Next Article in Journal
Nonlinear Adaptive Optimal Controller Design for Anti-Angiogenic Tumor Treatment
Next Article in Special Issue
Weighted Gene Co-Expression Network Analysis (WGCNA) Discovered Novel Long Non-Coding RNAs for Polycystic Ovary Syndrome
Previous Article in Journal
Conversion of M1 Macrophages to Foam Cells: Transcriptome Differences Determined by Sex
Previous Article in Special Issue
Modulating Morphological and Redox/Glycative Alterations in the PCOS Uterus: Effects of Carnitines in PCOS Mice
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomedicines
Volume 11
Issue 2
10.3390/biomedicines11020496
biomedicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Communication

Pharmacological Management of Obesity in Patients with Polycystic Ovary Syndrome

by
Christodoula Kourtidou
and
Konstantinos Tziomalos
*
First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece
*
Author to whom correspondence should be addressed.
Biomedicines 2023, 11(2), 496; https://doi.org/10.3390/biomedicines11020496
Submission received: 26 December 2022 / Revised: 3 February 2023 / Accepted: 7 February 2023 / Published: 8 February 2023
(This article belongs to the Special Issue Molecular Research on Polycystic Ovary Syndrome (PCOS) 2.0)
Versions Notes

Abstract

:
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. A substantial proportion of patients with PCOS are either overweight or obese, and excess body weight aggravates the hormonal, reproductive and metabolic manifestations of PCOS. In recent years, several studies evaluated the role of various pharmacological agents in the management of obesity in this population. Most reports assessed glucagon-like peptide-1 receptor agonists and showed a substantial reduction in body weight. More limited data suggest that sodium-glucose cotransporter-2 inhibitors and phosphodiesterase-4 inhibitors might also be effective in the management of obesity in these patients. In the present review, we discuss the current evidence on the safety and efficacy of these agents in overweight and obese patients with PCOS.

1. Introduction

The prevalence of obesity has rapidly increased over the past 25 years worldwide [1]. Obesity is associated with an increased risk for cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), cancer, chronic kidney disease, musculoskeletal disorders and reduced life expectancy [1,2]. On the other hand, polycystic ovary syndrome (PCOS) represents the commonest endocrine disorder among women of reproductive age [3,4]. The prevalence of PCOS varies depending on the diagnostic criteria applied; according to the diagnostic criteria of the National Institutes of Health, Rotterdam, and Androgen Excess and PCOS Society, the prevalence of PCOS is approximately 6%, 10% and 15%, respectively [5]. The components of PCOS are androgen excess, polycystic ovarian morphology and dysfunction in ovulation [6]. PCOS is linked to various metabolic disorders, including obesity, insulin resistance, T2DM and CVD [7,8,9,10].
Approximately 50–80% of patients with PCOS are obese [6,11]. In addition, women with PCOS predominantly have visceral adiposity [12]. Obesity affects fertility [13] and is associated with a worse metabolic profile in patients with PCOS [14]. Several epidemiologic studies suggested that weight loss and adipose fat loss improve fertility and ovulation rates in obese women with PCOS [15,16,17]. Indeed, a 5–10% weight loss is sufficient to ameliorate the metabolic and reproductive abnormalities in patients with PCOS [18].
Lifestyle changes represent the cornerstone of the management of obesity in patients with PCOS [18]. However, weight loss is frequently suboptimal, even in patients who adhere to lifestyle recommendations [18]. Moreover, weight regain often occurs in patients who originally lose weight [18]. Accordingly, several drugs, including orlistat, metformin and sibutramine, have been evaluated in the past for the management of obesity in PCOS [19,20]. However, these agents appear to have limited efficacy and/or unfavorable safety profile [19,20]. The aim of the present review is to summarize the evidence regarding the role of emerging pharmacologic agents for the treatment of obesity in patients with PCOS.

2. Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists

GLP-1 receptor agonists enhance glucose-dependent insulin secretion and inhibit glucagon release [21]. GLP-1 receptor agonists are currently indicated for the treatment of T2DM and obesity [22]. GLP-1 receptor agonists induce weight loss in patients with or without T2DM [23,24,25,26]. The effect of GLP-1 receptor agonists on weight control could be partly explained by the altered appetite signaling and the prolonged gastric emptying [27,28] mediated by several neural pathways [29,30]. Several preclinical studies evaluated the potential mechanisms underpinning the effect of GLP-1 receptor agonists on body weight and adiposity [31,32,33,34]. These studies showed the potential relationship between GLP-1 agonism and inhibition of fatty acid synthase expression [31], brown adipose tissue thermogenesis mediated by AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT-1) [32,34] and lipolysis and fatty acid oxidation mediated by SIRT-1 [33].
A number of studies evaluated the effect of GLP-1 agonists on weight in patients with PCOS (Table 1). Most of these studies assessed liraglutide at the dose of 1.2–1.8 mg/day, i.e., the dose recommended for the management of T2DM. In a double-blind trial, 65 overweight women with PCOS were randomized to receive liraglutide 1.8 mg/day or a placebo for 26 weeks [35]. Treatment with liraglutide resulted in a mean reduction in body weight of 5.2 kg, body mass index (BMI) of 1.8 kg/m2, total body fat mass of 2.8 kg and visceral adipose tissue (VAT) of 21.9 cm3, more than placebo [35]. In a 12-week, open-label, randomized study of 28 obese women with a new diagnosis of PCOS, liraglutide 1.2 mg/day and metformin 1000 bid induced similar reductions in weight (−2.52 kg), BMI (−0.98 kg/m2), waist circumference (−3.38 cm) and total body fat mass (−1.26%) [36].
A number of studies evaluated liraglutide in patients with PCOS who had inadequate weight loss response to metformin before the intervention (<5 kg or <5% weight loss). In an open-label, prospective study of 36 obese women with PCOS, patients were randomly assigned to metformin 1000 mg bid or liraglutide 1.2 mg/day or the combination of metformin 1000 mg bid and liraglutide 1.2 mg/day [37]. After 12 weeks, 22% and 16% of the patients in the combination treatment and liraglutide monotherapy group lost ≥5% body weight compared with none in the metformin monotherapy group [37]. In an observational study of 84 overweight/obese women with PCOS, treatment with liraglutide 1.2–1.8 mg/day for a mean period of 27.8 weeks induced a reduction in weight of 9.0 kg and a reduction in BMI of 3.2 kg/m2 [38]. In another study of 36 obese patients with PCOS, a transition from metformin to liraglutide 1.2 mg/day for 12 weeks reduced weight by 3.8 kg [39].
Table
Table 1. Major studies evaluating the effects of glucagon-like peptide-1 (GLP-1) receptor agonists on obesity in patients with polycystic ovary syndrome.
Table 1. Major studies evaluating the effects of glucagon-like peptide-1 (GLP-1) receptor agonists on obesity in patients with polycystic ovary syndrome.
ReferenceGLP-1 AgonistnFollow-Up
(Weeks)		Baseline Body Mass Index
(kg/m2)		Lifestyle InterventionMetformin TreatmentMain Results
[35]Liraglutide 1.2–1.8 mg/day652633.3NoNoGreater reduction in body weight than placebo
[36]Liraglutide 1.2 mg/day281239.5NoComparator armSimilar weight loss with metformin
[40]Liraglutide 3.0 mg/day673242.7Diet and exerciseNo57% experienced ≥5% weight loss compared with 22% in the placebo group
[41]Liraglutide 3.0 mg/day281238.3Diet and exerciseComparator armGreater reduction in body mass index and waist circumference and waist circumference than metformin 1000 mg bid and liraglutide 1.2 mg/day
Few studies evaluated the effects of liraglutide 3.0 mg/day, i.e., the dose indicated for the management of obesity. In a 32-week, randomized, double-blind, placebo-controlled trial of 67 obese women with PCOS, 57% of patients treated with liraglutide 3 mg/day experienced ≥5% weight loss compared with 22% in the placebo group [40]. Patients treated with liraglutide also experienced greater reductions in BMI (2.5 vs. 0.5 kg/m2), waist circumference (10 vs. 6 cm) and total body % fat (1.6 vs. 0.3%) compared with placebo. In a 12-week, randomized, open-label study of 28 obese patients with PCOS, the combination of metformin 1000 mg bid and liraglutide 1.2 mg/day induced similar weight loss with liraglutide 3 mg/day (3.6 vs. 6.3 kg, respectively) but the latter was associated with a greater reduction in BMI (1.3 vs. 2.2 kg/m2, respectively) and waist circumference (2.2 vs. 4.2 cm, respectively) [41]. In a meta-analysis of three randomized controlled studies, liraglutide reduced body weight more than metformin [42].
Several older studies evaluated another GLP-1 receptor agonist, exenatide, in overweight or obese patients with PCOS. In an open-label study of 20 overweight/obese patients with PCOS, exenatide 5 μg bid for 4 weeks and 10 μg bid for another 12 weeks reduced weight by 3%, reduced BMI by 1.2 kg/m2 and hip circumference by 3.0 cm but had no effect on waist circumference [43]. Compared with metformin, in a 24-week, open-label, randomized study of 158 overweight/obese patients with PCOS, exenatide 10 μg bid reduced weight and total fat % by 2.0 kg and 3.56% more than metformin 1000 mg bid, respectively [44]. In another randomized, comparative study of 63 overweight/obese patients with PCOS, exenatide 10 μg bid for 12 weeks resulted in a greater reduction in weight (by 1.7 kg), BMI (by 0.7 kg/m2) and abdominal girth (by 3.0 cm) compared with metformin 1000 mg bid [45]. Finally, some studies evaluated the combination of exenatide with metformin compared with monotherapy. In an open-label, randomized study of 40 overweight/obese patients with PCOS, the combination of metformin 500 mg bid and exenatide 2 mg/day reduced weight, BMI and waist circumference more than metformin monotherapy (by 1.7 kg, 0.7 kg/m2 and 2.9 cm more, respectively) [46]. In a 24-week, open-label, randomized study of 42 overweight patients with PCOS, monotherapy with exenatide 10 μg bid and combination therapy with exenatide 10 μg bid and metformin 1000 mg bid resulted in greater weight loss (by 1.6 and 4.0 kg more, respectively) than monotherapy with metformin 1000 mg bid [47]. Abdominal girth decreased in the combination group at 24 weeks, whereas it increased in the metformin monotherapy group (by 6.0 and 0.5 cm, respectively) [47].
Another GLP-1 receptor agonist, semaglutide, is approved for the management of obesity and appears to be the most effective member of this class in terms of weight loss [48]. However, in a recent single-blind study of 20 obese patients with PCOS, semaglutide 1.0 mg once weekly administered for 12 weeks induced similar weight loss with a placebo (5 and 2 kg, respectively) [49]. Tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic peptide (GIP) receptor agonist appears to induce even greater weight loss than semaglutide [48] but has not been evaluated in patients with PCOS.
GLP-1 receptor agonists were generally well-tolerated in these studies, and the most frequent adverse events were nausea and constipation [35,40].

3. Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

By blocking the degradation of GLP-1, DPP-4 inhibitors stimulate insulin secretion from pancreatic β-cells and inhibit glucagon secretion from pancreatic α-cells [50,51]. DPP-4 inhibitors are indicated for the treatment of T2DM [50,51]. In animal models, the DPP-4 inhibitor teneligliptin improved brown adipose tissue function, reduced body weight and fat mass and increased energy expenditure [51,52,53]. Furthermore, in mice, weight loss by DPP-4 inhibition was attributed to decreased food intake [54], greater energy expenditure and changes in the metabolic function of white adipose tissue [55]. Furthermore, DPP-4 inhibition was associated with improved energy expenditure and reduced adiposity mediated by GLP-1 and melanocortin-4 pathways [56]. However, in a rat model of PCOS, sitagliptin did not affect body weight [57].
Few studies evaluated the effects of DPP-4 inhibitors in patients with PCOS (Table 2). In a double-blind, randomized, placebo-controlled study of 18 overweight patients with PCOS, sitagliptin 100 mg/day for 1 month reduced VAT mass by 87.0 g and volume by 92.2 cm3 more than placebo [58]. In a randomized, open-label study of 28 obese patients with PCOS who had discontinued metformin, sitagliptin 100 mg/day combined with lifestyle intervention for 12 weeks, maintained body weight, waist circumference and VAT mass compared with an increase in these parameters with lifestyle intervention alone [59]. In a 12-week, randomized, open-label study of 24 obese patients with PCOS previously treated with liraglutide, sitagliptin 100 mg/day combined with metformin 1000 mg bid resulted in no change in weight, whereas monotherapy with metformin 1000 mg bid was associated with a weight gain of 4.7 kg [60]. In a randomized, single-blind study of 34 patients with PCOS, metformin 2000 mg/day, saxagliptin 5 mg, and the combination of saxagliptin 5 mg and metformin 2000 mg/day for 16 weeks induced similar reductions in BMI and waist circumference (by 0.8 kg/m2 and 2.5 cm, respectively) [61]. In these studies, the incidence of adverse events did not differ between patients who were treated with DPP-4 inhibitors and those who received a placebo or lifestyle intervention alone [58,59].

4. Sodium Glucose Contrasporter-2 (SGLT-2) Inhibitors

SGLT-2 inhibitors increase urinary glucose excretion by inhibiting renal glucose reabsorption and, in consequence, reduce hyperglycemia [62,63]. Apart from their role in the management of glycemia, SGLT-2 inhibitors facilitate weight loss [64,65]. The weight loss effect of SGLT-2 inhibitors was preserved in studies with follow-ups up to 4 years [66,67]. Several studies showed that in patients treated with SGLT-2 inhibitors, weight loss is accompanied by total body fat mass and VAT volume reduction [66,68]. SGLT-2 inhibitors enhance fat utilization and energy expenditure by the browning of fat [69,70]. In preclinical studies, canaglifozin and dapaglifozin increased sympathetic innervation [71,72] and enhanced mitochondrial function and fatty acid oxidation in adipose tissue [73]. Canaglifozin may enhance energy metabolism by activating the AMPK and SIRT-1 pathways [74] and activate lipolysis and fat mass reduction mediated by FGF21-related mechanisms [75]. Empagliflozin also reduced fat mass in a rat model [76].
In a 12-week, randomized, open-label study of 39 overweight or obese patients with PCOS, empagliflozin 25 mg/day reduced body weight, BMI, waist circumference, hip circumference and total body fat mass more than metformin 1500 mg/day (by 0.2%, 0.3%, 1.4%, 0.9% and 2.5%, respectively) (Table 3) [77]. In an open-label, randomized trial of 41 overweight/obese patients with PCOS, canaglifozin 100 mg/day combined with metformin 1000 mg bid for 3 months induced similar reductions in weight and BMI compared with metformin 1000 mg bid monotherapy (by 6.2 kg and 2.35 kg/m2, respectively) [78]. In a randomized, placebo-controlled, double-blind trial of 20 patients with PCOS, licogliflozin 50 mg tid, a dual SGLT1/2 inhibitor, did not induce weight loss after 2 weeks [79]. In a 24-week, randomized, single-blind study of 92 obese patients with PCOS, the combination of exenatide 2 mg weekly and dapaglifozin 10 mg/day induced similar body weight with phentermine/topiramate 7.5/46 mg per day and greater than exenatide or dapagliflozin monotherapy or dapaglifozin combined with metformin 2000 mg/day (by 6.0, 9.0, 4.1, 1.4 and 1.8 kg, respectively) [80]. The reduction in total body fat was also similar with exenatide/dapagliflozin combination and phentermine/topiramate and greater than exenatide or dapagliflozin monotherapy or dapaglifozin/metformin combination (by 1.8, 2.2, 0.8, 0.6 and 0.0%, respectively) [80]. Major studies that evaluated the effects of SGLT-2 inhibitors on obesity in patients with polycystic ovary syndrome are shown in Table 3. In these studies, the commonest adverse event in patients who received SGLT-2 inhibitors was genitourinary system infections [80].

5. Phosphodiesterase-4 (PDE-4) Inhibitors

PDE-4 inhibitors attenuate cAMP metabolism and its further signaling [81]. PDE-4 inhibitors have been evaluated for the treatment of several diseases, including chronic obstructive pulmonary disease [82] and metabolic disorders such as T2DM, obesity and hypertension [83]. Roflumilast, a PDE-4 inhibitor, has been associated with weight loss [84,85]. In overweight/obese patients, roflumilast was associated with reduced energy intake and decreased fat mass [86]. In mice, roflumilast prevented visceral fat and weight gain and reduced adipogenesis and lipolysis mediated by the AMPK pathway [87]. Other studies showed that PDE-4 inhibition lowers body weight by enhancing energy expenditure and lipolysis [88,89,90].
Only two studies evaluated the effects of PDE-4 inhibitors on obesity in patients with polycystic ovary syndrome (Table 4). In a 12-week, randomized, open-label study of 31 obese patients with PCOS, the combination of roflumilast 500 μg/day and metformin 1000 mg bid reduced body weight, BMI and VAT area more than metformin (by 3.3 kg, 2.5 kg/m2 and 36.9 cm2, respectively) [91]. In another 12-week, randomized, open-label study of 41 obese patients with PCOS, roflumilast 500 μg/day reduced body weight to a similar degree as liraglutide 1.2 mg/day and more than metformin 1000 mg bid (by 2.1, 3.1 and 0.2 kg, respectively) [92]. Nausea, diarrhea and headache were the most frequent adverse events in patients treated with roflumilast [92].

6. Conclusions

Several studies evaluated the safety and efficacy of various pharmacological agents in the management of obesity in patients with PCOS. However, most of these studies were small and had short follow-ups. Available evidence suggests that GLP-1 receptor agonists, particularly liraglutide, might represent the pharmacotherapy of choice in overweight/obese patients with PCOS. An important advantage of liraglutide is that it is licensed for the management of obesity. Other agents, including SGLT-2 inhibitors and PDE-4 inhibitors, also appear to be useful but are less well-studied in this population and are not yet licensed for weight loss. Even though GLP-1 receptor agonists are more expensive than DPP-4, SGLT-2 and PDE-4 inhibitors, they appear to be more cost-effective than the latter because they also induce considerably greater weight loss. Regarding the duration of treatment, it is possible that life-long therapy will be required to prevent weight regain. However, all these agents are contraindicated during pregnancy, and therefore appropriate contraceptive methods should be followed during treatment with these drugs. More studies are needed to evaluate whether combination therapy might be more effective than monotherapy in the management of obesity in PCOS. Moreover, all the studies that evaluated these agents in patients with PCOS had a short duration, and none assessed the effects of these treatments on cardiovascular morbidity. Therefore, larger studies with long follow-ups are needed to firmly establish the safety and efficacy of these therapies in patients with PCOS.

Author Contributions

C.K. wrote the first draft of the review. K.T. critically revised the draft. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. GBD 2015 Obesity Collaborators; Afshin, A.; Forouzanfar, M.H.; Reitsma, M.B.; Sur, P.; Estep, K.; Lee, A.; Marczak, L.; Mokdad, A.H.; Moradi-Lakeh, M.; et al. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N. Engl. J. Med. 2017, 377, 13–27. [Google Scholar] [CrossRef]
  2. Blüher, M. Obesity: Global epidemiology and pathogenesis. Nat. Rev. Endocrinol. 2019, 15, 288–298. [Google Scholar] [CrossRef]
  3. Lizneva, D.; Suturina, L.; Walker, W.; Brakta, S.; Gavrilova-Jordan, L.; Azziz, R. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil. Steril. 2016, 106, 6–15. [Google Scholar] [CrossRef]
  4. Goodarzi, M.O.; Dumesic, D.A.; Chazenbalk, G.; Azziz, R. Polycystic ovary syndrome: Etiology, pathogenesis and diagnosis. Nat. Rev. Endocrinol. 2011, 7, 219–231. [Google Scholar] [CrossRef]
  5. Bozdag, G.; Mumusoglu, S.; Zengin, D.; Karabulut, E.; Yildiz, B.O. The prevalence and phenotypic features of polycystic ovary syndrome: A systematic review and meta-analysis. Hum. Reprod. 2016, 31, 2841–2855. [Google Scholar] [CrossRef]
  6. Dumesic, D.A.; Oberfield, S.E.; Stener-Victorin, E.; Marshall, J.C.; Laven, J.S.; Legro, R.S. Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome. Endocr. Rev. 2015, 36, 487–525. [Google Scholar] [CrossRef]
  7. Zhu, T.; Cui, J.; Goodarzi, M.O. Polycystic Ovary Syndrome and Risk of Type 2 Diabetes, Coronary Heart Disease, and Stroke. Diabetes 2021, 70, 627–637. [Google Scholar] [CrossRef] [PubMed]
  8. Gilbert, E.W.; Tay, C.T.; Hiam, D.S.; Teede, H.J.; Moran, L.J. Comorbidities and complications of polycystic ovary syndrome: An overview of systematic reviews. Clin. Endocrinol. 2018, 89, 683–699. [Google Scholar] [CrossRef] [PubMed]
  9. Daan, N.M.; Louwers, Y.V.; Koster, M.P.; Eijkemans, M.J.; de Rijke, Y.B.; Lentjes, E.W.; Fauser, B.C.; Laven, J.S. Cardiovascular and metabolic profiles amongst different polycystic ovary syndrome phenotypes: Who is really at risk? Fertil. Steril. 2014, 102, 1444–1451.e3. [Google Scholar] [CrossRef]
  10. Anagnostis, P.; Tarlatzis, B.C.; Kauffman, R.P. Polycystic ovarian syndrome (PCOS): Long-term metabolic consequences. Metabolism 2018, 86, 33–43. [Google Scholar] [CrossRef]
  11. Lim, S.S.; Davies, M.J.; Norman, R.J.; Moran, L.J. Overweight, obesity and central obesity in women with polycystic ovary syndrome: A systematic review and meta-analysis. Hum. Reprod. Update 2012, 18, 618–637. [Google Scholar] [CrossRef]
  12. Durmus, U.; Duran, C.; Ecirli, S. Visceral adiposity index levels in overweight and/or obese, and non-obese patients with polycystic ovary syndrome and its relationship with metabolic and inflammatory parameters. J. Endocrinol. Investig. 2017, 40, 487–497. [Google Scholar] [CrossRef] [PubMed]
  13. Silvestris, E.; de Pergola, G.; Rosania, R.; Loverro, G. Obesity as disruptor of the female fertility. Reprod. Biol. Endocrinol. 2018, 16, 22. [Google Scholar] [CrossRef]
  14. Lim, S.S.; Norman, R.J.; Davies, M.J.; Moran, L.J. The effect of obesity on polycystic ovary syndrome: A systematic review and meta-analysis. Obes. Rev. 2013, 14, 95–109. [Google Scholar] [CrossRef] [PubMed]
  15. Legro, R.S.; Dodson, W.C.; Kunselman, A.R.; Stetter, C.M.; Kris-Etherton, P.M.; Williams, N.I.; Gnatuk, C.L.; Estes, S.J.; Allison, K.C.; Sarwer, D.B.; et al. Benefit of Delayed Fertility Therapy with Preconception Weight Loss over Immediate Therapy in Obese Women with PCOS. J. Clin. Endocrinol. Metab. 2016, 101, 2658–2666. [Google Scholar] [CrossRef]
  16. Kuchenbecker, W.K.; Groen, H.; van Asselt, S.J.; Bolster, J.H.; Zwerver, J.; Slart, R.H.; VdJagt, E.J.; Muller Kobold, A.C.; Wolffenbuttel, B.H.; Land, J.A.; et al. In women with polycystic ovary syndrome and obesity, loss of intra-abdominal fat is associated with resumption of ovulation. Hum. Reprod. 2011, 26, 2505–2512. [Google Scholar] [CrossRef]
  17. Legro, R.S.; Dodson, W.C.; Kris-Etherton, P.M.; Kunselman, A.R.; Stetter, C.M.; Williams, N.I.; Gnatuk, C.L.; Estes, S.J.; Fleming, J.; Allison, K.C.; et al. Randomized Controlled Trial of Preconception Interventions in Infertile Women with Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 2015, 100, 4048–4058. [Google Scholar] [CrossRef]
  18. Moran, L.J.; Pasquali, R.; Teede, H.J.; Hoeger, K.M.; Norman, R.J. Treatment of obesity in polycystic ovary syndrome: A position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil. Steril. 2009, 92, 1966–1982. [Google Scholar] [CrossRef] [PubMed]
  19. Glueck, C.J.; Goldenberg, N. Characteristics of obesity in polycystic ovary syndrome: Etiology, treatment, and genetics. Metabolism 2019, 92, 108–120. [Google Scholar] [CrossRef]
  20. Saleem, F.; Rizvi, S.W. New Therapeutic Approaches in Obesity and Metabolic Syndrome Associated with Polycystic Ovary Syndrome. Cureus 2017, 9, e1844. [Google Scholar] [CrossRef] [Green Version]
  21. Drucker, D.J. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab. 2018, 27, 740–756. [Google Scholar] [CrossRef]
  22. Drucker, D.J.; Habener, J.F.; Holst, J.J. Discovery, characterization, and clinical development of the glucagon-like peptides. J. Clin. Investig. 2017, 127, 4217–4227. [Google Scholar] [CrossRef]
  23. Astrup, A.; Rössner, S.; VanGaal, L.; Rissanen, A.; Niskanen, L.; AlHakim, M.; Madsen, J.; Rasmussen, M.F.; Lean, M.E.; NN8022-1807 Study Group. Effects of liraglutide in the treatment of obesity: A randomised, double-blind, placebo-controlled study. Lancet 2009, 374, 1606–1616. [Google Scholar] [CrossRef]
  24. Wilding, J.P.H.; Batterham, R.L.; Calanna, S.; Davies, M.; VanGaal, L.F.; Lingvay, I.; McGowan, B.M.; Rosenstock, J.; Tran, M.T.D.; Wadden, T.A.; et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N. Engl. J. Med. 2021, 384, 989–1002. [Google Scholar] [CrossRef]
  25. Vilsbøll, T.; Christensen, M.; Junker, A.E.; Knop, F.K.; Gluud, L.L. Effects of glucagon-like peptide-1 receptor agonists on weight loss: Systematic review and meta-analyses of randomized controlled trials. BMJ 2012, 344, d7771. [Google Scholar] [CrossRef]
  26. Le Roux, C.W.; Astrup, A.; Fujioka, K.; Greenway, F.; Lau, D.C.W.; Van Gaal, L.; Ortiz, R.V.; Wilding, J.P.H.; Skjøth, T.V.; Manning, L.S.; et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: A randomised, double-blind trial. Lancet 2017, 389, 1399–1409. [Google Scholar] [CrossRef] [PubMed]
  27. Seufert, J.; Gallwitz, B. The extra-pancreatic effects of GLP-1 receptor agonists: A focus on the cardiovascular, gastrointestinal and central nervous systems. Diabetes Obes. Metab. 2014, 16, 673–688. [Google Scholar] [CrossRef] [PubMed]
  28. Shah, M.; Vella, A. Effects of GLP-1 on appetite and weight. Rev. Endocr. Metab. Disord. 2014, 15, 181–187. [Google Scholar] [CrossRef] [PubMed]
  29. Gabery, S.; Salinas, C.G.; Paulsen, S.J.; Ahnfelt-Rønne, J.; Alanentalo, T.; Baquero, A.F.; Buckley, S.T.; Farkas, E.; Fekete, C.; Frederiksen, K.S.; et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight 2020, 5, e133429. [Google Scholar] [CrossRef]
  30. Baggio, L.L.; Drucker, D.J. Glucagon-like peptide-1 receptors in the brain: Controlling food intake and bodyweight. J. Clin. Investig. 2014, 124, 4223–4226. [Google Scholar] [CrossRef] [Green Version]
  31. Chen, J.; Zhao, H.; Ma, X.; Zhang, Y.; Lu, S.; Wang, Y.; Zong, C.; Qin, D.; Wang, Y.; Yang, Y.; et al. GLP-1/GLP-1R Signaling in Regulation of Adipocyte Differentiation and Lipogenesis. Cell. Physiol. Biochem. 2017, 42, 1165–1176. [Google Scholar] [CrossRef]
  32. Beiroa, D.; Imbernon, M.; Gallego, R.; Senra, A.; Herranz, D.; Villarroya, F.; Serrano, M.; Fernø, J.; Salvador, J.; Escalada, J.; et al. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 2014, 63, 3346–3358. [Google Scholar] [CrossRef]
  33. Xu, F.; Lin, B.; Zheng, X.; Chen, Z.; Cao, H.; Xu, H.; Liang, H.; Weng, J. GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1. Diabetologia 2016, 59, 1059–1069. [Google Scholar] [CrossRef]
  34. Zhou, J.; Poudel, A.; Chandramani-Shivalingappa, P.; Xu, B.; Welchko, R.; Li, L. Liraglutide induces beige fat development and promotes mitochondrial function in diet-induced obesity mice partially through AMPK-SIRT-1-PGC1-α cell signaling pathway. Endocrine 2019, 64, 271–283. [Google Scholar] [CrossRef]
  35. Frøssing, S.; Nylander, M.; Chabanova, E.; Frystyk, J.; Holst, J.J.; Kistorp, C.; Skouby, S.O.; Faber, J. Effect of liraglutide on ectopic fat in polycystic ovary syndrome: A randomized clinical trial. Diabetes Obes. Metab. 2018, 20, 215–218. [Google Scholar] [CrossRef]
  36. Jensterle, M.; Kravos, N.A.; 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 2015, 14, 81–90. [Google Scholar] [CrossRef]
  37. Jensterle Sever, M.; Kocjan, T.; Pfeifer, M.; Kravos, N.A.; 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, 451–459. [Google Scholar] [CrossRef]
  38. Rasmussen, C.B.; Lindenberg, S. The effect of liraglutide on weight loss in women with polycystic ovary syndrome: An observational study. Front. Endocrinol. 2014, 5, 140. [Google Scholar] [CrossRef]
  39. Jensterle, M.; Kocjan, T.; Kravos, N.A.; Pfeifer, M.; Janez, A. Short-term intervention with liraglutide improved eating behavior in obese women with polycystic ovary syndrome. Endocr. Res. 2015, 40, 133–138. [Google Scholar] [CrossRef] [PubMed]
  40. Elkind-Hirsch, K.E.; Chappell, N.; Shaler, D.; Storment, J.; Bellanger, D. 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 study. Fertil. Steril. 2022, 118, 371–381. [Google Scholar] [CrossRef]
  41. Jensterle, M.; Kravos, N.A.; Goričar, K.; Janez, A. Short-term effectiveness of low dose liraglutide in combination with metformin versus high dose liraglutide alone in treatment of obese PCOS: Randomized trial. BMC Endocr. Disord. 2017, 17, 5. [Google Scholar] [CrossRef] [PubMed]
  42. Ge, J.J.; Wang, D.J.; Song, W.; Shen, S.M.; Ge, W.H. The effectiveness and safety of liraglutide in treating overweight/obese patients with polycystic ovary syndrome: A meta-analysis. J. Endocrinol. Investig. 2022, 45, 261–273. [Google Scholar] [CrossRef] [PubMed]
  43. Dawson, A.J.; Sathyapalan, T.; Vince, R.; Coady, A.M.; Ajjan, R.A.; Kilpatrick, E.S.; Atkin, S.L. The Effect of Exenatide on Cardiovascular Risk Markers in Women with Polycystic Ovary Syndrome. Front. Endocrinol. 2019, 10, 189. [Google Scholar] [CrossRef] [PubMed]
  44. Liu, X.; Zhang, Y.; Zheng, S.Y.; Lin, R.; Xie, Y.J.; Chen, H.; Zheng, Y.X.; Liu, E.; Chen, L.; Yan, J.H.; et al. Efficacy of exenatide on weight loss, metabolic parameters and pregnancy in overweight/obese polycystic ovary syndrome. Clin. Endocrinol. 2017, 87, 767–774. [Google Scholar] [CrossRef]
  45. Zheng, S.; Liu, E.; Zhang, Y.; Long, T.; Liu, X.; Gong, Y.; Mai, T.; Shen, H.; Chen, H.; Lin, R.; et al. Circulating zinc-α2-glycoprotein is reduced in women with polycystic ovary syndrome, but can be increased by exenatide or metformin treatment. Endocr. J. 2019, 66, 555–562. [Google Scholar] [CrossRef]
  46. Ma, R.L.; Deng, Y.; Wang, Y.F.; Zhu, S.Y.; Ding, X.S.; Sun, A.J. Short-term combined treatment with exenatide and metformin for overweight/obese women with polycystic ovary syndrome. Chin. Med. J. 2021, 134, 2882–2889. [Google Scholar] [CrossRef]
  47. Elkind-Hirsch, K.; Marrioneaux, O.; Bhushan, M.; Vernor, D.; Bhushan, R. Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2008, 93, 2670–2678. [Google Scholar] [CrossRef]
  48. Alkhezi, O.S.; Alahmed, A.A.; Alfayez, O.M.; Alzuman, O.A.; Almutairi, A.R.; Almohammed, O.A. Comparative effectiveness of glucagon-like peptide-1 receptor agonists for the management of obesity in adults without diabetes: A network meta-analysis of randomized clinical trials. Obes. Rev. 2022. online ahead of print. [Google Scholar] [CrossRef]
  49. Jensterle, M.; Ferjan, S.; Ležaič, L.; Sočan, A.; Goričar, K.; Zaletel, K.; Janez, A. Semaglutide delays 4-hour gastric emptying in women with polycystic ovary syndrome and obesity. Diabetes Obes. Metab. 2022. online ahead of print. [Google Scholar] [CrossRef]
  50. Cahn, A.; Cernea, S.; Raz, I. Anupdate on DPP-4 inhibitors in the management of type 2 diabetes. Expert Opin. Emerg. Drugs 2016, 21, 409–419. [Google Scholar] [CrossRef]
  51. Stoian, A.P.; Sachinidis, A.; Stoica, R.A.; Nikolic, D.; Patti, A.M.; Rizvi, A.A. The efficacy and safety of dipeptidyl peptidase-4 inhibitors compared to other oral glucose-lowering medications in the treatment of type 2 diabetes. Metabolism 2020, 109, 154295. [Google Scholar] [CrossRef]
  52. Takeda, K.; Sawazaki, H.; Takahashi, H.; Yeh, Y.S.; Jheng, H.F.; Nomura, W.; Ara, T.; Takahashi, N.; Seno, S.; Osato, N.; et al. The dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin enhances brown adipose tissue function, thereby preventing obesity in mice. FEBS Open Bio. 2018, 8, 1782–1793. [Google Scholar] [CrossRef]
  53. Fukuda-Tsuru, S.; Kakimoto, T.; Utsumi, H.; Kiuchi, S.; Ishii, S. The novel dipeptidyl peptidase-4 inhibitor teneligliptin prevents high-fat diet-induced obesity accompanied with increased energy expenditure in mice. Eur. J. Pharmacol. 2014, 723, 207–215. [Google Scholar] [CrossRef]
  54. Lee, E.Y.; Kim, Y.W.; Oh, H.; Choi, C.S.; Ahn, J.H.; Lee, B.W.; Kang, E.S.; Cha, B.S.; Lee, H.C. Anti-obesity effects of KR-66195, a synthetic DPP-IV inhibitor, in diet-induced obese mice and obese-diabetic ob/ob mice. Metabolism 2014, 63, 793–799. [Google Scholar] [CrossRef]
  55. Chae, Y.N.; Kim, T.H.; Kim, M.K.; Shin, C.Y.; Jung, I.H.; Sohn, Y.S.; Son, M.H. Beneficial Effects of Evogliptin, a Novel Dipeptidyl Peptidase 4 Inhibitor, on Adiposity with Increased Ppargc1a in White Adipose Tissue in Obese Mice. PLoS ONE 2015, 10, e0144064. [Google Scholar] [CrossRef]
  56. Shimasaki, T.; Masaki, T.; Mitsutomi, K.; Ueno, D.; Gotoh, K.; Chiba, S.; Kakuma, T.; Yoshimatsu, H. The dipeptidyl peptidase-4 inhibitor des-fluoro-sitagliptinregulatesbrownadiposetissueuncouplingproteinlevels in mice with diet-induced obesity. PLoS ONE 2013, 8, e63626. [Google Scholar] [CrossRef]
  57. Wang, F.; Zhang, Z.F.; He, Y.R.; Wu, H.Y.; Wei, S.S. Effects of dipeptidyl peptidase-4 inhibitors on transforming growth factor-β1 signal transduction pathways in the ovarian fibrosis of polycystic ovary syndrome rats. J. Obstet. Gynaecol. Res. 2019, 45, 600–608. [Google Scholar] [CrossRef]
  58. Devin, J.K.; Nian, H.; Celedonio, J.E.; Wright, P.; Brown, N.J. Sitagliptin Decreases Visceral Fat and Blood Glucose in Women with Polycystic Ovarian Syndrome. J. Clin. Endocrinol. Metab. 2020, 105, 136–151. [Google Scholar] [CrossRef]
  59. Ferjan, S.; Janez, A.; Jensterle, M. Dpp4 Inhibitor Sitagliptin as a Potential Treatment Option in Metformin-Intolerant Obese Women with Polycystic Ovary Syndrome: A Pilot Randomized Study. Endocr. Pract. 2018, 24, 69–77. [Google Scholar] [CrossRef]
  60. Ferjan, S.; Janez, A.; Jensterle, M. Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Prevented Weight Regain in Obese Women with Polycystic Ovary Syndrome Previously Treated with Liraglutide: A Pilot Randomized Study. Metab. Syndr. Relat. Disord. 2017, 15, 515–520. [Google Scholar] [CrossRef]
  61. Elkind-Hirsch, K.E.; Paterson, M.S.; Seidemann, E.L.; Gutowski, H.C. Short-term therapy with combination dipeptidyl peptidase-4 inhibitor saxagliptin/metformin extended release (XR) is superior to saxagliptin or metformin XR monotherapy in prediabetic women with polycystic ovary syndrome: A single-blind, randomized, pilot study. Fertil. Steril. 2017, 107, 253–260.e1. [Google Scholar] [CrossRef] [PubMed]
  62. Abdul-Ghani, M.A.; Norton, L.; Defronzo, R.A. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr. Rev. 2011, 32, 515–531. [Google Scholar] [CrossRef] [PubMed]
  63. Mudaliar, S.; Polidori, D.; Zambrowicz, B.; Henry, R.R. Sodium-Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport: From Bench to Bedside. Diabetes Care 2015, 38, 2344–2353. [Google Scholar] [CrossRef] [PubMed]
  64. Ramírez-Rodríguez, A.M.; González-Ortiz, M.; Martínez-Abundis, E. Effect of Dapagliflozin on Insulin Secretion and Insulin Sensitivity in Patients with Prediabetes. Exp. Clin. Endocrinol. Diabetes 2020, 128, 506–511. [Google Scholar] [CrossRef] [PubMed]
  65. Lee, P.C.; Ganguly, S.; Goh, S.Y. Weight loss associated with sodium-glucose cotransporter-2 inhibition: A review of evidence and underlying mechanisms. Obes. Rev. 2018, 19, 1630–1641. [Google Scholar] [CrossRef]
  66. Bolinder, J.; Ljunggren, Ö.; Johansson, L.; Wilding, J.; Langkilde, A.M.; Sjöström, C.D.; Sugg, J.; Parikh, S. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes. Metab. 2014, 16, 159–169. [Google Scholar] [CrossRef]
  67. Del Prato, S.; Nauck, M.; Durán-Garcia, S.; Maffei, L.; Rohwedder, K.; Theuerkauf, A.; Parikh, S. Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data. Diabetes Obes. Metab. 2015, 17, 581–590. [Google Scholar] [CrossRef]
  68. Bolinder, J.; Ljunggren, Ö.; Kullberg, J.; Johansson, L.; Wilding, J.; Langkilde, A.M.; Sugg, J.; Parikh, S. Effects of dapagliflozin on bodyweight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J. Clin. Endocrinol. Metab. 2012, 97, 1020–1031. [Google Scholar] [CrossRef]
  69. Xu, L.; Nagata, N.; Nagashimada, M.; Zhuge, F.; Ni, Y.; Chen, G.; Mayoux, E.; Kaneko, S.; Ota, T. SGLT2 Inhibition by Empagliflozin Promotes Fat Utilization and Browning and Attenuates Inflammation and Insulin Resistance by Polarizing M2 Macrophages in Diet-induced Obese Mice. EBioMedicine 2017, 20, 137–149. [Google Scholar] [CrossRef]
  70. Xu, L.; Ota, T. Emerging roles of SGLT2 inhibitors in obesity and insulin resistance: Focus on fat browning and macrophage polarization. Adipocyte 2018, 7, 121–128. [Google Scholar] [CrossRef] [Green Version]
  71. Yang, X.; Liu, Q.; Li, Y.; Ding, Y.; Zhao, Y.; Tang, Q.; Wu, T.; Chen, L.; Pu, S.; Cheng, S.; et al. Inhibition of the sodium-glucose co-transporter SGLT2 by canagliflozin ameliorates diet-induced obesity by increasing intra-adipose sympathetic innervation. Br. J. Pharmacol. 2021, 178, 1756–1771. [Google Scholar] [CrossRef]
  72. Matthews, J.R.; Herat, L.Y.; Magno, A.L.; Gorman, S.; Schlaich, M.P.; Matthews, V.B. SGLT2 Inhibitor-Induced Sympathoexcitation in White Adipose Tissue: A Novel Mechanism for Beiging. Biomedicines 2020, 8, 514. [Google Scholar] [CrossRef]
  73. Wei, D.; Liao, L.; Wang, H.; Zhang, W.; Wang, T.; Xu, Z. Canagliflozin ameliorates obesity by improving mitochondrial function and fatty acid oxidation via PPARα in vivo and in vitro. Life Sci. 2020, 247, 117414. [Google Scholar] [CrossRef]
  74. Yang, X.; Liu, Q.; Li, Y.; Tang, Q.; Wu, T.; Chen, L.; Pu, S.; Zhao, Y.; Zhang, G.; Huang, C.; et al. The diabetes medication canagliflozin promotes mitochondrial remodelling of adipocytes via the AMPK-Sirt1-Pgc-1α signaling pathway. Adipocyte 2020, 9, 484–494. [Google Scholar] [CrossRef]
  75. Osataphan, S.; Macchi, C.; Singhal, G.; Chimene-Weiss, J.; Sales, V.; Kozuka, C.; Dreyfuss, J.M.; Pan, H.; Tangcharoenpaisan, Y.; Morningstar, J.; et al. SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms. JCI Insight 2019, 4, e123130. [Google Scholar] [CrossRef]
  76. Pruett, J.E.; Torres Fernandez, E.D.; Everman, S.J.; Vinson, R.M.; Davenport, K.; Logan, M.K.; Ye, S.A.; Romero, D.G.; Yanes Cardozo, L.L. Impact of SGLT-2 Inhibition on Cardiometabolic Abnormalities in a Rat Model of Polycystic Ovary Syndrome. Int. J. Mol. Sci. 2021, 22, 2576. [Google Scholar] [CrossRef]
  77. Javed, Z.; Papageorgiou, M.; Deshmukh, H.; Rigby, A.S.; Qamar, U.; Abbas, J.; Khan, A.Y.; Kilpatrick, E.S.; Atkin, S.L.; Sathyapalan, T. Effects of empagliflozin on metabolic parameters in polycystic ovary syndrome: A randomized controlled study. Clin. Endocrinol. 2019, 90, 805–813. [Google Scholar] [CrossRef]
  78. Zhang, J.; Xing, C.; Cheng, X.; He, B. Canagliflozin combined with metformin versus metformin monotherapy for endocrine and metabolic profiles in overweight and obese women with polycystic ovary syndrome: A single-center, open-labeled prospective randomized controlled trial. Front. Endocrinol. 2022, 13, 1003238. [Google Scholar] [CrossRef]
  79. Tan, S.; Ignatenko, S.; Wagner, F.; Dokras, A.; Seufert, J.; Zwanziger, D.; Dunschen, K.; Zakaria, M.; Huseinovic, N.; Basson, C.T.; et al. Licogliflozin versus placebo in women with polycystic ovary syndrome: A randomized, double-blind, phase 2 trial. Diabetes Obes. Metab. 2021, 23, 2595–2599. [Google Scholar] [CrossRef]
  80. Elkind-Hirsch, K.E.; Chappell, N.; Seidemann, E.; Storment, J.; Bellanger, D. Exenatide, Dapagliflozin, or Phentermine/Topiramate Differentially Affect Metabolic Profiles in Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab. 2021, 106, 3019–3033. [Google Scholar] [CrossRef]
  81. Spina, D. PDE4 inhibitors: Current status. Br. J. Pharmacol. 2008, 155, 308–315. [Google Scholar] [CrossRef] [PubMed]
  82. Schick, M.A.; Schlegel, N. Clinical Implication of Phosphodiesterase-4-Inhibition. Int. J. Mol. Sci. 2022, 23, 1209. [Google Scholar] [CrossRef] [PubMed]
  83. Wu, C.; Rajagopalan, S. Phosphodiesterase-4 inhibition as a therapeutic strategy for metabolic disorders. Obes. Rev. 2016, 17, 429–441. [Google Scholar] [CrossRef] [PubMed]
  84. Calverley, P.M.; Rabe, K.F.; Goehring, U.M.; Kristiansen, S.; Fabbri, L.M.; Martinez, F.J.; M2-124 and M2-125 Study Groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: Two randomised clinical trials. Lancet 2009, 374, 685–694. [Google Scholar] [CrossRef]
  85. Fabbri, L.M.; Calverley, P.M.; Izquierdo-Alonso, J.L.; Bundschuh, D.S.; Brose, M.; Martinez, F.J.; Rabe, K.F.; M2-127 and M2-128 Study Groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long acting bronchodilators: Two randomized clinical trials. Lancet 2009, 374, 695–703. [Google Scholar] [CrossRef]
  86. Muo, I.M.; MacDonald, S.D.; Madan, R.; Park, S.J.; Gharib, A.M.; Martinez, P.E.; Walter, M.F.; Yang, S.B.; Rodante, J.A.; Courville, A.B.; et al. Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss—Results of an exploratory study. Diabetes Metab. Syndr. Obes. 2019, 12, 743–759. [Google Scholar] [CrossRef]
  87. Xu, W.; Zhang, J.; Xiao, J. Roflumilast Suppresses Adipogenic Differentiation via AMPK Mediated Pathway. Front. Endocrinol. 2021, 12, 662451. [Google Scholar] [CrossRef]
  88. Möllmann, J.; Kahles, F.; Lebherz, C.; Kappel, B.; Baeck, C.; Tacke, F.; Werner, C.; Federici, M.; Marx, N.; Lehrke, M. The PDE4 inhibitor roflumilast reduces weight gain by increasing energy expenditure and leads to improved glucose metabolism. Diabetes Obes. Metab. 2017, 19, 496–508. [Google Scholar] [CrossRef]
  89. Kraynik, S.M.; Miyaoka, R.S.; Beavo, J.A. PDE3 and PDE4 isozyme-selective inhibitors are both required for synergistic activation of brown adipose tissue. Mol. Pharmacol. 2013, 83, 1155–1165. [Google Scholar] [CrossRef]
  90. Wang, H.; Edens, N.K. mRNA expression and antilipolyticrole of phosphodiesterase 4 in rat adipocytes in vitro. J. Lipid Res. 2007, 48, 1099–1107. [Google Scholar] [CrossRef] [Green Version]
  91. Jensterle, M.; Kocjan, T.; Janez, A. Phosphodiesterase 4 inhibition as a potential new therapeutic target in obese women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2014, 99, E1476–E1481. [Google Scholar] [CrossRef]
  92. Jensterle, M.; Salamun, V.; Kocjan, T.; VrtacnikBokal, E.; Janez, A. Short term monotherapy with GLP-1 receptor agonist liraglutide or PDE 4 inhibitor roflumilast is superior to metformin in weight loss in obese PCOS women: A pilot randomized study. J. Ovarian Res. 2015, 8, 32. [Google Scholar] [CrossRef] [Green Version]
Table
Table 2. Major studies evaluating the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on obesity in patients with polycystic ovary syndrome.
Table 2. Major studies evaluating the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on obesity in patients with polycystic ovary syndrome.
ReferenceDPP-4 InhibitornFollow-Up
(Weeks)		Baseline Body Mass Index (kg/m2)Lifestyle InterventionMetformin TreatmentMain Results
[55]Sitagliptin 100 mg/day18434.1NoNoGreater reduction in visceral adipose tissue than placebo
[56]Sitagliptin 100 mg/day281236.9Diet and exercisePriorStable body weight compared with an increase in body weight with lifestyle intervention
[58]Saxagliptin 5 mg/day341641.0NoComparator armSimilar reduction in body mass index and waist circumference with metformin and metformin/saxagliptin
Table
Table 3. Major studies evaluating the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on obesity in patients with polycystic ovary syndrome.
Table 3. Major studies evaluating the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on obesity in patients with polycystic ovary syndrome.
ReferenceSGLT-2 InhibitornFollow-Up
(Weeks)		Baseline Body Mass Index (kg/m2)Lifestyle InterventionMetformin TreatmentMain Results
[74]Empagliflozin 25 mg/day391237.9NoComparator armGreater reduction in body weight than metformin
[75]Canagliflozin 100 mg/day411230.2NoComparator armCanagliflozin/metformin induced similar reductions in body weight with metformin
[77]Dapagliflozin 10 mg/day922438.5Diet and exerciseComparator armDapagliflozin/exenatide induced similar body weight loss with phentermine/topiramate and greater than exenatide, dapagliflozin and dapaglifozin/metformin
Table
Table 4. Major studies evaluating the effects of phosphodiesterase-4 (PDE-4) inhibitors on obesity in patients with polycystic ovary syndrome.
Table 4. Major studies evaluating the effects of phosphodiesterase-4 (PDE-4) inhibitors on obesity in patients with polycystic ovary syndrome.
ReferencePDE-4 InhibitornFollow-Up
(Weeks)		Baseline Body Mass Index (kg/m2)Lifestyle InterventionMetformin TreatmentMain Results
[88]Roflumilast 500 μg/day311236.4NoComparator armRoflumilast/metformin reduced body weight more than metformin
[89]Roflumilast 500 μg/day411238.6NoComparator armSimilar reduction in body weight compared with liraglutide and greater than with metformin
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Kourtidou, C.; Tziomalos, K. Pharmacological Management of Obesity in Patients with Polycystic Ovary Syndrome. Biomedicines 2023, 11, 496. https://doi.org/10.3390/biomedicines11020496

AMA Style

Kourtidou C, Tziomalos K. Pharmacological Management of Obesity in Patients with Polycystic Ovary Syndrome. Biomedicines. 2023; 11(2):496. https://doi.org/10.3390/biomedicines11020496

Chicago/Turabian Style

Kourtidou, Christodoula, and Konstantinos Tziomalos. 2023. "Pharmacological Management of Obesity in Patients with Polycystic Ovary Syndrome" Biomedicines 11, no. 2: 496. https://doi.org/10.3390/biomedicines11020496

APA Style

Kourtidou, C., & Tziomalos, K. (2023). Pharmacological Management of Obesity in Patients with Polycystic Ovary Syndrome. Biomedicines, 11(2), 496. https://doi.org/10.3390/biomedicines11020496

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop