Diabetes Mellitus

Obesity as a CNS Disorder:Targeting the Neuronal Circuitry of Weight Loss

Learning Objectives
Upon completion of this activity, you should be able to: Differentiate the mechanisms of action of the new targeted pharmacotherapies for obesity in development from the current approaches to obesity management Evaluate the efficacy, safety, and tolerability of emerging antiobesity therapies, and where they may fit into the current obesity algorithms

What percentage of your patients are either overweight or obese?

< 25%25%-50%51%-75%> 75%I don’t see patients currently

Cardiovascular Hypertension Congestive heart failure Cor pulmonale Varicose veins Pulmonary embolism Coronary artery disease Neurologic Stroke Idiopathic intracranial hypertension Meralgia paresthetica Psychological Depression Body image disturbance Low self-esteem Impaired quality of life
Respiratory Dyspnea Obstructive sleep apnea Hypoventilation syndrome Pickwickian syndrome Asthma Endocrine Metabolic syndrome Type 2 diabetes mellitus Dyslipidemia Polycystic ovary syndrome/androgenicity Amenorrhea/infertility/menstrual disorders
Systems Review: Cardiovascular, Respiratory, Neurologic, Endocrine, and Psychological


Musculoskeletal Hyperuricemia and gout Immobility Osteoarthritis (knees/hips) Low back pain Carpal tunnel syndrome Integumentary Striae distensae (stretch marks) Stasis pigmentation of legs Cellulitis Acanthosis nigricans/skin tags Intertrigo, carbuncles
Gastrointestinal GERD Nonalcoholic fatty liver disease Cholelithiasis Hernias Colon cancer Genitourinary Urinary stress incontinence Obesity-related glomerulopathy Kidney stones Hypogonadism Breast and uterine cancer Pregnancy complications
Systems Review: Musculoskeletal, Integumentary, GI, and Genitourinary

Relationship Between BMI and Risk for Type 2 Diabetes Mellitus

Chan J, et al. Diabetes Care. 1994;17:961-969. Colditz G, et al. Ann Intern Med. 1995;122:481-486.
Age-Adjusted Relative Risk
Body Mass Index (BMI; kg/m2)
< 23
24-24.9
25-26.9
27-28.9
33-34.9
0
25
50
75
100
1.0
2.9
4.3
5.0
8.1
15.8
27.6
40.3
54.0
93.2
< 22
23-23.9
29-30.9
31-32.9
35+
1.0
1.5
4.4
6.7
11.6
21.3
42.1
1.0
2.2
Men
Women

Association of Waist-to-Hip RatioWithin BMI Categories With MI

Yusuf S, et al. Lancet. 2005;366:1640-1649.
Results expressed by waist-to-height ratio quintiles and BMI categories

Relative Risk for Death From Cardiovascular Disease, Cancer, and All Other Causes

Body Mass Index
Women
Relative Risk for Death
Body Mass Index
< 18.5 18.5-20.4
20.5-21.9 22.0-23.4
23.5-24.9 25.0-26.4
26.5-27.9 28.0-29.9
30.0-31.9 32.0-34.9
> 40.0
35.0-39.9
2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6
Cardiovascular disease Cancer All other causes
3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6
Relative Risk for Death
Men
< 18.5 18.5-20.4
20.5-21.9 22.0-23.4
23.5-24.9 25.0-26.4
26.5-27.9 28.0-29.9
30.0-31.9 32.0-34.9
> 35.0
Calle EE, et al. N Engl J Med. 1999;341:1097-1105.
The reference category consisted of participants with BMIs of 23.5-24.9 kg/m2.

BMI and All-Cause Mortality

Prospective Studies Collaboration. Lancet. 2009;373:1083-1096.
Hazard ratio (HR) per 5 kg/m2 higher BMI. HR less than 1 if BMI is inversely associated with risk . All analyses exclude the first 5 years of follow-up and adjust for study and age at risk (in 5-year groups). The overall and age-specific analyses also adjust for sex, and the all-participant analyses also adjust for baseline smoking status.

Effect of BMI on Lifespan

Prospective Studies Collaboration. Lancet. 2009;373:1083-1096.

All Healthcare Professionals Play a Role

Screening for Obesity in Adults. The US Preventive Services Task Force recommends that clinicians screen all adult patients for obesity and offer intensive counseling and behavioral interventions to promote sustained weight loss for obese adults (Grade B recommendation)
U.S. Preventive Services Task Force. Ann Intern Med. 2003;139:930-932.

All Healthcare Professionals Play a Role

Periodically monitor for change in weight by noting weight trajectory over timeProvide dietary, physical activity, and lifestyle counseling to “at-risk” patients, and consider pharmacologic and surgical treatment when indicated U.S. Preventive Services Task Force. Ann Intern Med. 2003;139:930-932.

I understand the role of the central nervous system in weight regulation.

Strongly agree Agree Disagree Strongly disagree Neither agree nor disagree


Sensory Factors: Taste Smell Texture Sight Effects of: Variety Sensory-specific satiety Palatability Food concentration Ready availability
Brain Mechanisms: Modulate sensory factors by satiety signals to produce reward value and appetite
Satiety/Hunger Signals: Fat cell hormones Gut hormones Gastric distention
Cognitive Factors: Conscious rational control Beliefs about the food Advertising
Eating
Mechanisms of Food Intake
Adapted from: Rolls ET. Obes Rev. 2007;8(suppl1):67-72.
Family & Social Influences

Woods SC, et al. J Clin Endocrinol Metab. 2008;93(suppl1):S37-S50.

Model Summarizing Different Levels of Control Over Appetite Regulation

Gut Peptides That Regulate Appetite

Murphy KG, Bloom SR. Nature. 2006;444:854-859.

Gut Peptides That Regulate Appetite

Murphy KG, Bloom SR. Nature. 2006;444:854-859.

The Importance of the Hypothalamus in Appetite Regulation

Injury or lesions in the hypothalamus may result in a pattern of weight gain that is characterized as abrupt in onset and rapidly accelerating = hypothalamic obesity Causes include: Craniopharyngioma Head trauma Sarcoidosis Aneurysm
Meningioma Metastasis Surgery Radiation

A Case of Hypothalamic Obesity

Neuroregulation of Energy Balance
5-HT2c receptors

Obesity Treatment Pyramid

Surgery
Pharmacotherapy
Lifestyle Modification
Diet
Physical Activity
BMI


How confident are you that your understanding of emerging pharmacotherapies for treatment of obesity is up-to-date?
Very confident Somewhat confident Not very confident


Emerging Antiobesity Drugs and Drug Combinations
Lorcaserin, a selective 5-HT2C receptor agonist Naltrexone + bupropion Phentermine and topiramate

Lorcaserin

Lorcaserin: selective 5-HT2C receptor agonist designed to promote weight loss 5-HT2C receptor activation of proopiomelanocortin (POMC) neurons results in α-MSH activation of melanocortin-4 receptorsSerotonin receptor as a pharmacologic target for weight loss was validated by fenfluramineFenfluramine in combination with phentermine (Fen-Phen) was highly efficacious for weight lossSafety concerns led to withdrawal: Fenfluramine activation of 5-HT2B receptor was linked to cardiac valvular disease Heisler LK, et al. Science. 2002;297:609-611.

Behavioral Modification and Lorcaserin for Obesity and Overweight Management (BLOOM)

Lorcaserin (Lorc) vs placebo (PBO): P < .0001 at all timepoints Lorc/Lorc vs Lorc/PBO: P < .0001 at all year 2 timepoints
N = 344 N = 140 N = 308

Echocardiographic Monitoring and Endpoints

Echoes were performed every 6 monthsHeart valve insufficiency (or regurgitation) is rated as follows:Aortic: absent; trace; mild; moderate; severeMitral: absent; trace; mild; moderate; severeTricuspid: absent; trace; mild; moderate; severePulmonic: absent; presentThe US Food and Drug Administration (FDA) defines significant valvular disease as MILD or greater aortic regurgitation, or MODERATE or greater mitral regurgitationMain endpoint: proportion of patients who develop “FDA valvulopathy”Secondary endpoints: shift analyses of individual heart valve regurgitant scores CDC. MMWR Morb Mortal Wkly Rep. 1997;46:1061-1066.

Lorcaserin Did Not Increase the Rate of FDA Valvulopathy

N = number of evaluable echo pairs; n = number (%) with FDA valvulopathy
Treatment
N
n (%)
P
Week 52
Lorcaserin 10 mg BID
1278
34 (2.66%)
.70a
Placebo
1194
28 (2.35%)
Week 104
Lorcaserin/lorcaserin
500
13 (2.6%)
.99a
Lorcaserin/placebo
258
5 (1.9%)
Placebo/placebo
627
17 (2.7%)
aVs placebo with Fisher’s exact test


Lorcaserin: Adverse Events Reported by 5% or More in Any Group in Year 1
* N (%)
Lorcaserin (N = 1593)
Placebo (N = 1584)
Headache
287 (18.0)
175 (11.0)
Dizziness
130 (8.2)
60 (3.8)
Nausea
119 (7.5)
85 (5.4)
Constipation
106 (6.7)
64 (4.0)
Fatigue
95 (6.0)
48 (3.0)
Dry mouth
83 (5.2)
37 (2.3)


Naltrexone and Bupropion Rationally Designed Around MOA to Initiate and Sustain Weight Loss
Obesity: complex, multiple pathways to defend body weight Preclinical/clinical evidence for drug synergy Naltrexone/bupropion synergistic increase in POMC activity Synergistic decrease in food intake and body weight
β-endorphin Bupropion
α-MSH Naltrexone
Weight loss
MC4R = melanocortin-4 receptor; MOA = mechanism of action; MSH = melanocyte-stimulating hormone; POMC = proopiomelanocortin Greenway FL, et al. Obesity. 2009;17:30-39.

COR-I, II: Body Weight, Percentage of Change From Baseline

COR-II
COR-I
ITT-LOCF
Observed#
ITT-LOCF
Observed
NB16 (N=471)
Completers: Placebo (N = 290): -1.8% , NB16 (N = 284): -6.7%* NB32 (N = 296): -8.1%*
Completers: Placebo (N = 267): -1.4% NB32 (N = 434): -8.2%*
NB = naltrexone/bupropion. #COR-II: NB observed data are NB32/NB48 pooled (N = 825); no differences were observed for patients rerandomized to NB32 vs NB48. LS mean ± SE; *P < .001 vs placebo at all timepoints. COR-II: week 56 ITT-LOCF data from patients rerandomized to NB32 are double weighted to account for the prespecified exclusion of patients rerandomized to NB48. ITT-LOCF: patients with a baseline and ≥ 1 postbaseline weight measurement while on study drug. Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irol-newsArticle&ID=1346886&highlight Accessed April 29, 2010. Placebo (N=456)
NB32 (N=702)
NB32 (N=471)
Placebo (N=511)

COR-I, II: Categoric Weight Loss at Week 56, ITT-LOCF

Data are for the ITT-LOCF population. *P < .001 vs placebo . COR-II: week 56 data from patients rerandomized to NB32 are double weighted to account for the prespecified exclusion of patients rerandomized to NB48. ITT-LOCF: patients with a baseline and ≥ 1 postbaseline weight measurement while on study drug. Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1346886&highlight Accessed April 29, 2010. COR-II ITT-LOCF
COR-I ITT-LOCF
Placebo (N=456)
NB32 (N=702)
Placebo (N=511)
NB32 (N=471)
patients
patients

COR-I: Improvements in Control of Eating, ITT-LOCF

Less
More
How difficult has it been to control your eating?
How often have you eaten in response to food cravings?
How difficult has it been to resist any food cravings?
COR-I
Placebo (N = 511)
NB32 (N = 471)
Change from baseline to week 56 endpoint for eating/craving-related items showing differences (P < .05) at weeks 8, 16, 28, and 56 in both COR-I and COR-II; responses reflect experiences during the 7 days prior to answering the questionnaire; ITT-LOCF: patients with a baseline and ≥ 1 postbaseline weight measurement while on study drug. Data are LS mean ± SE; *P < .05 vs placebo; the COEQ consists of 21 questions with responses given using a 100-mm visual analogue scale. COR-II: week 56 data from patients rerandomized to NB32 are double weighted to account for the prespecified exclusion of patients rerandomized to NB48. Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1346886&highlight Accessed April 29, 2010.


COR-II: Improvements in Control of Eating, ITT-LOCF
COR-II
How difficult has it been to control your eating?
How often have you had food cravings?
How difficult has it been to resist any food cravings?
Change from baseline to week 56 endpoint for eating/craving-related items showing differences (P < .05) at weeks 8, 16, 28, and 56 in both COR-I and COR-II; responses reflect experiences during the 7 days prior to answering the questionnaire; ITT-LOCF: patients with a baseline and ≥ 1 postbaseline weight measurement while on study drug. Data are LS mean ± SE; *P < .05 vs placebo; the COEQ consists of 21 questions with responses given using a 100-mm visual analogue scale. COR-II: week 56 data from patients rerandomized to NB32 are double weighted to account for the prespecified exclusion of patients rerandomized to NB48. Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1346886&highlight Accessed April 29, 2010. More
Placebo (N = 456)
NB32 (N = 702)
Less

COR-I, II: Most Common Treatment-Emergent Adverse Events (TEAE)

COR-I
COR-II
Placebo N=569
NB16 N=569
NB32 N=573
Placebo N=492
NB32/48 N=992
Nausea
5.3%
27.2%*
29.8%*
6.9%
29.2%*
Headache
9.3%
16.0%*
13.8%*
8.7%
17.5%*
Constipation
5.6%
15.8%*
15.7%*
7.1%
19.1%*
Dizziness
2.6%
7.7%*
9.4%*
3.7%
6.9%*
Vomiting
2.5%
6.3%*
9.8%*
2.0%
8.5%*
Dry mouth
1.9%
7.4%*
7.5%*
2.6%
9.1%*
Patients discontinuing due to a TEAE
9.8%
21.4%*
19.5%*
13.8%
24.3%*
Nausea
0.4%
4.6%*
6.3%*
0.2%
6.0%*
Dizziness
0.5%
2.3%*
1.2%
0.2%
1.0%
Headache
0.7%
1.6%
0.9%
0.8%
2.6%*
Vomiting
0.2%
0.7%
0.9%
0%
0.8%
Insomnia
0.2%
0.7%
0.7%
1.0%
0.8%
TEAEs > 5% in any NB group and 2x the incidence in the respective placebo group. Top 5 TEAEs leading to discontinuation in NB groups. Data are for the safety analysis set: patients taking ≥ 1 tablet of study drug and with ≥ 1 investigator contact/assessment at any time after the start of study treatment. *P < .05 vs placebo Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1346886&highlightAccessed April 29, 2010.


COR-I, II: Incidence of Nausea by Week and Intensity
Nausea events are shown during week of onset only. If a patient had multiple-event onsets during the same week, only the most severe event is shown. Safety analysis set: patients taking ≥ 1 tablet of study drug and with ≥ 1 investigator contact/assessment at any time after the start of study treatment. Placebo data are combined for COR-I and COR-II. All NB data are combined for COR-I and COR-II (NB16, NB32, NB48). Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1346886&highlightAccessed April 29, 2010. NB N = 2134
Placebo N = 1061
titration period
titration period


Activity Inhibits activity of glutamate at AMPA/kainate receptors Inhibits activation of L-type voltage-dependent Ca++ channels Inhibits carbonic anhydrase (CA-II, CA-IV) Modulates lipoprotein lipase activity Stimulates thermogenesis and energy expenditure (some models) Downregulation of corticotropin-releasing hormone, glucocorticoids (GC), and GC receptors (depends on model) Other preliminary data
Reduces body weight (?)
Significance to Body Weight Loss
Reduces body weight (?)
Reduces body weight (?)
Reduces fat deposition and triglycerides
Reduces body weight
Reduces body weight, other effects on energy metabolism
Effects on energy metabolism
Potential Activities of Topiramate Involved in Energy Balance

Placebo (n=48)

64 mg/d TPM (n=57)
96 mg/d TPM (n=49)
192 mg/d TPM (n=50)
384 mg/d TPM (n=44)
Topiramate in Obesity: Percentage of Body Weight Change From Baseline to Week 24
P < .05 from week 4 TPM = topiramateBray G, et al. Obes Res. 2003;11:722-733.
Weeks
Weight Change (%)

400 mg

Proprietary Investigational Treatment for Obesity
Once-daily, oral, controlled-release formulation of low-dose phentermine and topiramate Specifically designed to affect normal eating patterns over 24 hours -- simultaneously addressing appetite, satiety, and cravings
0
200
100
300
50
150
250
350
Topiramate
0
30 mg (free base)
15
5
10
25
3.75
7.5
Phentermine
Maximum Approved Doses
20
23
46
92
Low
Mid
Full
Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=407933 Accessed April 27, 2010.

Low (23T, 3.75P) -7.0%, 18 lb

Placebo -2.5%, 6 lb
Full (92T, 15P) -14.7%, 37 lb
Mean % Weight Loss
Weeks
Patients
Placebo
Low
Full
Completers (% of randomized)
241 (47%)
138 (57%)*
301 (59%)*
*Statistically greater number of patients completing study on combination drug vs placebo, P < .0001
EQUIP: Weight Loss Over Time (Completer Population)
Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010.
Data from patients who completed 56 weeks on treatment

Mid (46T, 7.5P) -10.5%, 24 lb

CONQUER: Weight Loss Over Time (Completer Population)

Placebo -2.4%, 6 lb

Mean % Weight Loss
Weeks
Patients
Placebo
Mid
Full
Completers (% of randomized)
564 (57%)
344 (69%)*
634 (64%)*
Full (92T, 15P) -13.2%, 30 lb
*Statistically greater number of patients completing study on combination drug vs placebo, P < .0001
Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010.
Data from patients who completed 56 weeks on treatment


EQUIP: Significant Categoric Weight Loss With Phentermine and Topiramate (Low and Full Dose)
% of Patients with:≥ 15% wt lossPlacebo 5%Low11%* Full43%**≥ 10% wt lossPlacebo 12%Low27%**Full60%**≥ 5% wt lossPlacebo 26%Low59%**Full84%** Completers
**P < .0001 vs placebo *P = .026 vs placebo
Weight Loss
Low
Full
Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010.


CONQUER: Significant Categoric Weight Loss With Phentermine and Topiramate (Mid and Full Dose)
% of Patients with:≥ 15% wt loss Placebo 4% Mid26%**Full39%**≥ 10% wt loss Placebo 10% Mid49%** Full64%**≥ 5% wt loss Placebo 26%Mid75%**Full85%** Completers
**P < .0001 vs placebo
Weight Loss
Low
Full
Placebo
Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010.

EQUIP & CONQUER: TEAEs > 5%

EQUIP (N = 1264)
CONQUER (N = 2485)
% of Patients (N = 3749)
Placebo
Low
Full
Placebo
Mid
Full
Dry mouth
3.7
6.7
17.0
2.4
13.5
20.8
Tingling
1.9
4.2
18.8
2.0
13.7
20.5
Constipation
6.8
7.9
14.1
5.9
15.1
17.4
Altered taste
1.0
1.3
8.4
1.1
7.4
10.4
Insomnia
4.9
5.0
7.8
4.7
5.8
10.3
Dizziness
4.1
2.9
5.7
3.1
7.2
10.0
Nausea
4.7
5.8
7.2
4.2
3.6
6.8
Blurred vision
3.1
6.3
4.5
3.6
4.0
6.0
Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010.


EQUIP & CONQUER: Discontinuation RateDue to AEs in All Doses Studied

Placebo

Low
Mid
Full
Number of patients
1508
241
498
1507
Discontinuation due to AEs
9%
12%
12%
18%
Blurred vision
0.5%
2.1%
0.8%
0.7%
Headache
0.7%
1.7%
0.2%
0.9%
Insomnia
0.4%
0.0%
0.4%
1.7%
Depression
0.2%
0.0%
0.8%
1.4%
Tingling
0.0%
0.4%
1.0%
1.2%
Irritability
0.1%
0.8%
0.8%
1.2%
Anxiety
0.3%
0.0%
0.2%
1.1%
Dizziness
0.2%
0.4%
1.2%
0.8%

Includes adverse events (AEs) by dose for EQUIP & CONQUER, which lead to discontinuation in > 1% of patients
Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010.


A Guide to Selecting Obesity Treatment
NIH, et al. NIH. 2000;00-4804:1-84.
BMI Category (kg/m2)
Treatment
25-26.9
27-29.9
30-34.9
35-39.9
 40 Diet, physical activity, and behavior therapy
With comorbidity
+-
+-
+ -
+ -
Pharmacotherapy
With comorbidity
+ -
+ -
+ -
Surgery
With comorbidity
+-

Summary

Appetite control and energy expenditure are regulated by peripheral and central signaling mechanisms Newer antiobesity agents target these processes Due to the complexity of the hypothalamic circuitry, combined drug therapy is likely to be more effective than monotherapy for weight control Antiobesity medications are anticipated to have a more significant role in the treatment of patients with obesity


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