Obesity in women’s life: role of GLP-1 agonists

According to the World Health Organization (WHO), overweight and obesity are defined as the abnormal or excessive fat accumulation that presents a risk to health, quality of life and life expectancy [1]. They are normally diagnosed through body mass index (BMI). A BMI above 25 kg/m² is defined as overweight and a BMI above 30 kg/m² is defined as obesity. Although BMI is universally accepted as the easiest tool to diagnose these conditions, it has some limitations. A significant one is its impossibility to provide information regarding body composition and cardiometabolic risk. For this reason, the Spanish Association for the Study of Menopause (AEEM) recently recommended in their Menoguía (Consensus on Menopause and Obesity) the use of waist circumference as an indirect tool to assess cardiometabolic risk and visceral fat [2].

Obesity has already become one of the most prevalent chronic conditions of the XXI century. Besides its chronicity, experts agree that it is relapsing and progressive [3]. The consequences of obesity can be classified into three categories: mental, metabolic, and mechanic [4]. There is sufficient scientific evidence that highlights the fact that obesity is a disease that affects women’s health throughout their lifespan [5]. Abnormal weight may have an impact on adolescent’s health, female fertility, pregnancy outcomes, and adult life adverse conditions. Another important factor to consider is the polycystic ovary syndrome (PCOS). A recent retrospective study [6] showed a 61.3% prevalence of central obesity in 462 women affected with PCOS, the metabolic syndrome present in 27.4% of women, and hypertension in 10.9%. Hence, it is a chronic and relapsing pathology that is present during women’s lifespan and that requires a proper diagnose and management by gynecologists, as they are specialized professionals responsible for the integral care of women’s health and wellbeing. In order to achieve a proper management, it is crucial to avoid stigmatizing the patient, using therefore an adequate language that fosters the empowerment and motivation of the people living with obesity [7].

Regarding the management of obesity, numerous publications [8, 9] underline the importance of the initial body weight reduction (by at least a 5–10%), which leads to clinically relevant improvements in glycaemic control, lipid profile, blood pressure, sleep apnea, and provides a psychological benefit and improved physical quality of life of people living with overweight and obesity.

Weight management should first include implementing and consolidating changes in lifestyle habits (i.e. diet and exercise) tailored to each patient. To this date, most clinical guidelines for the management of obesity consider these changes as the cornerstone of the treatment. Nonetheless, science has showed us that our organism defends itself against weigh loss by activating certain hormonal (i.e. ghrelin, leptin, insulin) and metabolic (i.e. fasting metabolical rate) pathways that lead to a reduction in thermogenesis [10], thus making it difficult to consolidate weight loss over time. This is the reason why obesity is a chronic and relapsing condition and the explanation why it is frequent to experience weight regain after starting healthier lifestyle habits based on caloric restriction, balanced nutrient intake and moderate physical exercise.

Pharmacological treatment for an individual with an increased BMI is indicated if the BMI is equal or greater than 27 kg/m² plus obesity-related comorbidities or the BMI greater than 30 kg/m². To date, there are four drugs approved in Europe, although one of them, Semaglutide at a 2.4 mg dosage [5], has not yet been commercialized. The three other available molecules are Orlistat, Naltrexone/Bupropion and Liraglutide (3 mg dose).

Orlistat [11] is an irreversible inhibitor of pancreatic amylase which impedes the absorption of dietary fat, provoking its fecal clearance. The main limitation of Orlistat is its side effect profile, with an important percentage of patients presenting flatulence and fecal incontinence. Naltrexone/Bupropion [12] have a synergistic mechanism of action which is cantered on the arcuate nucleus in the hypothalamus, activating satiety neurons that express POMC/CART receptors (pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript).

Liraglutide at a 3 mg dosage [13] has a 97% structural resemblance to the endogenous GLP-1 (Glucagon-like peptide 1). GLP-1 is an incretin physiologically produced and released in the gastrointestinal tract and the brain. Liraglutide was modified to achieve a greater half-life (from 3 min of endogenous GLP-1 to 13 h of Liraglutide) allowing a daily posology, via a subcutaneous administration in the abdomen, thigh or upper arm. The mechanism of action of Liraglutide is mainly in the arcuate nucleus of the hypothalamus by activating POMC/CART neurons [14], causing satiety and less appetite. In addition, it also has positive pleiotropic effects over GLP-1 receptors which are expressed in different organs such as the heart, liver and pancreas [15].

The SCALE programme [16] contains the phase III clinical development of Liraglutide at a 3 mg dosage, showing interesting efficacy and safety data in adults and adolescents living with overweight and obesity, which has led to various national and international obesity guidelines to consider Liraglutide as the first in-line drug for the treatment of obesity, always on top of an individualized and science-based lifestyle intervention [17].

Semaglutide at a 2.4 mg dosage [5] is approved by the FDA and the EMA, commercialized in United States but not in Europe. It is an agonist of the GLP-1 receptor, labeled to treat obesity (with or without type 2 diabetes mellitus). The clinical development phase III trial is the STEP programme [18]. Semaglutide at a 2.4 mg dose constitutes a paradigm shift in the treatment of individuals living with obesity, with weigh loss reductions averaging 17%, plus additional cardiometabolic benefits. The safety profile is similar to Liraglutide, with a better posology as it is to be used once a week (subcutaneously).

Other tools to be considered to treat obesity are bariatric surgery and endoscopic techniques which are out of the scope of this editorial.

Santiago Palacios
Medical Director of Palacios’s Institute, Madrid, Spain; Director of the Menopause Chair of the HM foundation, Madrid, Spain
[email protected]

Disclosure statement

The authors report no conflict of interest.

Funding

The author(s) reported there is no funding associated with the work featured in this article.