Soumya Ranjan Panda He is presently working as a senior Resident in the Department of Obstetrics and Gynecology, IMS,BHU, Varanasi, UP.
Background: Polycystic ovarian syndrome (PCOS), a commonly prevalent endocrinopathy among reproductive age group women, is most often associated with obesity. Increased insulin resistance appears to be the central pathophysiologic mechanism responsible for various complications of PCOS. This makes ‘weight loss’ as the first-line treatment approach in PCOS. So various trials have tried to compare metformin (an insulin-sensitizing agent) and orlistat (an anti-obesity drug) aiming to achieve weight loss and hence higher ovulation rate for the group of obese PCOS patients. Keeping an eye on all these background facts, we designed this systematic review and metaanalysis to compare the effects of metformin andorlistat on various aspects of PCOS and to pick the better among the two drugs.
Materials and Methods: This is a systemic review of randomized control trials that studied the effectiveness of orlistat versus metformin in terms of improvement in ovulation rate, weight loss, lipid profile, etc. Systematic literature search over the period January 2000–December 2016 was performed in the following electronic databases: Medline, embase, google scholar, pubmed and The Cochrane Library and only randomized controlled clinical trials were included in our study. All authors carefully went through all sources of information independently.
Results: According to this study, weight loss, testosterone level after 4 weeks of treatment, total serum cholesterol and triglyceride level showed significant fall in orlistattreated group.
Conclusion: Our review shows that orlistat is a more effective drug than metformin and should be the preferred drug in obese PCOS in combination with weight loss.
Keywords : Polycystic ovarian syndrome, Orlistat, Metformin, Obesity
Polycystic ovarian syndrome (PCOS) is the most commonly prevalent endocrinopathy of reproductive age group women and is characterized by chronic anovulation and androgen excess with the predominant clinical manifestation being oligomenorrhea, hirsutism, and acne. The prevalence is as high as 15% when Rotterdam criteria are used for its diagnosis [1]. Increased insulin resistance (IR) is the central pathophysiologic mechanism responsible for increased risk of developing type 2 diabetes, the adverse cardiovascular risk as well as androgen excess and infertility in PCOS patients. Obesity which has been recently designated as an epidemic is often associated with PCOS. The prevalence was 40–60% among women with PCOS [2]. This makes ‘weight loss’ as the first-line treatment approach in overweight PCOS women [2].
These pathophysiological mechanisms have led to trials involving pharmacotherapy like metformin (an insulinsensitizing agent) and orlistat (an anti-obesity drug) aiming to achieve weight loss and hence higher ovulation rate for the group of obese PCOS patients.
This is a systemic review of randomized control trials that studied the effectiveness of orlistat versus metformin in terms of improvement in ovulation rate, weight loss, lipid profile, etc.
Systematic literature search was performed in the following electronic databases: Medline, embase, google scholar, pubmed and The Cochrane Library. We performed a search over the period January 2000–December 2016 and only randomized controlled clinical trials (RCT) comparing the effects of orlistat and metformin were included. Search terms were as follows: ‘‘orlistat’’, ‘‘metformin’’, ‘‘polycystic ovary syndrome’’, ‘‘insulin resistance’’, etc. Six randomized control trials were eligible for our study. All authors carefully went through all sources of information independently. One review author extracted data from the included studies and the second author checked the extracted data. Information on the characteristics of a trial was extracted from each included trial. The characteristics of each study has been described in Table 1. All the statistical analysis was done using Statistical Software SPSS Version 20. Flow chart of the study selection is shown in Fig. 1.
As shown in Table 2, the ovulation rate is higher for orlistat group in the studies done by Metwally et al. [3] (40 vs. 25%; p value - 0.10) and Kumar et al. [4] (33.3 vs. 23.3%; p value - 0.418). On the contrary, Ghandi et al. [5] have shown higher ovulation rate for metformin (15% for orlistat group vs. 30% for metformin group; p value - 0.108). But none of these studies have statistically significant results.
In view of Table 3, Jayagopal et al. [6] showed that the reduction in weight and after treatment with orlistat was more significant than seen in the metformin-treated group (4.69 vs. 1.02%, p value - 0.006). Similarly according to Kujawska-Łuczak et al. [7], the percentage change of weight loss and BMI was more in orlistat-treated group than that of metformin (- 3.2 ± 0.8 vs. - 1.7 ± 0.4; p value \0.05 for weight loss and - 4.9 ± 1.3 vs. - 9.4 ± 2.3; p value\0.05 for BMI). On comparison, the difference between the above said groups was found to be statistically significant for the concerned parameters. On the other hand, the studies by Metwally et al. [3], Kumar et al. [4], Ghandi et al. [5] and Cho et al. [8] could not found a statistically significant result between both arms as far as weight loss or BMI is concerned (p value 0.40, 1.000, [0.05, 0.07 respectively for the above four studies).
Metwally et al. [3] have shown that there is a significant fall in testosterone level after 4 weeks of treatment with orlistat while for metformin this period appears to be 8 weeks, but without significant change in SHBG improvement in plasma concentrations of SHBG in any of the RCTs included in our study. So there must be other mechanisms that lead to decreased testosterone concentrations. The most logical explanation would be, moderate weight loss achieved by either metformin or orlistat, even though insufficient to improve serum SHBG concentrations, but may be sufficient enough to decrease serum testosterone levels via an attenuating effect on insulin like growth factor binding protein-I and thus inhibiting its stimulatory effect on P450c17a. (Thus decreased activity of P450c17a, leads to decreased levels of serum testosterone).
Although none of the RCTs showed any significant difference between effects of two drugs in terms of change in serum testosterone level, orlistat had its edge in preference to metformin as shown by Metwally et al. [3] and Ghandi et al. [5]. While orlistat showed an early effect (as early as 4 weeks) in the former study; metformin did not show any significant fall of serum testosterone level in the latter study. Also in another study, metformin reduced weight and waist circumference but did not affect testosterone level [11]. The delayed effect of metformin on androgen concentrations on some of the studies may indicate the need for a longer duration of therapy or may be a result of the initial low dose of metformin.
As shown by Ghandi et al. [5] and Kumar et al. [4] clearly orlistat has better effect than metformin in terms of improvement in lipid parameters.Cho et al. [8] showed a significant improvement in insulin resistance in the orlistat-treated arm only and the difference was statistically significant as compared to metformin-treated arm. Neither of the other two RCTs included in our systematic review showed any improvement in insulin resistance by any of the drugs.
This could be explained due to the large variability in HOMA-IR values, which can be prevented in the future studies using a larger study sample.
On summarizing our systemic review results (Table 7), the list of various aspects of PCOS that are found to be improved with orlistat treatment and bearing a statistically significant difference with that of metformin are: percentage change in BMI, percentage change in weight loss, serum LDL level, serum total cholesterol level and insulin resistance in terms of HOMA-IR. Nevertheless, nausea and diarrhoea are the side effects of metformin which reduce patients compliance and suitability of its use.
On the basis of our systematic review, we can now recommend to prefer orlistat over metformin for use in cases of PCOS, especially in conjunction with exercise. However, at this stage we need to address some of the common adverse effects and drug interactions of orlistat which should be kept in mind while prescribing this drug.
Common side effects, those have been identified with the consumption of orlistat, include increased bowel movement, oily stool, oily spotting and stomach pain [12]. But these gastrointenstinal adverse events generally resolve with ongoing orlistat treatment. Again as we have already discussed, treatment with metformin is also associated with similar gastrointenstinal side effects.
Some cases of serious liver injury have been reported since 1999. The US FDA review regarding the same identified a total of 13 cases of severe liver injury, between April 1999 and August 2009 out of an estimated 40 million people worldwide who had used orlistat. The U.S. FDA advised healthcare professionals to continue prescription of orlistat in August 2009, because severe liver injury was rare. Systemic adverse effects have rarely been reported with orlistat and, furthermore, many of the systemic adverse effects that have been associated with orlistat have not been reported in clinical trials, but in reports of weaker validity, such as case reports.
Chronic malabsorption syndrome or cholestasis is the contraindications for orlistat therapy.
Orlistat has been reported to interact with pharmacokinetics and pharmacodynamics of some drugs like fat-soluble vitamins, warfarin, amiodarone, ciclosporin, lamotrigine, valproic acid, vigabatrin, gabapentin, thyroxine [13]. To describe each and every interaction in detail is beyond the scope of this review. But here, we are highlighting some of the important interactions.
Orlistat is reported to cause decreased absorption of fat soluble vitamins. There is a significant reduction in absorption of betacarotene and vitamin E, but not vitamin A, in healthy volunteers with short-term use of orlistat [13]. In most of the studies although the plasma concentrations of fat soluble vitamins (A, D, E and betacarotene) decreased among subjects taking orlistat, but it remained within the clinical reference range during the entire study period [13].
To reduce the gastrointestinal events, orlistat should be taken with a low fat diet. Patients should be strongly encouraged to take a multivitamin supplement that contains fat-soluble vitamins to ensure adequate Nutrition.
Thyroxine absorption is influenced by the content of the GI tract. Orlistat may bind to thyroxine and prevent its absorption from the small bowel. Clinicians should be aware of this potential interference of this drug with thyroxine absorption [13]. Levothyroxine and orlistat should be administered at least 4 h apart.
Orlistat may reduce the absorption of fat-soluble vitamin K, thus resulting in a lowering of warfarin dose requirements. This is why patients on warfarin treatment should be closely monitored [13]. However, there is no conclusive evidence regarding the same.
At present, there is no guideline regarding the duration of use of orlistat for PCOS. However, based on the various randomized control trials that studied the various effects of orlistat, a treatment duration of minimum 3–6 month can be accepted as reasonable [3–8].
Relatively less number of study population of the RCTs included in our systematic review constitute the only relative limitation of our study. However, after gathering a lot of fact in favour of orlistat this systematic review can safely recommend it over metformin for treatment of PCOS.
Conflict of interest: The authors declare that they have no conflict of
interest.
