1. Obesity Treatment Pyramid
Diet
Physical Activity
Lifestyle Modification
Pharmacotherapy
Surgery
Obesity treatment pyramid
The clinical approach to obesity can be viewed as a pyramid consisting of several levels of therapeutic options. All patients should be involved in an effort to change their lifestyle behaviors to decrease energy intake and increase physical activity. Lifestyle modification also should be a component of all other levels of therapy. Pharmacotherapy can be a useful adjunctive measure for properly selected patients. Bariatric surgery is an option for patients with severe obesity, who have not responded to less-intensive interventions. The number of obese patients who require a specific level of treatment decreases as one moves up the pyramid.

2. Guide for Selecting Obesity Treatment
BMI Category (kg/m2)
Treatment
>40
Diet, Exercise, Behavior Tx +
Pharmaco-therapy
With co- morbidities
Surgery
Guide for selecting obesity treatment
This table summarizes the guidelines for selecting treatment options for obesity [1]. Any effective treatment plan must consider the patient’s willingness to undergo therapy, his/her ability to comply with specific treatment approaches, access to skilled caregivers, and financial considerations. Lifestyle modification, which involves a program of appropriate diet, physical activity, and behavior therapy, should be considered for all patients with a body mass index (BMI) 25 kg/m2. Long-term pharmacotherapy should be considered in appropriate patients who were unable to achieve adequate weight loss after 6 months of lifestyle therapy and who have a BMI 30 kg/m2, or 27 kg/m2 with concomitant obesity-related disease. Bariatric surgery may be necessary in patients with severe obesity who failed to lose weight with non-surgical therapy. Eligible surgical candidates should have a BMI 40 kg/m2 or a BMI 35 kg/m2 and a concomitant serious obesity-related disease.
The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. October 2000, NIH Pub No
The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. October 2000, NIH Pub. No

3. Obesity and Dietary Therapy “Duct Tape”

4. Short-term Obesity Therapy Does Not Result in Long-term Weight Loss
Diet alone
Behavior therapy
Combined therapy
Change in Weight (kg)
Short-term obesity therapy does not result in long-term weight loss
Obesity is a chronic disease that requires long-term therapy for successful long-term weight management. Often, patients who are able to lose weight with obesity therapy regain their lost weight after therapy is discontinued. This figure represents data from 76 obese women (mean body mass index 39.4 kg/m2) who were were randomly assigned to one of three treatment groups: 4 months of a very-low-calorie diet (VLCD) of 400–500 kcal/d, 6 months of behavior therapy and a 1000–1200 kcal/d balanced deficit diet, or 6 months of a combination of a VLCD and behavior therapy. Each treatment program was effective in achieving short-term weight loss. However, most subjects regained a considerable amount of weight by 1 year and had returned to their pretreatment weight at 5 years.
Wadden TA, Sternberg JA, Letizia KA, et al. Treatment of obesity by very low calorie diet, behavior therapy, and their combination: a five-year perspective. Int J Obes 1989;13 (suppl 2):39-46.
Baseline
End of Treatment
1-year Follow-up
5-year Follow-up
Wadden et al. Int J Obes 1989;13 (Suppl 2):39.

6. Sustained Weight Loss Can Be Achieved with Behavior Modification Therapy
Active Treatment
No Active Treatment
Women
Weight Loss (kg)
Men
Sustained weight loss can be achieved with behavior modification therapy
Long-term behavior modification therapy can result in long-term weight loss. This figure shows data from the longest reported study that evaluated the effect of behavior modification therapy on body weight. Extremely obese men and women (pretreatment body mass index: 41 kg/m2) underwent an intensive behavioral treatment program every weekday for 6 weeks followed by continuous booster sessions for 4 years [1]. The training program consisted of cognitive training, exercise, and nutrition advice. At the end of 4 years of treatment, mean weight loss for 68 subjects was 12.6 kg (27% of excess body weight). Long-term follow-up data were obtained for 72% of the initial participants, which showed that weight loss was maintained over the next 10 to 12 years. These data demonstrate that long-term (4 years) behavior and lifestyle modification therapy can lead to sustained (10-12 years) weight loss success without continued treatment.
Björvell H, Rossner S. A ten-year follow-up of weight change in severely obese subjects treated in a combined behavioural modification programme. Int J Obes Relat Metab Disord 1992;16: 2 4 6 8
10-12
Years
Björvell and Rössner. Int J Obes Relat Metab Disord 1992;16:623.

7. Cardinal Behaviors of Successful Long-term Weight Management National Weight Control Registry Data
Self-monitoring:
Diet: record food intake daily, limit certain foods or food quantity
Weight: check body weight >1 x/wk
Low-calorie, low-fat diet:
Total energy intake: kcal/d
Energy intake from fat: 20%-25%
Eat breakfast daily
Regular physical activity: kcal/wk (eg, walk 4 miles/d)
Cardinal behaviors of successful long-term weight management
Data obtained from the National Weight Control Registry (NWCR) have identified specific behaviors that are associated with successful long-term weight loss [1-3]. Participants enrolled in the registry must have maintained a weight loss of 13.6 kg (30 lb) for at least 1 year; on average, subjects have maintained a 32 kg (70 lb) weight loss for 6 years. The major behaviors reported by approximately 3000 NWCR participants were: 1) self-monitoring of food intake and body weight; 2) consuming a low-calorie (1300–1400 kcal/d) and low-fat diet (20%–25% of daily energy intake from fat), 3) eating breakfast every day, and 4) performing regular physical activity that expends 2500 to 3000 kcal per week (eg, walking 4 miles per day).
Klem ML, Wing RR, McGuire MT, et al. A descriptive study of individuals successful at long-term maintenance of substantial weight loss. Am J Clin Nutr 1997;66:
McGuire MT, Wing RR, Klem ML, et al. Long-term maintenance of weight loss: do people who lose weight through various weight loss methods use different behaviors to maintain their weight? Int J Obes Relat Metab Disord 1998;22:
Wyatt HR, Grunwald GK, Mosca CL et al. Long-term weight loss and breakfast in the National Weight Control Registry. Obes Res 2002;10:78-82.
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.

8. Principles of Pharmacotherapy in the Management of Obesity

9. Regulation of Food Intake
External factors
Emotions, Drugs
Food characteristics
Lifestyle behaviors
Environmental cues
Brain
Central Signals
Stimulate
Inibit
NPY
AGRP
galanin
Orexin-A
Dynorphin
ECS/CB1
α-MSH
CRH/UCN
GLP-I
CART NE
5-HT
Peripheral signals
Peripheral organs
Glucose
CCK, GLP-1, Apo-A-IV Vagal afferents
Insulin
Ghrelin Leptin Cortisol
Gastrointestinal tract + 
Regulation of food intake
The regulation of food intake involves a complex interaction of systems that determine the size, content, and frequency of feedings. Presumably, the brain is the final processing center that translates central and peripheral signals to initiate or stop feeding. Neuronal circuits have been identified in the hypothalamus that affect satiation (level of fullness during a meal which regulates the amount of food consumed) and satiety (level of hunger after a meal is consumed which regulates the frequency of eating). Regulatory mechanisms also must be present that integrate determinants of short-term energy intake with long-term energy requirements.
The discovery of leptin, the protein product of the ob/ob gene, in 1995 [1] led to a marked increase in our understanding of the regulation of food intake. Leptin is produced by fat cells, released into the circulation, and it crosses the blood-brain barrier to bind to its receptor in the hypothalamus, which stimulates the expression of neuropeptides and neurotransmitters that inhibit food intake. Therefore, leptin provides a unique feedback signaling system that transmits information regarding adipose tissue energy stores to the central nervous system. Other peripheral organs also communicate with the brain about energy intake through neural signaling and endocrine pathways. The gastrointestinal system, which is responsible for digesting and absorbing ingested nutrients, is particularly involved. The gastrointestinal tract produces cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), apolipoprotein A-IV (apo A-IV), ghrelin, insulin, and glucose, which are likely involved in short-term, and possibly long-term, regulation of food intake. Central neuropeptides and neurotransmitter signals produced in hypothalamic nuclei stimulate 1) neuropeptide Y (NPY), 2) agouti-related protein (AGRP), 3) galanin, 4) orexin-A, and 5) dynorphin, or inhibit 1) a-melanocyte-stimulating hormone (a-MSH), a peptide derived from proopiomelanocortin (POMC), 2) corticotropin-releasing hormone/urocortin (CRH/UCN), 3) glucagon-like peptide-1 (GLP-1), 4) cocaine- and amphetamine-regulated transcript (CART), 5) norepinephrine (NE), and 5) serotonin (5-HT) [2]. There is a hierarchy in the relative importance, magnitude, and duration of each afferent input, and certain signals can override the effect of others. The redundancy of these complex signaling pathways tend to defend food intake and provides a formidable barrier to treating obesity. Therefore, a clear understanding of the factors involved in regulating food intake has important implications in designing therapeutic agents for obesity management.
Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:
Schwartz MW, Woods SC, Porte D Jr, et al. Central nervous system control of food intake. Nature 2000;404:
Food Intake
Adipose tissue
Adrenal glands

10. Drugs Approved by FDA for Treating Obesity
Generic Name
Trade Names
DEA Schedule
Approved Use
Year Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia IV
1997
Diethylpropion
Tenulate
Short-term
1973
Phentermine
Adipex, lonamin
Phendimetrazine
Bontril, Prelu-2
III
1961
Benzphetamine
Didrex
1960
Drugs approved by FDA for treating obesity
This table lists the medications approved by the United States Food and Drug Administration (FDA) for treatment of obesity; only sibutramine (Meridia) and orlistat (Xenical) have been approved for long-term use. All the approved medications act as anorexiants, with the exception of orlistat, which blocks the absorption of dietary fat. Anorexiants increase satiation (level of fullness, which regulates the amount of food consumed during a meal) or satiety (level of fullness after a meal, which determines frequency of eating), or both. Methamphetamine is also approved by the FDA for short-term use, but it is a DEA schedule II drug and should be avoided because of its abuse potential. Three anorexiant medications have been removed from the marketplace because of increased risks of either valvular heart disease (fenfluramine and dexfenfluramine) [1] or hemorrhagic stroke (phenylpropanolamine) [2] associated with their use.
Khan MA, Herzog CA, St Peter JV, et al. The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med 1998;339:
Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000;343:

11. Meta-analysis of RCTs Evaluating Effect of Orlistat Therapy on Weight Loss at 1-Year
Study or Sub-category
WMD (random) 95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
Meta-analysis of RCTs evaluating effect of orlistat therapy on weight loss at 1-year
This figure shows the results of a systematic review of long-term double-blind randomized controlled trials that evaluated the effect of orlistat therapy on body weight in obese subjects [1]. Eleven trials that were at least of 1 year duration were identified. Three studies were conducted exclusively in subjects with type 2 diabetes, who may have more difficulty losing weight than obese subjects without diabetes. Average attrition rate among trials was 33%. All trials found a statistically significant beneficial weight loss effect of orlistat therapy. The pooled analysis showed that compared with placebo therapy, orlistat therapy caused a 2.7 kg (95% CI: kg) or 2.9% (95% CI: %) greater decrease in body weight. In addition, 12% (95% CI: 8-16%) more subjects achieved a 10% or greater weight loss with orlistat than with placebo therapy.
Padwal R, Li SK, Lau DCW. Long-term pharmacotherapy for overweight and obesity: a systematic review and meta-analysis of randomized controlled trials. Int J Obes 2003;27:
*All subjects had type 2 diabetes
WMD=weighted mean difference
-10 -5 5 10
Favours Treatment
Favours Control
Padwal et al. Int J Obes 2003;27:1437

12. Effect of Long-term Orlistat Therapy on Body Weight
-4.1 kg
Placebo
Change in Weight (kg)
-6.9 kg
Effect of long-term orlistat therapy on body weight
This figure shows the results of a 4-year randomized controlled trial, conducted in over 3000 obese subjects, that compared orlistat therapy plus lifestyle intervention with placebo therapy plus lifestyle intervention [1]. The lowest body weight was achieved during the first year, and was greater in the orlistat-treated group (11% weight loss) than in the placebo-treatment group (6% weight loss). Subjects regained weight during the remainder of the trial, so orlistat-treated subjects had lost 6.9% and placebo-treated subjects had lost 4.1% of their initial body weight at the end of 4 years. Orlistat therapy also resulted in a 37% reduction in the cumulative incidence of new-onset type 2 diabetes, primarily by preventing the development of diabetes in patients who had impaired glucose tolerance.
Torgenson JS, Boldrin MN, Hauptman J, et al. XENical in the prevention of diabetes in obese subjects (XENDOS) study. Diabetes Care 2004; 27:
Orlistat
P<0.001 vs placebo 52
104
156
208
Weeks
Torgenson et al. Diabetes Care 2004;27:155

13. Gastrointestinal Side Effects of Orlistat Therapy
Year 1
Year 2
Placebo
Orlistat
Fatty/oily stool 5 31 1 8
Increased defecation 7 20 2
Liquid stools 10 13
Fecal urgency 3
Flatulence
Flatus with discharge
Fecal incontinence
Oily evacuation 6
Low plasma vitamin conc:
Vitamin A
0.6
0.3
0.8
Vitamin D
5.1
3.1
Vitamin E
0.9
4.6
1.6
Gastrointestinal side effects of orlistat therapy
The most common side effects experienced with orlistat therapy are caused by the pharmacologic effect of orlistat on gastrointestinal lipases. In 1- and 2-year trials, 70% to 80% of subjects treated with orlistat reported one or more gastrointestinal events (listed in this table), compared with 50% to 60% of subjects treated with placebo [1]. Approximately 4% of subjects treated with orlistat and 1% of subjects treated with placebo withdrew from clinical trials because of gastrointestinal complaints. Most gastrointestinal events occurred early in treatment (within the first 4 weeks), occurred only once or twice, were considered by the subjects to be of mild to moderate intensity, and resolved spontaneously despite continued treatment. As shown in this table, the incidence of gastrointestinal side effects reported by subjects taking orlistat in year 2 were similar to those reported in year 1 in patients taking placebo. Concomitant therapy with a gel-forming fiber (psyllium mucilloid) can prevent many of the gastrointestinal side effects caused by orlistat [2].
Orlistat also impairs the absorption of fat-soluble vitamins and β-carotene [3,4]. The adverse effect of 1 and 2 years of treatment with orlistat on plasma vitamin concentrations is shown in this table. Mean serum concentrations remained within the normal range in most subjects even though they were not allowed vitamin supplementation. However, plasma vitamins D and E (and β-carotene) concentrations, fell below normal limits in approximately 5% of orlistat-treated subjects. The abnormalities in vitamin concentrations resolved rapidly with daily vitamin supplementation. Therefore, all patients who are treated with orlistat should routinely take a multivitamin supplement daily, at a time when orlistat is not being ingested.
Sjostrom L, Rissanen A, Andersen T, et al. Randomized placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet 1998;352:
Cavaliere H, Floriano I, Medeiros-Neto G. Gastrointestinal side-effects of orlistat by concomitant prescription of natural fibers (psyllium mucilloid). Int J Obes Relat Metab Disord 2001;25:
Zhi J, Melia AT, Kross-Twardy SG, et al. The effect of orlistat, an inhibitor of dietary fat absorption, on the pharmacokinetics of β-Carotene in healthy volunteers. J Clin Pharmacol 1996;36:
Melia AT, Kross-Twardy SG, Zhi J. The effect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamins A and E in healthy volunteers. J Clin Pharmacol 1996;36:
Values are percentage of subjects.
Sjostrom et al. Lancet 1998;352:167.

14. Meta-analysis of RCTs Evaluating Effect of Sibutramine Therapy on Weight Loss at 1-Year
Study or Sub-category
WMD (random) 95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
Meta-analysis of RCTs evaluating effect of sibutramine therapy on weight loss at 1-year
This figure shows the results of a systematic review of long-term, double-blind, randomized, controlled trials that evaluated the effect of sibutramine therapy on body weight in obese subjects [1]. Three trials that were at least of 1 year duration were identified. One study was conducted in subjects who had hypertension. Average attrition rate among trials was 48%. All trials found a statistically significant beneficial weight loss effect of sibutramine therapy. The pooled analysis showed that compared with placebo therapy, sibutramine therapy caused a 4.3 kg (95% CI: kg) or 4.6% (95% CI: %) greater decrease in body weight. In addition, 15% (95% CI: 4-27%) more subjects achieved a 10% or greater weight loss with sibutramine than with placebo therapy.
Padwal R, Li SK, Lau DCW. Long-term pharmacotherapy for overweight and obesity: a systematic review and meta-analysis of randomized controlled trials. Int J Obes 2003;27:
-10
Favours Treatment
Favours Control -5 10 5
All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437

15. Body Weight Change (kg)
Effect of Continuous vs Intermittent Subutramine Therapy on Body Weight
Placebo
Intermittent sibutramine
Continuous sibutramine
Body Weight Change (kg)
Effect of continuous vs intermittent sibutramine therapy on body weight
The effectiveness of continuous versus intermittent sibutramine therapy in achieving weight loss was evaluated in a 48-week randomized, controlled trial in 1102 obese subjects [1]. Subjects entered a 4-week open-label run-in period during which they received 15 mg of sibutramine daily. Patients with a weight loss of at least 2% or 2 kg were randomized to receive sibutramine continuously (15 mg daily for 44 weeks), sibutramine intermittently (15 mg from weeks 1 through 12, 19 through 30, and 37 through 48, and placebo during the off-sibutramine weeks), or placebo. During the 44-week treatment period, overall weight loss was similar in patients receiving either continuous (3.8 kg; 4.0%) or intermittent therapy (3.3 kg; 3.5%) (P=0.28 continuous vs intermittent), whereas the placebo group gained weight (0.2 kg; 0.2%) (P<0.001 placebo vs either treatment group). Overall weight loss during the 48-week period was 7.9 kg and 7.8 kg in the continuous and intermittent groups, respectively, compared with 3.8 kg in the placebo-treated group. During intermittent therapy, weight increased rapidly each time active drug was changed to placebo and decreased when active drug was restarted. In addition, intermittent treatment was associated with less serious adverse events. The results from this study demonstrate that long-term treatment with intermittent sibutramine therapy can be just as effective as continuous therapy in achieving successful weight loss in those who have an initial positive response to sibutramine treatment.
Wirth A, Krause J. Long-term weight loss with sibutramine. JAMA 2001;286:
Run-in
period 4 8 12 16 20 24 28 32 36 40 44 48
Time (wk)
Sibutramine dose=15 mg/d.
Wirth and Krause. JAMA 2001;286:1331.

16. Adverse Effects of Sibutramine Therapy
Subjects (%)
Adverse Effect
Placebo
Sibutramine
Headache
18.6
30.3
Dry mouth
4.2
17.2
Constipation
6.0
11.5
Insomnia
4.5
10.7
Dizziness
3.4
7.0
Hypertension
0.9
2.1
Tachycardia
0.6
2.6
Palpitation
0.8
2.0
Adverse effects of sibutramine therapy
In placebo-controlled trials, the most common side effects reported with sibutramine use were dry mouth, constipation, and insomnia, which were usually mild and transient [1,2]. Because of its noradrenergic action, sibutramine treatment is associated with a dose-related increase in blood pressure and heart rate [1,2]. A dose of 10 to 15 mg/d causes an average increase in systolic and diastolic blood pressure of 2 to 4 mm Hg and an average increase in heart rate of 4 to 6 beats/minute. Some patients experience much larger increases in blood pressure or heart rate and require dose reduction or discontinuation of therapy. The use of sibutramine is contraindicated in patients with poorly controlled hypertension, coronary heart disease, congestive heart failure, arrhythmias, stroke, severe renal or liver dysfunction, or concomitant monoamine oxidase inhibitor therapy.
Bray GA, Blackburn GL, Ferguson JM, et al. Sibutramine produces dose-related weight loss. Obes Res 1999;7:
Smith I, on behalf of the members of the Sibutramine Clinical Study 1047 Team and Goulder MA. Randomized placebo-controlled trial of long-term treatment with sibutramine in mild to moderate obesity. J Fam Pract 2001;50:
Meridia™ Package Insert, 2001.

17. Continuous Phentermine Alternate Phentermine and Dummy QOM
Effect of Continuous and Intermittent Phentermine Therapy on Body Weight
Continuous Dummy
Weight Loss (lbs)
Continuous Phentermine
Effect of continuous and intermittent phentermine therapy on body weight
Phentermine is a ß-phenethylamine derivative that stimulates the release of norepinephrine and dopamine from nerve terminals. Although phentermine is not approved by the FDA for long-term use, it is the most commonly prescribed anorexiant medication in the United States [1], presumably because it is less expensive than sibutramine. Phentermine was approved by the FDA more than 30 years ago, when the criteria needed for approval were less rigorous than they are today. Therefore, fewer studies have evaluated the efficacy and safety of phentermine therapy than have evaluated sibutramine and orlistat. Only one long-term (36 weeks) RCT evaluated the effect of phentermine therapy on body weight [2]. In that study, obese women were randomized to diet therapy and either treatment with daily phentermine, daily phentermine every other month alternating with daily placebo every other month, or daily placebo. Approximately two-thirds of the 108 enrolled subjects completed the study; among completers, the groups receiving either continuous or intermittent phentermine therapy lost about 13% of their initial weight, compared with a 5% weight loss in the placebo group. The most common side effects of phentermine are dry mouth, insomnia, and constipation. Although all sympathomimetic agents can increase blood pressure and heart rate, these side effects are uncommon when there is adequate weight loss.
Stanfford RS, Radley DC. National trends in antiobesity medication use. Arch Int Med. 2003;163:
Munro JF, MacCuish AC, Wilson EM, Duncan LJP. Comparison of continuous and intermittent anorectic therapy in obesity. Br Med J 1968;1:
Alternate Phentermine and Dummy QOM 4 8 12 16 20 24 28 32 36
Time (weeks)
Munro JF et al. Brit Med J 1:352, 1968

18. Regulation of Food Intake
External factors
Emotions, Drugs
Food characteristics
Lifestyle behaviors
Environmental cues
Brain
Central Signals
Stimulate
Inibit
NPY
AGRP
galanin
Orexin-A
Dynorphin
ECS/CB1
α-MSH
CRH/UCN
GLP-I
CART NE
5-HT
Peripheral signals
Peripheral organs
Glucose
CCK, GLP-1, Apo-A-IV Vagal afferents
Insulin
Ghrelin Leptin Cortisol
Gastrointestinal tract + 
Regulation of food intake
The regulation of food intake involves a complex interaction of systems that determine the size, content, and frequency of feedings. Presumably, the brain is the final processing center that translates central and peripheral signals to initiate or stop feeding. Neuronal circuits have been identified in the hypothalamus that affect satiation (level of fullness during a meal which regulates the amount of food consumed) and satiety (level of hunger after a meal is consumed which regulates the frequency of eating). Regulatory mechanisms also must be present that integrate determinants of short-term energy intake with long-term energy requirements.
The discovery of leptin, the protein product of the ob/ob gene, in 1995 [1] led to a marked increase in our understanding of the regulation of food intake. Leptin is produced by fat cells, released into the circulation, and it crosses the blood-brain barrier to bind to its receptor in the hypothalamus, which stimulates the expression of neuropeptides and neurotransmitters that inhibit food intake. Therefore, leptin provides a unique feedback signaling system that transmits information regarding adipose tissue energy stores to the central nervous system. Other peripheral organs also communicate with the brain about energy intake through neural signaling and endocrine pathways. The gastrointestinal system, which is responsible for digesting and absorbing ingested nutrients, is particularly involved. The gastrointestinal tract produces cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), apolipoprotein A-IV (apo A-IV), ghrelin, insulin, and glucose, which are likely involved in short-term, and possibly long-term, regulation of food intake. Central neuropeptides and neurotransmitter signals produced in hypothalamic nuclei stimulate 1) neuropeptide Y (NPY), 2) agouti-related protein (AGRP), 3) galanin, 4) orexin-A, and 5) dynorphin, or inhibit 1) a-melanocyte-stimulating hormone (a-MSH), a peptide derived from proopiomelanocortin (POMC), 2) corticotropin-releasing hormone/urocortin (CRH/UCN), 3) glucagon-like peptide-1 (GLP-1), 4) cocaine- and amphetamine-regulated transcript (CART), 5) norepinephrine (NE), and 5) serotonin (5-HT) [2]. There is a hierarchy in the relative importance, magnitude, and duration of each afferent input, and certain signals can override the effect of others. The redundancy of these complex signaling pathways tend to defend food intake and provides a formidable barrier to treating obesity. Therefore, a clear understanding of the factors involved in regulating food intake has important implications in designing therapeutic agents for obesity management.
Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:
Schwartz MW, Woods SC, Porte D Jr, et al. Central nervous system control of food intake. Nature 2000;404:
Food Intake
Adipose tissue
Adrenal glands

19. Gastrointestinal Peptides Hormones
Vagus
nerve
Ghrelin
Insulin
Amylin
Glucagon
Leptin
PYY
GLP-1
CCK
food intake regulation
Slide Index CI0001
L: A-F
DISCUSSION POINTS:
SLIDE BACKGROUND:
Status as of March 2003.
Anti-obesity potential
digestion and metabolism
Anti-diabetes potential
Modified from Marx, Science 2003 February 7; 299: (in News)

20. GLP-1 GLP-1: incretin hormone Exenatide (Byetta); incretin mimetic
Enhances insulin secretion
Suppresses elevated glucagon secretion
Reduces food intake and body weight
Slows gastric emptying
Increase in beta-cell mass
DISCUSSION POINTS:
--Exenatide shares several glucoregulatory effects with glucagon-like peptide-1 (GLP-1) (as listed above).
SLIDE BACKGROUND:
--The incretin effect was first described in the 1960s during an experiment in which similar elevations in plasma glucose, elicited by administration of glucose by either oral or intravenous routes, resulted in a greater insulin secretory response when glucose was administered through the oral route.
--This incretin effect suggested that incretins, and not merely the direct actions of plasma glucose, affect the insulin secretory response.
Toft-Nielsen M, et al. J Clin Endocrinol Metab 2001; 86:
Drucker DJ. Mol Endocrinol 2003; 17:
Nielsen LL, et al. Reg Pept 2004; 117:77-88

21. Neuroendocrinology of Food Intake Regulation Hindbrain as a Target for Peripheral Satiety Signals
Area Postrema:
part of dorsal vagal complex
chemoreceptive (no BBB)
site of neural integration
bi-directional projections to the GI tract (via vagal afferents and efferents)
bi-directional projections to the hypothalamus, amygdala and other regions
Slide Index CI0001
L: A-F
DISCUSSION POINTS:
SLIDE BACKGROUND:
Status as of March 2003.
Hypothalamus
ARC
NTS/AP
Vagus
Spinal nerves
CCK
GI tract
Ghrelin
PYY
Leptin
Insulin
Amylin
other circulating gut peptides
Modified from Marx, Science 2003 February 7; 299: (in News)

22. Open-Label Extension – Combined BYETTA Continued to Reduce Weight
Required
DISCUSSION POINTS:
--87% of the subjects who completed the 30-week placebo-controlled, double-blind, Phase 3 studies chose to continue in open-label extension (OLE) studies.
--All subjects were given 5 mcg BYETTA for the first 4 weeks of the OLE (overall, Weeks 30 to 34), after which they received 10 mcg BYETTA for the remainder of their participation in the OLE.
--Shown is 82-week data (30 weeks from placebo-controlled, double-blind study and 52 weeks from OLE) for 393 patients.
--Of the 1446 subjects randomized to the three 30-week, blinded, placebo-controlled trials, 1125 completed and were eligible for enrollment into the OLE.
--Of the 1125 subjects, 977 (87%) enrolled into the OLEs. At the time of this data analysis, 795 had completed treatment through 52 weeks and 393 had completed treatment through 82 weeks.
--Using the intent-to-treat (ITT) and Last Observation Carried Forward (LOCF) analysis method, the 977 ITT population had A1C and weight reductions at 82 weeks consistent with the 82-week completer population shown here.
--Placebo cohort upon receiving BYETTA showed an immediate decrease of weight similar to that observed with BYETTA treatment in the first 30 weeks.
--Mean body weight reductions mediated by BYETTA during the first 30 weeks were sustained and appeared to be progressive through 82 weeks.
SLIDE BACKGROUND:
--Diet and exercise counseling were not provided during the study.

23. Safety and Tolerability Exenatide Open-Label Extensions
Exenatide generally well tolerated
Adverse events
Nausea (30-40%)
Diarrhea (7%)
Vomiting (9%)
Feeling jittery (5%)
Dizziness (3%)
Headache (3%)
DISCUSSION POINTS:
--Exenatide was generally well-tolerated.
--Most frequent adverse event of nausea, which was mostly mild to moderate in intensity, greatest frequency at initiation of exenatide, and resulted in relatively few withdrawals.

24. Amylin: A Neuroendocrine Hormone
Amylin Receptor Identified N N
Slide Index AP0004
L: A-E
DISCUSSION POINTS:
Click 1: Sagittal section of rodent brain
Amylin is a neuroendocrine hormone, with binding sites in the brain. This slide shows a sagittal section of rodent brain highlighting amylin binding in three areas:
nucleus accumbens
dorsal raphe
area postrema
The area postrema appears to be a key target site for amylin action. This region has no blood brain barrier; thus it is exposed to changes in plasma concentrations of glucose and glucoregulatory hormones.
Click 2: Receptor inset appears
Receptors that bind amylin have now been characterized.
SLIDE BACKGROUND:
No amylin binding sites have been detected in pancreatic alpha-cells or the stomach; this suggests that glucagonostatic and gastric emptying actions are not direct peripheral effects but instead mediated via the central nervous system.
In animals, amylin’s gastrointestinal effects are lost after destruction of the area postrema or bilateral vagotomy.
Muff R et al. Endocrinology 1999; 140:
These receptors are found at the cell surface and each comprises two components:
A seven alpha-helix trans-membrane receptor molecule (calcitonin receptor or CTR on slide)
An accompanying single trans-membrane molecule called a RAMP (Receptor Activated Modifying Protein).
Both molecules must be associated at the cell surface to create a receptor that binds amylin.
Amylin Binding Sites in the Brain
Dorsale Raphe C C
RAMP
1 or 3
CTR
Nucleus Accumbens
Area Postrema
Beaumont K, et al. Mol Pharm 1993; 44:
Adapted from Muff R, et al. Endocrinology1999; 140:

25. Effects of Pramlintide in Type 2 Diabetes
Pooled 120 µg BID Pramlintide Intent to Treat Populations
Placebo + Insulin
120 µg Pramlintide
Slide Index PE0014
L: A,B,D,E
DISCUSSION POINTS:
This slide summarizes a post-hoc analysis of pooled data from patients with type 2 diabetes who received 120 µg BID pramlintide doses in pivotal phase 3 trials.
At Week 26, the approximate mean change in A1C from baseline was 0.6% for the pramlintide group.
In this subset of patients using pramlintide + insulin, there was an ~5% insulin dose adjustment difference compared to the placebo + insulin group.
This reduction in A1C was accompanied by a reduction in body weight of ~3 pound in the pramlintide + insulin group, whereas the placebo + insulin group experienced an ~0.5 pound weight gain.
SLIDE BACKGROUND:
Pooled data analysis includes patients in all insulin-using type 2 diabetes studies ( ; ) in phase 3 program who received 120 µg pramlintide BID.
Reference: Amylin_Adhoc_12_SDS_1_Adhoc_13_ADA_1,2,4
Change in A1C (%)
Change in Insulin Use (%)
Change in Weight (lb)
Week 4
Week 13
Week 26
Week 4
Week 13
Week 26
Week 4
Week 13
Week 26 6
2.5
2.0
-0.1 5
1.5 4
-0.2
1.0 3
-0.3
0.5 2
-0.4 1
-0.5
-0.5
-1.0
-0.6
-1.5 -1
-2.0
-0.7 -2
-2.5
-0.8 -3
-3.0
Placebo + Insulin (N=284; Baseline A1C 9.3%)
120 µg Pramlintide BID Dose + Insulin (N=292; Baseline A1C 9.1%)
Data on file, Amylin Pharmaceuticals, Inc.

27. Adipose Tissue Metabolism27
Endocannabinoid System (CB-1) as a Potential Target of Action for Modulation of Energy Homeostasis and Obesity
Energy Balance
Feeding Behavior
Gastric emptying
GI motility
Hypothalamus
Hunger/satiety
Limbic forebrain
Motivation for palatable food
Ghrelin, PYY
The endocannabinoid system affects a number of physiologic processes.
Some of the processes in which the endocannabinoid system plays a role are those which involve the stimulus to consume nutrients, the digestion and transport of ingested nutrients and the storage or metabolism of substrates.
The presence of CB1 receptors in the organs or tissues that participate in these processes has been documented.
Evidence from animal studies has shown that the endocannabinoid system modulates food intake and energy balance, hepatic lipogenesis through stimulation of lipogenic enzymes, insulin-mediated glucose disposal, and adipose tissue metabolism.
Hepatic Lipogenesis
Adipose Tissue Metabolism
Glucose Homeostasis
Hepatic glucose output
Lipogenesis
Lipolysis
Lipogenesis
Glucose uptake
Glucose, lipid oxidation
Bensaid M, Gary-Bobo M, Esclangon A, et al. The cannabinoid CB1 receptor antagonist SR increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol. 2003;63:
Osei-Hyiaman D, DePetrillo M, Pacher P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J. Clin. Invest. 2005;115:
Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2005;Online Nov 23.

28. The ECS is Overactivated in:28
The ECS is Overactivated in:
Animal models of genetic obesity
Animal models of diet-induced obesity
Human obesity

29. Endocannabinoids Stimulate Food Intake in Mice29
Anandamide mg/kg
Vehicle 7 6 5 4 3
*P<0.05; **P<0.01 vs vehicle * *
Food intake
(grams/day) ** *
Effects of endocannabinoids on feeding behavior can be shown by administering the endocannabinoid itself, evaluating the impact of CB-receptor blockade, or by studying transgenic animals that lack the CB receptors.
This figure illustrates the stimulation of food intake by administration of the endocannabinoid anandamide in mice. Food intake was increased by roughly 44% compared with vehicle.
Day
Hao S et al. Eur J Pharmacology. 2000; 392:
Hao S, Avraham Y, Mechoulam R, Berry EM. Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice. European Journal Of Pharmacology 2000;392:

30. The ECS is Upregulated in Human Obesity30
The ECS is Upregulated in Human Obesity
Activation of the central endocannabinoid system increases food intake and promotes weight gain. Conversely, blockade of the CB1 receptor reduces body weight in animals through central and peripheral actions.
While the central endocannabinoid system was described first, it is now evident that the peripheral endocannabinoid system plays an equally important role in modulating a number of physiological process.
The role of the peripheral endocannabinoid system in human obesity is now being studied. Engeli et al measured circulating endocannabinoid concentrations and studied the expression of CB1 and the main degrading enzyme, fatty acid amide hydrolase (FAAH), in adipose tissue of lean (n=20) and obese (n=20) women and after a 5% weight loss in a second group of women (n=17).
Circulating levels of anandamide and 2-arachidonoylglycerol were increased by 35%, and 52% in obese compared with lean women (P<0.05).
Adipose tissue mRNA levels were reduced by –4% for CB1 and –59% for FAAH in obese subjects (P<0.05).
A strong negative correlation was found between FAAH expression in adipose tissue and circulating endocannabinoids.
Circulating endocannabinoids and CB1 or FAAH expression were not affected by 5% weight loss. The expression of CB1 and FAAH was increased in mature human adipocytes compared with that in preadipocytes and was found in several human tissues.
These findings support the presence of a peripheral endocannabinoid system that is upregulated in human obesity.
* P<0.05 vs lean women
Engeli S, et al. Diabetes 2005; 54:2838–2843.
Engeli S, Bohnke J, Feldpausch M, et al. Activation of the peripheral endocannabinoid system in human obesity. Diabetes.2005;54:

31. Percent of subjects with FAAH 385 A/A genotype by BMI category31
A Mutation in the Enzyme That Degrades Endocannabinoids is Associated with Increased BMI
Percent of subjects with FAAH 385 A/A genotype by BMI category
* vs normal BMI
Caucasians African Americans 10 8 6 4 2 16 14 12 10 8 5 4
P<0.01*
P<0.05*
P<0.05*
% of subjects with FAAH 385 A/A
This study investigated the relationship between the FAAH cDNA 385 A/A (P129T) polymorphism and overweight disorders in subjects of multiple ethnic backgrounds attending a medical screening clinic. FAAH (fatty acid amide hydrolase) is the primary enzyme involved in the degradation of anandamide.
METHODS: 2667 white, black, and Asian subjects were genotyped and stratified by a standardized clinic-based assessment of BMI. Subjects were genotyped for the FAAH cDNA 385 C --> A polymorphism using allele-specific oligonucleotide hybridization methods by investigators blinded to all clinical information. BMI was calculated based on exact clinical measurements, and World Health Organization ranges were used to stratify subjects.
RESULTS: The homozygous FAAH 385 A/A genotype was significantly associated with overweight and obesity in white subjects (P=0.005) and in black subjects (P=0.05). The median BMI for all subjects was significantly greater in the FAAH 385 A/A genotype group compared with heterozygote and wild-type groups (P=0.0001). In white subjects, there was an increasing frequency of the FAAH 385 A/A genotype with increasing BMI categories of overweight (P=0.02) and obese (P=0.006), and the same trend was seen in black subjects.
CONCLUSIONS: These results suggest a role for the FAAH missense polymorphism as an endocannabinoid risk factor in overweight/obesity and may provide indirect evidence to support the role of the endocannabinoid system in overweight and obesity and the related cardiovascular and metabolic disorders.
SIGNIFICANCE: Endocannabinoid levels and associated changes in the adipose endocannabinoid system remained unchanged after 5% weight loss, suggesting that dysregulation of the endocannabinoid system may begin early in the development of obesity or possibly even before the development of obesity because of an underlying genetic predisposition. This concept is supported by the finding in the present study of a strong association of an FAAH missense mutation with human obesity.
>30.0
>30.0
BMI (kg/m2)
BMI (kg/m2)
Sipe JC et al. Int J Obes Relat Metab Disord.2005;29:
Sipe J, Waalen J, Gerber A, Beutler E. Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH). Int J Obes Relat Metab Disord.2005;29:

32. CB1 Blockade Produces a Dose-Related Reduction in Food Intake in Mice32
2.0
1.5
1.0
0.5
0.0
Food
intake
(g)
Rimonbant produces a dose response reduction in food intake
Recent research suggests that the CB1 cannabinoid receptor antagonist SR141716A may suppresses appetite.
This study represents a further, systematic investigation of the role of CB1 cannabinoid receptors in the pharmacological effects of cannabinoids on food intake.
Mice were food-restricted for 24 h and then allowed access to their regular rodent chow for 1 h.
The CB1 antagonist SR141716A dose-dependently decreased food consumption at doses that did not affect motor activity. In contrast, delta(9)-tetra-hydrocannabinol (Delta(9)-THC) increased food consumption at doses that had no effect on motor activity (not shown)
The CB2 cannabinoid receptor antagonist SR did not affect food intake, indicating that the effect of SR was specific to the CB1 receptor. These results suggest that SR141716A may affect the actions of endogenous cannabinoids in regulating appetite or (such as an inverse agonist effect on the receptor) aside from antagonism of cannabinoid effects.
Rimonabant Dose (mg/kg-1)
Wiley JL et al. Br J Pharmacol. 2005;145:
Wiley JL, Burston JJ, Leggett DC, et al. CB1 cannabinoid receptor-mediated modulation of food intake in mice. Br J Pharmacol. 2005;145:

33. Supporting Evidence: 33
Adipose tissue metabolism
EC stimulation with CB1 agonist increases adipose tissue LPL expression while CB1 blockade inhibits this effect
CB1 stimulation reduces while blockade increases adiponectin synthesis
CB1 blockade reverses the histological changes in adipose tissue produced by diet-induced obesity
EC stimulation reduces the expression of AMP kinase in visceral fat
Cota D et al. J Clin Invest. 2003;112:423.
Matias I, et al. XV ICRS Symposium June 24-27, 2005; Clearwater, Fla. Jbilo O, et al. FASEB J. 2005;19:

34. The Peripheral ECS in Adipose Tissue34
The Peripheral ECS in Adipose Tissue
Standard Diet
High Fat Diet
High Fat Diet + Rimonabant
Adipose tissue of obese mice fed a high fat diet (HFD) plus rimonabant resembles that of lean mice fed a standard diet (STD)
Jbilo et al3 demonstrated that SR (rimonabant) reversed the histology of obese adipocytes. Shown here is the effect of SR on the histological changes in white adipose tissue produced by diet-induced obesity. White adipocytes in vehicle-treated HFD mice were large and exhibited heterogeneous sizes, while fat cells in SR treated animals were significantly smaller than those in vehicle-treated animals. The difference in the mean cell diameter was –57%. The mean cell diameter of SR treated HFD white adipocytes was slightly smaller (around 10%) than STD mice. Significant fat cell hypertophy is associated with insulin resistance; specifically, resistance to the antilipolytic effect of insulin. This hypertrophy was reversed by CB1 blockade with rimonabant.
Jbilo O, et al. FASEB J. 2005;19:
Cota D, Marsicano G, Tschop M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest ;112:
Matias I, et al. Presented at the XV ICRS Symposium June 24-27, 2005; Clearwater, Fla.
Jbilo O, Ravinet-Trillou C, Arnone M, et al. The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance. FASEB J. 2005;19:

35. Impaired Glucose Homeostasis35
ECS Stimulation, Centrally and Peripherally, Favors Metabolic Processes that Lead to:
Weight Gain
Lipogenesis
Insulin Resistance
Dyslipidemia
Impaired Glucose Homeostasis

36. RIO: Rimonabant In Overweight/Obesity CB-1 Blockade in Human Studies36
RIO: Rimonabant In Overweight/Obesity CB-1 Blockade in Human Studies
(>6600 patients enrolled) 1
year
1047
Obese or
overweight
with
type 2
diabetes
1033 u
ntreated
dyslipidemia (
excluding )
years
1507 /
without
comorbidities
1+1 Re
3040
Design
Population
Study
Rerandomized
N=6627 1
The RIO study program
The RIO program enrolled over 6,600 patients in an investigation of the impact of rimonabant on cardiovascular and metabolic risk factors in the overweight/obese population.
RIO-North America and RIO-Europe were 2-year studies that enrolled patients with BMI ≥30 kg/m2 or BMI >27 kg/m2 with comorbidity (ie, treated or untreated hypertension and/or treated or untreated dyslipidemia).
RIO-Lipids was a 1-year study, designed to specifically evaluate rimonabant in patients with untreated dyslipidemia. Accordingly, dyslipidemia was one of the inclusion criteria for this study. In addition, RIO-Lipids included measurement of additional parameters related to atherosclerotic risk, including adiponectin levels, LDL particle size and density and CRP levels.
RIO-Diabetes was a 1-year study conducted in type 2 diabetic patients inadequately controlled with metformin or sulfonylurea.
The design of RIO-North America differed from the other RIO trials in that a second randomization was included after year 1, with patients subsequently randomly allocated to continue their original study therapy or switch to placebo. In this way, this trial evaluated the effects of rimonabant on the change in cardiometabolic factors at 1 year, the maintenance of these effects in the second year, and the impact of discontinuing the drug.
The RIO studies all used a similar protocol: after screening there was a 4-week placebo single-blind run-in period. During this run-in period, the patients were instructed to consume a hypocaloric diet to produce a daily energy deficit of about 600 kcal/d and to increase their physical activity. This diet and exercise regimen was maintained for the duration of trial. At the end of this run-in period, the patients were randomized to placebo, rimonabant 5 mg, or rimonabant 20 mg.
Pi-Sunyer FX.Obes Res. 2004;12(suppl):08-OR, A27.

37. RIO-Europe and RIO-Lipids: Weight Change at 1 Year37
RIO-Europe and RIO-Lipids: Weight Change at 1 Year
Completers ITT (LOCF)
-1.5
-2.3 -2
-1.8
Placebo -4
Rimonabant
20 mg
Weight change (kg)
-3.6 -6
-6.6
The effect of rimonabant 20 mg on body weight was similar in RIO-Europe and RIO-Lipids, and was statistically significantly greater than the weight loss observed in the placebo group.
Body weight declined significantly more in with rimonabant treatment vs placebo with a clear divergence between the rimonabant 20 mg and placebo groups by 4 weeks. The primary analysis of weight change was applied to intent-to-treat population, consisting of all patients who were randomized and received at least 1 dose of study medication and had at least 1 follow-up assessment of weight. This method used the last-observation-carried-forward method to impute missing values for patients who discontinued prematurely.
In the ITT analysis, a mean body weight loss of over 6.5 kg from randomization was observed in the rimonabant 20 mg group at 1 year (P<0.001 vs placebo)
In RIO-Europe weight loss at 1 year was significantly greater in patients treated with rimonabant 20 mg (–6·6+7.2 kg) compared with placebo (–1·8+6.4 kg); P<0.001
In RIO-Lipids weight loss (ITT, LOCF) at 1 year was significantly greater in patients treated with rimonabant 20 mg (-6.9±6.1 kg), P<0.001) vs placebo (–1.5±5.0 kg); P <0.001 weight loss occurred during the first 9 months of the study period, after which body weight stabilized until the end month 12.
In both RIO-Europe and RIO-Lipids a mean body weight loss of 8.6 kg was observed in patients treated for 1 year (completers) with rimonabant 20 mg (P<0.001 vs placebo).
The double-blind treatment period followed a 4-week diet run-in period during which the patients lost an average of 2 kg. Taking into account this 2 kg body weight loss during the run-in period, the overall weight loss in those completing the 1-year treatment exceeded 10 kg.
-8.6
-6.9 -8
-8.6
Placebo
Rimonabant
20 mg
-10 16 32
ITT
LOCF
Weeks
Van Gaal et al. The Lancet 2005; 365:
Despres J-P, et al. N Engl J Med. 2005;353:
Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. The Lancet.2005;365:
Despres J-P, Golay A, Sjostrom L, the Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med.2005;353:

38. RIO-NA: Weight Change over 2-Years in Re-randomized Patients38
RIO-NA: Weight Change over 2-Years in Re-randomized Patients
Placebo
ITT (LOCF)
Rimonabant 20 mg/PLB
Rimonabant 20 mg
-7.4 kg ± 0.4
-2.3 kg ± 0.5
-3.2 kg ± 0.4
-10 -8 -6 -4 -2 8 16 24 32 40 48 56 64 72 80 88 96
104
LOCF
Weeks
Weight change (Kg)
Weight (kg) Change from Baseline over 2 Years (Mean +/- SEM)
Pi-Sunyer FX et al. JAMA 2006;295:

39. RIO-NA: HDL-C and TG over 2 Years*39
*Patients on same treatment for 2 years
Placebo
Rimonabant 20 mg
Rimonabant 5 mg
ITT, LOCF
HDL-cholesterol
Triglycerides 30 15
-1.9% p<0.001
+6.6%
+4.0% ns
LOCF 25 10 20 5
+14.1%
p<0.001
+8.4% ns
+7.8%
LOCF
Change in Triglycerides (%)
Change in HDL-cholesterol (%) 15 10 -5 5
-10
-15 24 48 72
104 24 48 72
104
Weeks
Weeks
Pi-Sunyer FX et al. JAMA 2006;295:

40. RIO-Lipids: Percent Change in HDL-C and TG Levels at 1 Year40
Rimonabant 20 mg
Rimonabant 5 mg
Placebo
Completers 30 25 20 15 10 5 10 5 -5
-10
-15
-20
P<0.001
22.9
+0.4
P=0.017
Change in TG (%)
Change in HDL-C (%)
-3.6
15.6
11.8
P<0.001
Effect of Placebo or Rimonabant for 52 Weeks on Plasma Fasting Triglyceride and HDL-C Levels.
Plasma HDL-C and triglyceride levels were measured at randomization (week 0) and every 3 months thereafter until week 52.
Baseline TG levels were 2.05 and 2.12 mmol/L (181 and 188 mg/dL) in the placebo and rimonabant 20 mg groups, respectively. Baseline HDL-C levels were 1.10 and 1.11 mmol/L (approximately 42 mg/dL) in the placebo and rimonabant 20 mg groups, respectively. Values are shown as means ± SE for all patients for whom measurements were taken at each visit (lines); P values were obtained after the repeated-measures analysis. P values correspond to the difference between each of the rimonabant groups and the placebo group.
In the completers population, the increase in HDL-C was significantly greater with rimonabant 20 mg vs placebo (~23% vs 12%). The change in TG levels was also greater in the rimonabant 20 mg group (–16% vs –4%).
In the ITT population (LOCF) the increase in HDL-C was significantly greater with rimonbant 20 mg vs placebo (19.1% vs 11. 8%); P< The change in TG was also significantly greater in the rimonabant 20 mg group vs placebo (–12.6% vs 0.0%).
It is noteworthy that a 4-week placebo plus dietary run-in preceded randomized double-blind treatment. During this run-in the subjects lost approximately 2 kg and both HDL-C and TG levels decreased by 3-6%.
-15.7
Week
Week
ITT, LOCF
Placebo : %
R5 mg : 14.2% (ns v. placebo)
R20 mg : 19.1% (p< v. placebo)
Placebo : 0.0. %
R5 mg : 1.2%
R20 mg :-12.6% (p < v. placebo)
Despres J-P, et al. N Engl J Med. 2005;353:
Despres J-P, Golay A, Sjostrom L, the Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med.2005;353:

41. RIO-DIABETES Results: Weight Changes
End Point
Placebo
Rimonabant 5 mg
Rimonabant 20 mg
P-value
PLB vs 20 mg
Weight loss (kg)
- 1.4±0.2
- 2.3±0.2
- 5.3±0.3
<0.001
Decrease in waist circumference (cm)
- 1.9±0.3
- 2.9±0.3
- 5.2±0.3
% of patients with weight loss ≥ 10%
2.0
6.2
16.4
% of patients with weight loss ≥ 5%
14.5
21.7
49.4
After one year, significant reductions in weight and waist circumference were observed, with rimonabant reducing body weight by more than 5 kg. Approximately half of the patients treated with the drug lost at least 5% of their baseline body weight. Similar reductions were also observed in the other rimonabant nondiabetic studies, but these newest results show the agent is capable of tackling weight in a group of patients typically resistant to weight-loss efforts, Scheen said.
All results shown on the slides are intent to treat analysis.
For % of patients with weight loss ≥ 10% and % patients with weights loss ≥ 5% completers results were also available:
% of patients with weight loss ≥ 10%, completers:
PLB RIO 5mg RIO 20 mg
3% 8.2% 21.4%** ** p< 0.001
% of patients with weight loss ≥ 5%, completers:
19.5% 27.2% 55.9%**
Scheen A. Late Breaking Clinical Trials. ADA Scientific Session 2005.

42. RIO-NA: Overall Safety Year 142
RIO-NA: Overall Safety Year 1
Placebo
Rimonabant
Rimonabant
n = 607
5 mg
n = 1214
20 mg
n = 1219
Overall discontinuations
49.1 %
49.0 %
44.9 %
Subjects with any adverse event
82.0 %
83.4 %
85.5 %
Subjects with any serious adverse event
3.5 %
3.8 %
4.5 %
Subjects discontinued due to adverse event
7.2 %
9.4 %
12.8 %
Pi-Sunyer FX et al. JAMA 2006;295:

43. RIO-NA: Adverse Events Leading To Drug Discontinuation in Year 143
Placebo
Rimonabant
(N=607)
(%)
5 mg
(N=1214)
20 mg
(N=1219)
Psychiatric disorders
2.3
3.6
6.2
Depressed mood disorders
1.3
2.1
2.2
Anxiety
0.3
0.6
1.0
Irritability
0.2
0.5
Insomnia
<0.1
Nervous system disorders
1.2
Headache
Dizziness
0.7
Gastrointestinal disorders
1.6
Nausea
0.9
According to MedDRA, in any rimonabant groups : in main SOCs (>=1% ) and in at least 6 patients (0.5%).
One patient may report several events
Pi-Sunyer FX et al. JAMA 2006;295:

44. RIO-NA: Main Adverse Events Leading to Drug Discontinuation in Year 2*44
RIO-NA: Main Adverse Events Leading to Drug Discontinuation in Year 2*
Placebo
Rimonabant
(N=298) N (%)
5 mg
(N=300) N (%)
20 mg
(N=333) N (%)
Psychiatric disorders
4 (1.3)
6 (2.0)
7 (2.1)
Depressed mood disorders
3 (1.0)
4 (1.3)
4 (1.2)
Anxiety
0 (0)
1 (0.3)
2 (0.6)
*Patients receiving the same treatment for 2 years
Pi-Sunyer FX et al. JAMA 2006;295:

45. Conclusions Obesity is a chronic disease
Modest weight loss (5% -10% of body weight) can have considerable medical benefits
Lifestyle change (diet and physical activity) is the cornerstone of therapy
Pharmacotherapy can be useful in properly selected patients
Bariatric surgery is the most effective therapy for severe obesity
Conclusions
Obesity is a chronic disease that is the result of long-term positive energy balance. The mechanisms responsible for this energy imbalance are complex and variable, involving genetic, metabolic, cultural, environmental, and psychosocial factors. Obesity causes impaired function and disease in many organ systems, which often can be reversed or prevented by modest weight loss. Appropriate obesity therapy involves many of the same principles used in the management of other chronic diseases and requires continued support from physicians and other caregivers as part of a long-term treatment plan. An effective weight loss program combines diet therapy, physical activity, and behavior therapy. Furthermore, certain patients may benefit from the addition of weight loss drugs to the basic treatment regimen. Bariatric surgery is the most effective available weight loss therapy, but is associated with the highest risk of complications. Therefore, surgery is reserved for patients with severe obesity, who have failed non-surgical attempts to lose weight.

46. Obese Patients Have Unrealistic Weight Loss Goals
Outcome
Weight (lbs)
% Reduction
Initial
218
Dream
135 38
Happy
150 31
Acceptable
163 25
Disappointed
180 17
Obese patients have unrealistic weight loss goals
Most obese patients have unrealistic weight loss goals. In patients seeking weight loss therapy, there is considerable disparity between weight loss expectations and weight loss that can be reasonably achieved. This table shows data from a study of obese women who were about to start a weight loss program [1]. On average, they reported their goal was to lose 32% of their weight. These women also reported that their “dream” was to lose 38% of their weight, they would be “happy” with a 31% weight loss, they would “accept” a 25% weight loss, but they would be “disappointed” with a 17% weight loss [1]. Therefore, an acceptable weight loss for most patients is 2 to 3 times more than that achieved with current behavioral and pharmacologic treatments. After 48 weeks of intensive diet and exercise therapy, subjects participating in this study lost an average of 16% of their initial weight, and end-of-treatment weights for 47% of patients were lower than that defined as disappointing. Patients who seek bariatric surgery also have unrealistically high weight loss expectations [2].
These studies illustrate the need to help patients accept more modest, but clinically important, weight loss outcomes. This can be done by redefining success as an improvement in health and quality of life, discussing limits to weight loss, congratulating patients on weight that has been lost, and empathizing with their disappointment if they do not reach their goal weight.
Foster GD, Wadden TA, Vogt RA, Brewer G. What is a reasonable weight loss? Patients’ expectations and evaluations of obesity treatment outcomes. J Consult Clin Psychol 1997;65:79-85.
Rabner JG, Greenstein RJ. Obesity surgery: expectations and reality. Int J Obes Relat Metab Disord 1991;15:
Foster et al. J Consult Clin Psychol 1997;65:79.