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 Downloaded from www.pharmacy123.blogfa.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 Downloaded from www.pharmacy123.blogfa.com

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. Downloaded from www.pharmacy123.blogfa.com

Obesity Trends* Among U.S. Adults BRFSS, 2001 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10. Downloaded from www.pharmacy123.blogfa.com

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

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Costs of Obesity Costs the US health-care system more than $99 billion each year Consumers also spend over $33 billion annually on weight-reduction 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 Downloaded from www.pharmacy123.blogfa.com

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Pharmacology of Obesity Downloaded from www.pharmacy123.blogfa.com

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 Sibutramine/Meridia Phentermine/ Adipex, Fastin, Ionamin and others 120 mg with each meal 5-15 mg/d 15-37.5 mg per day as a single or split dose Peripheral: Blocks absorption of about 30% of consumed fat Central: Inhibits synaptic reuptake of norepinephrine and serotonin Central: Stimulates release of norepinephrine GI symptoms (oily spotting, flatus with discharge, fecal urgency, oily stools, incontinence) Dry mouth, constipation, headache, insomnia, increased blood pressure, tachycardia 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 Bupropion/Wellbutrin Topiramate/Topamax Varies: usually 75-150 mg ephedrine and 100-150 mg caffeine 100-300 mg/d 96-192 mg/d Central: Stimulates adrenergic receptors Central: Inhibits reuptake of dopamine norepinephrine and serotonin Uncertain: Central ? CNS stimulation, tachycardia, dry mouth, insomnia, palpitations CNS stimulation, dry mouth, headache, GI effects CNS: paresthesia, 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 Downloaded from www.pharmacy123.blogfa.com

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 anti-obesity 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

After 4 years’ treatment, the cumulative incidence of diabetes was: 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

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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 fat-mass 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 -11.2%, 96-mg -16.3% (P </= .001) 192-mg -17.3% (P </= .001) Visceral abdominal fat (VAF) measured by MRI after 32 wks: Placebo -27.1%, 96-mg -36.7% (P </= .001) 192-mg -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

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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

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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