ACADEMIA Letters Treating obesity as a disease Carel W le Roux, Diabetes Complications Research Centre, University College Dublin, Ireland Heshma Alruwaili, Diabetes Complications Research Centre, University College Dublin, Ireland Obesity is defined as a chronic, complex, metabolic disease, characterized by excessive fat accumulation, adipose tissue dysfunction, and abnormal fat mass, resulting in adverse metabolic, biomechanical, and psychosocial health consequences.[1] Obesity was previously considered a lifestyle or behavioural disorder caused by increased calorie intake or reduced physical activity. Several governments and medical organizations have recently defined obesity as a chronic disease, similar to hypertension and type 2 diabetes.[2, 3] The World Health Organization (WHO) declared obesity to be the largest global chronic health problem in adults, which is increasingly turning into a more severe problem than malnutrition. A disease is defined as “any deviation of the normal structural or functional state of a body part, organ, or system, caused by underlying etiologies, generally characterized by specific symptoms and signs, and resulting in pathological consequences that negatively impact health, feeling, or functioning.[4] Obesity meets all these criteria [5], however, obesity is not treated as a disease. This may change as our understanding improves, especially as current evidence suggests that obesity is caused by a disruption of homeostatic control of body weight and a failure to maintain constant body fat mass. Obesity is associated with disordered hunger, satiety (the feeling of fullness), and satiation (the state of fullness), hence individuals with obesity experience symptoms that manifest because of dysregulation of subcortical areas of the brain.[6] Obesity has a complex multifactorial nature resulting from genetic, biological, neurological, environmental, and hormonal factors that disturb the normal function of the subcortical areas of the brain involved with appetite control.[7, 8] Once excess collections of adipose tissue has occurred then more than 200 complications of obesity may negatively Academia Letters, July 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Carel W le Roux, carel.leroux@ucd.ie Citation: le Roux, C.W., Alruwaili, H. (2021). Treating obesity as a disease. Academia Letters, Article 2012. https://doi.org/10.20935/AL2012. 1 impact individuals health as evident by hypertension, dyslipidemia, type 2 diabetes mellitus (T2DM), cardiovascular, nonalcoholic fatty liver disease (NAFLD), certain types of cancers (e.g. endometrial, colon, breast cancer), sleep disturbances, depression, neurocognitive disorders and osteoarthritis.[9-13] Body mass index (BMI), and epidemiological tool, was previously used in clinical practice to diagnose obesity. BMI is a calculation made by body weight (kg) divided by height squared (m2). Epidemiologists used a BMI >30 kg/m2 as a proxy tool for patients with obesity and a BMI between 25 and 29.9 kg/m2 as a proxy tool for defining overweight. They tried to adjust these by using lower BMI cut-off points for some ethnic groups (e.g. Southeast Asians). [14] There is a need to go beyond BMI when thinking of obesity as a disease, because several patients can have excess adipose tissue causing a deterioration in health with BMIs below the cut-points, while others may have BMIs above the cut-points without excess adipose tissue causing a worsening of health. Finally, patients with treated obesity may have a BMI within the normal range, but they should still be considered as having the disease of obesity, albeit “treated obesity”. The objectives of managing obesity as a chronic disease is to achieve health gain and not focus on weight loss alone. The first step is to alleviate the symptoms of excess hunger or reductions in satiety. Once that is achieved, the treatments need to prevent or address the complications of obesity while simultaneously improving the patient’s quality of life. Successful obesity treatments address the dysfunction in the subcortical area of the brain including the brainstem and hypothalamus. This does not diminish the importance of the other parts of the brain, such as the cortical area and its role in food-seeking behaviours and the crucial role of cognitive-behavioural therapy in obesity management. Appropriate goals of obesity management emphasis realistic weight loss, maintenance, and prevention of weight regain. Patients should understand that since obesity is a chronic disease, it is never cured but can be controlled, and weight management needs to continue lifelong, similar to other chronic diseases (e.g., type 2 diabetes, hypertension, and dyslipidemia). Available options for treating obesity include lifestyle modifications (dietary changes, increased physical activity, cognitive behavioural therapy), pharmacotherapy, and bariatric surgery. Double digit weight loss results in significant benefits[15]. This can be achieved by lifestyle modification (improved nutritional content of the diet and modest increases in physical activity and fitness). Typically 1 in every 5 patients respond to lifestyle modification, while 1 in 2 can respond to pharmacotherapy and almost all patients achieve reductions in hunger, increases in satiety and 10% weight loss with bariatric surgery within the first year[16-18]. Pharmacotherapy should be prescribed with the intent of lifelong use if a patient respond to the medication. This is best done as part of a comprehensive management plan. Current obeAcademia Letters, July 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Carel W le Roux, carel.leroux@ucd.ie Citation: le Roux, C.W., Alruwaili, H. (2021). Treating obesity as a disease. Academia Letters, Article 2012. https://doi.org/10.20935/AL2012. 2 sity drugs target the underlying neurohormonal dysregulations that cause obesity. Changes in hormones in response to diet-induced weight loss, such as reduction in the anorexigenic hormone leptin, peptide YY or glucagon-like peptide 1 and increase in the orexigenic hormone ghrelin, create a physiologic environment conducive to the body returning to its previously established, higher body weight set point [19, 20]. Additional adaptation responses to dietinduced weight loss affecting energy expenditure, including reductions in basal metabolic rate, also challenge weight loss maintenance [21, 22]. Medications for obesity are recommended by regulators for patients with a BMI ≥ 30 kg/m2 or a BMI ≥ 27 kg/m2 with an obesity-related complications.[23] Pharmacotherapy reduces the symptoms of obesity and as a result attenuates appetitive behaviour. Consequently, patients who respond to the medications can maintain body weight loss and have a decrease in obesity-related complications. The patient’s response to an obesity medications should be evaluated after the first three months. Typically, those patients who respond report significant reductions in symptoms and often effortless weight loss of more than 5%. In these patients, treatment should be continued. Treatment should be discontinued in non-responders because the risks of side effects outweigh the benefits [14]. Currently, the Food and Drug Administration (FDA)-approved anti-obesity medications are orlistat, phentermine/topiramate extended release (ER), lorcaserin, naltrexone sustained-release (SR)/bupropion SR, setmelanotide, and liraglutide (the only injectable formulation).[1] The FDA is currently considering semaglutide 2.4mg once weekly for approval. Bariatric surgery is the most effective treatment for obesity in reducing symptoms, long-term weight loss, attenuation of complications, improvement of quality of life improvement, and overall mortality reduction [14]. Bariatric Surgery is recommended for patients with a BMI ≥ 40.0 kg/m2 or with BMI between 35.0 and 39.9 kg/m2 and obesity complications [24]. In parallel with other chronic diseases, combination therapy is theoretically advantageous because multiple factors contribute to obesity. Achieving control of obesity with a single therapy acting through one particular mechanism may not always be possible. Hence, a combination of two or three treatment strategies may be needed when the patient experiences weight stabilization or weight regain after one treatment strategy. Combination therapy involves lifestyle modification with pharmacotherapy or bariatric surgery or both, a combination of two pharmacotherapies, and a combination of pharmacotherapy with bariatric surgery if obesity remains resistant or relapses. Obesity is a chronic disease and rather than thinking that overeating causes obesity we are now realizing that obesity may be the cause of overeating. Complimentary follow-up pathways (surgical and medical) should be provided to all patients, ideally through a multidisciplinary team. The responsibilities of clinicians include alleviation of symptoms, prevention or treatment of complications, and long term follow-up and support. Academia Letters, July 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Carel W le Roux, carel.leroux@ucd.ie Citation: le Roux, C.W., Alruwaili, H. (2021). Treating obesity as a disease. Academia Letters, Article 2012. https://doi.org/10.20935/AL2012. 3 References 1. E. Pilitsi et al., “Pharmacotherapy of obesity: available medications and drugs under investigation,” Metabolism, vol. 92, pp. 170-192, 2019. 2. A. Pollack, “AMA recognizes obesity as a disease,” The New York Times, vol. 18, 2013. 3. P. Rich, “CMA recognizes obesity as a disease,” Ottawa: Canadian Medical Association News and Announcements, 2015. 4. J. L. Scully, “What is a disease? 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