Treating obesity to optimize women’s health outcomes

As a chronic disease, treatment of obesity requires long-term, individualized care that considers different stages of a woman’s life. Once treatment goals have been agreed upon, there are multiple options to consider. Lifestyle intervention is recommended for all individuals with overweight or obesity.1,2 However, lifestyle intervention alone is typically not sufficient to achieve substantial and sustained weight loss, with many people regaining weight due to compensatory biological mechanisms that increase appetite and compromise metabolism.3,4 Guidelines, therefore, recommend additional interventions, such as obesity medications and/or bariatric surgery for individuals who meet eligibility criteria, as an adjunct to lifestyle intervention to promote long-term weight loss maintenance and reduce the risk of obesity-related complications.1,2 As shown in Fig. 1, lifestyle intervention alone is typically associated with approximately 2%-5% weight loss at 1 year of follow-up,5 while lifestyle intervention combined with older obesity medications (ie, oral medications such as naltrexone/bupropion, orlistat, phentermine/topiramate, or subcutaneous liraglutide 3.0 mg) is associated with approximately 5%-10% weight loss.6-11 Bariatric surgery has the greatest degree of expected weight loss, at around 20%-30% at 1 year.12 More recently approved obesity medications -- including the glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide 2.4 mg and the GLP-1/glucose-dependent insulinotropic polypeptide (GIP) RA tirzepatide -- are associated with approximately 15%-20% weight loss, and these medications are beginning to close the weight loss gap between older medications and bariatric surgery.13-15 This article will discuss these different options for obesity treatment, together with the associated guideline recommendations and considerations in the obstetric-gynecology (OB-GYN) clinic.FIG. 1: Expected approximate degree of weight loss after approximately 1 year of treatment with different options for obesity management.5–17LIFESTYLE INTERVENTION Current guidelines recommend structured lifestyle intervention, specifically tailored for weight loss, for all individuals with overweight or obesity.1,2 Programs should comprise healthy reduced-calorie meal plans, physical activity, and behavioral changes.2,7 The Dietary Guidelines for Americans recommend consumption of nutrient-dense forms of foods, with high intake of fruits, vegetables, and whole grains, and low intake of added sugars, saturated fat, sodium, and alcohol.18 A wealth of evidence supports consumption of a Mediterranean diet for cardiovascular protection,19 in addition to prevention of other obesity-related diseases.20,21 The Mediterranean diet is characterized by high consumption of fruit, vegetables, nuts, cereals, and whole grains, moderate consumption of fish and poultry, and low consumption of red meat, dairy products, and added sugar.22 An important change to the food environment in recent years has been increased availability of ultra-processed foods, defined by the NOVA classification system as formulations of industrial sources of energy that are designed to be hyper-palatable.23 Ultra-processed foods are nutrient poor, energy-dense, and high in unhealthy fats, refined starches, salt, and added sugars.23 These foods have been identified as a key driver of obesity,24 with randomized controlled trial (RCT) data and observational studies showing that consumption of ultra-processed foods is associated with weight gain.24,25 There is a need for coordinated public health action to reduce the obesogenic environment and support reduction of ultra-processed food consumption.24 Specific to women’s health, nutrition and physical activity counseling are recommended for women with overweight or obesity who wish to become pregnant, in addition to during pregnancy and postpartum.26,27 These lifestyle changes are also recommended as part of the management strategy for other women’s health conditions. For instance, recommendations from the International PCOS Network -- authored by experts from the United States, Europe, and Australia -- advocate diet and exercise strategies for all women with polycystic ovary syndrome (PCOS) to improve their metabolic health, quality of life, and body composition.28 For those who require weight loss, the recommendations state that tailored energy deficit should be considered, accounting for body weight, physical activity levels, and energy requirements.28 The PCOS guidelines do not advocate a particular type of dietary intervention over others, recommending “sustainable healthy eating tailored to individual preferences and goals”.28 The authors suggest that lifestyle interventions may include goal setting with SMART (specific, measurable, achievable, realistic, and timely) goals, in addition to behavioral strategies such as self-monitoring and relapse prevention.28 Moreover, dietary and physical activity interventions have been shown to improve health outcomes in the postmenopausal setting. In a meta-analysis (N=32 studies), different types of training -- including endurance, interval, resistance, and aerobic plus resistance -- were associated with significant improvement in different measures of vascular function in postmenopausal women.29 Another meta-analysis of 26 studies showed that resistance training is associated with an increase in lean body mass in postmenopausal women,30 while a meta-analysis of 5 studies found a decrease in the frequency and severity of vasomotor symptoms with resistance training.31 Studies have shown mixed results regarding high-intensity exercise; data from a pilot study suggest that high-intensity interval training is a feasible approach for weight loss and improvements in body composition among postmenopausal women with obesity.32 On the other hand, an RCT of different exercise intensities found a heterogenous response to intensive exercise among postmenopausal women with overweight or obesity, indicating that intensive exercise is not a guarantee of weight loss. All exercise groups experienced a significant reduction in waist circumference, however, suggesting a reduction in visceral adiposity.33 In terms of diet-induced weight loss, one study of over 17,000 postmenopausal US women who were enrolled in the Women’s Health Initiative showed that women who lost weight through a dietary intervention had a significantly higher likelihood of vasomotor symptom elimination than those in the control group, who did not receive the intervention.34 The EMPOWIR randomized controlled trial found that a novel carbohydrate-modified diet combined with metformin improved weight loss and body composition outcomes after 12 months in women with midlife weight gain.35 Although not in the context of weight loss, a systematic review showed that higher consumption of wholegrains, vegetables, and unprocessed foods is associated with lower intensity of sleep disorders and psychological, vasomotor, somatic, and urogenital symptoms among postmenopausal women.36 The authors of the systematic review concluded that research on the associations between dietary intake and menopausal symptoms is limited and that more studies are needed.36 While lifestyle intervention is the cornerstone of obesity management strategies, with associated health benefits for many conditions affecting women’s health, it is important to note that only around 15%-25% of people can lose and maintain≥10% weight loss with lifestyle intervention alone,4 and sustained weight loss of≥10%-15% is needed for the greatest health benefits (outlined in article 2 of this supplement, Talking About Obesity in the OB-GYN Clinic, Volume 32, Issue S1, S10-S18).37-41 OB-GYNs, therefore, need to reassure women with obesity about the challenges associated with sustained weight loss and discuss the rationale for considering adjunctive treatment approaches. OBESITY MEDICATIONS Multiple guidelines for the treatment of obesity recommend the use of pharmacotherapy in addition to lifestyle intervention.1,2,42 Obesity medications can be considered for people with body mass index (BMI)≥30 kg/m2, or BMI≥27 kg/m2 and≥1 weight-related comorbidity.1 There are several processes involved in the pathophysiology of obesity that represent therapeutic targets for medications. The gut-brain axis is a bidirectional communication system that regulates food intake by linking the gastrointestinal (GI) tract with the central nervous system (CNS).3,43 One important target for medications is dietary fat absorption from the GI tract. Orlistat acts on this target by functioning as an intestinal lipase inhibitor, blocking digestion and absorption of up to 30% of dietary fat without impacting appetite.3 The CNS is another key target, with medications acting to increase satiety via modulation of dopaminergic, noradrenergic, or serotonergic action.43 Combination medications targeting the CNS have been developed to provide complementary effects, thereby increasing weight loss effectiveness.3 Phentermine works primarily by increasing norepinephrine, while phentermine-topiramate increases norepinephrine, augments γ-aminobutyric acid, and inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainite excitatory glutamate receptors.3 Another medication combination targeting the CNS is naltrexone-bupropion, which activates proopiomelanocortin neurons.3 All of these medications targeting the CNS act to reduce appetite.3,43 Nutrient-stimulated hormones represent a newer biological target for obesity medications in the gut-brain axis.3 Naturally occurring entero-pancreatic hormones play an important role in the mechanisms involved in energy homeostasis, satiety, and lipolytic activity.44 Examples include the incretin hormones GLP-1 and GIP, in addition to glucagon, amylin, and proglucagon-derived peptides.3,44,45 Medications that simulate the metabolic effects of these hormones are approved by the US Food and Drug Administration (FDA) for the treatment of obesity,46-48 and several others are under investigation.3 Observations that gut hormone levels change significantly following bariatric surgery were instrumental in defining the key role of gut-derived peptides in appetite regulation, and in recognizing their potential as targets for obesity medications. One of the most widely studied gut hormones -- GLP-1 -- in addition to others including peptide YY and cholecystokinin, are increased postprandially following Roux-en-Y gastric bypass and vertical sleeve gastrectomy,49 and these changes in hormonal regulation are considered key mechanisms of surgical weight loss.49 The GLP-1 RAs have pleiotropic cardiometabolic effects mediated by widespread distribution of receptors in the body. For instance, GLP-1 RAs work centrally in the hypothalamus, brainstem, and reward centers to stimulate glucose-dependent insulin secretion, delay gastric emptying inhibit glucagon release, and induce satiety.3,44,50 These medications are also associated with reductions in inflammation and blood pressure.3,51 GLP-1 RAs were initially approved for the treatment of type 2 diabetes (T2D), and the GLP-1 RAs liraglutide and semaglutide were subsequently approved for the treatment of obesity.46,47,52,53 More recently, semaglutide 2.4 mg weekly (the dose approved for treating obesity) was shown to reduce cardiovascular (CV) risk in the SELECT trial of people with overweight or obesity who did not have diabetes. Specifically, rates of CV death, nonfatal myocardial infarction, or nonfatal stroke over an average follow-up of 39.8 months were 6.5% in people treated with semaglutide (n=8803), and 8.0% in those given Nutrient-stimulated hormones can have complementary activity, support for the use of medications the action of more than one hormone for the treatment of obesity and other metabolic The agonist to be approved for the treatment of obesity is the RA GLP-1 was initially approved for and more recently for The of the GLP-1 RAs and RA for the treatment of obesity a in obesity given the benefits of these for weight loss in addition to their and effects on risk for cardiometabolic and are also to the role of these medications in chronic other designed to simulate the action of hormones are under for obesity including and of the GIP, and glucagon as as other involved in to the that have additional effects on The obesity medications approved for long-term use are in 1, which and is important to note that all obesity medications are during and that be In it is to changes in and with all obesity 1: Obesity medications approved for long-term of obesity medications on women’s health outcomes to their effects on body weight and improvement in cardiometabolic obesity medications have shown benefits for women’s health outcomes For women with a meta-analysis in showed that orlistat, and semaglutide are to for studies of liraglutide mg showed that the GLP-1 RA is associated with and waist circumference, regulation of improved cardiovascular fat and visceral and For subcutaneous treatment with from mg weekly than the approved 2.4 mg weekly dose for obesity) has been associated with weight loss, improvements in CV and metabolic and of An RCT is the of subcutaneous semaglutide dose 2.4 mg metformin for weight loss, hormonal and metabolic quality of life, and CV risk in women with PCOS and An RCT at the of found that treatment with oral semaglutide plus metformin was associated with significantly weight loss than plus metformin in women with PCOS weight loss at However, more in the semaglutide For a study at the for showed that tirzepatide to metformin was associated with increased weight loss in women with PCOS and overweight or Specifically, average weight loss during the follow-up 1 was for women tirzepatide plus with for those metformin to in the benefits of obesity medications weight loss in women with and the of long-term treatment for sustained weight reduction and health However, it is important to note that there are only a of studies on obesity medications in women with with of and that recommendations on of obesity medication be There therefore, an need for with of follow-up to of obesity medication in women with of the benefits in studies of obesity medications in women with PCOS on medications may also have benefits for postmenopausal those hormone In a study of postmenopausal women with overweight or obesity, treatment with semaglutide for at months was associated with weight loss, with significantly weight loss in those Specifically, women in the had weight loss at 12 months of with in those not The authors concluded that more research is needed to the between obesity medication and use in postmenopausal Studies have also the of on obesity-related While evidence not support a of on data suggest that improve of metabolic For in the 1 postmenopausal women had more and insulin and lower visceral fat mass than those not obesity as a chronic As with other chronic disease, obesity requires treatment to weight loss and associated health that of obesity medication is associated with weight and of For the trial semaglutide 2.4 mg in people with overweight or obesity who had of treatment with the GLP-1 during which lost of their body weight on to an average of over the those with semaglutide to lose weight, with an average additional loss of blood also and to and physical functioning improved in those who those who to experienced an increase in and and a decrease in physical functioning These the of the chronic of obesity and need for long-term treatment with and of treatment that are for the it is to that weight loss with obesity medications will not and individuals should be to a weight that may a in the obesity treatment strategy from one that primarily on weight loss to one that centers on weight and health These considerations are important in the OB-GYN given that obesity medications are in pregnancy and be in women to a with different medications different recommended of to OB-GYN be to discuss options for weight loss maintenance in women who are to obesity medications to that exercise may to improve weight loss maintenance after of obesity medications. In one women with PCOS and obesity were treated with semaglutide mg metformin mg plus lifestyle intervention for during which their weight from to all semaglutide the other interventions for an additional 2 the of the follow-up body weight was with of women lost weight from While of obesity is in women a of metformin with exercise pregnancy is a The use of metformin during pregnancy is given that metformin the with that can studies that metformin during pregnancy is not associated with or a meta-analysis in found that metformin during pregnancy is associated with and On the other hand, more recent study results suggest of metformin on at 2 years of studies have that metformin use in women with PCOS during the may reduce the risk of other studies have not a reduction of In of metformin pregnancy may be metformin for obesity management is not for use during in the of metformin use may also weight loss maintenance following of obesity A of a trial weight loss maintenance in people who weight through dietary intervention and were to receive liraglutide 3.0 mg interventions, or 1 given a combination of liraglutide and exercise lost the most weight weight loss approximately by those given liraglutide only weight loss approximately 1 while those in the exercise only and weight weight 2 and were and after an additional year of to liraglutide plus exercise had the of weight from by those in the exercise and liraglutide The authors concluded that exercise to obesity medications has the potential to weight after treatment with obesity medications These data that exercise interventions should be in women of who are obesity medications to support weight loss maintenance the medication is subsequently due to a individuals to increase dietary and reduce fat intake may also weight loss In addition to lifestyle intervention and obesity guidelines for obesity include recommendations for bariatric surgery as a treatment The from the for and Bariatric and the International for the of Obesity and in bariatric surgery for individuals with of at kg/m2, or of at kg/m2 with The and also that bariatric surgery should be considered for people with of kg/m2 without substantial or body weight reduction or improvement in with weight loss The guidelines that do not in the to all for that of at kg/m2 is of obesity in and to surgery should not be on studies have shown that bariatric surgery is associated with substantial weight loss, improvement in metabolic disease, and reduction in While the mechanisms these benefits are evidence that several processes may play a of gut peptides that reduce increased of and from the increased and increased increased energy and changes in food that increased satiety and The of bariatric surgery on women’s health outcomes to the of bariatric surgery on weight loss and metabolic health, evidence effects on women’s health In those with bariatric surgery has been associated with improvement in insulin resistance, of hormone levels, and improved One study bariatric surgery with treatment plus oral for months by metformin alone for found that women in the surgery were more to PCOS over 1 year of at rates of and this and multiple other health improvements with increasing evidence that weight loss -- and bariatric surgery in particular -- can studies have shown that bariatric surgery is associated with a increase in reductions in and an increased risk of women may be to the of bariatric surgery on due to their increased risk for loss and As health is an important women who be for bariatric and strategies to health be a in surgery care Bariatric surgery has been associated with a lower risk of several obesity-related during and after including and However, studies suggest that bariatric surgery is associated with an increased risk of for and an is bariatric surgery increases the risk of and A systematic review found that there is evidence to on the between bariatric surgery and with more data guidelines on support for individuals bariatric -- by several including and the Obesity -- that pregnancy should be for months following bariatric Moreover, the guidelines recommend that women who become following surgery should and for in addition to counseling and on and on and after bariatric surgery is also recommended for all women of of other obesity following bariatric surgery As with all weight loss interventions, the response to bariatric surgery is with a in weight loss response in different For a study of people bariatric surgery found that the weight loss following 2 types of bariatric surgery gastric bypass or sleeve from need to be of this the benefits and of different obesity treatment options with women under their that other treatment strategies for obesity, including physical activity and obesity may to improve weight loss maintenance and many other of health in the setting. activity has been shown to lean mass and improve weight loss as as insulin CV and Moreover, in with bariatric exercise has been associated with increased and in addition to and obesity including and naltrexone/bupropion, have been associated with weight following bariatric One observational study different options following bariatric surgery showed that GLP-1 with or without other obesity were associated with weight loss after surgery than RA obesity medications or in combination with lifestyle Specifically, the body weight reduction at months of follow-up was in the GLP-1 RA group, with in the RA A study different GLP-1 RAs found that semaglutide 1 mg weekly is associated with a higher of individuals weight loss after bariatric surgery than liraglutide mg with at weight is important to note that to obesity medications are in the setting in other and that medications should be as part of an individualized approach on and OBESITY OB-GYN As there are multiple long-term options for obesity and it is important that OB-GYN have and on the options with women under their provide the it is important for OB-GYN to a approach to obesity with other such as and behavioral work together with women by obesity to individualized treatment tailored to health goals and Guidelines from Obesity provide to around management In with the in article 2 of this About Obesity in the OB-GYN Clinic, Volume 32, Issue S1, the guidelines recommend that should discuss and individualized and goals for health the chronic of obesity, treatment be and should strategies that the of to and provide care obesity treatment that there are multiple affecting of or to body on improvement in health as a goal of and defining as healthy changes of body weight or at different in In the approach to obesity treatment to their For instance, all obesity medications are during pregnancy and and is recommended for women with pregnancy potential obesity is with obesity different have different recommended of as in women bariatric surgery should pregnancy to the and in the months Obesity recommendations to a woman’s years for those with In the the weight loss, by weight of during and weight loss weight at a Lifestyle interventions are recommended during including at of physical activity in those without to regarding pregnancy with different obesity to their the OB-GYN in the bidirectional associations between obesity and treatment These are important considering Obesity is associated with an increased risk of and such as and these associations be considered about with evidence a for over oral due to lower CV to obesity treatment Obesity management can be in the OB-GYN and there are several and that can about obesity and weight loss. Examples of to nutrition and physical activity are in these include from such as the of and and Obesity in addition to for people with for lifestyle interventions with individuals with obesity and for Health The Obesity for Obesity weight loss for a for a activity and to be for a to at The of and US for and of For obesity there are several to that can be in the OB-GYN The Obesity a for use in the with considerations such as to goals, and is important to however, that this was in to the of tirzepatide for treating In the has a and on the including those for the management of obesity in The 5 in is another This of and and for of (ie, obesity medications with other interventions such as and and The 5 approach can provide a approach to the chronic of obesity, long-term and treatment are and the approach can also in this of treatment and the need for dose is for people obesity medications. women in and to the of treatment and achieve the 5 approach to obesity medication In obesity has a on physical and health in women at multiple stages life. OB-GYN are to obesity and provide care to improve long-term health There are multiple options to obesity -- including diet and exercise interventions, several obesity and bariatric surgery -- and OB-GYN should be to discuss these options with women in their the most for obesity management in the women’s setting should be a such as in life, and this supplement, all to part in of to to the In these will in the to on the most to care for different of women with