Consensus on pharmacological treatment of obesity in Latin America

A panel of 10 experts in obesity from various Latin American countries held a Zoom meeting intending to reach a consensus on the use of anti‐obesity medicines and make updated recommendations suitable for the Latin American population based on the available evidence. A questionnaire with 16 questions was developed using the Patient, Intervention, Comparison, Outcome (Result) methodology, which was iterated according to the modified Delphi methodology, and a consensus was reached with 80% or higher agreement. Failure to reach a consensus led to a second round of analysis with a rephrased question and the same rules for agreement. The recommendations were drafted based on the guidelines of the American College of Cardiology Foundation/American Heart Association Task Force on Practice. This panel of experts recommends drug therapy in patients with a body mass index of ≥30 or ≥27 kg/m2 plus at least one comorbidity, when lifestyle changes are not enough to achieve the weight loss objective; alternatively, lifestyle changes could be maintained while considering individual parameters. Algorithms for the use of long‐term medications are suggested based on drugs that increase or decrease body weight, results, contraindications, and medications that are not recommended. The authors concluded that anti‐obesity treatments should be individualized and multidisciplinary.


Funding information
Adium Pharma

| INTRODUCTION
Chronic non-communicable diseases (CNCDs) are the primary cause of death worldwide, accounting for 60% of the overall mortality.The frequency of CNCDs continues to increase, particularly in low-and medium-income countries (most Latin American countries), and their economic burden for the current period (2011-2025) is estimated to generate losses of USD 7 billion."These diseases drive inequity; contribute to poorer economic outcomes for individuals, communities, and societies; and create significant challenges to development.The economic impact of CNCDs must be better understood, and their negative consequences for societies mitigated." 1 The global prevalence of obesity has almost tripled since 1975.
Most of the population lives in countries where overweight and obesity are causing more deaths than underweight. 2In 1997, the World Health Organization (WHO) acknowledged obesity as a global health problem, which was previously associated only with high-income countries; however, evidence shows that overweight and obesity in adults are much more frequent than underweight in Latin America and Northern Africa.Therefore, this CNCD is currently among the primary public health challenges, with México as the second highest combined prevalence of overweight and obesity in adults globally. 3abetes, cardiovascular diseases, musculoskeletal system disorders, and certain types of cancers are attributable to overweight and obesity. 4 2000, Peña and Bacallao published data from several countries in Central and South America, warning that poverty was a new public health challenge. 5These data were considered by the Pan American Health Organization, because the global prevalence of overweight in the adult population was 36.6% and that of obesity was 11.5%; however, the prevalence was 59% and 24.6% in the Americas, respectively.This figure is more than double the world average, making our region the highest in obesity in the world; furthermore, there is a sex difference, because women are more likely to develop obesity than men. 6 2008, a panel of experts from The Obesity Society of North America examined the evidence and argued the importance of classifying obesity as a disease.The panel unanimously and definitively stated that obesity is "a complex condition with several causal contributors, including many factors that, to a large extent, are beyond the control of the individual; this disease results in a lot of distress, is a cause of poor health, functional impairment, impaired quality of life, severe illnesses, and higher mortality.Successful treatment, though difficult to achieve, results in a significant number of benefits." 7e definition of overweight and obesity suggested by the WHO is "abnormal or excessive fat accumulation that presents a health risk" 3 ; it is estimated using the body mass index (BMI) (body weight in kilograms divided by the square height in meters [kg/m 2 ]).The suggested values for obesity classification are presented in Table 1. 2 This universal classification, which is useful for population studies, has some limitations in assessing individuals in clinical practice because of the presence of other factors that increase the risk of comorbidities beyond BMI, in particular, the amount and distribution of body fat.Sharma and Kushner suggested that the Edmonton Obesity Staging System, which considers clinical, psychological, and functional comorbidities, allows for the assessment of the effect of these comorbidities in individuals beyond body weight and optimizes treatment decision-making (Table 2). 8ppelletti and Katz, in their manual Obesity Crossroads and Approaches, define obesity as a "Chronic, multifactorial disease with an impact on the neuro-immune-metabolic and psychosocial balance.
Its inflammatory condition resulting from increased dysfunctional adipose tissue, accounts for the association with its comorbidities." 9 The results of the Awareness, Care, and Treatment In Obesity maNagement International Observation trial 10 should be highlighted with regard to obesity treatment; its primary objective was to identify perceptions, attitudes, behaviors, and potential barriers to the effective care of patients with obesity and healthcare practitioners using a T A B L E 1 Classification based on body mass index (BMI).Grade II 35.0-39.9

Grade III ≥40
Source: Based on https://www.who.int/es/news-room/fact-sheets/detail/obesity-and-overweight. with obesity said they did not talk to their physician about how to lose weight.When looking into the reasons, the primary reason was the lack of initiative from the practitioners.Healthcare providers said that they believe that patients have little interest or motivation to control their weight, which may be an obstacle for discussions on weight control.However, 68% of people with obesity said that they would like their physician to start a conversation on the topic, and only 3% felt insulted by such a conversation. 10e Argentinean Society of Nutrition (Sociedad Argentina de Nutrici on [SAN]) published the "SAN Position: obesity is a chronic disease," with regard to the condition "… is a chronic disease with a very high and growing prevalence with a complex pathogenic etiology and results in multiple comorbidities exhibiting a high early mortality; therefore, obesity is an urgent public health imperative."Among its proposals, it highlights the need for universal coverage, including nonpharmacological and pharmacological strategies. 11 2020, a joint international consensus statement was published in the Nature Medicine journal to put an end to weight stigmatization.
The document involved the participation of a multidisciplinary team of international experts, including representatives of scientific organizations, who reviewed the available evidence on the causes and damage of obesity and developed recommendations to eliminate any obesity-associated biases."The research indicates that the weight stigmatization may result in physical and psychological harm and that the individuals affected have a decreased probability of receiving adequate care; for these reasons, this stigmatization is detrimental to health, undermines human and social rights and is inacceptable in modern societies." 12e challenge raised in relation to containing the global obesity epidemic requires a multisectoral, multidisciplinary, and relevant approach based on the individual culture of each specific population. 13 date, political and public health measures have so far been insufficient to address this situation.Accordingly, continuous education of the treating or primary care physician is essential, 14 as they are the first contacts of the patient with the healthcare system; hence, they are the ones who may initiate the correct approach to the disease.According to the consensus of the authors of this document, the approach for people living with obesity should be based on five pillars: 1. healthy diet sustainable over time; 2. avoiding sedentarism; 3. reliable and safe medication; 4. long-term management and follow-up; and 5. acceptance of the frustration of "not always doing what is perfect" in the obesogenic environment we live in.
Key international guidelines [15][16][17][18][19][20][21][22] indicate that lifestyle changes to achieve a 5%-10% body weight reduction are the foundation for treatment, with a view to improve comorbidities.European guidelines state that achieving the maximum weight loss in the shortest possible time is not the key to successful treatment."Reducing waist circumference should be considered even more important than weight loss per se, as it is linked to a decrease in visceral fat and associated cardiometabolic risks.Finally, preventing weight regain is the cornerstone of lifelong treatment, for any weight loss technique used: behavioural or pharmaceutical treatments or bariatric surgery." 20w obesity management guidelines from different countries highlight the importance of avoiding the stigmatization of people living with obesity, including the management of psychological issues, such as self-esteem, body image, and quality of life.1][22][23] This therapeutic approach should be complemented with adjuvant pharmacotherapy when considered appropriate.
According to the available literature, properly prescribed antiobesity medications improve patient compliance and prevent longterm weight regain.However, some barriers prevent their adequate use by practitioners, probably related to the history of such drug therapy and poor knowledge of obesity as a chronic, complex, and relapsing disease. 24

| DEVELOPING LATIN AMERICAN GUIDELINES ON PHARMACOLOGICAL MANAGEMENT OF OBESITY
The Latin American Federation of Endocrinology took the initiative to bring together Latin American experts who shared concerns about the need to develop guidelines for the pharmacological management of obesity in the region.All participants in this consensus had over 10 years of academic training and experience in the treatment of overweight and obese people living with obesity; they were members of institutions and scientific societies in their respective countries, although they did not act on behalf of these organizations.The objective of this study was to update and provide scientific evidence-based recommendations for the pharmacological treatment of adult patients living with obesity with access to all levels of care and suitable for inclusion in the multidisciplinary management of the disease.

| Methodology
To accomplish these goals, the 10 experts embraced the following methodology: 1.A questionnaire with 16 questions was developed using the Patient, Intervention, Comparison, Outcome (Result) (PICO) methodology.Once the questionnaire was completed, a pilot test was conducted with 10 specialists with the same characteristics as the selected group.The result was a complete understanding of the document, so the original design was maintained (Appendix A).
2. The modified Delphi methodology was used to reach a consensus on a particular topic through iteration of questions.Each question was subjected to iteration; then, a consensus answer was obtained with 80% agreement or higher.Failure to reach a consensus led to a second round of analysis with the reformulated question.
3. Literature review according to evidence-based medicine (EBM): the EBM scale was used to classify the information into levels of evidences A, B, and C (Table 3).The classes of recommendations were based on the American College of Cardiology Foundation/ American Heart Association (ACCF/AHA) standards, determining Classes I, II (IIa and IIb), and III (Table 4). 25nsensus coordination was employed to develop the PICO questionnaire and submit it for validation.An initial literature search was conducted and continued during the consensus discussion; four expert meetings were held in October, November, and December 2021.The questions were iterated until the experts reached an agreement of 80% or higher (Figure 1).

| Anti-obesity drugs available in Latin America
Notwithstanding the fact that Latin America is a region with ethnic and cultural similarities among the 20 member countries, the availability of anti-obesity medications varied broadly, with very dissimilar reg-ulatory frameworks in each country.In some countries, drugs and pharmacological compounds may be prescribed without any regulation and may even be purchased with non-medical prescriptions.In other countries, the rules are very strict, so approval, regulations, controls, and monitoring differ significantly from one country to another.
The experts participating in this consensus conducted a comprehensive search on the approval and current regulations for the prescription of anti-obesity medications in each country.However, access to information was difficult, limited, and confusing, which hindered the possibility of obtaining a list of approved drugs.
During discussions, concerns were expressed regarding the indiscriminate prescription of medications by physicians who were not specialists in obesity, as well as the sale of over-the-counter substances with no evidence of effectiveness or safety, contrary to medical ethics, which jeopardizes the health of patients living with the disease.Hence, general practitioners and specialists are advised to keep themselves updated on the comprehensive therapeutic management of this pathology, so that the patients receive the necessary benefits from the management of their condition.
This consensus focused on analyzing the available evidence on the efficacy and safety of approved medications or on the process of approval in most Latin American countries.Table 5 lists the mechanisms of action, indications, doses, adverse reactions, contraindications, and warnings.  Obesis associated with multiple comorbidities, which improve with a body weight reduction of 5%-10%.The clinical comorbidities are listed in Table 6. 16,79-82

| CONSENSUS STATEMENT
The experts participating in this consensus emphasized the importance of comprehensive therapy management for obesity, including the following: 1. healthy and enjoyable diet sustainable over time; 2. increased daily physical activity;

Class IIa
The weight of the evidence is in favor of its use and efficacy

Class IIb
The use or efficacy is milder according to the evidence or opinions

Class III
The general evidence agrees that a particular treatment or procedure is neither useful nor effective and, in some cases, may even be detrimental Source: Based on Jacobs et al. 25

Other individual parameters to consider include
• patient motivation level; • patient willingness to undergo long-term treatment; • availability of medicines in each country; and • purchasing power of patients.
Evidence is insufficient to make a recommendation for the maximum age for pharmacological therapy.However, this group of experts considers that medication prescriptions should be specifically individualized after 65 years old. 16,85,93,96,97BMI is strongly correlated with total body fat mass, but it is not an accurate indicator of cardiometabolic risk at the individual level. 98ist circumference (measured at the end of normal expiration at the midpoint between the upper part of the iliac crest and the lower margin of the last palpable rib in the mid-axillary line) 17,21,[92][93][94][95] is considered the best anthropometric parameter to define central obesity.
It is a direct indicator of intra-abdominal fat and a good predictor of cardiometabolic diseases.It also provides independent and additional information to BMI to predict morbidity and mortality 93 ; however, there are different suggestions regarding the measurement site and cutoff points.[91][92][93][94][95] Based on the above, this consensus group suggested the following pharmacological treatment algorithm for people living with obesity that is always associated with lifestyle modification strategies (Figure 2).

| Treatment duration
0][101] Treatment may be discontinued under the following circumstances: 16,20,85,90 • lack of therapeutic response (<5% weight loss after 12 weeks with the optimal recommended dose); • intolerance of active components; • changes in clinical scenario; and • women wanting to become pregnant or pregnant during therapy (R: I).
Short-term pharmacotherapy may be considered in special situations, for instance, bariatric surgery, to improve the patient's general condition prior to the intervention (LE: C; R: IIa). 102ce the therapeutic objective is achieved, patients should be followed up and monitored regularly.If the weight loss is regained Sequence of experts' participation in the consensus.
T A B L E 5 Anti-obesity medications available in Latin America.-Gastrointestinal: Unpleasant taste, diarrhea, constipation.
-Uncontrolled high blood pressure.
-History of cardiovascular disease.
-History of drug abuse.
-Known hypersensitivity or idiosyncrasy to sympathomimetic amines.-Co-administration with other weight-lowering medications is not recommended.
-Caution in activities requiring alertness.
-May increase seizures in patients with epilepsy.
-Discontinue the medication in case of intolerance.
-In diabetic patients may lower the requirements for insulin or antidiabetic agents.-Gastrointestinal: Mouth dryness, nausea, vomiting, diarrhea, -Pregnancy and lactation.
-Hypersensitivity to the drug.
-Patients with idiosyncrasy to sympathomimetic amines.
-Arousal, emotionally unstable individuals susceptible or with a history of drug or alcohol abuse.
-Do not administer together with or less than 14 days after using monoaminoxidase inhibitors (risk of hypertensive crisis).
-May increase seizures in some epileptic patients.
-Extended use may lead to dependency with withdrawal syndrome upon discontinuation of therapy.
-During the 14 days following the administration of monoaminoxidase inhibitors.
-Known hypersensitivity or idiosyncrasy to sympathomimetic amines.
-Monitor heart rate and blood pressure.
-Avoid high doses in patients with depression (doses of 15/92 mg/day).
-In case of history of seizures, taper the dose progressively.
-May reduce the effect of oral contraceptives.
-Potentiates the effect of loop diuretics with risk of hypokalemia.
-Epilepsy or seizures or anticonvulsant therapy.
-Treatment with other bupropion-containing medications.
-Recent abrupt discontinuation of alcohol use.
-Abrupt discontinuation of benzodiazepines or anticonvulsants.
-Allergy to naltrexone or bupropion.
-Treatment with levodopa or amantadine.
-Should not be used in association with highfat foods.
-Watch for any behavioral changes or suicidal ideation.
-Hypersensitivity to semaglutide or to any of its excipients.
-Personal or family history of bone marrow cancer, thyroid cancer, or multiple endocrine neoplasms (MEN2).
-Pregnancy and lactation.
-Patients with a history or existing eating disorders, such as bulimia and anorexia.
-Patients receiving other central action weight loss medications or medications for psychiatric disorders.

| Treatment success
Treatment success should be defined as achievement of the following goals (LE: A; R: I): 16,83,85 • sustained weight loss of 5%-10% over time; • permanent lifestyle changes; • improvement or prevention of comorbidities; and • improved quality of life.
In responders, medications improve weight loss and enhance the management of concomitant metabolic diseases.A responder or rapid responder patient is defined as a patient that loses 5% or more of their initial weight after 12 weeks of treatment at optimal medication doses. 104idence is limited, and further clinical trials are required for pharmacological treatment for weight regain or insufficient weight loss after bariatric surgery.[108][109][110][111][112][113] The following parameters are suggested for follow-up purposes and to define treatment success: • quality of life; • BMI; • metabolic comorbidities; and • functional comorbidities.

| Non-recommended therapies
To establish which medications should not be prescribed for the treatment of patients with obesity, experts state that the following medications are not considered anti-obesity and therefore should not be prescribed for weight loss purposes (LE: B; R: III): 18,83,88,90,115,116 • thyroid hormones; • human chorionic gonadotrophin; • growth hormone;  91 Batsis and Zagaria, 92 and Aschner et al. 93 • diuretics; • laxatives; and • drugs that have not been approved or that have been recalled.
Additionally, considering that obesity is a chronic disease, the panel of experts does not recommend the use of drugs that are exclusively approved for short-term use (LE: A; R: III).
Specific contraindications for each drug are listed in Table 5. Women of childbearing age are recommended to use contraceptives during anti-obesity drug therapy, and these medications should be discontinued for at least four to five half-lives before trying to become pregnant.
T A B L E 8 Medications associated with weight gain and therapeutic options.a Controversial evidence about the effect of these drugs on body weight.Source: Based on Apovian et al., 18 Li et al., 82 Erlandson et al., 83 Bray et al., 129 Verhaegen and Van Gaal, 130 Gafoor et al., 131 and Arterburn et al.  (Table 8). .What is the level of evidence for natural products in terms of prescription, ADR, and treatment success that justify their prescription, either alone or in combination?
In the patient living with obesity The use of nutritional adjuvants and/or natural products Is there any evidence as compared to medications For the treatment of obesity In the patient living with obesity relapsing after bariatric surgery

Pharmacological therapy
In contrast to patients that do not relapse Is indicated to achieve control of the disease

3. progression to practicing aerobic and anaerobic programmed exercise; 4 . 25 T A B L E 4
motivational and behavioral management of the patient and family environment; 5. increasing self-control and self-esteem; and 6. avoiding stigmatization of individuals with obesity.The following recommendations are based on one of the key approaches for treating patients with obesity: pharmacological therapy.The level of evidence (LE) and grade of recommendation (R) are indicated at the end of each consensus recommendation.Based on evidence and in accordance with the current treatment philosophy, pharmacological treatment plays a vital and complementary role in lifestyle changes and behavioral cognitive therapy for people with obesity.T A B L E 3 Levels of evidence.A level evidence Data derived from multiple randomized clinical trials or meta-analyses B level evidence Data derived from a randomized clinical trial or numerous non-randomized trials C level evidence Consensus of expert opinions and/or small, retrospective trials and registries Source: Based on Jacobs et al.Classes of recommendations.Recommendation Class I Evidence or general agreement on the benefits, usefulness, and effectiveness of a particular treatment or intervention Class II Conflicting evidence and/or divergent opinions about the use/efficacy of a specific therapy or intervention Abbreviations: BP, blood pressure; CART, cocaine-and amphetamine-regulated transcript; DDP4, dipeptidyl peptidase 4; DM, diabetes mellitus; ECG, electrocardiogram; GI, gastrointestinal; HR, heart rate; MAO, monoamine oxidase; NYHA, New York Heart Association; TIA, transient ischemic attack.

3. 6 |
Medications associated with weight gain and therapeutic alternativesDrugs prescribed to treat obesity comorbidities should be carefully managed to avoid those that may result in weight gain.There is a list of drugs used in the treatment of various chronic diseases that result what it is intended to accomplish, morbidity, mortality, complications 12.What treatment regimens are available for each drug?The treatment success of the patient living with obesity Drug prescription, dose In contrast with conventional treatment Achieves an adequate weight and improves quality of life 13.Is there any special indication for the management of comorbidities while the patient is receiving pharmacological treatment for obesity?The patient with comorbidities Treatment of these comorbidities Is there any difference with regards to treatment considerations To maintain adequate control 14.What is the role of drugs approved for short-term use in the treatment of obesity?Patient living with obesity Treated with pharmacological options Compared with conventional therapy Long-term effect of the intervention 15.What is the long-term follow-up once the treatment objective is achieved?In the patient living with obesity Treated with pharmacological options Versus conventional therapy Which are the control parameters in the long term 16.Is pharmacological treatment indicated in post-bariatric weight regain? Continued) Algorithm for in obesity.BMI, body mass index; CVD, cardiovascular disease; CVR, cardiovascular risk; DM2, diabetes mellitus type 2; HBP, high blood pressure; KD, kidney disease; NAFLD, non-alcoholic fatty liver disease; OSAS, obstructive sleep apnea syndrome; PCOS, polycystic ovary syndrome; SEL, socioeconomic level.Cutoff points used for waist circumference in different guidelines or studies.Based onRoss et al., What are the time periods (minimum and maximum) for the use of pharmacological therapy?Which drugs should be prescribed or should not be considered as anti-obesity medications?
tion, association with amphetamines, and a history of recalled drugs due to adverse effects.In contrast to other chronic diseases, medications approved for long-term treatment and access to these medications remain limited, which further hinders their adequate use.The objective of this process was to provide guidelines for the management of anti-obesity medications for physicians at all levels of care adapted for Latin American and Caribbean populations.APP E NDIX A: BASELINE QUESTIONS FOR CONSENSUS ON PHARMACOLOGICAL TREATMENT OF OBESITY IN LATIN AMERICA