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Published in: BMC Endocrine Disorders 1/2017

Open Access 01-12-2017 | Research article

Short-term effectiveness of low dose liraglutide in combination with metformin versus high dose liraglutide alone in treatment of obese PCOS: randomized trial

Authors: Mojca Jensterle, Nika Aleksandra Kravos, Katja Goričar, Andrej Janez

Published in: BMC Endocrine Disorders | Issue 1/2017

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Abstract

Background

Liraglutide 3 mg was recently approved as an anti-obesity drug. Metformin is weight neutral, yet it could enhance the therapeutic index of GLP-1 agonist. We compared weight-lowering potential of liraglutide 1.2 mg in combination with metformin to liraglutide 3 mg monotherapy in obese PCOS.

Methods

Thirty obese women with PCOS (aged 33.1 ± 6.1 years, BMI 38.3 ± 5.4 kg/m2) were randomized to combination (COMBO) of metformin (MET) 1000 mg BID and liraglutide 1.2 mg QD (N = 15) or liraglutide 3 mg (LIRA3) QD alone (N = 15) for 12 weeks. The primary outcome was change in anthropometric measures of obesity.

Results

Both treatments led to significant weight loss (−3.6 ± 2.5 kg, p = 0.002 in COMBO vs −6.3 ± 3.7 kg, p = 0.001 in LIRA3). BMI and waist circumference reduction in LIRA3 was greater than in COMBO (−2.2 ± 1.3 vs −1.3 ± 0.9 kg/m2 , p = 0.05 and −4.2 ± 3.4 vs −2.2 ± 6.2 cm, p = 0.014, respectively). Both interventions resulted in a significant decrease of post-OGTT glucose levels. COMBO significantly reduced total testosterone and was associated with less nausea.

Conclusions

Short-term interventions with COMBO and LIRA3 both led to significant improvement of measures of obesity in obese PCOS, LIRA3 being superior to COMBO. However, COMBO further improved androgen profile beyond weight reduction and was associated with better tolerability.

Trial registration

The study was retrospectively registered with ClinicalTrials.gov (NCT02909933) on 16th of September 2016.
Literature
1.
go back to reference Lim SS, Davies MJ, Norman RJ, Moran LJ. Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2012;18:618–37.CrossRefPubMed Lim SS, Davies MJ, Norman RJ, Moran LJ. Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2012;18:618–37.CrossRefPubMed
2.
go back to reference Lass N, Kleber M, Winkel K, Wunsch R, Reinehr T. Effect of lifestyle intervention on features of polycystic ovarian syndrome, metabolic syndrome, and intima-media thickness in obese adolescent girls. J Clin Endocrinol Metab. 2011;96:3533–40.CrossRefPubMed Lass N, Kleber M, Winkel K, Wunsch R, Reinehr T. Effect of lifestyle intervention on features of polycystic ovarian syndrome, metabolic syndrome, and intima-media thickness in obese adolescent girls. J Clin Endocrinol Metab. 2011;96:3533–40.CrossRefPubMed
3.
go back to reference Crosignani PG, Colombo M, Vegetti W, Somigliana E, Gessati A, Ragni G. Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarian physiology and fertility rate induced by diet. Hum Reprod. 2003;18:1928–32.CrossRefPubMed Crosignani PG, Colombo M, Vegetti W, Somigliana E, Gessati A, Ragni G. Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarian physiology and fertility rate induced by diet. Hum Reprod. 2003;18:1928–32.CrossRefPubMed
4.
go back to reference Thomson RL, Buckley JD, Noakes M, Clifton PM, Norman RJ, Brinkworth GD. The effect of a hypocaloric diet with and without exercise training on body composition, cardiometabolic risk profile, and reproductive function in overweight and obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93:3373–80.CrossRefPubMed Thomson RL, Buckley JD, Noakes M, Clifton PM, Norman RJ, Brinkworth GD. The effect of a hypocaloric diet with and without exercise training on body composition, cardiometabolic risk profile, and reproductive function in overweight and obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93:3373–80.CrossRefPubMed
5.
go back to reference Avenell A, Broom J, Brown TJ, Poobalan A, Aucott L, Stearns SC, et al. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement. Health Technol Assess. 2004;8:1–182.CrossRef Avenell A, Broom J, Brown TJ, Poobalan A, Aucott L, Stearns SC, et al. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement. Health Technol Assess. 2004;8:1–182.CrossRef
6.
go back to reference Food and Drug Administration. FDA Guidance for Industry: developing products for weight management. 2007. Food and Drug Administration. FDA Guidance for Industry: developing products for weight management. 2007.
7.
go back to reference National Institute for Health and Clinical Excellence. Obesity - guidance on the prevention, identification, assessment and management of overweight and obesity in adults and children. NICE clinical guideline 43. 2006. National Institute for Health and Clinical Excellence. Obesity - guidance on the prevention, identification, assessment and management of overweight and obesity in adults and children. NICE clinical guideline 43. 2006.
8.
go back to reference Blonde L, Russell-Jones D. The safety and efficacy of liraglutide with or without oral antidiabetic drug therapy in type 2 diabetes: an overview of the LEAD 1–5 studies. Diabetes Obes Metab. 2009;11:26–34.CrossRefPubMed Blonde L, Russell-Jones D. The safety and efficacy of liraglutide with or without oral antidiabetic drug therapy in type 2 diabetes: an overview of the LEAD 1–5 studies. Diabetes Obes Metab. 2009;11:26–34.CrossRefPubMed
9.
go back to reference Astrup A, Rossner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374:1606–16.CrossRefPubMed Astrup A, Rossner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374:1606–16.CrossRefPubMed
10.
go back to reference Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjoth TV, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes the SCALE diabetes randomized clinical trial. Jama-J Am Med Assoc. 2015;314:687–99.CrossRef Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjoth TV, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes the SCALE diabetes randomized clinical trial. Jama-J Am Med Assoc. 2015;314:687–99.CrossRef
11.
go back to reference Vilsboll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ. 2012;344:d7771.CrossRefPubMedPubMedCentral Vilsboll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ. 2012;344:d7771.CrossRefPubMedPubMedCentral
12.
go back to reference Wilding JP, Overgaard RV, Jacobsen LV, Jensen CB, le Roux CW. Exposure-response analyses of liraglutide 3.0 mg for weight management. Diabetes Obes Metab. 2016;18:491–9.CrossRefPubMedPubMedCentral Wilding JP, Overgaard RV, Jacobsen LV, Jensen CB, le Roux CW. Exposure-response analyses of liraglutide 3.0 mg for weight management. Diabetes Obes Metab. 2016;18:491–9.CrossRefPubMedPubMedCentral
13.
go back to reference Palomba S, Falbo A, Zullo F, Orio Jr F. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr Rev. 2009;30:1–50.CrossRefPubMed Palomba S, Falbo A, Zullo F, Orio Jr F. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr Rev. 2009;30:1–50.CrossRefPubMed
14.
go back to reference Diamanti-Kandarakis E, Christakou CD, Kandaraki E, Economou FN. Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. Eur J Endocrinol. 2010;162:193–212.CrossRefPubMed Diamanti-Kandarakis E, Christakou CD, Kandaraki E, Economou FN. Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. Eur J Endocrinol. 2010;162:193–212.CrossRefPubMed
15.
go back to reference Dunaif A. Drug insight: insulin-sensitizing drugs in the treatment of polycystic ovary syndrome - a reappraisal. Nat Clin Pract Endoc. 2008;4:272–83.CrossRef Dunaif A. Drug insight: insulin-sensitizing drugs in the treatment of polycystic ovary syndrome - a reappraisal. Nat Clin Pract Endoc. 2008;4:272–83.CrossRef
16.
go back to reference Pasquali R, Gambineri A. Targeting insulin sensitivity in the treatment of polycystic ovary syndrome. Expert Opin Ther Targets. 2009;13:1205–26.CrossRefPubMed Pasquali R, Gambineri A. Targeting insulin sensitivity in the treatment of polycystic ovary syndrome. Expert Opin Ther Targets. 2009;13:1205–26.CrossRefPubMed
17.
go back to reference Panidis D, Tziomalos K, Papadakis E, Kandaraki EA, Katsikis I. The guidelines issued by the European society for human reproduction and embryology and the American society for reproductive medicine regarding the induction of ovulation with metformin in patients with the polycystic ovary syndrome potentially require reconsideration. Horm-Int J Endocrino. 2013;12:192–200. Panidis D, Tziomalos K, Papadakis E, Kandaraki EA, Katsikis I. The guidelines issued by the European society for human reproduction and embryology and the American society for reproductive medicine regarding the induction of ovulation with metformin in patients with the polycystic ovary syndrome potentially require reconsideration. Horm-Int J Endocrino. 2013;12:192–200.
18.
go back to reference Jensterle M, Goricar K, Janez A. Metformin as an initial adjunct to low-dose liraglutide enhances the weight-decreasing potential of liraglutide in obese polycystic ovary syndrome: Randomized control study. Exp Ther Med. 2016;11:1194–200.PubMedPubMedCentral Jensterle M, Goricar K, Janez A. Metformin as an initial adjunct to low-dose liraglutide enhances the weight-decreasing potential of liraglutide in obese polycystic ovary syndrome: Randomized control study. Exp Ther Med. 2016;11:1194–200.PubMedPubMedCentral
19.
go back to reference Maida A, Lamont BJ, Cao X, Drucker DJ. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-alpha in mice. Diabetologia. 2011;54:339–49.CrossRefPubMed Maida A, Lamont BJ, Cao X, Drucker DJ. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-alpha in mice. Diabetologia. 2011;54:339–49.CrossRefPubMed
20.
go back to reference Mannucci E, Ognibene A, Cremasco F, Bardini G, Mencucci A, Pierazzuoli E, et al. Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care. 2001;24:489–94.CrossRefPubMed Mannucci E, Ognibene A, Cremasco F, Bardini G, Mencucci A, Pierazzuoli E, et al. Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care. 2001;24:489–94.CrossRefPubMed
21.
go back to reference Mannucci E, Tesi F, Bardini G, Ognibene A, Petracca MG, Ciani S, et al. Effects of metformin on glucagon-like peptide-1 levels in obese patients with and without Type 2 diabetes. Diabetes, Nutrition Metab. 2004;17:336–42. Mannucci E, Tesi F, Bardini G, Ognibene A, Petracca MG, Ciani S, et al. Effects of metformin on glucagon-like peptide-1 levels in obese patients with and without Type 2 diabetes. Diabetes, Nutrition Metab. 2004;17:336–42.
22.
go back to reference Yasuda N, Inoue T, Nagakura T, Yamazaki K, Kira K, Saeki T, et al. Enhanced secretion of glucagon-like peptide 1 by biguanide compounds. Biochem Biophys Res Commun. 2002;298:779–84.CrossRefPubMed Yasuda N, Inoue T, Nagakura T, Yamazaki K, Kira K, Saeki T, et al. Enhanced secretion of glucagon-like peptide 1 by biguanide compounds. Biochem Biophys Res Commun. 2002;298:779–84.CrossRefPubMed
23.
go back to reference American Diabetes Association. Standards of medical care in diabetes-2013. Diabetes Care. 2013;36:S11–66. American Diabetes Association. Standards of medical care in diabetes-2013. Diabetes Care. 2013;36:S11–66.
24.
go back to reference Greco D. Normal pregnancy outcome after first-trimester exposure to liraglutide in a woman with Type 2 diabetes. Diabet Med. 2015;32:e29–30.CrossRefPubMed Greco D. Normal pregnancy outcome after first-trimester exposure to liraglutide in a woman with Type 2 diabetes. Diabet Med. 2015;32:e29–30.CrossRefPubMed
25.
go back to reference Dupont WD, Plummer Jr WD. Power and sample size calculations. A review and computer program. Control Clin Trials. 1990;11:116–28.CrossRefPubMed Dupont WD, Plummer Jr WD. Power and sample size calculations. A review and computer program. Control Clin Trials. 1990;11:116–28.CrossRefPubMed
26.
go back to reference Jensterle Sever M, Kocjan T, Pfeifer M, Kravos NA, Janez A. Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin. Eur J Endocrinol. 2014;170:451–9.CrossRefPubMedPubMedCentral Jensterle Sever M, Kocjan T, Pfeifer M, Kravos NA, Janez A. Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin. Eur J Endocrinol. 2014;170:451–9.CrossRefPubMedPubMedCentral
27.
go back to reference Jensterle M, Kravos NA, Pfeifer M, Kocjan T, Janez A. A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome. Hormones (Athens). 2015;14:81–90. Jensterle M, Kravos NA, Pfeifer M, Kocjan T, Janez A. A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome. Hormones (Athens). 2015;14:81–90.
28.
go back to reference Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes Relat Metab Disord. 1992;16:397–415.PubMed Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes Relat Metab Disord. 1992;16:397–415.PubMed
29.
go back to reference Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond). 2012;36:843–54.CrossRef Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond). 2012;36:843–54.CrossRef
30.
go back to reference Lean ME, Carraro R, Finer N, Hartvig H, Lindegaard ML, Rossner S, et al. Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults. Int J Obes (Lond). 2014;38:689–97.CrossRef Lean ME, Carraro R, Finer N, Hartvig H, Lindegaard ML, Rossner S, et al. Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults. Int J Obes (Lond). 2014;38:689–97.CrossRef
31.
go back to reference Davies MJ, Kela R, Khunti K. Liraglutide - overview of the preclinical and clinical data and its role in the treatment of type 2 diabetes. Diabetes Obes Metab. 2011;13:207–20.CrossRefPubMed Davies MJ, Kela R, Khunti K. Liraglutide - overview of the preclinical and clinical data and its role in the treatment of type 2 diabetes. Diabetes Obes Metab. 2011;13:207–20.CrossRefPubMed
Metadata
Title
Short-term effectiveness of low dose liraglutide in combination with metformin versus high dose liraglutide alone in treatment of obese PCOS: randomized trial
Authors
Mojca Jensterle
Nika Aleksandra Kravos
Katja Goričar
Andrej Janez
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Endocrine Disorders / Issue 1/2017
Electronic ISSN: 1472-6823
DOI
https://doi.org/10.1186/s12902-017-0155-9

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