The Pharmacology of Obesity Thomas Repas D.O. Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program Member, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WI Member, Diabetes Steering Committee, Network Health Plan, Appleton, WI Website: www.endocrinology-online.com Overview • • • • Epidemic of obesity Why treat obesity? Pathophysiology of obesity Pharmacology of obesity – Pharmacology of drugs currently approved for treatment of obesity – Pharmacology of investigational agents • Conclusion Topics that I will not cover today…… • Dietary and nutritional recommendations • Physical activity and other lifestyle changes • Surgical options for weight loss The Epidemic of Obesity Obesity in the U.S. • More than 97 million adults in US are overweight or obese (BMI >30) – 19.9% of men – 24.9% for women Obesity Trends* Among U.S. Adults BRFSS, 1985 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10. Obesity Trends* Among U.S. Adults BRFSS, 2001 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10. Why Treat Obesity? • Contributes to approximately 300,000 deaths a year, making it 2nd only to smoking as a cause of death • Contributes or causes to many other health problems including: – – – – – Type 2 Diabetes Mellitus Coronary Artery Disease Degenerative Joint Disease Certain Types of Cancer Nonalcoholic Steatohepatitis Obesity Effects on Blood Pressure and Cholesterol Costs of Obesity • Costs the US health-care system more than $99 billion each year • Consumers also spend over $33 billion annually on weightreduction products and services • Annual health-care costs for patients with BMIs of 20 to 24.9 were 20% lower than costs for patients with BMIs from 30 to 34.9 and almost 33% lower than for patients who had BMIs of 35 or more. Pathophysiology of Obesity Pharmacology of Obesity Potential Strategies for Anti-Obesity Drug Action • Reducing food intake. Either amplify effects of signals/factors that inhibit food intake or block signals/factors that augment food intake • Blocking nutrient absorption (especially fat or carbohydrates) in the intestine. • Increasing thermogenesis. Either increase metabolism and dissipate food energy as heat or increase energy expenditure through the enhancement of physical activity. • Modulating fat metabolism/storage. Regulate fat synthesis/breakdown by making appropriate adjustments to food intake or energy expenditure. • Modulating the central regulation of body weight. Either alter the internal set point or modulate the signals presented regarding fat stores. Currently Available Agents Indicated for Treatment of Obesity Generic/Brand Name Usual Dose Mechanism of Action Side Effects •Orlistat/Xenical 120 mg with each meal GI symptoms (oily Peripheral: Blocks absorption of about spotting, flatus with discharge, fecal urgency, 30% of consumed fat oily stools, incontinence) •Sibutramine/Meridia 5-15 mg/d Central: Inhibits synaptic reuptake of norepinephrine and serotonin Dry mouth, constipation, headache, insomnia, increased blood pressure, tachycardia •Phentermine/ Adipex, Fastin, Ionamin and others 15-37.5 mg per day as a single or split dose Central: Stimulates release of norepinephrine CNS stimulation, tachycardia, dry mouth, insomnia, palpitations Agents sometimes used for Treatment of Obesity NOT Indicated or FDA approved Generic/Brand Name Usual Dose Mechanism of Action Side Effects •ephedrine+/-caffeine "Elsinore"pill Varies: usually 75-150 mg ephedrine and 100-150 mg caffeine Central: Stimulates CNS stimulation, adrenergic receptors tachycardia, dry mouth, insomnia, palpitations •Bupropion/Wellbutrin 100-300 mg/d Central: Inhibits reuptake of dopamine norepinephrine and serotonin CNS stimulation, dry mouth, headache, GI effects CNS: paresthesia, •Topiramate/Topamax 96-192 mg/d Uncertain: Central ? fatigue, dizziness, memory difficulty, concentration difficulty, and depression INDICATIONS FOR USE OF OBESITY DRUGS •A combined intervention of behavior therapy, dietary changes and increased physical activity should be maintained for at least 6 months before considering pharmacotherapy. NHLBI Obesity Education Initiative, Expert Panel on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults INDICATIONS FOR USE OF OBESITY DRUGS • BMI of 30 kg/m² or more or a BMI of 27 kg/m² or more with comorbid condition • Understand that drug therapy is adjunctive to lifestyle intervention • Have realistic expectations about weight loss goals and outcomes • Demonstrate readiness for change • Are unable to lose/maintain weight with lifestyle change alone • Comply with medication use • Have no medical or psychiatric contraindications ADDITIONAL CONSIDERATIONS WHEN USING ANTI-OBESITY DRUGS •Weight loss drugs should never be used without continued concomitant lifestyle modifications and as part of a comprehensive weight loss program. •Continual assessment of drug therapy for efficacy and safety is necessary. •If the drug is efficacious in helping the patient to lose and/or maintain weight loss and there are no serious adverse effects, it can be continued. •If not, it should be discontinued. NHLBI Obesity Education Initiative, Expert Panel on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults CONTRAINDICATIONS OR CAUTIONS TO THE USE OF OBESITY DRUGS • • • • • • Pregnancy or lactation Unstable cardiac disease Uncontrolled hypertension (SBP >180, DBP > 110 mmHg) Unstable severe systemic illness Unstable psychiatric disorder or history of anorexia Other drug therapy, if incompatible (eg MAO inhibitors, migraine drugs, adrenergic agents, arrhythmic potential) • Closed angle glaucoma (caution) • General anesthesia NHLBI Obesity Education Initiative, Expert Panel on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults Pharmacology of Drugs Currently Approved for Treatment of Obesity Sibutramine (Meridia) • Appetite suppressant that works by blocking reuptake of serotonin and norepinephrine. • Some experts have postulated that this agent may be the most effective in helping maintain weight loss. • Maintaining weight loss has long been the major downfall to most diet programs. • Until recently, the longest clinical trials with this agent have lasted 1 year. •Meridia Video Sibutramine (Meridia) Indications Among obese patients who should undergo drug therapy, sibutramine works best for those who: • • • • Experience difficulty controlling food intake Do not feel full Think about food a lot Do not have increased cardiovascular disease risk or multiple risk factors • Are younger Sibutramine is taken once daily with or without food. Sibutramine (Meridia) Contraindications The use of sibutramine is contraindicated in patients: • Taking concomitant monoamine oxidase inhibitor (MAOI) therapy • With anorexia nervosa • Using any other centrally-acting appetite suppressant • With hypersensitivity to ingredients of sibutramine Sibutramine (Meridia) Contraindications • In addition, sibutramine should not be used by patients who have: – – – – – – uncontrolled hypertension coronary heart disease congestive heart failure Arrhythmias stroke severe renal or liver dysfunction • Sibutramine should be used with caution in patients with narrow-angle glaucoma. Sibutramine Sibutramine Trial of Obesity Reduction and Maintenance (STORM) • Half of the patients who began therapy achieved a 10% weight loss • More than a third of these patients maintained that weight loss for 2 years. • As expected, the subjects who were able to maintain weight loss experienced predictable improvement in metabolic risk factors. Sibutramine – Side Effects • Can result in dry mouth, constipation, headache, insomnia, increased blood pressure, tachycardia. • Should monitor all patients once a month for hypertension and side effects • Should take in the morning to avoid insomnia Orlistat (Xenical) • Pancreatic lipase inhibitor that blocks the absorption of up to one third of ingested fat. • In addition to helping reduce weight, orlistat has been shown to also: – lower plasma low-density lipoprotein cholesterol (LDL) cholesterol levels. – The decline in LDL cholesterol is greater than that expected due to weight loss alone. – Lower HgbA1C in diabetic patients Orlistat Video Orlistat (Xenical) Indications Among obese patients who meet the criteria for antiobesity drug therapy, orlistat is most likely to benefit those who: – – – – Do not feel hungry Are not preoccupied with food Eat out or order-in often Have increased cardiovascular disease risk or multiple cardiovascular risk factors – Are older – Take multiple medications Orlistat is taken 3 times daily with meals Orlistat Effect of orlistat on dietary cholesterol absorption • 18 obese (average BMI, 37 kg/m2) subjects with and without orlistat therapy. • Radiolabeled cholesterol tracer was given as part of a meal Orlistat treatment was associated with a reduction in cholesterol absorption from 53% to 40%, representing a 25% reduction in cholesterol absorption (P < .05). B. Mittendorfer, et al. Orlistat Figure 3. A: Data from volunteers randomized to Int + P. B: Data from volunteers randomized to Int + O. Baseline for plasma FFA ( ) and during a 4-h insulin infusion and are plotted with corresponding values at 6 months ( ). There were significant postintervention changes in plasma FFA in both groups. The changes were greater with Int + O. *P < 0.05; †P < 0.01. [Diabetes Care 27(1):33-40, 2004. © 2004 American Diabetes Association, Inc.] Orlistat EGP = endogenous glucose production and Rd = glucose utilization [Diabetes Care 27(1):33-40, 2004. © 2004 American Diabetes Association, Inc.] Orlistat • 6 obese (BMI, 38 kg/m2), insulin-resistant males treated with orlistat for 3 months. • All subjects were instructed to maintain their weight at a constant level. • Using a euglycemic-hyperinsulinemic clamp technique, these investigators measured insulin sensitivity before starting orlistat, after 3 months of therapy, and at 3 months after stopping therapy. • Insulin sensitivity increased by 42% after 3 months of orlistat treatment despite no change in weight. • Insulin sensitivity declined to baseline again after stopping orlistat treatment. D. B. Dahl et al. Orlistat- Effect on HgbA1C in T2DM The improvement in HbA1c achieved with orlistat therapy exceeded that of the placebo group and there was a 0.62% improvement in HbA1c relative to the baseline value for the participants randomized to orlistat. Figure 4—HbA1c over 1 year of double-blind treatment with placebo (E) or 120 mg orlistat (F). P0.002, least-squares mean difference from placebo in the change from baseline over 52 weeks. DIABETES CARE, VOLUME 25, NUMBER 6, JUNE 2002 Orlistat- XENDOS • 4-year, double-blind, prospective study • 3,305 patients we randomized to lifestyle changes plus either orlistat 120 mg or placebo, three times daily. • Participants had a BMI 30 kg/m2 and normal (79%) or impaired (21%) glucose tolerance (IGT). • Primary endpoints were time to onset of type 2 diabetes and change in body weight. Orlistat- XENDOS Orlistat- XENDOS • After 4 years’ treatment, the cumulative incidence of diabetes was: – 9.0% with placebo – 6.2% with orlistat • This corresponds to a risk reduction of 37.3% in all patients (P 0.0032). • Risk reduction in patients with IGT was 45.0% Orlistat- XENDOS Orlistat – Side effects • Because it blocks intestinal absorption of fat it can result in diarrhea and steatorrhea • This is minimized by maintaining a strict low fat diet (<30% of diet) • Another concern is the loss of fat soluble vitamins with a potential for malnutrition. • To prevent this, recommend a daily multivitamin for all patients on this therapy Investigational Agents for Treatment of Obesity Topiramate • Topiramate is a novel antiepileptic drug approved by the FDA as an antiseizure medication. • When reports surfaced that patients enrolled in initial trials of the drug and also in clinical practice were experiencing unexpected weight loss, the effects of the drug on weight began to be studied. • Mechanism for weight loss is still poorly understood Topiramate • 34 patients being treated for epilepsy. • 12-month open-label trial without dietary intervention, patients took combinations of drugs to treat their epilepsy. Dr. Ulf Smith, Sahlgrenska University Hospital, Göteborg, Sweden Topiramate • Results: – Body weight for the group as a whole declined from 77.5 kg to 71.6 kg (P </= .01). – Weight loss was most pronounced in obese subjects, whose average body weight dropped from 96.5 kg to 85.5 kg at 12 months. – The weight loss was almost completely in fat mass rather than in lean body mass. – In the group that lost more than 10% of their body weight, the fatmass reduction averaged 28%. • Although some reduction in caloric intake was noted, energy expenditure studies were not performed. Dr. Ulf Smith, Sahlgrenska University Hospital, Göteborg, Sweden Topiramate • Another study: Effects of topiramate on body fat after a low-calorie diet induced weight loss. • Obese subjects (BMI >/= 30 and </= 50 kg/m2) who lost 8% of their weight after 8 weeks of 800-1000 kcal/day diet were randomized to receive placebo, 96 mg topiramate daily, or 192 mg topiramate daily. Topiramate • After 32 weeks, the changes in body weight were: – Placebo – 96-mg – 192-mg -11.2%, -16.3% (P </= .001) -17.3% (P </= .001) • Visceral abdominal fat (VAF) measured by MRI after 32 wks: – Placebo – 96-mg – 192-mg -27.1%, -36.7% (P </= .001) -34.7% (P </= .001) Leptin •Naturally occurring hormone that plays a role in satiety and weight maintenance. •Produced in adipocytes •Its role in weight regulation is related to its effects on the hypothalamus, where it leads to: • satiety •decreased food intake •increased energy expenditure in the periphery Leptin • Initial human trials with recombinant leptin were modestly successful. • Most subjects in the initial trial developed local reactions at the injection site. • Weight loss was relatively modest. • However, the hormone needs to be given subcutaneously and has a short half-life. • Thus a modified recombinant human leptin (m-leptin) was created that has a longer half-life. Leptin • 270 obese (average BMI, 33 kg/m2) volunteers were recruited and advised to begin a 500 kcal/d dietary deficit. • Subjects were divided into 3 groups: – Group 1 received either 20 mg/d of m-leptin or placebo. – Group 2 received either 80 mg of m-leptin 3 times per week or placebo, – Group 3 received either 240 mg of m-leptin per week or placebo. Dr. Ken Fujioka, Director of the Nutrition and Metabolic Research Center at Scripps Clinic, La Jolla, California. Leptin • Results: – Group 1: strong placebo effect, both the m-leptin-treated and placebo-treated subjects experiencing comparable weight loss. – Groups treated with the higher doses of m-leptin had greater weight loss – Those who received m-leptin at any dose lost an average of 3% of their body weight (6 or 7 lb) during 6 months. • Some subjects, however, lost much more weight, but this was mostly in the groups receiving the higher doses. – Eleven percent of the m-leptin-treated patients in group 3 lost 10% or more of their body weight. • The weight that was lost was almost completely fat. Dr. Ken Fujioka, Director of the Nutrition and Metabolic Research Center at Scripps Clinic, La Jolla, California Conclusion Pharmacotherapy of Obesity • Diet/lifestyle changes remain the mainstay of the treatment of obesity • In patients not reaching goals, drugs can be an important tool • Expect only modest weight loss at best with current drugs • Be aware of Rx indications and contraindications • Off label use of non-indicated products is not recommended • Investigational agents may offer hope for treatment of obesity in the future