KPhA’s 134th Annual Meeting
and Trade Show
The Future of the Medical Management of Obesity
September 4, 2014
Shadrach Smith, MD Director of Weight, Health and Wellness
Kansas City Internal Medicine
KPhA’s 134th Annual Meeting and
Trade Show “The Future is Now: Envision, Educate, Empower”
KU Memorial Union
Lawrence, Kansas
Disclosures
• Speaker’s Bureau Eli Lilly-Boehringer Ingelham Vivus inc
• No financial interest in KPhA
• No honoraria from KPhA for this presentation
3
Learning Objectives
4
• Review the health risks associated with obesity • Discuss the biological factors that result in food
seeking behavior and energy deposition • Define goals for “successful” pharmacotherapy in
treatment • Review currently approved anti-obesity meds. • Identify weight “friendly” and “unfriendly”
medications used to treat co-morbid conditions • Discuss the results of studies of two new anti-obesity
medications which may be approved soon.
5
Pre-Test
A. 5% or greater weight loss B. Decrease in BMI to less than 30 kg/m2
C. 10% or greater weight loss D. Decrease in BMI to less than 25 kg/m2.
1. What is considered a successful response to pharmacotherapoy for obesity?
6
Pre-Test
A. Orlistat 120 mg TID B. Qsymia 15-92 QD C. Phentermine 37.5 mg QD D. Locasarin 10 mg BID
2. Based on double blind, placebo controlled studies, which of the following medications is likely to produce the greatest weight loss at the end of a year?
7
Pre-Test
3. Which medication is most associated with an increased risk for the serotonin syndrome?
A. Orlistat 120 mg TID B. Qsymia 15-92 QD C. Phentermine 37.5 mg QD D. Locasarin 10 mg BID
8
Pre-Test
4. Which medication has been associated with cleft palate birth defects?
A. Orlistat 120 mg TID B. Qsymia 15-92 QD C. Phentermine 37.5 mg QD D. Locasarin 10 mg BID
Two Sides of the Modern Civilization: The Good
We live the comfortable life
– We have 24-7 access to great tasting food
– We get where we want to go very quickly
– We have 24-7 access to entertainment
– Modern medicine has us living longer than ever
But…
Two Sides of the Modern Civilization: The Bad
… Too much food, too little physical activity, and too little sleep makes us unhealthy
Health problems more common in Civilized societies – Cardiovascular Heart disease
– High blood pressure
– Obesity
– Type 2 diabetes
– Arthritis
– Cancer (e.g., breast, uterine, cervical, colon)
70% of health problems are from an unhealthy lifestyle
Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome
Nonalcoholic fatty liver
disease cirrhosis
Coronary heart disease
Diabetes
Dyslipidemia
Hypertension
Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome
Osteoarthritis
Skin
Gall bladder disease
Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate
Phlebitis venous stasis
Gout
Medical Complications of Obesity Idiopathic intracranial hypertension
Stroke
Cataracts
Severe pancreatitis
BMI-Associated Disease Risk Classification BMI (kg/m2) Risk
Underweight <18.5 Increased
Normal 18.5-24.9 Normal
Overweight 25.0-29.9 Increased
Obese I 30.0-34.9 High
II 35.0-39.9 Very High
III >40 Extremely high
Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults—The Evidence Report. Obes Res 1998;6(suppl 2).
Additional risks: • Large waist circumference (men>40 in; women >35 in) • 5 kg or more weight gain since age 18-20 y • Poor aerobic fitness • Specific races and ethnic groups
Apples, Pears, and Carrots
• Large waist circumference: Men>40 in (102 cm) Women >35 in (88 cm)
Learning Objectives
14
• Review the health risks associated with obesity
• Discuss the biological factors that result in food seeking behavior and energy deposition
• Define goals for “successful” pharmacotherapy in treatment
• Review currently approved anti-obesity meds. • Identify weight “friendly” and “unfriendly”
medications used to treat co-morbid conditions • Discuss the results of studies of two new anti-obesity
medications which may be approved soon.
Causes of Obesity
Genetics/
Biology
Behavior/
Motivation
Environment/
Culture
Regulation of Food Intake Brain
NPY
AGRP
galanin
Orexin-A
dynorphin
Stimulate α-MSH
CRH/UCN
GLP-I
CART
NE
5-HT
Inhibit
Central Signals
Glucose
CCK, GLP-1, Amylin Vagal afferents
Insulin
Ghrelin Leptin Cortisol
Peripheral signals Peripheral organs
+
+
Gastrointestinal tract
Adipose tissue
Food Intake
Adrenal glands
External factors Emotions
Food characteristics
Lifestyle behaviors
Environmental cues
How to become Obese? More calories in than calories burned
Metabolic abnormalities Hypothyoidism, Metabolic Syndrome (insulin resistance), PCOS, Medications (insulin, anti-depessants, etc), Cushing Disease
Sedentary Lifestyle
Emotional Overeating, Binge Eating Disorder
Sleep deprivation
Neurological: Pseudotumor Cerebri Genetic Disorders: MCR-4 def , Prader-Willi
Leptin- Newer Piece of the Puzzle
• 1950- Discovery of genetically obese mice with very high insulin levels, but were not diabetic.
• Surgical obesity- Caused by removing portions of the lower brain that controls metabolism and connects to the emotional brain.
• Obese mice had very slow metabolic rates
• Dec 1994- Leptin discovered
• Leptin may be responsible for the long term control of weight
Leptin Deficiency
Clinical Effects of Leptin
Before After
Ghrelin
• Ghrelin is a gastric peptide that functions as short term satiety signal
• Therefore it is an appetite-stimulating hormone
• Levels of Ghrelin rise when the stomach is empty inducing hunger and then fall quickly when the stomach is full
• So ghrelin participates in “meal-to-meal” control of food intake.
• Elevated in Prader-Willi Syndrome
Learning Objectives
23
• Review the health risks associated with obesity • Discuss the biological factors that result in food
seeking behavior and energy deposition
• Define goals for “successful” pharmacotherapy in treatment
• Review currently approved anti-obesity meds. • Identify weight “friendly” and “unfriendly”
medications used to treat co-morbid conditions • Discuss the results of studies of two new anti-obesity
medications which may be approved soon.
0
10
20
30
40
Modest Weight Loss Prevents Diabetes in Overweight and Obese Persons with Impaired Glucose Tolerance
Diabetes Prevention Program Research Group. N Eng J Med 2002;346:393. Copyright © 2002. Massachusetts Medical Society. All rights reserved.
Cu
mu
lati
ve In
cid
ence
of
Dia
bet
es (
%)
0
Year
0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Placebo
Lifestyle
58% (48-66%)
Obesity Treatment Pyramid
Surgery
Pharmacotherapy
Lifestyle Modification
Diet Physical Activity
BMI
Currently Available Options
• Accept weight where it is
• Diet/Exercise: 3-10% weight loss
• Drugs: 5-12% weight loss
• Medically Supervised/Combination
of Diet + Drug: 10-15% weight loss
• Surgery: 15-30% weight loss
Low
High
Effectiveness
Currently Available Options
• Accept weight where it is
• Diet/Exercise: 3-10% weight loss
• Drugs: 5-12% weight loss
• Medically Supervised/Combination
of Diet + Drug: 10-15% weight loss
• Surgery: 15-30% weight loss
Low
High
Risks/Time/Money
Guide for Selecting Obesity Treatment
The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. October 2000, NIH Pub. No.00-4084
Treatment 25-26.9 27-29.9 30-34.9 35-39.9 >40
Diet,
Exercise,
Behavior Tx + + + + +
Pharmaco-
therapy
With co-
morbidities + + +
Surgery With co-
morbidities +
BMI Category (kg/m2)
Chronic Disease Treatment
• Long-term therapy is required for successful treatment and management.
• Drugs do not cure chronic diseases • Drugs do not work when they are not taken • Type 2 diabetes and hypertension respond well to
diet and exercise - but the primary treatments are drugs “due” to poor adherence
• Obesity responds well to diet and exercise- but primary treatment is diet and exercise “despite” poor adherence.
Learning Objectives
30
• Review the health risks associated with obesity • Discuss the biological factors that result in food
seeking behavior and energy deposition • Define goals for “successful” pharmacotherapy in
treatment
• Review current anti-obesity medications. • Identify weight “friendly” and “unfriendly”
medications used to treat co-morbid conditions • Discuss the results of studies of two new anti-obesity
medications which may be approved soon.
History
• Many anti-obesity drugs in the past proved to have significant toxicity
Amphetamines Digitalis
“Rainbow pills”
Weintraub Fhen-phen
1940-60
1992
Dexfenfluramine
Withdrawal 14 million
1997
30% BMI<30 14% BMI <27 BRFSS
Dinitrophenol Thyroxine
1933
Rimonabant approval in
Europe
2006-08
Orlistat
1998
Sibutramine 1997-2010
Qnexa Locaserin
Not approved
Contrave Dec 2010 approval Feb 2011 rejected
2010
Alli
History of Obesity Medication Problems
Phases of Obesity Treatment
Phase I (Weight Loss)
3-6 months
Phase II (Weight-Loss Maintenance)
Indefinitely
Wei
ght
www.drsharma.ca
Obesity: Unmet Medical Need in Metabolic Disease Space
Weight loss (%)
10 15
50-
100-
0-
Pills
80-
5
Current goal
25 20 0 30
Surgery Future Pharmacotherapy
FDA 2007 draft guidance
Primary efficacy criteria (one of the following)
• 5% greater (statistically significant) weight loss than placebo at 1 year.
• At least 35% patients achieving 5% weight loss on drug and approximately double the proportion in the placebo-treated group.
Sample size
• 3000 randomized to active dose of drug and no fewer than 1500 on placebo for 1 year.
FDA Guidance for industry developing products for weight management, draft guidance, revision 1, Feb 2007
Drugs Approved by FDA for Treating Obesity- Aug 2014
Generic Name
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Locasarin Belviq® IV Long-term 2012
Phentermine/
Topiramate XR Qsymia® IV Long-term 2012
Orlistat Xenical® None Long-term 1999
Diethylpropion Tenuate® IV Short-term 1973
Phentermine Adipex, ®
lonamin® IV Short-term 1973
Phendimetrazine Bontril®,
Prelu-2® III Short-term 1961
-32
-28
-24
-20
-16
-12
-8
-4
0
Effect of Continuous and Intermittent Phentermine Therapy on Body Weight
0
Time (weeks)
8 24 28
Munro JF et al. Brit Med J 1:352, 1968
Wei
ght
Loss
(lb
s)
36 4 12 16 20 32
Alternate Phentermine and Dummy QOM
Continuous Phentermine
Continuous Dummy
Orlistat
• Causes roughly 30% of dietary fat to not be absorbed via inhibition of GI lipases in gut lumen
• 120mg tid + a daily multivitamin
• Weight loss of up to 9% in one year
• Difficult to counsel patients regarding potential side effects of: • Flatulence with discharge
• Fecal incontinence
• Steatorrhea
• Oily spotting
• Increased frequency of defecation
-12
-9
-6
-3
0
Effect of Long-term Orlistat Therapy on Body Weight
0
Weeks
52
Torgenson et al. Diabetes Care 2004;27:155
Ch
ange
in W
eigh
t (k
g)
104 156 208
P<0.001 vs placebo
-4.1 kg
-6.9 kg
Placebo
Orlistat
Categorical Weight Loss With Orlistat
Weight loss during the 4-week lead-in was 5.58 lbs for the 5%–<10% group, 7.08 lbs for the 10%–<15% group, and 9.46 lbs for the 15% group. Completers population. Pooled Data (Ref. 038-024). Please see complete Product Information.
Weight Loss Category 5%–<10%
27%
10%–<15%
23%
15%
19%
-50
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
-16
- 45
-26
Percent of Patients (N = 1071)
Newer Weight loss Medications (approved 2012)
• Phentermine-topiramate XR combination (Qsymia®) – Approved for long term weight maintenance
– 10 % or more weight loss in most patients
– Significant side effects
– Has REMs program • Can potentially harm the fetus in a pregnant woman
• Lorcaserin (Belviq®) – Approved for long term weight maintenance
– Serotonin receptor agonist
– Low number of side effects
Lorcaserin (Belviq)
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 receptors
Serotonin receptor as a pharmacologic target for weight loss was validated by fenfluramine
Fenfluramine in combination with phentermine (Fen-Phen) was highly efficacious for weight loss
Safety 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
8 16 24 32 40 48
-10
-8
-6
-4
-2
064 72 80 88 96 104
Lorc/LorcPBO/PBO Lorc/PBO
ITT/LOCF
ITT/LOCF
Per
Protocol
Study WeekW
eig
ht
ch
an
ge (
kg
)
N = 344 N = 140 N = 308
Smith SR, et al. ADA 2009. Late-Breaking Abstract 96.
Lorcaserin – main results
• Two phase III trials – BLOOM (2 yrs) and BLOSSOM (1yr)
• Weight change at 1 yr
• -5.8% (lorcaserin 10 mg bid) vs -2.5% (placebo)
• 5% weight loss – 47%
• FDA defined valvulopathy
• RR 1.07 (0.74, 1.55)
FDA briefing document, Advisory committee meeting for lorcaserin, 16 Sep 2010
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
Smith SR, et al. ADA 2009. Late-Breaking Abstract 96.
Lorcaserin: Adverse Events Reported by 5% or More in Any Group in Year 1
46
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)
Smith SR, et al. ADA 2009. Late-Breaking Abstract 96.
Lorcasarin (Belviq®)
• Weight loss: 5-10%
• Side effects: headache, dizziness and nausea
• Cost: $150 to 220/month
• Unclear if physicians will prescribe off label with phentermine (no data on safety or efficacy)
Phentermine + Topiramate XR
• Phentermine available since 1959 for short-term treatment of obesity.
• Topiramate has been well studied for obesity. – Consistently demonstrated dose-dependent weight loss efficacy in
numerous trials ranging from 6 months to more than a year in obese and overweight patients with and without type 2 diabetes and hypertension.
– Reduction of BP and improvement of glycaemic control.
– Neuropsychiatric adverse events have hindered its further development for treatment of obesity.
Bray GA et al., Obes Res 2003;11:722-33. Wilding J et al., Int J Obes 2004;28:1399-1410. Toplak H et al., Int J Obes 2007;31:138-46. Rosenstock J et al., Diabetes Care 2007;30:1480-6. Tonstad S et al., Am J Cardiol 2005;96:243-51. Stenlof K et al., Diabetes Obes Metab 2007;9:360-8.
-10
-8
-6
-4
-2
0
0 2 4 6 8 10 12 14 16 18 20 22 24
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 = topiramate Bray G, et al. Obes Res. 2003;11:722-733.
Weeks
We
igh
t C
han
ge (
%)
400 mg
Qsymia™ for Obesity
• Once-daily, oral, controlled-release formulation of low-dose phentermine and topiramate extended release.
• 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
Me
an %
We
igh
t Lo
ss
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
Me
an %
We
igh
t Lo
ss
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 & CONQUER: Discontinuation Rate Due 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
Phentermine/Topiramate XR
• Risk of birth defects: women need – pregnancy test on starting and monthly while using.
• Reduces blood pressure, glucose, insulin, triglycerides and raises HDL
• Unclear if physicians will prescribe off label using generic phentermine and topiramate.
• Most effective medication available 10-15% weight loss.
Phentermine/Topiramate XR
• Combination gives greater effectiveness with fewer side effects
• Cost: $150-$200/month
• Side effects: dry mouth, numbness, tingling, insomnia, dizziness, anxiety, irritability and disturbance in attention
Learning Objectives
56
• Review the health risks associated with obesity • Discuss the biological factors that result in food
seeking behavior and energy deposition • Define goals for “successful” pharmacotherapy in
treatment • Review currently approved anti-obesity meds. • Identify weight “friendly” and “unfriendly”
medications used to treat co-morbid conditions • Discuss the results of studies of two new anti-obesity
medications which may be approved soon.
Selected Medications That Can Cause Weight Gain
• Psychotropic medications
– Tricyclics
– MOA inhibitors
– Specific SSRIs
– Atypical antipsychotics
i.e. Zyprexa
– Lithium
– Anticonvulsants
i.e. Lyrica
• -adrenergic receptor blockers
Diabetes medications
– Insulin
– Sulfonylureas
– Thiazolidinediones
Highly active antiretroviral
therapy
Tamoxifen
Steroid hormones
– Glucocorticoids
– Progestational steroids
58
Produce Weight Loss Are Weight Neutral Produce Weight Gain
Bupropion Haloperidol Tricyclic
antidepressants*
Desvenlafaxine Aripiprazole Monoamine oxidase
inhibitors
Venlafaxine Paroxetine
Topiramate Escitalopram
Zonisamide Lithium
Lamotrigine Olanzapine
Ziprasidone Clozapine
Risperidone
Carbamazepine
Valproate
Divalproex
Mirtazapine
Table 3.
Categorization of Neurobehavioral Drugs
by Their Effects on Body Weight
•↵* Nortriptyline, amitriptyline, doxepin.
59
Produce Weight Loss Are Weight Neutral Produce Weight Gain
Metformin Dipeptidyl peptidase-4
inhibitors (DPP-4) Insulin
Pramlintide Acarbose Sulfonylureas*
Exenatide Miglitol Glitinides
Liraglutide Bromocriptine Thiazolidinediones†
SGLT-2
Categorization of Antidiabetic Drugs by Their Effects on Body Weight
•↵* Glipizide, glimepiride, glibenclamide, chlorpropamide.
•↵† Pioglitazone, rosiglitazone.
0 10 20 30 40 50 60 70 80 90
Me
an
We
igh
t (k
g)
Exenatide Continued to Reduce Weight
Open-Label Extension – Combined
Time (wk)
Baseline Weight
98 kg 100 kg 100 kg Placebo BID
5 µg Exenatide BID 10 µg Exenatide BID
-5
-4
-3
-2
-1
0
1
82-wk completers; N = 393; Mean ± SE; Weight was a secondary endpoint Data on file, Amylin Pharmaceuticals, Inc.
Open-Label Extension Placebo-Controlled
Week number
1 3 5 7 9 13 21 29 37 45 53 17
Placebo
Fluoxetine
N = 16
N = 14
N = 23
N = 22
Wei
ght
Loss
(kg
) Fluoxetine 60 mg and Weight Loss*
Darga et al, AJCN, 1991.
-16
-14
-12
-10
-8
-6
-4
-2
0
Pharmacotherapy- Weight Friendly
• Obese + diabetes metformin~ -5 lbs, GLP-1 agonist - exenatide~-12 lbs, liraglutide, albiglutide pramlinatide (Symlin®) ~–5 lbs, SGLT-2 : i.e. canagliflozin (Inkovana®) ~–6-10 lbs DDP-IV inhibitors, bromocryptine-QR
• Obese + depression Bupropion ~ -10 lbs, duloxetine, vilazodone (Viibryd®) desvenlafaxine (Prestiq®), vortioxetine (Brintellix™)
• Obese + PMS fluoxetine or sertraline
• Obesity + Seizure disorders Topiramate and Zonisamide
• Obesity + Migraine Headaches Topiramate
Pharmacotherapy Common Side Effects • Xenical and Alli (orlistat)- Oily stools and gas
• Appetite Suppressants – stimulants buproprion, phentermine, diethylpropion- increase blood pressure, insomnia, dry mouth palpitations, nausea, anxiety and constipation.
• Appetite Suppressant – serotonergic Locaserin- fatigue, depression, nausea
• Metformin- nausea, gas and loose stools
• GLP-1 /Amylin Agonist – Exenatide, liraqlutide and pramlinatide - Nausea and requires injections
• Topiramate- Fatigue, change in taste, tingling, word searching.
• SSRI’s- Fatigue, apathy, sexual dysfunction, weight gain?
Learning Objectives
64
• Review the health risks associated with obesity • Discuss the biological factors that result in food
seeking behavior and energy deposition • Define goals for “successful” pharmacotherapy in
treatment • Review currently approved anti-obesity meds. • Identify weight “friendly” and “unfriendly”
medications used to treat co-morbid conditions • Discuss the results of studies of new anti-obesity
medications which may be approved soon.
DRUGS FOR OBESITY: THE FUTURE
Medications that may be approved in 2014 (medications are available for other indications)
• Bupropion-naltrexone – Combination depression medication
with opiate blocker
– 5% to 10% weight loss
– Will have safety data in high risk cardiovascular patients
• Liraglutide 3.0 mg/day– (Victoza®) – approved for Diabetes
– Injectible GLP-1 receptor agonist
– 5% to 10% weight loss
– Will be particularly useful in patients with pre-diabetes and diabetes
Proportion of individuals who lost at least 5, 7, and 10% of baseline weight.
Kim S H et al. Dia Care 2013;36:3276-3282
Copyright © 2014 American Diabetes Association, Inc.
New Drugs
• Contrave® –(Naltrexone & Bupropion),
• Opioid receptor antagonist plus a selective inhibitor of neuronal re-uptake of noradrenaline and dopamine
• September 2014 – FDA will review
• ‘Light’ study interim analysis submitted Dec 13
• April 2011- 7.5% weight loss vs 2.5% placebo over 1 year period
Bupropion + naltrexone
• Bupropion, primarily norepinephrine-dopamine reuptake inhibitor, is marketed for treatment of depression and as a smoking cessation aid.
• Bupropion showed modest weight loss efficacy in three obesity trials.1
• Naltrexone, an opioid receptor antagonist, is marketed to treat alcoholism and opioid addiction.
• Animal studies suggest pharmacodynamic synergy.2
1Gadde KM et al., Exp Rev Neurother 2007;7:17-24. 2Greenway FL et al., Obesity 2009;17:30-39
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
0 8 16 24 32 40 48 56-10
-8
-6
-4
-2
0
56
-1.3%
-5.0%*
-6.1%*
-1.9%
-6.8%*
-8.2%*
Week
Change fro
m b
ase
line (
%)
0 8 16 24 32 40 48 56-10
-8
-6
-4
-2
0
56
-1.2%
-6.4%*
-1.4%
-8.1%*
Week
Change fro
m b
ase
line (
%)
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)
0
20
40
60
80
16.4%
48.0%
24.6%
*
*
7.4%
11.9%*
2.0%
5% 10% 15%
Perc
enta
ge o
f su
bje
cts
0
20
40
60
80
17.1%
50.5%
28.3%
*
*
5.7%
13.5%*
2.4%
5% 10% 15%
56.3%*
Perc
enta
ge o
f su
bje
cts
patients
patients
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&highlight Accessed April 29, 2010.
0
5
10
15
100
MildModerateSevere
4 8 12 16 20 24 28 32 36 40 44 48 52 56
Week
Inci
dence
of nause
a (
%)
0
5
10
15
100
MildModerateSevere
4 8 12 16 20 24 28 32 36 40 44 48 52 56
Week
Inci
dence
of nause
a (
%)
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&highlight Accessed April 29, 2010.
NB N = 2134
Placebo N = 1061 titration period
titration period
Gastric Bypass Lap Band
Effectiveness
Risk
Low High
Sleeve Gastrectomy
Weight loss in the SOS
JAMA. 2012;307(1):56-65
Program Summary
78
• Obesity is serious medical problem that is a driver of the increase in health care cost
• Even modest weight loss (5%–10%) can reduce cardiometabolic risk factors
• Newer strategies for weight loss should include a) Limiting weight gaining pharmacotherapy b) Consideration of pharmacotherapy targeted to change the energy-balance equation c) Long term treatment because obesity is a chronic disease
Questions?
Post-Test
80
A. 5% or greater weight loss B. Decrease in BMI to less than 30 kg/m2
C. 10% or greater weight loss D. Decrease in BMI to less than 25 kg/m2.
1. What is considered a successful response to pharmacotherapoy for obesity?
Post-Test
81
A. Orlistat 120 mg TID B. Qsymia 15-92 QD C. Phentermine 37.5 mg QD D. Locasarin 10 mg BID
2. Based on double-blind, placebo controlled studies, which of the following medications is likely to produce the greatest weight loss at the end of a year?
Post-Test
82
3. Which medication is most associated with an increased risk for the serotonin syndrome?
A. Orlistat 120 mg TID B. Qsymia 15-92 QD C. Phentermine 37.5 mg QD
D. Locasarin 10 mg BID
Post-Test
83
4. Which medication has been associated with cleft palate birth defects?
A. Orlistat 120 mg TID B. Qsymia 15-92 QD C. Phentermine 37.5 mg QD D. Locasarin 10 mg BID
References • Clinical Assessment and Management of Adult Obesity,
Circulation. 2012;126:2870-2877,
• Bray GA, Ryan D. Medical Therapy for the Patient With Obesity. Circulation. 2012;125:1695-1703
• Ness-Abramof R, Appovian CM. Drug-induced weight gain. Drugs Today.2005; 41: 547–555.
• Hendricks EJ, Rothman RB, Greenway FL . How physician obesity specialists use drugs to treat obesity. Obesity (Silver Spring). 2009; 17: 1730–1735.
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