Liraglutide and Metformin Combination on Weight Loss, Metabolic - Endocrine Parameters and Pregnancy Rate in Women With PCOS, Obesity and Infertility

Obesity Clinical Trial

Official title:

Effectiveness of the Combination Liraglutide and Metformin on Weight Loss, Metabolic - Endocrine Parameters and Pregnancy Rate in Women With Polycystic Ovarian Syndrome, Obesity and Infertility

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05952882
• Other study ID #: 08/23/DD-BVMD
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: November 1, 2023
• Est. completion date: December 31, 2025

Study information

• Verified date: October 2023
• Source: M? Ð?c Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and one of the leading causes of infertility. PCOS and obesity affect up to 12.5% - 48.3% Asian women, increase incidence of impaired glucose tolerance, type 2 diabetes and aggravate insulin resistance, cause ovulatory dysfunction and menstrual disorders, and negatively impact outcomes of Assited Reproductive Technology (ART), with higher miscarriage rate when receiving ART. Weight loss decrease insulin resistance and hyperandrogenism, improve ovulation rate and menstrual cycle, significantly higher conception and live birth rates. Weight loss prior to IVF procedures has been associated with significantly improved pregnancy rates (PR) and live birth rates. Furthermore, a decreased number of IVF cycles required to achieve a pregnancy has also been reported after weight loss interventions. Based on the principles of fetal programming, improving a lifestyle before conception might lead to improved longterm health of the offspring. Studies on the effect of anti-obesity medication combined with lifestyle changes on body weight and composition and metabolic - endocrine parameters and pregnancy rate in obese women diagnosed with PCOS are lacking. There is a growing need to develop pharmacologic interventions to improve metabolic function in women with polycystic ovary syndrome (PCOS).

Description:

The drug, liraglutide 3.0 mg was approved for chronic weight management in management in obese adults with an initial BMI of 30 kg/m2 or greater or in overweight adults BMI of 27 kg/m2 or greater with at least one weight-related co-morbid condition as an adjunct to a reduced-calorie diet and increased physical activity. Liraglutide is an acylated human glucagon-like peptide -1 (GLP-1) analog that binds to and activates the GLP-1 receptor. It lowers body weight through decreased caloric intake while stimulating insulin secretion and reducing glucagon via a glucose-dependent mechanism. For obesity management, patients may lose weight with GLP-1 receptor agonists due to other unique actions. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) can slow gastric emptying and increase satiety. While predictors of weight loss success for the general population are available (protein intake, weight loss medications), predictors of weight loss success may differ between normal and hyperandrogenic women. Glucagon-like peptide 1 agonists are linked with dose dependent weight lowering potential in different obesity related populations. The weight loss effects of GLP-1RAs previously demonstrated in diabetic and obese non-diabetic patients, offer a unique opportunity to expand the medical options available to patients with PCOS. Metformin was recommended for women with PCOS and obesity (BMI ≥ 25 kg/m2) or at metabolic risks and shown beneficial effects on menstrual disorders, anovulation, hyperandrogenism, and cardiovascular abnormalities.

The aim of this study was to evaluate the impact of liraglutide in combination with metformin compared to metformin alone on weight reduction, the multifaceted metabolic - endocrine disturbances, and oocyte and embryo quality, IVF PRs and cumulative PRs (IVF and spontaneous pregnancies) in infertile obese women with PCOS who had been previously poor responders to weight reduction with lifestyle modification.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 188
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Female gender

• 18-65 years of age

• Diagnosis of polycystic ovary syndrome according to the revised Rotterdam criteria (2003)

• BMI = 27 kg/m2

• Infertility

• Agree to participate in the study

Exclusion Criteria:

• Type 1 or type 2 diabetes.

• History of acute or chronic pancreatitis.

• Family or individual history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2

• Known hypersensitivity or contraindication to the use of GLP-1 receptor agonists.

• Used of hormonal drugs, drugs causing clinically significant weight changes and drugs affecting glucose tolerance for at least 8 weeks.

• Used a anti-androgen drugs for at least 4 weeks.

• History of malignancy requiring chemotherapy.

• History of taking antidiabetic drugs other than gestational diabetes or weight-loss drugs discontinued for at least 4 weeks.

• History of gastrectomy or device-based intervention to manage obesity

• Eating disorders (anorexia or bulimia) or digestive disorders.

• Substance abuse (Tobacco or alcohol)

• History of major depression or other serious mental disorder.

• Inability or refusal to adhere treatment regimens.

Related Conditions & MeSH terms

• Infertility
• Infertility, Female
• Obesity
• Polycystic Ovary Syndrome
• Syndrome
• Weight Loss

Intervention

Drug:
• Liraglutide + Metformin
Metformin XR (extended-release) was initiated at 750 mg once daily and increased to 1500 mg once daily after 2 week. Concomitantly, Liraglutide was initiated at a subcutaneous dose of 0.6 mg once daily for 1 week, then titrated in increments of 0.6 mg once daily every 1 to 3 weeks to a maintenance dose of 3.0 mg once daily for up to 12 weeks
• Metformin
Metformin XR (extended-release) was initiated at 750 mg once daily and increased to 1500 mg once daily after 2 week

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
M? Ð?c Hospital

References & Publications (27)

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Best D, Avenell A, Bhattacharya S. How effective are weight-loss interventions for improving fertility in women and men who are overweight or obese? A systematic review and meta-analysis of the evidence. Hum Reprod Update. 2017 Nov 1;23(6):681-705. doi: 1 — View Citation

Cena H, Chiovato L, Nappi RE. Obesity, Polycystic Ovary Syndrome, and Infertility: A New Avenue for GLP-1 Receptor Agonists. J Clin Endocrinol Metab. 2020 Aug 1;105(8):e2695-709. doi: 10.1210/clinem/dgaa285. — View Citation

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 Feb;162(2):193-212. doi: 10.1530/ — View Citation

Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989 Sep;38(9):1165-74. doi: 10.2337/diab.38.9.1165. — View Citation

Dunaif A. Drug insight: insulin-sensitizing drugs in the treatment of polycystic ovary syndrome--a reappraisal. Nat Clin Pract Endocrinol Metab. 2008 May;4(5):272-83. doi: 10.1038/ncpendmet0787. Epub 2008 Mar 25. — View Citation

Frossing S, Nylander M, Chabanova E, Frystyk J, Holst JJ, Kistorp C, Skouby SO, Faber J. Effect of liraglutide on ectopic fat in polycystic ovary syndrome: A randomized clinical trial. Diabetes Obes Metab. 2018 Jan;20(1):215-218. doi: 10.1111/dom.13053. E — View Citation

Han Y, Li Y, He B. GLP-1 receptor agonists versus metformin in PCOS: a systematic review and meta-analysis. Reprod Biomed Online. 2019 Aug;39(2):332-342. doi: 10.1016/j.rbmo.2019.04.017. Epub 2019 Apr 25. — View Citation

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 Endocrin — View Citation

Knudsen LB, Lau J. The Discovery and Development of Liraglutide and Semaglutide. Front Endocrinol (Lausanne). 2019 Apr 12;10:155. doi: 10.3389/fendo.2019.00155. eCollection 2019. — View Citation

Kort JD, Winget C, Kim SH, Lathi RB. A retrospective cohort study to evaluate the impact of meaningful weight loss on fertility outcomes in an overweight population with infertility. Fertil Steril. 2014 May;101(5):1400-3. doi: 10.1016/j.fertnstert.2014.01 — View Citation

Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, Welt CK; Endocrine Society. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013 Dec;98(12):4565-92. doi: — View Citation

Legro RS, Dodson WC, Kris-Etherton PM, Kunselman AR, Stetter CM, Williams NI, Gnatuk CL, Estes SJ, Fleming J, Allison KC, Sarwer DB, Coutifaris C, Dokras A. Randomized Controlled Trial of Preconception Interventions in Infertile Women With Polycystic Ovar — View Citation

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 Nov-Dec;18(6):618-37. doi: 10.1093/humupd/dms030. Epub 2012 Jul 4. — View Citation

Metwally M, Ong KJ, Ledger WL, Li TC. Does high body mass index increase the risk of miscarriage after spontaneous and assisted conception? A meta-analysis of the evidence. Fertil Steril. 2008 Sep;90(3):714-26. doi: 10.1016/j.fertnstert.2007.07.1290. Epub — View Citation

Norman RJ, Masters L, Milner CR, Wang JX, Davies MJ. Relative risk of conversion from normoglycaemia to impaired glucose tolerance or non-insulin dependent diabetes mellitus in polycystic ovarian syndrome. Hum Reprod. 2001 Sep;16(9):1995-8. doi: 10.1093/h — View Citation

Nylander M, Frossing S, Clausen HV, Kistorp C, Faber J, Skouby SO. Effects of liraglutide on ovarian dysfunction in polycystic ovary syndrome: a randomized clinical trial. Reprod Biomed Online. 2017 Jul;35(1):121-127. doi: 10.1016/j.rbmo.2017.03.023. Epub — View Citation

Palomba S, Falbo A, Zullo F, Orio F Jr. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr Rev. 2009 Feb;30(1):1-50. doi: 10.1210/er.2008-0030. Epub 2008 Dec 4. — View Citation

Panidis D, Farmakiotis D, Rousso D, Kourtis A, Katsikis I, Krassas G. Obesity, weight loss, and the polycystic ovary syndrome: effect of treatment with diet and orlistat for 24 weeks on insulin resistance and androgen levels. Fertil Steril. 2008 Apr;89(4) — View Citation

Practice Committee of the American Society for Reproductive Medicine. Electronic address: asrm@asrm.org; Practice Committee of the American Society for Reproductive Medicine. Obesity and reproduction: a committee opinion. Fertil Steril. 2021 Nov;116(5):12 — View Citation

Rosenfield RL, Ehrmann DA. The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited. Endocr Rev. 2016 Oct;37(5):467-520. doi: 10.1210/er.2015-1104. Epub 2016 Jul 26. — View Citation

Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004 Jan;19(1):41-7. doi: 10.1093/humrep/deh098. — View Citation

Salamun V, Jensterle M, Janez A, Vrtacnik Bokal E. Liraglutide increases IVF pregnancy rates in obese PCOS women with poor response to first-line reproductive treatments: a pilot randomized study. Eur J Endocrinol. 2018 Jul;179(1):1-11. doi: 10.1530/EJE-1 — View Citation

Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. — View Citation

Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, Rienzi L, Sunde A, Schmidt L, Cooke ID, Simpson JL, van der Poel S. The International Glossary on Infertility and Fertility Care, 2017. Fertil Steril. 2017 Sep;108(3):393-406. doi: — View Citation

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* Note: There are 27 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Absolute Body Weight (BW)	Treatment impact on change in body weight after 12 weeks of treatment.	12 weeks of treatment
Primary	Change in Percent Body Weight	Treatment effect on reducing body weight expressed as percent body weight loss from baseline	12 weeks of treatment
Secondary	Body Mass Index (BMI)	Treatment effect in reducing body mass	12 weeks of treatment
Secondary	Abdominal Adiposity (Waist Circumference [WC])	Treatment effect on loss of waist circumference (abdominal adiposity) with drug treatment	12 weeks of treatment
Secondary	Waist-to-Hip Ratio (WHR)	Change in central adiposity with treatment as measured by waist-to-hip ratio. A reduction in ratio indicates a decrease in truncal fat.	12 weeks of treatment
Secondary	Waist-to Height Ratio [WHtR]	Treatment effect on loss of central adiposity as determined by Waist-to Height Ratio. The lower the ratio indicates less abdominal adiposity.	12 weeks of treatment
Secondary	Total Fat Mass Evaluated by BIA	Treatment effect on reduction of fat mass (kg)	12 weeks of treatment
Secondary	Total Body Fat (%) by BIA (Bioelectrical Impedance Analysis) machine	Treatment effect on reduction of percent body fat by BIA	12 weeks of treatment
Secondary	Visceral Fat Level (VFL)	Treatment effect on reduction of visceral fat level by BIA	12 weeks of treatment
Secondary	Total lean body mass	Treatment impact on total lean body mass	12 weeks of treatment
Secondary	Glucose OGTT 0 min	Treatment effect on fasting glucose prior to an oral glucose tolerance test (OGTT)	12 weeks of treatment
Secondary	Glucose OGTT 120 min	Treatment effect on glucose measured at 120 minutes of an oral glucose tolerance test (OGTT)	12 weeks of treatment
Secondary	Insulin OGTT 0 min	Treatment effect on fasting insulin prior to an oral glucose tolerance test (OGTT)	12 weeks of treatment
Secondary	Insulin OGTT 120 min	Treatment effect on insulin measured at 120 minutes of an oral glucose tolerance test (OGTT)	12 weeks of treatment
Secondary	Fasting Insulin Sensitivity (HOMA-IR)	Treatment effect on the HOMA-IR which is an insulin resistance measured derived from fasting blood glucose and insulin . The higher the number the more insulin resistant.	12 weeks of treatment
Secondary	Matsuda Insulin Sensitivity Index Derived From the OGTT (SI OGTT)	The SI OGTT is a measure of peripheral insulin sensitivity derived from the insulin and glucoses measured during an OGTT. A increase in SI OGTTindicates greater insulin sensitivity	12 weeks of treatment
Secondary	Total Cholesterol Levels	Treatment impact on improving total cholesterol levels	12 weeks of treatment
Secondary	High Density Lipoprotein Cholesterol (HDL-C)	Impact of treatment on HDL levels after 12 weeks of treatment	12 weeks of treatment
Secondary	Triglyceride Levels (TRG)	Drug effect of TRG levels after treatment	12 weeks of treatment
Secondary	Low Density Lipoprotein Cholesterol (LDL-C)	Treatment impact on improving LDL-C after treatment	12 weeks of treatment
Secondary	Systolic Blood Pressure	Treatment impact on systolic blood pressure	12 weeks of treatment
Secondary	Diastolic Blood Pressure	Treatment impact on reducing diastolic blood pressure	12 weeks of treatment
Secondary	Menstrual Cycle Frequency	Drug treatment impact on normalization of cycle frequency (cycle every 28-30 days). All cycle data is expressed as number of menses annualized to one year.	12 weeks of treatment
Secondary	Free Androgen Index (FAI)	Drug treatment effect on free androgen levels as calculated as FAI= total testosterone (T) concentrations divided by sex hormone binding globulin (SHBG) levels. A higher score indicates a worse outcome (more androgenic).	12 weeks of treatment
Secondary	Total Testosterone Concentrations (T)	Drug treatment effect on total testosterone concentrations	12 weeks of treatment
Secondary	Sex Hormone Binding Globulin (SHBG)	Drug treatment effect on SHBG	12 weeks of treatment
Secondary	Adrenal Dehydroepiandrosterone Sulfate (DHEAS)	Treatment efficacy in reducing adrenal hyperandrogenism	12 weeks of treatment
Secondary	17(OH)-progesterone	Treatment efficacy in reducing adrenal hyperandrogenism	12 weeks of treatment
Secondary	Androstenedione	Drug treatment effect on androstenedione	12 weeks of treatment
Secondary	Progesterone	Drug treatment effect on progesterone	12 weeks of treatment
Secondary	Luteinizing Hormone (LH)	Drug treatment effect on LH	12 weeks of treatment
Secondary	Follicle Stimulating Hormone (FSH)	Drug treatment effect on FSH	12 weeks of treatment
Secondary	Ovary Volume	Treatment efficacy in reducing ovary volume	12 weeks of treatment
Secondary	Spontaneous Pregnancy Rate	Treatment effect on spontaneous pregnancy rate	12 months after treatment
Secondary	Assisted Reproductive Therapy Pregnancy Rate	Treatment effect on Assisted Reproductive Therapy Pregnancy Rate	12 months after treatment
Secondary	Cumulative Pregnancy Rate	Treatment effect on Cumulative Pregnancy Rate	12 months after treatment
Secondary	Total dosage gonadotropin (GNT)	Drug treatment impact on total dosage GNT	12 weeks of treatment
Secondary	No. of retrieved oocytes/patient	Drug treatment impact on No. of retrieved oocytes/patient	12 weeks of treatment
Secondary	No. of mature (MII) oocytes/patient	Drug treatment impact on No. of mature (MII) oocytes/patient	12 weeks of treatment
Secondary	Fertilization rate	Drug treatment impact on fertilization rate	12 weeks of treatment
Secondary	Oocyte degeneration rate	Drug treatment impact on oocyte degeneration rate	12 weeks of treatment
Secondary	Immaturity rate	Drug treatment impact on immaturity rate	12 weeks of treatment
Secondary	No. of embryos on day 5/patient	Drug treatment impact on No. of embryos on day 5/patient	12 weeks of treatment
Secondary	No. of blastocysts/patient	Drug treatment impact on No. of blastocysts/patient	12 weeks of treatment
Secondary	Blastulation rate	Drug treatment impact on blastulation rate	12 weeks of treatment
Secondary	No. of transferred embryos	Drug treatment impact on No. of transferred embryos	12 weeks of treatment
Secondary	Pregnancy rate per cycle	Drug treatment impact on pregnancy rate per cycle	12 weeks of treatment
Secondary	Pregnancy rate per Embryo Transfer (ET)	Drug treatment impact on pregnancy rate per ET	12 weeks of treatment
Secondary	Implantation rate	Drug treatment impact on implantation rate	12 weeks of treatment
Secondary	No. of cancelled fresh Embryo Transfer (ET) because of hyperstimulation risk	Drug treatment impact on No. of cancelled fresh Embryo Transfer (ET because of hyperstimulation risk	12 weeks of treatment
Secondary	Cryopreservation	Drug treatment impact on cryopreservation	12 weeks of treatment
Secondary	No. of cryopreserved embryos/patient	Drug treatment impact on No. of cryopreserved embryos/patient	12 weeks of treatment
Secondary	Ectopic Pregnancy Rate	Drug treatment impact on Ectopic Pregnancy Rate	12 weeks of treatment
Secondary	Stillbirth Rate	Drug treatment impact on Stillbirth Rate	24 months after treatment
Secondary	Abortion Rate	Drug treatment impact on Abortion Rate	24 months after treatment
Secondary	Gestational Diabetes Mellitus Rate	Drug treatment impact on Gestational Diabetes Mellitus Rate	24 months after treatment
Secondary	Gestational hypertensive disorder (GHD) Rate	Drug treatment impact on Gestational hypertensive disorder (GHD) Rate	24 months after treatment
Secondary	Live Birth Rate	Drug treatment impact on Live Birth Rate	24 months after treatment
Secondary	Gestational age at birth	Drug treatment impact on gestational age at birth	24 months after treatment
Secondary	Type of Delivery Method	Drug treatment impact on Type of Delivery Method	24 months after treatment