Beyond diet and exercise: another option for patients with obesity and polycystic ovary syndrome?

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries (1American College of Obstetricians and GynecologistsACOG practice bulletin no. 194: polycystic ovary syndrome.Obstet Gynecol. 2018; 131: e157-e171Crossref PubMed Scopus (77) Google Scholar). Importantly, PCOS is also a metabolic disorder associated with obesity, diabetes mellitus, and cardiovascular disease (1American College of Obstetricians and GynecologistsACOG practice bulletin no. 194: polycystic ovary syndrome.Obstet Gynecol. 2018; 131: e157-e171Crossref PubMed Scopus (77) Google Scholar). Although having obesity is not a criterion for PCOS, up to 80% of women with PCOS are either overweight or have obesity (1American College of Obstetricians and GynecologistsACOG practice bulletin no. 194: polycystic ovary syndrome.Obstet Gynecol. 2018; 131: e157-e171Crossref PubMed Scopus (77) Google Scholar). For individuals diagnosed with PCOS, a multidisciplinary approach is an effective strategy to prevent various disease manifestations and improve the burden of health associated with conditions such as diabetes, obesity, and hypertension. Among patients who are overweight and those with obesity, weight loss is a key strategy for disease management. Indeed, a 5% weight loss has been shown to positively impact the endocrine system as evidenced by lowering of androgen levels and resumption of menses (1American College of Obstetricians and GynecologistsACOG practice bulletin no. 194: polycystic ovary syndrome.Obstet Gynecol. 2018; 131: e157-e171Crossref PubMed Scopus (77) Google Scholar). The use of lifestyle or behavioral modifications (i.e., diet and exercise), pharmacologic agents (i.e., orlistat), or surgical treatment for reduction in body weight in women with PCOS and obesity have been suggested as effective treatment strategies to improve ovarian function and metabolic or cardiovascular health (1American College of Obstetricians and GynecologistsACOG practice bulletin no. 194: polycystic ovary syndrome.Obstet Gynecol. 2018; 131: e157-e171Crossref PubMed Scopus (77) Google Scholar). The effectiveness of these treatment strategies must be balanced with the patient’s willingness to make lifestyle changes, the safety profiles of weight loss medications, and the comorbidities or long-term consequences associated with surgical procedures. Furthermore, few pharmacologic treatments have been recommended for weight loss in patients with PCOS. Although metformin is often used in women with PCOS who have clinical features of prediabetes or diabetes, this is typically used for the treatment or prevention of diabetes, not for obesity management.A class of medications used to treat type 2 diabetes mellitus has been recently approved for weight loss by the United States Food and Drug Administration (2Wadden T.A. Bailey T.S. Billings L.K. Davies M. Frias J.P. Koroleva A. et al.Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial.JAMA. 2021; 325: 1403-1413Crossref PubMed Scopus (150) Google Scholar). This class of medications falls under the category of glucagon-like peptide 1 receptor agonists (GLP1RAs). Glucagon-like peptide 1 receptors are found on beta cells of the pancreas and are involved in blood glucose control through the enhancement of insulin secretion from the pancreas (3Roder P.V. Wu B. Liu Y. Han W. Pancreatic regulation of glucose homeostasis.Exp Mol Med. 2016; 48: e219Crossref PubMed Scopus (355) Google Scholar). There are many different types of GLP1RAs, such as dulaglutide, exenatide, semaglutide, liraglutide, and exenatide, which differ mainly in their route of administration and dosage strength (3Roder P.V. Wu B. Liu Y. Han W. Pancreatic regulation of glucose homeostasis.Exp Mol Med. 2016; 48: e219Crossref PubMed Scopus (355) Google Scholar). In 2015, a randomized controlled trial (RCT) included 3,721 patients who were either overweight or had obesity and compared the effectiveness of daily injectable liraglutide with a placebo, reporting a mean loss of 8% body weight in the liraglutide group compared with 2.6% in the placebo group (4Pi-Sunyer X. Astrup A. Fujioka K. Greenway F. Halpern A. Krempf M. et al.A randomized, controlled trial of 3.0 mg of liraglutide in weight management.N Engl J Med. 2015; 373: 11-22Crossref PubMed Scopus (973) Google Scholar). This study was conducted over 56 weeks, and >63% of participants in the liraglutide group lost >5% of their body weight and 33.1% lost >10% of their body weight (4Pi-Sunyer X. Astrup A. Fujioka K. Greenway F. Halpern A. Krempf M. et al.A randomized, controlled trial of 3.0 mg of liraglutide in weight management.N Engl J Med. 2015; 373: 11-22Crossref PubMed Scopus (973) Google Scholar). Another RCT that used once-weekly semaglutide and included 611 participants who were either overweight or had obesity reported a statistically significant reduction in body weight (16% vs. 5.7%) in those treated with semaglutide vs. those treated with a placebo over 68 weeks (2Wadden T.A. Bailey T.S. Billings L.K. Davies M. Frias J.P. Koroleva A. et al.Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial.JAMA. 2021; 325: 1403-1413Crossref PubMed Scopus (150) Google Scholar). Thus, when combined with lifestyle modifications, GLP1RAs appear to result in significant weight loss in patients who are overweight and those with obesity.The RCT by Elkind-Hirsch et al. (5Elkind-Hirsch K.E. Chappell N. Shaler D. Storment J. Bellanger D. Liraglutide 3 mg on weight, body composition, hormonal and metabolic parameters in women with obesity and polycystic ovary syndrome: a randomized placebo-controlled phase 3 study.Fertil Steril. 2022; 118: 371-381Abstract Full Text Full Text PDF Scopus (2) Google Scholar) aimed to demonstrate the efficacy and safety of the glucagon-like peptide 1 analogue liraglutide vs. those of a placebo in the reduction of both weight and hyperandrogenism in women with obesity and PCOS. The 32-week study included a total of 82 women with PCOS (55 in the 3-mg liraglutide group and 27 in the placebo group). The main outcomes measured included body weight and free androgen index (FAI). The results for both the outcomes were statistically significant. The investigators found that more individuals in the liraglutide group achieved at least a 5% weight reduction compared with those in the placebo group (approximately 57% vs. 22%), with an average body weight change of 5.7% in the treatment group. Additionally, the liraglutide group had a reduced FAI compared with the placebo group, in which the FAI increased slightly. There were also noted improvements in menstrual cycle patterns and certain cardiometabolic parameters, such as triglyceride concentrations and triglyceride/high-density lipoprotein ratios. The most common adverse event noted was nausea (25.5% in the liraglutide group vs. 11% in the placebo cohort). The study concluded that 3 mg of liraglutide once daily is superior to a placebo for reducing body weight and androgenicity in nondiabetic women with obesity and PCOS. The strengths of the study include the importance of the study question, in-depth metabolic and endocrine assessment, and study design. Some of the limitations include the lack of gold-standard measures for various study variables, such as insulin sensitivity. Additionally, the study was limited to 32 weeks, which may have constrained the total weight loss and improvement in FAI. This may also explain why weight loss was not as high as previously reported in a general population of adults who were overweight and adults with obesity treated with liraglutide (4Pi-Sunyer X. Astrup A. Fujioka K. Greenway F. Halpern A. Krempf M. et al.A randomized, controlled trial of 3.0 mg of liraglutide in weight management.N Engl J Med. 2015; 373: 11-22Crossref PubMed Scopus (973) Google Scholar). At this time, it is unknown whether the differences in weight loss seen in the population with PCOS were due to the follow-up period, sample size, or, perhaps, a function of the underlying PCOS.In summary, the detrimental metabolic impact of PCOS and the expanding population of women of reproductive age who have obesity highlight the importance of actively helping our patients achieve weight loss. For a large proportion of patients, options beyond traditional diet and exercise are needed. This study demonstrates an important option for assisting patients who struggle with weight management. Future studies assessing long-term effects, reproductive outcomes, and diverse cohorts will be important to further add to this study and help inform patient care. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries (1American College of Obstetricians and GynecologistsACOG practice bulletin no. 194: polycystic ovary syndrome.Obstet Gynecol. 2018; 131: e157-e171Crossref PubMed Scopus (77) Google Scholar). Importantly, PCOS is also a metabolic disorder associated with obesity, diabetes mellitus, and cardiovascular disease (1American College of Obstetricians and GynecologistsACOG practice bulletin no. 194: polycystic ovary syndrome.Obstet Gynecol. 2018; 131: e157-e171Crossref PubMed Scopus (77) Google Scholar). Although having obesity is not a criterion for PCOS, up to 80% of women with PCOS are either overweight or have obesity (1American College of Obstetricians and GynecologistsACOG practice bulletin no. 194: polycystic ovary syndrome.Obstet Gynecol. 2018; 131: e157-e171Crossref PubMed Scopus (77) Google Scholar). For individuals diagnosed with PCOS, a multidisciplinary approach is an effective strategy to prevent various disease manifestations and improve the burden of health associated with conditions such as diabetes, obesity, and hypertension. Among patients who are overweight and those with obesity, weight loss is a key strategy for disease management. Indeed, a 5% weight loss has been shown to positively impact the endocrine system as evidenced by lowering of androgen levels and resumption of menses (1American College of Obstetricians and GynecologistsACOG practice bulletin no. 194: polycystic ovary syndrome.Obstet Gynecol. 2018; 131: e157-e171Crossref PubMed Scopus (77) Google Scholar). The use of lifestyle or behavioral modifications (i.e., diet and exercise), pharmacologic agents (i.e., orlistat), or surgical treatment for reduction in body weight in women with PCOS and obesity have been suggested as effective treatment strategies to improve ovarian function and metabolic or cardiovascular health (1American College of Obstetricians and GynecologistsACOG practice bulletin no. 194: polycystic ovary syndrome.Obstet Gynecol. 2018; 131: e157-e171Crossref PubMed Scopus (77) Google Scholar). The effectiveness of these treatment strategies must be balanced with the patient’s willingness to make lifestyle changes, the safety profiles of weight loss medications, and the comorbidities or long-term consequences associated with surgical procedures. Furthermore, few pharmacologic treatments have been recommended for weight loss in patients with PCOS. Although metformin is often used in women with PCOS who have clinical features of prediabetes or diabetes, this is typically used for the treatment or prevention of diabetes, not for obesity management. A class of medications used to treat type 2 diabetes mellitus has been recently approved for weight loss by the United States Food and Drug Administration (2Wadden T.A. Bailey T.S. Billings L.K. Davies M. Frias J.P. Koroleva A. et al.Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial.JAMA. 2021; 325: 1403-1413Crossref PubMed Scopus (150) Google Scholar). This class of medications falls under the category of glucagon-like peptide 1 receptor agonists (GLP1RAs). Glucagon-like peptide 1 receptors are found on beta cells of the pancreas and are involved in blood glucose control through the enhancement of insulin secretion from the pancreas (3Roder P.V. Wu B. Liu Y. Han W. Pancreatic regulation of glucose homeostasis.Exp Mol Med. 2016; 48: e219Crossref PubMed Scopus (355) Google Scholar). There are many different types of GLP1RAs, such as dulaglutide, exenatide, semaglutide, liraglutide, and exenatide, which differ mainly in their route of administration and dosage strength (3Roder P.V. Wu B. Liu Y. Han W. Pancreatic regulation of glucose homeostasis.Exp Mol Med. 2016; 48: e219Crossref PubMed Scopus (355) Google Scholar). In 2015, a randomized controlled trial (RCT) included 3,721 patients who were either overweight or had obesity and compared the effectiveness of daily injectable liraglutide with a placebo, reporting a mean loss of 8% body weight in the liraglutide group compared with 2.6% in the placebo group (4Pi-Sunyer X. Astrup A. Fujioka K. Greenway F. Halpern A. Krempf M. et al.A randomized, controlled trial of 3.0 mg of liraglutide in weight management.N Engl J Med. 2015; 373: 11-22Crossref PubMed Scopus (973) Google Scholar). This study was conducted over 56 weeks, and >63% of participants in the liraglutide group lost >5% of their body weight and 33.1% lost >10% of their body weight (4Pi-Sunyer X. Astrup A. Fujioka K. Greenway F. Halpern A. Krempf M. et al.A randomized, controlled trial of 3.0 mg of liraglutide in weight management.N Engl J Med. 2015; 373: 11-22Crossref PubMed Scopus (973) Google Scholar). Another RCT that used once-weekly semaglutide and included 611 participants who were either overweight or had obesity reported a statistically significant reduction in body weight (16% vs. 5.7%) in those treated with semaglutide vs. those treated with a placebo over 68 weeks (2Wadden T.A. Bailey T.S. Billings L.K. Davies M. Frias J.P. Koroleva A. et al.Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial.JAMA. 2021; 325: 1403-1413Crossref PubMed Scopus (150) Google Scholar). Thus, when combined with lifestyle modifications, GLP1RAs appear to result in significant weight loss in patients who are overweight and those with obesity. The RCT by Elkind-Hirsch et al. (5Elkind-Hirsch K.E. Chappell N. Shaler D. Storment J. Bellanger D. Liraglutide 3 mg on weight, body composition, hormonal and metabolic parameters in women with obesity and polycystic ovary syndrome: a randomized placebo-controlled phase 3 study.Fertil Steril. 2022; 118: 371-381Abstract Full Text Full Text PDF Scopus (2) Google Scholar) aimed to demonstrate the efficacy and safety of the glucagon-like peptide 1 analogue liraglutide vs. those of a placebo in the reduction of both weight and hyperandrogenism in women with obesity and PCOS. The 32-week study included a total of 82 women with PCOS (55 in the 3-mg liraglutide group and 27 in the placebo group). The main outcomes measured included body weight and free androgen index (FAI). The results for both the outcomes were statistically significant. The investigators found that more individuals in the liraglutide group achieved at least a 5% weight reduction compared with those in the placebo group (approximately 57% vs. 22%), with an average body weight change of 5.7% in the treatment group. Additionally, the liraglutide group had a reduced FAI compared with the placebo group, in which the FAI increased slightly. There were also noted improvements in menstrual cycle patterns and certain cardiometabolic parameters, such as triglyceride concentrations and triglyceride/high-density lipoprotein ratios. The most common adverse event noted was nausea (25.5% in the liraglutide group vs. 11% in the placebo cohort). The study concluded that 3 mg of liraglutide once daily is superior to a placebo for reducing body weight and androgenicity in nondiabetic women with obesity and PCOS. The strengths of the study include the importance of the study question, in-depth metabolic and endocrine assessment, and study design. Some of the limitations include the lack of gold-standard measures for various study variables, such as insulin sensitivity. Additionally, the study was limited to 32 weeks, which may have constrained the total weight loss and improvement in FAI. This may also explain why weight loss was not as high as previously reported in a general population of adults who were overweight and adults with obesity treated with liraglutide (4Pi-Sunyer X. Astrup A. Fujioka K. Greenway F. Halpern A. Krempf M. et al.A randomized, controlled trial of 3.0 mg of liraglutide in weight management.N Engl J Med. 2015; 373: 11-22Crossref PubMed Scopus (973) Google Scholar). At this time, it is unknown whether the differences in weight loss seen in the population with PCOS were due to the follow-up period, sample size, or, perhaps, a function of the underlying PCOS. In summary, the detrimental metabolic impact of PCOS and the expanding population of women of reproductive age who have obesity highlight the importance of actively helping our patients achieve weight loss. For a large proportion of patients, options beyond traditional diet and exercise are needed. This study demonstrates an important option for assisting patients who struggle with weight management. Future studies assessing long-term effects, reproductive outcomes, and diverse cohorts will be important to further add to this study and help inform patient care. Liraglutide 3 mg on weight, body composition, and hormonal and metabolic parameters in women with obesity and polycystic ovary syndrome: a randomized placebo-controlled-phase 3 studyFertility and SterilityVol. 118Issue 2PreviewTo study the efficacy and safety of the GLP-1 analog liraglutide 3 mg (LIRA 3 mg) vs. placebo (PL) for reduction of body weight (BW) and hyperandrogenism in women with obesity and polycystic ovary syndrome (PCOS). Full-Text PDF Open Access