Regis University IP2 Obesity Notes Fall 2024 PDF

Obesity RHCHP School of Pharmacy Integrated Pharmacotherapy 2 Fall 2024 Facilitators Reading and References Peter Clapp, PhD Required pcla...

Obesity RHCHP School of Pharmacy Integrated Pharmacotherapy 2 Fall 2024 Facilitators Reading and References Peter Clapp, PhD Required [email protected] Integrated Pharmacotherapy 2 Obesity course notes Optional Flier Jeffrey S, Maratos-Flier Eleftheria, “Chapter 401 and 402: Obesity” (Chapter). Harrison’s Principles of Internal Medicine, Bianca Calderon, PharmD, 21e. Available on-line at www.accesspharmacy.com. [email protected] Larry A. Bauer, “Chapter 3. Drug Dosing in Special Populations...” (Chapter). Applied Clinical Pharmacokinetics, 3e: Available on-line at www.accesspharmacy.com. Video: Super Size Me, Kathbur Pictures, 2004. Podcast: A Review of Weight Loss Medications. CorConsult Rx: Evidence-Based Medicine and Pharmacy Learning Objectives 1. Provide a description or definition for each of the bolded words in the notes. 2. Define basal metabolic rate and daily energy expenditure. 3. Explain the imbalance of energy input and expenditure leading to obesity. 4. Describe the metabolic fate of ingested carbohydrates, proteins, and fats. 5. Describe the process of triglyceride storage from fats and carbohydrates. 6. Discuss the processes of lipogenesis and lipolysis and their role in the availability of free fatty acids and fat storage. 7. Recognize the various regulators of lipolysis, including hormones that regulate lipase activity, the sympathetic nervous system, and the relative abundance of available energy sources. 8. Describe the mechanisms of appetite and body weight regulation. 9. List the factors that contribute to the pathophysiology of obesity. 10. Explain the role of nutrition, physical activity, appetite, and medical conditions in the development of obesity. 11. Recognize complications of obesity and increased visceral fat and mechanisms of obesity-related morbidity. 12. Recognize signs, symptoms, and components of assessment in the clinical presentation of obesity. 13. **Calculate body mass index (BMI) given a weight in kilograms or pounds and height in centimeters or inches. 14. Classify a weight category given a body mass index (BMI) or information used to obtain BMI. 15. Recognize increased risk for cardiovascular disease and obesity-related complications given a waist circumference (WC). 16. **Determine when lifestyle intervention, pharmacotherapy, or bariatric surgery is indicated for overweight or obesity management. 17. Discuss treatment goals for overweight and obese patients. 18. Describe the role and components of nonpharmacologic therapy in managing overweight and obesity. 19. Identify, describe, and compare and contrast the products available for weight loss (pharmacologic classification, mechanism of action, administration, absorption, side effects, adverse drug reactions, interactions, and contraindications) 20. Explain the relationship between amphetamine and noradrenergic anorectics. 21. Differentiate between phase I and phase II drug metabolism reactions in the metabolism of obesity drugs. 22. Describe the importance of drug metabolism with regard to drug activity and elimination. 23. Describe pharmacokinetic differences between healthy and obese patients, including when to use ideal versus total body weight in dosing calculations. 24. **When given physicochemical and elimination data for a drug, predict the effect of obesity on pharmacokinetics. 25. Describe drug delivery and medication considerations and medications to avoid or use with caution post-bariatric surgery. 26. Recognize common nutritional deficiencies and recommend macronutrient, vitamin, and mineral supplementation in patients who have had bariatric surgery. 27. Recognize, monitor, and address obesity-related complications. 28. **Formulate an evidence-based therapeutic and monitoring plan that includes nonpharmacologic and pharmacologic interventions to initiate and maintain weight loss and decrease obesity related complications. 29. Describe clinical controversies for sibutramine, lorcaserin, and the combination of fenfluramine and phentermine, and reasons for their withdrawal. ** Learning Objectives marked with a double asterisk will require in-class application prior to achieving mastery of the objective INTRODUCTION TO OBESITY Definitions Overweight and obesity refers to abnormal or excessive body weight or fat accumulation. These terms are generally classified by body mass index (BMI), which takes height and weight into account. The World Health Organization definition of overweight is a BMI greater than or equal to 25 kg/m2, and obese is a BMI of greater than or equal to 30 kg/m2. Epidemiology Over the past thirty years, worldwide obesity rates have nearly tripled, resulting in an obesity epidemic, especially within the United States. Worldwide, 1.9 billion adults, 18 years and older, were overweight in 2016, with over 650 million of these individuals being obese. In the United States, it is estimated that 71.6% of adults are overweight or obese, and nearly 42.5% are classified as obese according to data from the National Health and Nutrition Examination Survey (NHANES) from 2017-2018. The CDC reports that at least 1 in 5 people in each of the 50 states is obese. Obesity is the 5th leading cause of global deaths, resulting in 2.8 million adult deaths annually. Preventable conditions related to obesity include heart disease, stroke, type II diabetes, and some types of cancer. Obese individuals spend $1429 more per year in medical costs than individuals of normal weight. Screening, Health Promotion, and Disease Prevention The U.S. Preventive Services Task Force (USPSTF) recommends that clinicians screen all adult patients for obesity. Screening for overweight and obesity can be easily performed in health fairs, physician offices, or pharmacies with inexpensive tools such as a scale and tape measure. The scale can be used to measure height and weight to determine BMI, and a tape measure for WC to assess for cardiovascular risk factors. Screening children aged 6 years and older for obesity is also recommended by the USPSTF. Offering or referring children and their families to comprehensive, intensive behavioral interventions to promote improvement in weight status should also be performed. BMI can be measured at routine health maintenance visits. Screening and referral become particularly important in light of the association between early childhood obesity and the increased likelihood of adult obesity. PHYSIOLOGY/BIOCHEMISTRY Obesity is a disease in which food intake or energy input greatly exceeds the energy output or expenditure leading to increased fat storage in adipose tissue. In order to better understand how obesity occurs, it is important to discuss basic nutritional concepts and nutrient metabolism. Nutrition Basics The human diet consists of four macronutrients: carbohydrates, fats, protein, and fiber. Dietary reference intakes (DRIs), developed by the Food Key Points and Nutrition Board, recommend that adult daily caloric intake should be Nutrition Basics compromised of approximately 45 to 65% carbohydrates, 20 to 35% fat, and 10 Nutritional components of the diet and caloric requirements to 35% protein. Nutritional requirements will vary among individuals based Explanation of energy expenditure on age, sex, medical conditions, nutrition status, and physical activity level. Energy Utilization An individual’s daily energy or calorie requirement can be calculated based Conversion of diet to energy to work on population estimates of calories required per kilogram of body weight. In a Tricarboxylic Acid (TCA) cycle and ATP healthy individual with normal nutrition status, the estimate would be: 20 to 25 Energy Balance kcal/kg per day. This generalized calculation does not account for age or gender Intake vs. Energy Need differences. More complex equations exist that consider age, height, weight, Endogenous stores and conversion of stores to energy gender, and clinical condition. The basal metabolic rate is the energy expended to perform resting functions such as breathing, circulation, and metabolic processes. In contrast, the daily energy expenditure not only includes energy to support basal metabolism, but also physical activity and the energy required to digest, absorb, distribute, and store nutrients (diet-induced thermogenesis). It is important to remember that these values are only estimates; the most accurate method to determine energy expenditure is by indirect calorimetry or metabolic gas monitoring. These methods are not used frequently as they require trained personnel and can be costly and cumbersome to perform. Integrated Pharmacotherapy 2 2 Obesity Energy Balance The first law of thermodynamics states that energy is not created nor destroyed but converted Figure 1. Nutrient storage. from one form to another. This directly applies to the energy balance between caloric intake and energy output. If caloric intake is less than the energy expended, the body uses Glucose endogenous stores for energy supply. In the case of obesity, caloric intake often exceeds energy expended and the body stores the excess energy leading to weight gain. Oxidation Storage If energy intake exceeds energy expenditure by 5% every day, the result is a gain of 11 pounds Energy Glycogen of fat mass over 1 year. A continuation of this lifestyle can easily result in a person achieving Triglycerides morbid obesity in only a few years. Synthesis Many compounds Dietary Nutrients Nutrients from the diet provide the fuel necessary for the body to perform basal functions Fats as well as thermogenesis, unconscious physical activity, occupational labor, and purposeful exercise. The main fuels we obtain from our diet are carbohydrates, fat, and proteins. These molecules are ingested during a meal and subsequently digested in the stomach and Oxidation Storage intestines; carbohydrates to glucose, proteins to amino acids, and fats to free fatty acids and Energy Triglycerides monoacylglycerides. These digestion products are then absorbed into the body and are used to meet the immediate energy needs of the body. The excess is transported to the storage Synthesis depots and stored (Figure 1). Membrane lipids Nutrient Storage Amino Acids Carbohydrates Carbohydrates are digested to monosaccharides. The major monosaccharide in practically all Oxidation Protein synthesis human diets is glucose, which is either used for energy or stored as glycogen in the liver and Energy muscle (glycogenesis). Glycogen storage has a limited capacity that is regulated by cellular metabolism and by hormone signals. Once liver glycogen stores are completely normalized, Synthesis of surplus glucose is instead converted to fatty acids and triglycerides. The metabolic pathways nitrogen-containing that govern glucose storage in the form of glycogen will be discussed in more detail in the compounds upcoming IP 3 Diabetes Mellitus. Proteins Proteins are digested to amino acids. The amino acids enter the blood stream where they are used by cells for protein synthesis and synthesis of nitrogen containing compounds or oxidized for energy. It is important to Figure 2. Cellular respiration Macromolecule Caloric Content point out that proteins are not solely stored Fatty acids Carbohydrate 4 kcal/g as an energy source. Protein 4 kcal/g Glucose Amino acids Fat 9 kcal/g Fats Triglycerides are the major fats in the e- diet. They are digested to free fatty acids e- Acetyl CoA e- and monoacylglycerides and absorbed by the intestinal epithelial cells. They are then packaged with proteins and other fats into lipoprotein complexes and enter the blood. These lipoprotein complexes are broken down to free fatty acids and monoacylglycerides which TCA cycle are taken up by the cell. Fatty acids are used for synthesis of membrane lipids, stored as triglycerides in adipose tissue, or oxidized for energy. Triglyceride storage is a very efficient CO 2 fuel store. Adipose tissue does not contain much water (which dramatically increases body weight) and triglycerides contain more calories per gram than carbohydrate or protein. e- The caloric content of fats is 9 kcal/g and each gram of protein or carbohydrate yields approximately 4 kcal/g of energy. Electron ATP transport chain Nutrient Oxidation In order to generate energy from carbohydrates, fats, and amino acids, these nutrients must O2 be oxidized to CO2 and H2O through a process called cellular respiration (Figure 2). Prior to H2O respiration, stored nutrients are converted back to their monomers; glycogen is converted to Integrated Pharmacotherapy 2 3 Obesity glucose, triglycerides are converted to fatty acids, and proteins are converted to amino acids. The initial steps of oxidation for glucose, fatty acids, and amino acids similarly generate the 2-carbon molecule acetyl coenzyme A (acetyl CoA). Acetyl CoA is utilized by the tricarboxylic acid (TCA) cycle completing the oxidation of fuels to CO2. Energy from oxidative reactions is conserved in the form of reduced electron-accepting coenzymes, NADH and FADH2. NADH and FADH2 are then oxidized by the electron transport chain reducing oxygen to water. The process of converting energy from the reduction of oxygen converts adenosine diphosphate (ADP) and inorganic phosphate (Pi) to adenosine triphosphate (ATP) is called oxidative phosphorylation. ATP provides the energy that drives most energy-consuming processes in the cell. During these cellular processes, ATP is hydrolyzed to ADP and Pi. Control of Lipid Storage and Release During fasting, stored triglycerides undergo lipolysis by a hormone-sensitive lipase (HSL) to form free fatty acids and glycerol. The fatty acids can either be modified to reform triglycerides or diffuse into the blood to form a protein complex with albumin for energy utilization by other tissues. Many organs such as the heart use fatty acids as their primary source of energy. The hormones that control lipolysis by stimulating hormone-sensitive lipases include glucagon, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone, and α- and β-melanocyte-stimulating hormone (MSH). The sympathetic nervous system mediates lipolysis and the mobilization of free fatty acids. Adipose tissue is heavily innervated by the sympathetic nervous system as mobilization of fatty acids for energy is required during a “fight or flight” situation. When there is an excess of food intake, free fatty acids are taken up by adipose tissue and stored as triglycerides. The synthesis of triglycerides from glucose, also called lipogenesis, occurs when cellular ATP and glucose levels are high. This process converts glucose to acetyl CoA which is then transformed to fatty acids. Lipogenesis occurs Figure 3. Metabolic regulatory systems. primarily in the liver, and to a lesser extent, in adipose tissue. Pancreas Insulin is a mediator that promotes triglyceride storage. Insulin is released by Gastrointestinal the beta cells of the pancreatic islets as a result of rising blood glucose levels Adipose tissue Insulin tract Ghrelin after a carbohydrate-containing meal. Insulin stimulates glucose uptake into Leptin GLP-1, PYY3-36 cells, the conversion of glucose to glycogen, and, in adipose tissue and the CCK liver, conversion of glucose to triglycerides. Insulin inhibits the activity of HSL, Hypothalamus reducing the release of free fatty acids from adipose tissue. Adipocytes are a major site of insulin action. Satiation/Satiety Regulatory Systems of Appetite and Body Weight Metabolic regulatory systems (Figure 3) of the central and autonomic nervous Reduced food intake system, endocrine glands, and adipose tissue work to influence hunger and Adrenal Gland satiety (absence of hunger after eating). These systems involve both short-term and long-term mechanisms. Short-term mechanisms involve gastrointestinal Decreased nutrient storage in adipose tissue hormones that either stimulate appetite (ghrelin) or stimulate satiety (cholecystokinin (CCK), peptide YY3-36 (PYY3-36), and glucagon-like peptide 1 (GLP-1). Afferent neurons within the gastrointestinal tract also respond to intestinal contents, triggering the hypothalamus to produce a feeling of satiety. Table 1. Known regulators of appetite Long term energy regulation of body weight also includes brainstem and Simulate Appetite Stimulate Satiety hypothalamic regulatory systems. These complex systems integrate neural and hormonal signals derived from the periphery regulating energy intake and Ghrelin Cholecystokinin (CCK) expenditure. Monoamine neurotransmitters such as norepinephrine and serotonin Neuropeptide Y Peptide YY3-36 (PYY3-36) have been shown to play a role in food intake. It is thought that these molecules act on the brainstem and hypothalamus promoting satiety and utilization of body fat for Orexin Glucagon-like Peptide 1 (GLP-1) energy. Molecules that regulate appetite are summarized in Table 1. Norepinephrine and Serotonin Neuropeptides β-melanocyte-stimulating hormone (MSH) Many neuropeptides that influence appetite exert their effects within the hypothalamus. The key peptides are currently thought to be neuropeptide Y and MSH. Leptin Neuropeptide Y is the most potent known stimulator of eating, and MSH is one of the Insulin crucial inhibitors of eating. The lateral hypothalamus is often called the hunger center of the brain. A lateral hypothalamic peptide, orexin, increases food intake stimuli within the lateral hypothalamus. Neurons in the lateral hypothalamus use orexin to communicate with other neurons and thereby affect a number of functions beyond appetite. Integrated Pharmacotherapy 2 4 Obesity Peripheral Control of Appetite Peripheral appetite signals also dramatically affect food intake. Adipose cells secrete a hormone called leptin that acts on the brain to decrease appetite and increase energy expenditure. Studies in humans have shown that exogenous leptin administration produced significant weight loss. However, leptin replacement Figure 4. Factors affecting energy storage (fat). therapy trials in obese humans have failed, as obese people appear to be leptin resistant. Although hunger and satiety functions are regulated by hormones and neuropeptides in the hypothalamus, people eat for a variety of reasons, such as reward, pleasure, learning, and memory. PATHOPHYSIOLOGY OF OBESITY Contributing factors Obesity is the result of energy imbalance, and can be due to increased energy intake, decreased energy expenditure, or a combination of both. There are multiple factors that contribute to energy intake and expenditure. These factors include genetic predisposition, environmental factors, nutrition, appetite, activity, and medical conditions. In most cases, it is a complex combination of many of these factors that influence weight gain and loss. It is often difficult to determine to what degree each factor affects individual patients (Figure 4). Each factor is discussed in more detail below. Conditions More Prevalent in Obese Populations Studies of families and twins demonstrate a link between genetics and obesity and fat distribution. Variations in body fat determined Cardiovascular Musculoskeletal by genes are not known and estimates range from 20% to 80%. Hypertension Degenerative joint disease There are some genetic syndromes that are characterized by Left ventricular hypertrophy Skin diminished energy expenditure and severe obesity, but these are Congestive heart failure Acanthosis nigricans very rare. Environmental factors that have been determined to impact obesity include cultural and social influences, such as Coronary artery disease Stretch marks lifestyle choices, nutritional selection, and food supply. Stroke Hirsutism Pulmonary Skin tags The impact of nutrition on obesity is often debated. It is clear that total caloric intake above expenditure needs results in weight gain, Obstructive airway disease Gastrointestinal but the impact of nutritional composition is uncertain. Dietary Sleep apnea Cholelithiasis fat is more energy dense (contains more calories per gram than Pulmonary hypertension Esophageal reflux protein and carbohydrates) and is stored with greater efficiency, Metabolic Hiatal hernia making it a common target of most diet plans in the United States. Hypercholesterolemia Psychological Whether a sedentary lifestyle is the cause or result of obesity, Hypertriglyceridemia Eating disorders physical activity increases energy expenditure and is an important component to weight control or weight loss. In addition, physical Low serum high-density lipoprotein Depression exertion may also protect against the complications associated Diabetes mellitus Affective disorders with obesity. Hyperinsulinemia Social stigma As previously discussed, appetite is under the influence of the Polycystic ovary syndrome Neoplasm hypothalamus. The hypothalamus receives stimuli from neural Increased serum urate Breast cancer and hormonal mechanisms. Neural mechanisms include nerve Colon cancer signals indicating gut distention after a meal and serve to decrease Adapted from Chen JT, et al. In: DiPiro JT, et al. Pharmacotherapy: A Patho- appetite. Hormone signals include leptin, insulin, and cortisol; physiologic Approach, 8th Ed. Table 154-1. these stimulate the hypothalamus to release various proteins that can increase or decrease appetite. Certain medical conditions lead to weight gain and often obesity. These include Cushing’s syndrome and hypothyroidism, and obese patients should be screened for these conditions if clinical suspicion exists. Several drugs can induce weight gain including insulin, antidepressants, and atypical antipsychotics. A more comprehensive list is available in Table 2 on page 6. Integrated Pharmacotherapy 2 5 Obesity Complications of Obesity Obesity raises the risk of morbidity from hypertension, dyslipidemia, type 2 diabetes mellitus, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea, respiratory problems, and some forms of cancer. These effects are summarized in “Appendix A” on page 20. Obesity is considered an independent risk factor for the development of cardiovascular disease. It raises the risk of all-cause mortality and cardiovascular disease mortality. Increased body mass places strain on various body systems. The gastrointestinal system can be affected, with common complaints of gastroesophageal reflux and cholelithiasis. Osteoarthritis of the knees, hips, and ankles and degenerative joint disease develop secondary to trauma from weight bearing. Not uncommon are low back pain, immobility, social stigma, and depression in these individuals. Increased fat in the thoracic and abdominal cavities can restrict lung expansion and reduce lung filling capacity, leading to sleep apnea and obstructive airway disease. Apnea symptoms are often greatly reduced with weight loss. Obesity has also been associated with certain forms of cancer, such as of the breast, colon, endometrium, and prostate. Reproductive abnormalities due to hypogonadism can also result from complications of obesity. Impaired glucose tolerance is associated with the development of insulin resistance and diabetes mellitus. Insulin resistance can also affect lipid metabolism. Increased cholesterol and triglycerides, as well as decreased high-density lipoproteins (HDL, also known as the “good” cholesterol), often result. With the development of insulin resistance, pancreatic beta-cells (β-cells) produce a state of hyperinsulinemia. You will learn more about insulin resistance mechanisms in IP 3 Diabetes Mellitus. In addition, increased fat deposition in the pancreatic islet cells decreases the release of insulin. Table 2. Drugs that cause weight gain or weight loss. Obese individuals have a 5-fold increased risk of developing hypertension due to an increased production of angiotensinogen (a Drug Class Weight Gain Weight Loss precursor of a hormone that vasoconstricts blood vessels), increased Amitriptyline blood volume, and increased blood viscosity. Hypertension in obese Nortriptyline individuals is associated with atherosclerosis, increased heart volume, Antidepressants Imipramine Bupropion ischemia, and ventricular wall thickening. Therefore, excessive central Mirtazapine adiposity increases the risk for the development of hypertension, Paroxetine dyslipidemia, and type 2 diabetes mellitus, increasing risk of cardiovascular disease and stroke. Valproate Anticonvulsants Carbamazepine Topiramate Gabapentin Olanzapine CLINICAL PRESENTATION Antipsychotics Quetiapine Risperidone Although overweight and obesity are significant problems, many Clozapine patients do not seek medical attention until obesity-related conditions Insulin GLP-1 or complications arise. Routine assessment of complications of obesity Antidiabetic Agents Sulfonylureas Metformin should be performed. Many have hypertension; therefore, blood Thiazolidinediones SGLT-2i pressure should be monitored regularly. In order to obtain an accurate Oral Contraceptives Hormones blood pressure, it is critical that an appropriately sized blood pressure Glucocorticoids cuff is used. Patients should be observed for labored breathing, signs Data represents general trends; opposite effects may occur in some of osteoarthritis (particularly in hips, knees, and ankles), edema, and patients. Adapted from Ann Intern Med 2008;149(7):ITC4-1-15. skin changes (such as striae). Since abdominal (central) adiposity can increase pressure on the diaphragm leading to decreased lung capacity, auscultation of the lungs should be performed to identify hypoventilation syndrome. Medical and drug-induced causes of weight gain should be part of the routine assessment. Medical causes of weight gain include hypothyroidism, Cushing’s syndrome, polycystic ovary syndrome, and depression. There are many medications that can contribute to weight gain. It is important for pharmacists to identify medications that can cause weight gain (see Table 2 on page 6). The patient’s family history should also be collected, such as information about obesity, diabetes mellitus, hypertension, coronary artery disease, sleep apnea, and osteoarthritis. A history of the patient’s past weight loss attempts and eating habits should be evaluated. Patients may underestimate their daily food intake and/or overestimate their energy expenditure with exercise. It is important to use an objective means to estimate a patient’s current caloric intake. Calorie counting is inconvenient and has demonstrated inaccuracy, and it has been suggested that completing a diary of cooking habits, portion sizes, and purchases of oils, fatty foods, fast foods, drinks (soft drinks and alcohol), and sugar may more closely reflect dietary habits. An exercise diary may also be helpful. Most importantly, the patient must be assessed for motivation and readiness to lose weight. Classification Body mass index (BMI) is used to classify a patient as overweight (≥25 kg/m2) or obese (≥30 kg/m2). BMI is a convenient measure to Integrated Pharmacotherapy 2 6 Obesity estimate levels of excess weight or adipose tissue in clinical practice and in epidemiological studies. Formulas for calculating BMI are provided in Table 3. Table 3. Calculating body mass index. BMI = Weight (kg) / [Height (m)]2 Although BMI is a quick way to assess obesity, there are limitations on the effectiveness and appropriateness of using BMI as a true Example: Weight 68 kg, Height 165 cm = 1.65 m measurement of health. BMI does not distinguish between bones, fat Calculation: 68 kg ÷ (1.65 m)2 = 24.98 kg/m2 and muscles. Often people who have normal BMI scores have a high OR percentage of body fat (a risk factor for cardiovascular disease) and many labeled as obese by the BMI (because of increased muscle mass) BMI = [Weight (lb) / (Height (in)2] x 703 have a normal percentage of body fat. Incorrect BMI categorization may Example: Weight 150 lb, Height 5’5” = 65” prevent some people from receiving necessary weight loss treatment Calculation: [150 lb ÷ (65 in)2] x 703 = 24.96 lb/in2 and may mislabel others as obese when they have a healthy body composition. BMI measurements may place older adults into the Conversion factors you should know: 2.2 lb = 1 kg; healthy weight category without taking any other body composition 2.54 cm = 1 inch; 100 cm = 1 m; 12 in = 1 ft factors into consideration. Whereas an older adult may have a normal BMI, they may have a high percentage of body fat and minimal amounts of lean muscle mass. It is common for adults > 60 years old to Table 4. Classification of weight category by BMI, WC, and associated disease risk. lose muscle mass over time, and the Disease Risk* for Normal WC Disease Risk* for High WC BMI may not be representative of a Weight Category BMI (kg/m2) (Men ≤40 in, Women ≤35 in) (Men >40 in, Women >35 in) healthy weight. Underweight < 18.5 -- -- Normal Weight 18.5 to 24.9 -- Increased In addition to height and weight, the Overweight 25 to 29.9 Increased High patient’s waist circumference should Obesity 30 to 34.9 High Very high be measured. Waist circumference (Class I Obesity) (WC) and BMI each provide clinical Obesity 35 to 39.9 Very high Very high measures of excess body fat, and (Class II Obesity) they provide a better assessment of total body fat than weight alone. Extreme (Severe) Obesity ≥ 40 Extremely high Extremely high (Class III Obesity) BMI and WC are each independent predictors of disease risk related to Key: BMI = body mass index; WC = waist circumference; CV = cardiovascular; kg = kilograms; m = meter; in = inches obesity, and both measurements *Disease risk for hypertension, type 2 diabetes mellitus, and cardiovascular disease. should be taken at initial assessment Adapted from National Heart, Lung, and Blood Institute. and routinely while being treated for obesity. Waist circumference refers to the narrowest circumference measured between the bottom-most rib and top of iliac crest. A WC of >35 inches in women and >40 inches in men places a patient at higher risk for obesity-related complications. Table 4 provides weight categories based on BMI, as well as cardiovascular disease risk based on WC. The combination of central obesity and metabolic syndrome (Figure 5) is associated with an increased risk of Figure 5. Risk Determinants for the Metabolic Syndrome cardiovascular disease. Risk Factor Critical Value* Abdominal Obesity Waist Circumference Diagnostic Tests Men > 102 cm (> 40 in) Women > 88 cm (> 35 in) WC and BMI are considered acceptable measures of the Triglycerides > 150 mg/dL risk for metabolic syndrome in clinical practice. Fasting HDL-C blood glucose should be measured to rule out diabetes. A Men < 40 mg/dL fasting lipid panel should be drawn to assess the presence Women < 50 mg/dL of dyslipidemia. Renal function should be assessed by Blood Pressure > 130/85 mm Hg measuring plasma BUN, serum creatinine, and electrolytes since these tests can identify renal injury due to diabetes or Fasting Glucose > 100 mg/dL hypertension. Liver function tests should be obtained to rule A person must have 3 of 5 determinants to meet the criteria of metabolic out nonalcoholic steatohepatitis (fatty liver). syndrome. Goals of Therapy The goals of treatment for obesity are to initiate safe weight loss, maintain weight loss, and decrease the risk of obesity-related Integrated Pharmacotherapy 2 7 Obesity complications. It is important to set specific, realistic goals for patients. A modest weight reduction of 3 to 5% is associated with clinically meaningful reductions in HbA1c and blood glucose (markers of glucose tolerance), blood pressure, and triglycerides in patients with type 2 diabetes mellitus, hypertension, and dyslipidemia, respectively. Greater amounts of weight loss can reduce blood pressure, improve LDL–C and HDL–C (“bad” and “good” cholesterol), and reduce the need for medications to control blood pressure, blood glucose and lipids. Although 3 to 5% weight loss can lead to clinically meaningful reductions in cardiovascular disease risk factors, an initial 5 to 10% weight loss goal within 6 months is recommended for greater benefits. Lifestyle intervention, including dietary changes, exercise, and behavioral therapy, is first line therapy as it has been shown to have a positive impact on weight loss. However, evidence demonstrates that lifestyle intervention alone can be ineffective as some patients regain the lost weight as a result of an inability to sustain these changes. Patient readiness to make the changes necessary for long-term weight loss is extremely important. Medications and surgery are options as adjunctive therapy to lifestyle intervention. Nonpharmacotherapy Many individuals attempt fad diets, over-the-counter (OTC) medications, herbal preparations, and/or nutritional supplements to lose weight before seeking the help of healthcare providers. Many complementary and alternative medicines (CAAM) are not required to undergo the rigorous testing that is required of prescription and nonprescription medications as long as they do not pose a significant risk to the patient. Manufacturers of CAAM therapies cannot make claims that their products can treat a disease, but they can claim to reduce the risk of a disease. Therefore, many manufacturers have marketed nutritional supplements and herbal products as promoters of weight loss. Some of these products contain compounds such as linoleic acid, chromium, chitosan, ephedra alkaloids, and raspberry ketone. There is little evidence to support the use of these agents for the treatment of obesity. Ephedra (also known as Ma Huang), an adrenergic agent promoted to suppress appetite and promote thermogenesis, was widely used in the past with caffeine for weight loss. However, ephedra alkaloids have a significant side effect profile that includes hypertension, cardiac arrhythmias, seizures, strokes, and increased mortality. As a result, ephedra was banned by the FDA in 2004. Because of the risk for these and other adverse effects and inconsistent quantities of active ingredients in CAAM products, the National Institutes of Health (NIH) has developed guidelines that state that herbal preparations are not recommended for the treatment of obesity. This underscores the importance of a thorough medication history that includes not only prescription medications, but also OTC medications and supplements. Comprehensive lifestyle intervention that includes a reduced calorie diet, physical activity, and behavioral therapy (preferably with a trained interventionist) is recommended for ≥6 months for overweight and obese individuals. Examples of trained interventionists include registered dietitians, psychologists, exercise specialists, health counselors, or professionals in training. Weight loss can be achieved by creating an energy deficit through caloric restriction, physical activity, or both. An energy deficit of ≥500 kcal/day typically may be achieved with dietary intake of 1200 to 1500 kcal/day for women and 1500 to 1800 kcal/day for men, though kilocalorie levels are adjusted to an individual’s body weight. Other approaches would be to prescribe a 500 to 750 kcal/day deficit or an evidence-based diet that restricts certain types of foods (such as high-carbohydrate, low-fiber, or high-fat foods). Physical activity combined with reduced caloric intake appears to be more effective than exercise alone. At least 30 minutes of moderate physical activity most days of the week is recommended to supplement weight loss and reduce cardiovascular risk factors and obesity- related complications. Overweight and obese individuals should start slowly and gradually increase intensity as tolerated. In addition, a medical examination should be performed in obese patients by a physician prior to starting an exercise program. Behavioral therapy is another key component for successful weight loss. Techniques to learn desirable behaviors such as stimulus control and reinforcement, self-monitoring of diet and exercise to increase awareness, social support, relapse prevention, and behavioral contracts can support weight loss efforts. THERAPEUTIC AGENTS FOR OBESITY Glucagon-like Peptide-1 (GLP-1) Agonists GLP-1 agonists were initially approved for diabetes before noting their effect on weight loss. The first to receive FDA approval for weight loss was liraglutide (Saxenda®) in 2014 for adults. By 2020, the FDA extended its approval to include patients aged 12 and older who are obese. In June 2021, the FDA approved semaglutide (Wegovy®) for chronic weight management in adults who are either obese (BMI of 30 kg/m2 or greater) or overweight (BMI of 27 kg/m2 or greater) with at least one weight-related condition (e.g, high blood pressure, type 2 diabetes, high cholesterol). Tirzepatide (Mounjaro®) was approved for diabetes in 2022. Its mechanism is different from semaglutide and liraglutide in which it is a dual agonist of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Integrated Pharmacotherapy 2 8 Obesity One year later, tirzepatide was approved for obesity under the brand name, Zepbound. Remember, Saxenda® is the brand name of liraglutide that is Drugs for Obesity indicated for weight loss. Victoza® is indicated for type 2 diabetes and contains Liraglutide (Saxenda®) liraglutide at a lower dose. Similarly, while Wegovy® is indicated for weight Route: Injection loss, Ozempic® , another brand of semaglutide, is indicated for type 2 diabetes Availablity: Rx at a lower dose. Victoza® and Ozempic® are commonly used for weight loss Semaglutide (Wegovy®) in those with diabetes due to better insurance coverage. Route: Injection Availability: Rx Drug Formulation, Delivery and Absorption Tirzepatide (Zepbound®) Liraglutide, semaglutide, tirzepatide are administered by subcutaneous Route: Injection injections. Liraglutide can be administered without regard to meals but Availability: Rx should be taken once a day and at the same time each day. During week 1, the Naltrexone/bupropion (Contrave®) daily dose is 0.6 mg, this increases by 0.6 mg each week until week 5 when 3 Route: PO Availability: Rx mg is administered daily. Absolute bioavailability of liraglutide is 55%. Peak concentrations of liraglutide occur within 11 hours of dose administration. Phentermine (Adipex-P®, Suprenza™)* Route: PO Although liraglutide is administered once a day, semaglutide is administered Availability: Rx only (Schedule IV) once per week , on the same day each week; however, it can be administered Diethylpropion (Tenuate)* any time of day, with or without meals. Semaglutide must be increased Route: PO gradually over 16 to 20 weeks to 2.4 mg once weekly to reduce gastrointestinal Availability: Rx only (Schedule IV) side effects. Tirzepatide dosing strategy is similar to semaglutide, dosed weekly Benzphetamine (Regimex™, Didrex) and by titration to avoid gastrointestinal side effects. Route: PO Semaglutide has an absolute bioavailability of 89%, and its maximum Availability: Rx Only (Schedule III) concentration is reached 1 to 3 days post dose. Both liraglutide and Phendimetrazine (Bontril PDM) semaglutide are extensively bound to plasma albumin (>98%). Route: PO Availability: Rx Only (Schedule III) Because of the popular use and limited supply of semaglutide, some Phentermine-Topiramate (Qsymia™) pharmacies have started compounding semaglutide. However, compounded Route: PO semaglutide is not FDA approved or recommended for use due to the lack of Availability: Rx only (Schedule IV) in certified pharmacies (REMS) regulations and risk of adverse drug reactions. Orlistat (Xenical®, Alli™) Route: PO Drug Distribution, Action and Elimination Availability: Rx (Xenical®), OTC (Alli™) Liraglutide (Figure 66) is GLP-1 modified at a lysine residue. This causes Setmelanotide (Imcivree®) noncovalent, but strong binding to human serum albumin and also reduces Route: Injection degradation by DPP4. This structural change increases the half-life to ~13 Availability: Rx hours and allows for once daily dosing. The role of GLP-1 appears to be *Approved for short-term use only (few weeks) in preparing the body for surges of glucose resulting from sudden rises in glucose plasma concentrations. Thus, when food is consumed while using GLP-1 agonists, it can properly process glucose and not store excess calories as fat. Liraglutide is degraded by enzymatic cleavage of the DPP-4 enzyme. The modifications of liraglutide compared with native GLP-1 give liraglutide an elimination half-life of ~13 hours. Semaglutide is degraded via proteolytic cleavage and has an elimination half-life of approximately 1 week, which accounts for its ability to remain in the circulation for about 5 to 7 weeks after the last 2.4 mg dose. Figure 6. Structure of the peptide liraglutide. Letters represent Drug Effects and Interactions amino acids Liraglutide is expected to lower body weight by about 6% while semaglutide has seen much larger benefit with about 15% reduction in weight. SURMOUNT trials have shown up to 20% weight loss in participants who received tirzepatide after 72 weeks. In addition, 95% of participants in SURMOUNT 3 achieved at least 5% reduction in body weight from baseline. This is the most weight loss seen in the market to date. GLP-1 agonists were found to cause thyroid C-cell tumors in mice and a Black Box warning for the risk of thyroid C-cell tumors such as medullary thyroid carcinoma. Therefore, these medications are contraindicated in patients with a history or family history of medullary thyroid carcinoma and/or multiple endocrine neoplasia syndrome type 2. GLP-1 agonists can also increase the risk of pancreatitis and gallbladder disease. GLP-1 agonists delay gastric emptying and can interfere with the absorption of orally administered drugs. The risk of hypoglycemia is Integrated Pharmacotherapy 2 9 Obesity increased when used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin in which home glucose readings should be monitored while titrating GLP-1 agonists. These medications may cause fetal harm and are contraindicated for use during pregnancy. Because of its long half-life, Wegovy® should be discontinued at least two months prior to trying to conceive. Interestingly, tirzepatide is the only agent in this class that currently carries a warning about birth control pill effectiveness on its label. Patients should be counseled about using a second form of contraception while taking tirzepatide and birth control pills. Bupropion and Naltrexone Drug Formulation, Delivery and Absorption Contrave® was given FDA approval in September 2014 as a combination 8 mg naltrexone HCl/90 mg bupropion HCl extended release tablet. The administration of Contrave® occurs in the morning and evening and is titrated to therapeutic levels over the course of four weeks. During week 1, one tablet is given in the morning and none in the evening. During week 2, one tablet is taken in the morning and one in the evening. During week 3, two tablets are taken in the morning, and one in the evening. From week 4 and onward, two tablets are taken in the morning and two tablets are taken in the evening. After administration of Contrave®, the mean time to peak concentration of naltrexone is around 1 hour, while the mean time to peak concentration of bupropion is 3 hours. When Contrave® is taken with a high fat meal, absorption and peak naltrexone and bupropion concentrations increase ~2 fold. This results in systemic exposure above the therapeutic range of Contrave®, thus Contrave® should not be taken with high fat meals. Drug Distribution, Action and Elimination Contrave® is a mixture of the opioid antagonist naltrexone and the antidepressant bupropion and is recommended along with decrease caloric intake and increased physical activity. Naltrexone is an antagonist of the µ-opioid receptor, to a lesser extent the k-opioid receptor, and to an even lesser extent the d-opioid receptor. The common theme among the opioid receptors that naltrexone inhibits is that they are all coupled to the Gi protein, the inhibitor protein of adenylyl cyclase. Inhibiting these receptors results in increased levels of the second messenger cAMP in the brain. Bupropion’s exact mechanism of action is poorly understood, but is thought to involve norepinephrine-dopamine reuptake. Contrave® is thought to involve two areas of the brain that regulate food intake in order to suppress appetite. Naltrexone is thought to act on the hypothalamus (appetite regulation), while bupropion is thought to act on the mesolimbic dopamine circuit (reward system). Naltrexone is excreted ~70% renally, therefore Contrave® should be dose adjusted in patients with decreased glomerular filtration rates (GFR). In healthy individuals, the elimination half-life of naltrexone is ~5 hours. Bupropion is extensively metabolized by CYP2B6 with three active metabolites. The elimination half-life is ~21 hours. Drug Effects and Interactions Contrave® is expected to lower weight by about 6%. There is a contraindication with patients who are taking or have taken an MAOI within 14 days as the combination can lead to hypertensive events. Bupropion inhibits CYP2D6, so Contrave® doses should be decreased if the patient is on drugs metabolized by CYP2D6. It is contraindicated with patients undergoing opioid therapy, or taking benzodiazepines, barbiturates, and antiepileptic drugs. It is also contraindicated in patients with uncontrolled hypertension, seizure disorders, eating disorders, or alcoholics who have abruptly stopped alcohol intake. Bupropion/naltrexone extended-release tablets (Contrave®) has a Black Box warning for increased risk for suicidal thoughts and behaviors and neuropsychiatric reactions. Noradrenergic Agents Drug Formulation, Delivery and Absorption Phentermine hydrochloride is available in generic tablets (8 and 37.5 mg) and capsules (15, 30, and 37.5 mg) for oral administration. Phentermine is also available under the brand name Adipex-P® as a 37.5 mg scored tablet. Tablets and capsules are to be taken every morning before breakfast or approximately 1-2 hours after breakfast. Administration in the late evening should be avoided because of possible insomnia. The duration of action for appetite suppression is 12 to 14 hours for once daily dosing. In June 2011, the FDA approved Suprenza™, an oral disintegrating tablet formulation of phentermine for use as a short-term adjunct in a comprehensive weight reduction plan. The rate and extent of phentermine exposure is equivalent regardless of which oral Integrated Pharmacotherapy 2 10 Obesity formulation is administered. Diethylpropion is available in 25 mg immediate-release and 75 mg Introduction to Monoamines: controlled-release generic tablets. The 25 mg tablets are taken three Noradrenergic and Serotonergic agents times per day, one hour before meals or in the mid-evening if desired Monoamine neurotransmitters include catecholamine (epinephrine, to overcome night-time hunger. The 75 mg controlled-release tablets norepinephrine, and dopamine) and non-catecholamine (serotonin, should be taken once a day at mid-morning. melatonin, and histamine) derivatives that are released from nerve terminals in the central and peripheral nervous systems. The term “noradrenergic” is derived from the name “noradrena- Drug Distribution, Action and Elimination lin.” Adrenalin is another name for epinephrine and noradrenalin is Phentermine and diethylpropion (as well as benzphetamine, and another name for norepinephrine (NE). The “nor” refers to the loss phendimetrazine) are derivatives of the CNS stimulant amphetamine of a methyl group in NE relative to epinephrine. Both NE and epi- (Figure 7) and share similar pharmacologic activity. Diethylpropion nephrine are important catecholamine neurotransmitters in the sympathetic division of the autonomic nervous system, and their role itself is inactive but undergoes extensive first-pass metabolism to active in autonomic pharmacology will be presented in detail during IP 2 metabolites following oral absorption. Both drugs enhance the release Hypertension. of norepinephrine (NE) from presynaptic neurons, resulting in an Serotonin, or 5-hydroxytryptamine (5-HT), is synthesized from the increase in adrenergic receptor activity in the CNS. All of these drugs amino acid tryptophan in specialized neurons and in cells that line cause an anorectic effect (appetite suppression), helping patients restrict the gastrointestinal tract. The synthesis and control of serotonin in the brain will be presented in more detail during IP 3 Major Depres- their daily caloric intake. This effect is likely due to a stimulatory effect sive Disorders. on the hypothalamus, although the exact mechanism is unknown. Although phentermine is not extensively metabolized, CYP3A4 accounts for the Figure 7. Noradrenergic agents. primary mode of metabolism. Approximately 70% of the parent drug remains NH2 unchanged and is excreted in the urine. The mean phentermine terminal half-life is about 20 hours. Diethylpropion is extensively metabolized in the liver to active metabolites and then excreted in the urine. Amphetamine Drug Effects and Interactions O The adrenergic stimulation caused by noradrenergic agents raises the potential for NH2 N several adverse effects. Mydriasis, which is a prolonged abnormal dilation of the pupil secondary to adrenergic stimulation, may worsen symptoms in patients with glaucoma. The dosage requirements of insulin and oral hypoglycemic medications Phentermine Diethylpropion used for diabetes may change during therapy. These drugs may cause an increase in blood pressure and other cardiovascular events, and are contraindicated in patients with cardiovascular disease, moderate-to-severe hypertension, and pulmonary hypertension. When combined with other anorectics, phentermine has been associated with valvular heart disease and pulmonary hypertension. Phentermine and diethylpropion increase levels and/or effects of monoamine neurotransmitters in the CNS. Use within 14 days of taking a monoamine oxidase inhibitor (MAOI) is contraindicated due to the potential to enhance the hypertensive effect of the sympathomimetic properties of MAOIs. Agents that increase monoamine neurotransmitter activity, including amphetamines, have abuse potential secondary to CNS stimulation effects. Accordingly, phentermine and diethylpropion are schedule IV drugs and are contraindicated in patients with substance abuse history. Figure 8. Chemical structure of topiramate Phentermine and Topiramate Drug Formulation, Delivery and Absorption A combination of phentermine hydrochloride and topiramate (Qsymia™) was approved by the FDA in July 2012 as an adjunct for chronic weight management. Qsymia™ is available as an extended-release capsule at the following strengths (phentermine/ topiramate): 3.75 mg/23 mg, 7.5 mg/46 mg, 11.25 mg/69 mg, and 15 mg/92 mg. The topiramate component of the combination capsule is formulated as an extended- release medication, and consistent with good practices, capsules should not be opened, crushed or chewed. Qsymia™ is administered once daily in the morning with or without food. Administration of Qsymia™ in the late evening should be avoided because of the possibility of insomnia. Drug Distribution, Action and Elimination The mechanism of action of Qsymia™ is related to the activities of the drug’s components, Integrated Pharmacotherapy 2 11 Obesity phentermine and topiramate (Figure 8). Phentermine has been described above, and the mechanism of topiramate, an anticonvulsant, on chronic weight management is not known. Its effects on obesity may be due to appetite suppression, increased satiety or both. Known targets of topiramate include receptors for the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), voltage-gated sodium ion channels, and excitatory glutamate-gated ion channels. Additionally, the effects of topiramate to block the spread of seizure will be discussed in detail during IP 7 Seizure Disorders. The majority of an administered dose (about 70%) is eliminated unchanged in the urine. Since both phentermine and topiramate are cleared by renal excretion, exposure to Qsymia™ is increased in patients with moderate (CrCl > 50 ml/min) and severe (CrCl 30-50 ml/ min) renal impairment. Although topiramate does not undergo metabolism to a great extent, some hepatic CYP3A4 enzyme inducers have been shown to significantly reduce topiramate serum concentrations. In addition, topiramate may induce CYP3A4 and weakly inhibit CYP2C19. The mean topiramate terminal half-life is about 65 hours. Drug Effects and Interactions Qsymia™ is expected to lower weight by 10%. Remember, phentermine is contraindicated within 14 days of administering MAOIs. It is contraindicated in patients with a history of cardiovascular disease and uncontrolled hypertension. In addition, Qsymia™ is contraindicated in patients with glaucoma, hyperthyroidism, and during pregnancy. Topiramate is teratogenic in which Qsymia™ use is limited under a Risk Evaluation and Mitigation Strategy (REMS) program where only certified pharmacies may distribute the medication and a negative baseline and monthly pregnancy tests are required in females of reproductive potential. In addition, the FDA requires a medication guide to be dispensed with this medication. Other causes for concern from earlier clinical trials prior to its approval included suicidal behavior and ideation, tachycardia, and cognitive impairment. Lipase Inhibitors Figure 9. Orlistat. Drug Formulation, Delivery and Absorption Orlistat is available by prescription in 120 mg capsules (Xenical®) and as a O non-prescription product in 60 mg capsules (Alli™). One capsule of orlistat O O is taken orally with each main meal that contains fat or may be administered up to one O hour after consuming the meal. When a meal is missed, or after meals that contain HN O no fat, the dose may be omitted. Orlistat Drug Distribution, Action, Elimination Orlistat is one FDA approved oral drugs for weight loos that has low bioavailability (less than 1%) due to poor absorption and first- pass metabolism in which the systemic absorption is also low. Orlistat is a chemical analog of the naturally occurring pancreatic lipase inhibitor lipostatin that has been chemically modified to enhance stability (Figure 99). Orlistat forms covalent bonds with serine residues in the active sites of pancreatic and gastric lipases, inhibiting the formation of free fatty acids from dietary triglycerides. The digestion and absorption of dietary fats will be described in more detail in IP3 Dyslipidemia. The pharmacologic outcome of lipase inhibition is a dose-related decrease in fat absorption (up to about 30% of dietary fat) and subsequent weight loss. In essence, orlistat works by preventing the digestion of dietary fat. This mechanism depends on the presence of food. Orlistat must be taken with fat-containing foods to work properly. Due to low oral absorption, orlistat does not undergo appreciable systemic metabolism. Instead, the majority of orlistat is excreted unchanged in the feces. Drug Effects and Interactions Orlistat has not shown great reduction in weight loss with an average body weight reduction of 3%. The major adverse effect of orlistat is directly related to the mechanism of action. Decreased dietary fat absorption results in excretion of dietary fat in the feces, resulting in steatorrhea (fatty, oily stools), fecal incontinence, fecal urgency, flatulence, and abdominal and rectal pain. These effects tend to decrease over time and may be minimized by limiting dietary fat intake. A low fat diet is recommended to improve tolerance to orlistat. Post-marketing data revealed reports of hepatotoxicity, and in May 2010, the FDA completed a safety review, resulting in a revised label for orlistat to include safety information about rare cases of severe hepatotoxicity. Patients should be warned of symptoms of liver injury, including itching, jaundice (yellow eyes or skin), dark urine, fatigue, loss of appetite, abdominal pain, nausea, vomiting, and light-colored stools. Orlistat may decrease the absorption of fat-soluble vitamins (e.g., vitamins A, D, E, K and beta carotene). Supplementation with a daily Integrated Pharmacotherapy 2 12 Obesity multivitamin at least 2 hours before or after orlistat administration (i.e., bedtime) is recommended. The administration of fat-soluble drugs with orlistat should be separated by at least 2 to 4 hours (e.g., cyclosporine, levothyroxine). Chronic malabsorption syndrome or cholestasis (a block in the flow of bile) may also occur with orlistat. Melanocortin Receptor Agonist Setmelanotide (Imcivree®) became FDA approved November 2020 for the chronic weight management in adults and pediatric patients 6 years and older with Bardet-Biedl Syndrome (BBS). BBS is a rare condition where patients may present with obesity, retinal degeneration, reduced kidney function, or extra digits on hands or feet. It is also indicated for patients with certain genetic conditions, including proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency, that are linked to obesity. Drug Formulation, Delivery and Action For adults, setmelanotide’s initial regimen is 2 mg via subcutaneous injection daily. Patients between 6 and 11 years old should begin with 1 mg daily for 2 weeks before increasing to 2 mg. Maximum dose for both populations is 3 mg daily. Setmelanotide is an 8 amino acid cyclic peptide analog of melanocortin peptide alpha- melanocyte stimulation hormone. It acts as a melanocortin 4 (MC4) receptor agonist. These receptors in the brain regulate hunger, satiety, and energy expenditure. Patients with BBS or genetic conditions have insufficient use of the MC4 receptor. Setmelanotide acts to increase the activity of the MC4 receptor, thereby reducing hunger, promoting satiety, and increasing metabolism. Drug Effects Other agents are generally unsuccessful at treating BBS-induced obesity, supporting the need for this new agent. In clinical trials, setmelanotide reduced patients’ BMI by 7.9% on average. Patients included in the study required adults have a BMI of 30 kg/m2 or greater and pediatric patients be within the 97th percentile. Of this population, 61% of subjects lost 5% or more of their BMI. Common adverse reactions include skin hyperpigmentation, injection site reactions, gastrointestinal reactions (nausea, vomiting, diarrhea), and spontaneous penile erection. Setmelanotide is associated with disturbance in sexual arousal which could lead to priapism (erection lasting FYI Only - Belviq® longer than 4 hours) or hypersensitivity of the labia. It is also associated with Lorcaserin hydrochloride (Belviq®) is a serotonin receptor agonist that suicidal ideation in which individuals should be monitored for mood changes. was a previously used adjunct to a reduced-calorie diet with exercise It may also cause skin pigmentation to existing moles. Patients should undergo for the treatment of obesity. However, Eisai Inc. voluntarily withdrew a skin examination before starting this medication. this drug from the market in February 2020 upon the request of the FDA after clinical trials revealed that the potential risks of cancer associated with lorcaserin administration outweighed the benefit. CLINICAL CONTROVERSY The appropriateness of pharmacotherapy for obesity is controversial based on questions over the safety and effectiveness of these medications. A good example is the recent withdrawal of sibutramine (Meridia®). Sibutramine had been on the market since 1997 for weight loss and the maintenance of weight loss for obese patients and overweight patients with cardiac risk factors, with weight loss approximating 5% beyond that of placebo. Like phentermine and diethylpropion, sibutramine is chemically related to amphetamine, but halogenation of the phenyl ring imparts neurotransmitter reuptake inhibition activity, particularly for 5-HT. Sibutramine worked by inhibiting the reuptake transporters for several neurotransmitters including NE and 5-HT, and dopamine to lesser extent. The term “serotonergic” refers to drugs that enhance the action of the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT). In November 2009, the FDA notified healthcare providers of preliminary findings from the Sibutramine Cardiovascular OUTcomes Trial (SCOUT), which showed patients with cardiovascular disease at increased risk of cardiovascular events. The trial (N Eng J Med 2010;363:905-17), demonstrated the sibutramine-treated group with a higher incidence of nonfatal myocardial infarction and stroke compared to placebo. FDA advisory committee members met on September 15, 2010, with 8 of 16 members recommending the removal of sibutramine from the U.S. market. On October 8, 2010, Abbott Laboratories announced a voluntary withdrawal of sibutramine. Another example illustrating potential risks of anorexiants is the combination of fenfluramine (Pondimin®) and phentermine (commonly known as Fen-Phen). Each drug was approved in the 1970s for the short-term management of obesity. Like phentermine, fenfluramine is structurally related to amphetamine and works as a central anorexiant with serotonergic activity. The off-label combination of Fen- Phen became widely popular in the 1990s for weight loss. Each drug alone is known to cause pulmonary hypertension, and post- Integrated Pharmacotherapy 2 13 Obesity  marketing reports revealed an increased risk for developing valvular heart disease (N Eng J Med 1997;337(9):581- 8 and N Eng J Med 1998;339(11):713-8). As a result, fenfluramine and its dextro enantiomer dexfenfluramine (Redux®) were both withdrawn from the market in 1997. Liability costs to the manufacturer resulted in multibillion-dollar lawsuits. For a PBS Frontline story on Fen-Phen click here. For the American Home Products diet drug settlement site click here. THERAPEUTIC APPLICATIONS OF EVIDENCE BASED MEDICINE FOR OBESITY The recommendations presented here are based on the following guidelines: 2022 AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity, 2015 Pharmacological Management of Obesity: An Endocrine Society Clinical Practice Guideline, and the 2013 American Heart Association/American College of Cardiology/The Obesity Society (AHA/ACC/TOC) Guideline for the Management of Overweight and Obesity in Adults. The 2013 AHA/ACC guideline recommends the measurement of BMI and WC at annual visits or more frequently. Patients who are overweight (BMI >25 to 29.9 kg/m2) and obesity (BMI ≥30 kg/m2) should be monitored closely for signs and symptoms of obesity- related complications. They should be regularly counseled about the health benefits of weight loss even if they are not currently motivated to lose weight. Patient readiness is a key component of any weight loss program. Once the patient is ready and motivated to lose weight, the overweight or obese patient should be evaluated by a healthcare provider qualified to assess nutritional requirements and make specific dietary recommendations. Treatment guidelines make similar recommendations for the management of overweight and obesity: Diet, exercise, and behavioral modification for all overweight and obese patients (BMI ≥25 kg/m2) Consider pharmacotherapy as adjunctive therapy to behavioral modification in patients with a BMI ≥27 kg/m2 with comorbidity or BMI >30 kg/m2 to reduce food intake and increase physical activity when possible Consider bariatric surgery as adjunctive therapy for patients ≥35 kg/m2 with comorbidity or BMI >40 kg/m2 to reduce food intake and increase physical activity when possible Comorbidities include hypertension, dyslipidemia, coronary heart disease, type 2 diabetes mellitus, and obstructive sleep apnea. The 2015 guideline on the pharmacological management of obesity recommends: Efficacy and safety of weight loss medications be assessed at least monthly for the first 3 months, then at least every 3 months. If a patient’s response to a weight loss medication is deemed effective (weight loss ≥5% of body weight at 3 months) and safe, continue pharmacotherapy. If deemed ineffective (100 to 200 g/day) should be avoided to prevent refeeding syndrome. If patients have had limited oral intake for a prolonged period, supplementation must be started slowly and increased gradually as tolerated. Refeeding syndrome can occur due to insulin-mediated intracellular influx of electrolytes and resulting retention of renal salt and water. Symptoms include swelling with signs of volume overload associated with hypokalemia, hypophosphatemia, and hypomagnesemia. Bariatric surgery decreases the absorption of micronutrients, and daily supplementation is necessary. All patients should take an adult multivitamin with mineral (with elemental iron 45-65 mg, folic acid 400 mcg, and thiamine 25-100 mg) chewable tablet (2 tablets for RYGB and 1 tablet for LAGB) daily, 1200-1500 mg of elemental calcium (from diet, and supplemental calcium citrate in 2-3 divided doses as necessary to meet daily Narrow Therapeutic Index Drugs requirements), at least 3000 international units of vitamin D3 daily (to therapeutic levels of 25-hydroxyvitamin D >30 ng/mL), and vitamin B12 to maintain adequate vitamin B12 Anticonvulsants Other medications Carbamazepine Digoxin levels (typically 1000 mcg sublingual daily or oral if adequately absorbed; vitamin B12 Ethosuximide Warfarin can also be administered as a subcutaneous or intramuscular injection). Phenobarbital Levothyroxine Calcium and vitamin D deficiencies are common because calcium is typically absorbed Phenytoin Lithium in the duodenum and proximal jejunum, while vitamin D in absorbed in the jejunum Immunosuppressants Theophylline Cyclosporine Procainamide and ileum. In addition, calcium requires vitamin D and an acidic environment for absorption. Calcium citrate is preferred over calcium carbonate, which requires an Mycophenolate Sirolimus acidic environment for absorption. Thiamine (vitamin B1) deficiency can occur in up Tacrolimus to 30% of patients as a result of bypass of the jejunum, where most thiamine absorption occurs. Symptoms can manifest as neuropathy or other neurological deficits. Iron deficiency anemia is common after RYGB. Iron supplementation in the ferrous form (Fe2+) is preferred over the ferric form (Fe3+), as the latter requires gastric acid to be reduced to the ferrous form, resulting in decreased absorption. Vitamin A deficiency has been reported in up to 69% of patients after BPD (with or without DS). Because malabsorptive procedures often induce steatorrhea, deficiencies in fat-soluble vitamins (in addition to vitamin D) can occur. Malabsorptive procedures (such as BPD/DS) should be screened for vitamin A deficiency, which may present as ocular complications and results from poor nutritional intake, malabsorption, and impaired hepatic release of vitamin A. Oral vitamin A supplementation alone or with other fat-soluble vitamins (such as vitamin D, E, and K) may be recommended for some patients. Integrated Pharmacotherapy 2 16 Obesity PHARMACOKINETICS AND OBESITY Effect of Obesity on Pharmacokinetics Obese patients have a lower proportion of lean body weight relative to total body weight than non-obese patients. Some drugs preferentially distribute into either lean or fat tissues. Accordingly, differences in drug distribution may exist between obese and non- obese patients for some drugs. An altered volume of distribution profile may subsequently alter drug concentration at the site of action and overall drug effect. Usually the pharmacokinetic differences between obese and non-obese patients are not clinically relevant. However, for some drugs the pharmacokinetic differences that occur secondary to obesity may require dose adjustments in drug therapy, particularly for drugs with weight-based dosing. Some drugs require total body weight (TBW, sometimes referred to as actual body weight), while others require ideal body weight (IBW). In some cases, an adjusted body weight needs to be calculated to determine the dose. Drugs with High Affinity for Adipose Tissue Many drugs have relatively high lipid solubility leading to high affinity for distribution and binding to fat tissues. This type of drug will have a higher Key Points: Obesity & Pharmacokinetics volume of distribution (Vd) in obese patients than non-obese patients because there is a greater volume for drug distribution (i.e., the excess Volume of Distribution (Vd) adipose tissue). Therefore it is appropriate to use TBW when using patient Vd unchanged in obese patients for drugs with low affinity for adipose weight to calculate doses for lipid soluble drugs, because the TBW better tissue represents the body mass that the drug is distributing to than the IBW. For Larger Vd in obese patients for drugs with high affinity for adipose tissue most drugs that are dosed based on patient weight, TBW is the appropriate For some drugs it is important to use IBW or an adjusted body weight weight to use in the dosing calculation. rather than TBW for dosing Clearance Drugs with Low Lipid Affinity Glomerular filtration rate is increased in obese patients and may increase clearance for drugs mostly cleared by this route Drugs that are relatively water soluble (polar) distribute preferentially into Increase in clearance = decrease in half-life, and may require higher doses lean body mass and do not distribute and bind well in lipid tissues. The and/or more frequent dosing Vd for this type of drug is usually unchanged by the percentage of body fat and is therefore usually the same in obese versus non-obese patients. For Example Patient drugs with low lipid affinity that are dosed using the patient weight, it Patient A is a 28 year old male weighing 180 lbs (81.8 kg). Patient B is generally preferable to use the patient’s IBW, as this better represents is a 28 year old male weighing 240 lbs (109 kg). Both are 6 feet tall. the body mass in which the drug is distributed. If TBW is used instead, Both are admitted into the hospital and are receiving two different drugs. then there is a risk of overestimating the dose of drug and potentially overdosing the patient. Clinically relevant examples of this type of Drug X is a highly lipid soluble agent that is dosed 5 mg/kg per day. Because this drug will distribute into fat, the volume of distri- drug include digoxin (a cardiovascular agent) and cyclosporine (an bution for this drug will be higher in obese patients (Patient B). To immunosuppressant to prevent organ transplant rejection). calculate the dose for each patient, TBW should be used as it best represents the body mass that the drug will distribute into. Drugs that Distribute into Extracellular Fluid of Adipose Tissue Drug Y is a water soluble drug that is dosed the same as Drug X Some drugs distribute into adipose tissue not because of high lipid affinity, (5 mg/kg per day). This drug prefers lean body mass and will not distribute well into fat tissue. Therefore, the volume of distribution but rather due to distribution into the extracellular fluid contained in of this drug is not greatly affected by percent body fat. To calculate adipose tissue. For these drugs, it may be appropriate to use an adjusted the dose for each patient, IBW should be used as it best represents body weight for dosing calculations. A clinically relevant example of this the body mass that the drug will distribute into. type of drug is the aminoglycoside class of antibacterials (e.g., gentamicin, Patient A Patient B tobramycin, amikacin). BMI (kg/m ) 2 24.5 32.6 IBW (kg) 79.6 79.6 Increased Clearance Secondary to Obesity The glomerular filtration rate of some drugs is increased in obese ABW (kg) 81.8 109 patients. If the main route of clearance is renal elimination as unchanged Drug X 410 550 drug, then this increase in glomerular filtration may result in a clinically Lipophilic mg/kg/day mg/kg/day significant increase in systemic clearance. For example, the clearance Drug Y 400 400 of vancomycin (an antibacterial agent effective for certain Gram- Hydrophilic mg/kg/day mg/kg/day positive infections) is increased in obese patients such that the average elimination half-life decreases from 8 hours to 3 to 4 hours. This is due to increased glomerular filtration of unchanged vancomycin into the urine (the primary route of vancomycin elimination). While the Vd of vancomycin is unaffected by obesity, the dosing for vancomycin should still be based on TBW to compensate for the increased clearance. Integrated Pharmacotherapy 2 17 Obesity OPPORTUNITIES FOR FUTURE RESEARCH - FYI ONLY Oral semaglutide is currently approve for diabetes, not weight loss. Previous research did not show a large weight loss benefit with this formulation; however, more trials are coming out with potential. The most recent trials, OASIS and PIONEER PLUS, have studied this formulation at higher doses than what is labeled for diabetes with anticipation of greater weight loss benefit than what was seen previously. There are two upcoming oral GLP-1 agonists in clinical trials, orforglipron and danuglipron. Orforglipron, designed specifically for weight loss, decreased weight by up to 15% after 36 weeks (ACHIEVE trial). Danuglipron is currently being studied for use in diabetes. There are two dual GLP-1 and glucagon receptor agonists, survodutide and pemvidutide. Pemvidutide is studied for obesity and nonalcoholic steatohepatitis (NASH), in the MOMENTUM trial right now. Unlike most GLP-1 agonists, pemvidutide will not be indicated for diabetes due to its neutral effect on glucose. Boehringer is currently studying survodutide and released preliminary results of their Phase II trial. Of those who received survodutide, 40% achieved at least 20% reduction in weight. Retatrutide is a triple-hormone receptor agonist, acting on GLP-1, GIP, and glucagon receptors. It is anticipated to become the most efficacious weight loss medication option showing 25% reduction in baseline weight after 48 weeks (TRIUMPH trial). Of the patients taking the highest dose, 83% achieved at least 15% reduction in weight where most drugs currently on the market only achieved 5-10% reduction. References 1. Obesity and Overweight. 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PL Detail-Document, Raspberry Ketone for Weight Loss. Pharmacist’s Letter/Prescriber’s Letter. 2012 May:280503. 29. Qsymia (phentermine and topiramate extended-release) capsules, for oral use, CIV [package insert]. Mountain View, CA: VIVUS, Inc; 2012 Jul. 30. Ogden CL, Carroll MD, Kit BK, et al. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA. 2014;311(8):806-14. 31. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014 Jun 24;129(25 Suppl 2):S102-38. Epub 2013 Nov 12. Integrated Pharmacotherapy 2 19 Obesity APPENDIX A Integrated Pharmacotherapy 2 20 Obesity