Obesity Treatment

Treatment Goals

• To reduce health risks and improve health 
  • Prevent complications
  • Prevent or manage existing comorbidities
  • Restore positive body image and self-esteem
• Address the principal cause of weight gain (treat primary and secondary causes of obesity) and focus management on both weight loss and patient-centered health outcomes 
• Short-term goal is loss of 5-15% of body weight over 6 months with long-term goal of weight maintenance 
  • Depends on the severity of obesity and obesity-related comorbidity (ORC), eg poorly controlled DM despite best medical treatment, nonalcoholic steatohepatitis and obstructive sleep apnea may require ≥10% weight loss
• Regain of <3 kg in 2 years and sustained reduction of waist circumference of at least 4 cm

Strategy

• Aim for realistic goals (ie 10% body weight reduction over 6 months or not exceeding 0.5-1 kg/week)
• Multidisciplinary approach (combination of dietary change, physical activity and behavioral modification) is recommended
  • Intensive interventions should be considered in obese patients with T2DM or poorly controlled ORC (eg use of very low-calorie diet, anti-obesity agents or bariatric metabolic surgery) 
    • Reduction of global CVD risk (eg diet modification, physical activity, weight loss, smoking cessation and control of blood glucose, BP and serum lipids) should be undertaken by patients with obesity and T2DM or hypertension

• Pharmacotherapy may aid compliance with dietary restriction, augment diet-related weight loss program, and help achieve weight maintenance after weight loss
• It may be recommended in patients who failed to achieve meaningful weight loss (ie >5% of total body weight) and to sustain weight loss and for patients with BMI ≥30 kg/m² or a BMI of ≥27 kg/m² with presence of risk factors or obesity-related illnesses such as hypertension, dyslipidemia, diabetes mellitus and obstructive sleep apnea
• Considered in patients who have not lost 1 lb/week after combination with non-pharmacological therapy
• Check for efficacy and safety at least monthly for the first 3 months of pharmacotherapy
  • Successful pharmacotherapy is considered if at least 2 kg (4.4 lb) weight loss is achieved in the first 4 weeks after starting treatment, otherwise, re-assessment should be considered
• Pharmacotherapy when used for 6 months-1 year, together with lifestyle modifications and physical activity, produces an average weight loss of 3.1-8.4% above placebo
• For successful weight maintenance, weight regain should be <3 kg (6.6 lb) in 2 years and a sustained reduction in waist circumference of at least 4 cm
• Since obesity is a chronic disease, some propose the need for chronic pharmacological therapy; FDA-approved agents for chronic weight management include Orlistat, Phentermine/Topiramate, Naltrexone/Bupropion, Liraglutide, Semaglutide and Tirzepatide
  • If there are no safety concerns with long-term use, continue treatment as long as benefit outweighs risk
• Prioritize treatment of acute illness (eg markedly increased blood glucose and/or BP, severe dyslipidemia, acute thrombosis, CVD or cancer) with concomitant treatment of obesity

Centrally Acting Anti-Obesity Agents¹

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

• Eg Liraglutide, Semaglutide 
• Approved for the treatment of diabetes and were found to be associated with weight loss
  • Act centrally through the GLP-1 receptors in the brain to induce postprandial satiety and to decrease hunger and prospective food intake 
• Adjunct to a reduced calorie diet and increased physical activity for chronic weight management of obese patients with a BMI of ≥30 kg/m², or overweight patients with a BMI of ≥27 kg/m² to <30 kg/m² with at least one weight-related comorbidity (eg type 2 diabetes, dyslipidemia or hypertension)
• Liraglutide can be used for weight management for up to 2 years
  • Reduces HbA1c, BP, insulin resistance, lipid levels, risk of stroke and use of oral glucose lowering agents in patients with T2DM
• Studies showed a statistically significant reduction in body weight after 68 weeks of treatment with Semaglutide compared with placebo
  • Reduces HbA1c, BP, lipid levels and risk of stroke

GLP-1 Receptor and Glucose-dependent Insulinotropic Polypeptide (GIP) Receptor Agonist 

• Eg Tirzepatide   
• Indicated for chronic weight management as an adjunct to a reduced-calorie diet and increased physical activity in adults with an initial BMI of ≥30 kg/m² or ≥27 kg/m² with at least one weight-related comorbid condition (eg hypertension, dyslipidemia, T2DM, OSA or CVD)
• Advise patients regarding the potential risk of medullary thyroid carcinoma and symptoms of thyroid tumors

Naltrexone/Bupropion  

• Naltrexone is an opioid receptor antagonist while Bupropion is a dopamine and norepinephrine reuptake inhibitor
• Anorectic effect may be a result of sustained activation of anorexigenic neurons in the hypothalamus
• Reduces food craving
• Also decreases glucose levels, insulin resistance and lipid levels and decreases the requirement for glucose lowering drugs in T2DM
• May be used in patients with obesity and depressed mood
• Treatment should be discontinued if patient has not lost ≥5% of total body weight after 12 weeks of therapy

Norepinephrine Agents² 

• Eg Phentermine, Mazindol
• Enhance catecholamine neurotransmission leading to increased sympathetic activity and reduced appetite
• Not recommended in patients with uncontrolled hypertension or a history of heart disease
• Phentermine
  
  • Most commonly used noradrenergic agent for the treatment of obesity
  • Does not affect dopamine neurotransmission, hence, little potential for abuse
  • Recommended for short-term use (<12 weeks) only; no longer recommended for long-term treatment of obesity
  • Reduces total cholesterol and LDL-C
  • Use with caution in patients with anxiety disorders and closely monitor for changes in behaviors and moods
  • Severe mental depression may result from abrupt discontinuation after prolonged high-dose intake; it is recommended to gradually withdraw Phentermine therapy
• Phentermine/Topiramate
  • Associated with greater mean weight loss than the other weight loss preparations
  • Approved for the long-term use in the management of obesity 
  • Increases energy expenditure and decreases energy efficiency and caloric intake
  • Perform a pregnancy test prior to initiation of therapy and monthly thereafter as fetal toxic effects are linked to Topiramate 

¹Lorcaserin has been withdrawn from the market after a safety clinical trial demonstrated an increased occurrence of cancer in treated patients. 

²Amphetamines are no longer recommended for treatment due to their potential for abuse. Some agents (eg Benzphetamine and Phendimetrazine) are considered to be of high potential for abuse and are not recommended.

Peripherally Acting Anti-Obesity Agent

Orlistat

• The only lipase inhibitor approved for management of weight loss
  • Inhibits pancreatic lipase, prevents fat hydrolysis into absorbable fatty acid and thereby decreases fat absorption
• Indicated for the treatment of obese patients with a BMI of ≥30 kg/m², or overweight patients with a BMI of ≥28 kg/m² with associated risk factors, eg type 2 diabetes, hyperlipidemia and hypertension
• May be used in patients who prioritize modest amount of weight loss and are not bothered by the possibility of gastrointestinal adverse effects
• Studies have shown that patients taking Orlistat as part of a nutritional program and physical activity changes had a weight loss of 3.9-10.6 kg after 1 year of treatment and 4.6-7.6 kg after 2 years of treatment
• Has been shown to reduce BP and glucose levels and improve lipid profile
• When 120 mg is taken immediately before, during or up to 1 hour after each main meal, ¹/₃ of dietary fat ingested is excreted in stool, reducing fat and calorie intake
  
  • Also inhibits digestion of TG
  • Current data noted rare cases of severe liver injury with the use of this medication
• Can be used for long-term (up to 4 years) weight management

Other Agents

Antidiabetic Medications in Patients with T2DM Who are Overweight or Obese

• Antidiabetic medications can result in weight loss (eg GLP-1 receptor agonists, Tirzepatide, Metformin, sodium-glucose linked transporter 2 [SGLT2] inhibitors) or are weight neutral (eg dipeptidyl peptidase-4 [DPP-4] inhibitors and Acarbose)           
  • GLP-1 receptor agonists and SGLT2 inhibitors reduce risk for CVD events 
• The optimal medication dose for patients with obesity and T2DM would be the dose most available to the patient if the medication has proven benefits for weight reduction, improvement of glycemic control and CVD risk reduction
• Contraception or active precautions against pregnancy should be advised before and during treatment with antidiabetic medications
  • May consider consulting a specialist regarding stopping antidiabetic medications before a planned pregnancy
• Consider giving Metformin and psychological therapy for weight gain prevention to patients with severe mental illness who are receiving antipsychotic drugs associated with weight gain 

Lisdexamfetamine and Topiramate

• May be considered as adjunctive therapeutic agents to psychological treatment in overweight or obese patients with binge-eating disorder

Dietary Supplements and Herbal Preparations

• There is insufficient evidence to recommend dietary supplements and herbal preparations for the management of obesity
• May contain unpredictable amount of active ingredients, have unpredictable efficacy and unknown safety profiles

Behavioral and Psychological Therapy

• Provides methods to overcome barriers to weight loss (ie socio-cultural beliefs, stress, denial), such as motivational counseling
• Should include counseling, self-monitoring, portion control, stimulus control, contingency management, stress management, cognitive behavioral strategies and weight loss support groups
• If weight loss of 2.5% within the first month of treatment was not achieved, intensification of behavioral intervention and support should be done 
  • Behavioral therapy combined with diet and exercise result in greater weight reduction compared to diet or exercise alone
• There is evidence supporting that intensive, multicomponent behavioral interventions for obese patients can improve glucose tolerance and other physiologic factors for cardiovascular disease
• Integration of multicomponent behavioral and psychological approaches in the management of obesity are recommended and include:
  • Enhancement of communication and avoidance of stigmatizing
  • Psychoeducation which emphasizes on achieving behavioral and psychological goals to improve health, function and quality of life
  • Motivational interviewing and behavioral interventions
    • Motivational interviewing includes patient engagement, focusing on 1 behavior at a time and evoking patient’s internal motivation
    • Behavioral strategies help improve adherence to lifestyle intervention programs
  • Psychological interventions which include cognitive behavioral therapy (CBT) and Acceptance and Commitment therapy
    • CBT combined with diet or exercise resulted to greater weight loss compared to diet or exercise alone
    • Acceptance and Commitment therapies center on value-directed actions and commitment to multicomponent behavioral interventions
• Information and communication technology (ICT)-based weight loss tools (eg structured websites, internet-enabled mobile phone applications) which allow patients to track and monitor their behaviors online compared to standard non ICT-based interventions were found to significantly increase weight loss, decrease total energy and saturated fat intake, and have minimal but positive effect on physical activity
  • ICT-based interventions must include the following treatment components: Tailoring, goal setting, self-monitoring, social support and targeted feedback

Comorbidities

• Prevention and treatment of comorbidities are recommended