOMA-IR (%) in groups during the study.

Metformin and orlistat therapies were well tolerated and no subject discontinued therapy because of adverse events. Five patients in the combination group experienced mild gastrointestinal discomfort that was transient.

Discussion

Many studies have confirmed the close associations between obesity and type II diabetes, hypertension, dyslipidemia, and insulin resistance.1, 2, 22 A weight reduction of 5–10% has been shown to improve the cardiovascular risk profile and insulin sensitivity.4, 5, 6, 7

Various pharmacological agents have been used in efforts to improve success with long-term weight maintenance. One of them, orlistat, inhibits gastric and pancreatic lipases and thus promotes the excretion of approximately one-third of all ingested fat.4, 5, 12 Previous studies have confirmed the efficacy of orlistat in weight reduction, and mean weight loss has the greatest efficacy in the 120-mg tid regimen.12, 13 McDuffie et al15 reported 4.4±4.6 kg (3.8±4.1%) weight loss after 3 months of 120 mg orlistat tid, and our patients lost approximately 4.8 kg (5.28%) on this same protocol. In addition, Orlistat treatment is associated with significant improvement in the insulin sensitivity indicators.4, 5, 6, 7 We also detected a significant improvement in the HOMA-IR indices after 3 months of orlistat treatment.

The effect of metformin on weight loss in obese diabetic and nondiabetic subjects was controversial.7, 14, 24, 25, 26, 27, 28, 29 Use of metformin decreases the weight gain or causes a slight weight loss by decreasing energy intake, and is therefore a useful adjunct to insulin therapy in patients with type II diabetes mellitus.24, 25 Compared to the placebo group, the metformin group had greater weight loss (6.5%) and greater decrease in body fat.30 In contrast, metformin has not caused difference in BMIs during the 6 months in another study.31 In Arslanian et al's study27 after 3 months of metformin treatment, weight loss has been reported but it had not reached statistical significance.

Several studies have demonstrated that insulin-sensitizing agents such as metformin decrease hyperinsulinemia, increase insulin-stimulated glucose disposal and a progressive improve hepatic insulin sensitivity in obese women with polycystic ovary syndrome or diabetes. Metformin treatment in the recent study was associated with a 15% improvement in insulin sensitivity.7, 14, 27, 31 In contrast, insulin sensitivity, as assessed by the ratio of fasting insulin to glucose concentrations and homeostasis model assessment insulin resistance index indices, increased slightly in the metformin-treated participants in another study.31 Moreover, first- and second-phase insulin levels during the hyperglycemic clamp were not different before and after metformin treatment.27

Gokcel et al14 evaluated the effect of metformin and orlistat per se on weight loss and insulin resistance. After 6 months of treatment, both orlistat and metformin groups showed significantly reduced body weight (8 kg in orlistat and 9 kg in metformin groups). This degree of weight loss is greater than has been reported previously with metformin due to hypocaloric diet. Insulin resistance as assessed by the homeostasis model for assessment of insulin resistance was reported as showing a 32.7% decrement after 6 months orlistat and 39.2% decrement after 6 months metformin therapy. We detected 22% decrement on HOMA-IR after 3 months orlistat therapy.

Studies suggest that the ‘desired’ weight loss of obese patients is 2–3 times greater (a 22–34% reduction in body weight) than the feasible and health-promoting levels that are recommended by physicians.11 However, an overwhelming majority of studies have shown that monodrug therapy may not be enough to reach patient targets. In light of these considerations, the opinion of polypharmacy has risen.19, 20, 23 In this connection, an additional effect of metformin plus orlistat therapy on weight loss and insulin resistance is expected. Surprisingly, on the contrary to our hypothesis, the combination of metformin and orlistat therapy did not significantly induce greater weight loss and decrement on insulin resistance as compared to orlistat alone.

Recently, Wadden et al32 reported that the addition of orlistat to sibutramine did not induce further weight loss as compared to treatment by sibutramine alone. However, their results should be interpreted with caution, because of the study that did not include combination therapy initially. In similar, our study has two major limitations, which are the relatively short study period and relatively small sample size. The estimated power for two-sample comparison of weight loss was 28% in our study.

The effect of orlistat and metformin therapy on serum lipid levels and its relation with weight loss is controversial.4, 12, 13, 14, 27, 28, 31 Orlistat and metformin were shown to reduce total cholesterol, LDL-cholesterol, and triglyceride levels in a previous trial.33 After 3-month metformin therapy, no significant change occurred in any lipid parameter in some reports.27, 32 The beneficial effects of metformin on serum lipids have been shown to be dose dependent.34 We have not noted any significant change in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglyceride levels in the two groups. We have recommenced a short study period using metformin dose, as have other researchers who have achieved greater patient improvement in lipid levels than other studies.

Metformin and orlistat therapies were well tolerated. The combination of these two medications did not appear to result in any unexpected side effects. Five patients in the combination group experienced mild gastrointestinal discomfort, which was transient.

In conclusion, these two regimens are effective in weight loss and insulin resistance in obese women. A combination of orlistat with metformin did not result in a significant additional effect on weight loss and insulin resistance when compared to orlistat alone. Our results should be interpreted with caution because of relatively low estimated statistically power. Therefore, new studies that have more sample sizes, a longer study period and, high statistically power are necessary for this purpose.

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Sari, R., Balci, M., Coban, E. et al. Comparison of the effect of orlistat vs orlistat plus metformin on weight loss and insulin resistance in obese women. Int J Obes 28, 1059–1063 (2004). https://doi.org/10.1038/sj.ijo.0802707

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Keywords

  • treatment
  • orlistat
  • metformin
  • combination

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