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      Metformin as an initial adjunct to low-dose liraglutide enhances the weight-decreasing potential of liraglutide in obese polycystic ovary syndrome: Randomized control study

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          Abstract

          Liraglutide (LIRA) treatment is associated with the dose-dependent reduction of weight. Higher doses are more effective than lower doses, although higher doses are also more poorly tolerated. Metformin may enhance the weight-lowering potential of LIRA via the stimulatory modulation of incretin in addition to its direct beneficial effects in PCOS. The aim of the present study was to evaluate whether metformin as an adjunct to low-dose LIRA affects body weight with increased efficacy compared with low-dose LIRA alone in obese patients with PCOS. In a 12-week study, 44 obese women with PCOS were randomly offered either combined treatment (COMBO) with 1,000 mg metformin twice a day and 1.2 mg LIRA once a day, or treatment with 1.2 mg LIRA alone. The primary outcome of treatment was an alteration in the levels of obesity. A total of 43 patients [aged 30.3±4.4 years; body mass index (BMI) 37.2±4.5 kg/m 2; mean ± standard deviation] completed the study. The subjects treated with COMBO lost on average 6.2±2.4 kg compared with a 3.8±3.5 kg weight loss in the patients treated with LIRA alone (P=0.024). The BMI decreased by 2.2±0.8 kg/m 2 in patients treated with COMBO and by 1.4±1.2 kg/m 2 in patients treated with LIRA alone (P=0.024). A clinically significant ≥5% weight reduction was achieved in 59.1% of patients treated with COMBO and 42.9% of patients treated with LIRA alone. Reductions in glucose levels following oral glucose tolerance testing, as well as in androstenedione levels in the COMBO group were significantly greater compared with those in the LIRA group. The side effects were mild and transient in the two treatment groups. A combination of metformin and low-dose LIRA was more effective than low-dose LIRA alone in reducing body weight in obese patients with PCOS.

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          Mechanism by which metformin reduces glucose production in type 2 diabetes.

          To examine the mechanism by which metformin lowers endogenous glucose production in type 2 diabetic patients, we studied seven type 2 diabetic subjects, with fasting hyperglycemia (15.5 +/- 1.3 mmol/l), before and after 3 months of metformin treatment. Seven healthy subjects, matched for sex, age, and BMI, served as control subjects. Rates of net hepatic glycogenolysis, estimated by 13C nuclear magnetic resonance spectroscopy, were combined with estimates of contributions to glucose production of gluconeogenesis and glycogenolysis, measured by labeling of blood glucose by 2H from ingested 2H2O. Glucose production was measured using [6,6-2H2]glucose. The rate of glucose production was twice as high in the diabetic subjects as in control subjects (0.70 +/- 0.05 vs. 0.36 +/- 0.03 mmol x m(-2) min(-1), P < 0.0001). Metformin reduced that rate by 24% (to 0.53 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0009) and fasting plasma glucose concentration by 30% (to 10.8 +/- 0.9 mmol/l, P = 0.0002). The rate of gluconeogenesis was three times higher in the diabetic subjects than in the control subjects (0.59 +/- 0.03 vs. 0.18 +/- 0.03 mmol x m(-2) min(-1) and metformin reduced that rate by 36% (to 0.38 +/- 0.03 mmol x m(-2) x min(-1), P = 0.01). By the 2H2O method, there was a twofold increase in rates of gluconeogenesis in diabetic subjects (0.42 +/- 0.04 mmol m(-2) x min(-1), which decreased by 33% after metformin treatment (0.28 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0002). There was no glycogen cycling in the control subjects, but in the diabetic subjects, glycogen cycling contributed to 25% of glucose production and explains the differences between the two methods used. In conclusion, patients with poorly controlled type 2 diabetes have increased rates of endogenous glucose production, which can be attributed to increased rates of gluconeogenesis. Metformin lowered the rate of glucose production in these patients through a reduction in gluconeogenesis.
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            Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis.

            BACKGROUND Polycystic ovary syndrome (PCOS) is closely associated with obesity but the prevalence of obesity varies between published studies. The objective of this research was to describe the prevalence of overweight, obesity and central obesity in women with and without PCOS and to assess the confounding effect of ethnicity, geographic regions and the diagnostic criteria of PCOS on the prevalence. METHODS MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL) and PSYCINFO were searched for studies reporting the prevalence of overweight, obesity or central obesity in women with and without PCOS. Data were presented as prevalence (%) and risk ratio (RR) [95% confidence interval (CI)]. Random-effect models were used to calculate pooled RR. RESULTS This systematic review included 106 studies while the meta-analysis included 35 studies (15129 women). Women with PCOS had increased prevalence of overweight [RR (95% CI): 1.95 (1.52, 2.50)], obesity [2.77 (1.88, 4.10)] and central obesity [1.73 (1.31, 2.30)] compared with women without PCOS. The Caucasian women with PCOS had a greater increase in obesity prevalence than the Asian women with PCOS compared with women without PCOS [10.79 (5.36, 21.70) versus 2.31 (1.33, 4.00), P < 0.001 between subgroups). CONCLUSIONS Women with PCOS had a greater risk of overweight, obesity and central obesity. Although our findings support a positive association between obesity and PCOS, our conclusions are limited by the significant heterogeneity between studies and further studies are now required to determine the source of this heterogeneity. Clinical management of PCOS should include the prevention and management of overweight and obesity.
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              Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society.

              To summarize current evidence on lifestyle management (dietary, exercise, or behavioral interventions) of obesity in women with polycystic ovary syndrome (PCOS), to indicate gaps in knowledge, and to review the medical and surgical alternatives for weight management. Expert panel appointed by the Androgen Excess and PCOS Society (AEPCOS Society) to review the literature and draft the initial report after a consensus process via electronic communication. The initial report was reviewed and critiqued by all expert panel members and the AEPCOS Society Board of Directors and modified based on their comments. Lifestyle management should be used as the primary therapy in overweight and obese women with PCOS for the treatment of metabolic complications. For reproductive abnormalities, lifestyle modification may improve ovulatory function and pregnancy. Data are preliminary for improvement in pregnancy and live-birth rates, and further research is needed. There is currently no evidence that modifying dietary macronutrient composition offers additional benefits over conventional dietary approaches for weight loss, and further research is needed. Emerging evidence suggests that exercise offers additional benefits to dietary energy restriction for reproductive features of PCOS.
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                Author and article information

                Journal
                Exp Ther Med
                Exp Ther Med
                ETM
                Experimental and Therapeutic Medicine
                D.A. Spandidos
                1792-0981
                1792-1015
                April 2016
                16 February 2016
                16 February 2016
                : 11
                : 4
                : 1194-1200
                Affiliations
                [1 ]Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre, SI-1000 Ljubljana, Slovenia
                [2 ]Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia
                Author notes
                Correspondence to: Professor Andrej Janez, Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre, University of Ljubljana, Zaloška 7, SI-1000 Ljubljana, Slovenia, E-mail: andrej.janez@ 123456kclj.si
                Article
                ETM-0-0-3081
                10.3892/etm.2016.3081
                4812364
                27073422
                711c62c1-0c6b-43a9-8fd2-8ab2961af7a6
                Copyright: © Jensterle et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 27 July 2015
                : 08 December 2015
                Categories
                Articles

                Medicine
                low-dose liraglutide,metformin,obesity,weight loss,polycystic ovary syndrome
                Medicine
                low-dose liraglutide, metformin, obesity, weight loss, polycystic ovary syndrome

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