Medical Management of Obesity:
Filling the Treatment Gap
May 19, 2011
Bradley Javorsky, MD
Assistant Professor of Medicine
Endocrinology Center and Clinics
Medical College of Wisconsin
Disclosures
None
Overview
Prevalence
Physiology
Pathogenesis
Comprehensive Management
Medical Management
–
–
–
–
FDA approved medications
FDA reviewed medications
Non-FDA approved medications
Future approaches
Clinical case
HPI: 39 y/o female with obesity and metabolic syndrome
– “Always heavy”
– Family overweight or obese
– Slow progressive weight gain, worse after high school and pregnancies x3
– Tried many diets, exercise trainer
PMH: Migraine headaches, metabolic syndrome, knee OA, tubal ligation
SH: no tobacco; 1 EtOH/week; works desk job
FH: CAD (MI in father 52 y/o), DM2
Medications: HCTZ, fish oil, sumatriptan prn, ibuprofen prn
PE: BP 135/85, P 81, BMI 39; Euthyroid, no features of Cushings
syndrome or acromegaly, no edema
Labs: TSH 3.2, Hgb A1c 6.0%, Trig 189, HDL 38, LDL 110, LFTs wnl
Clinical case
If lifestyle changes (diet, exercise, behavioral
modification) are unsuccessful, what would
you offer this patient?
A.
B.
C.
D.
E.
F.
G.
Nothing, she is weak willed and lazy.
Straight to bariatric surgery.
Metformin.
Orlistat.
Phentermine.
Exenatide or liraglutide.
Phentermine plus topiramate.
Growth of a nation
Weight (lbs.)
Male
Female
Height (in.)
Male
Female
BMI (kg/m2)
Male
Female
1960-62*
2003-06**
166.3
140.2
194.7
164.7
68.3
63.1
69.4
63.8
25.1
24.9
28.4
28.4
Source: CDC/NCHS, NHANES
*Adults age 20-74
**Adults age >20
NHANES obesity prevalence in adults
1960 to 2000
1962
2000
Medical Complications of Obesity
Pulmonary disease
abnormal function
obstructive sleep apnea
hypoventilation syndrome
Nonalcoholic fatty liver
disease
Idiopathic intracranial
hypertension
Stroke
Cataracts
steatosis
steatohepatitis
cirrhosis
Coronary heart disease
Diabetes
Dyslipidemia
Hypertension
Gall bladder disease
Severe pancreatitis
Gynecologic abnormalities
Cancer
abnormal menses
infertility
polycystic ovarian syndrome
breast, uterus, cervix
colon, esophagus, pancreas
kidney, prostate
Osteoarthritis
Skin
Gout
Phlebitis
venous stasis
Obesity as a Risk Factor for Type 2 Diabetes:
Importance of Abdominal Fat Accumulation
15.2
20
13.5-Year
15
Incidence of
10
Type 2
Diabetes (%)
12.5
9.1
9.1
2.9
5
0
2.9
0.5
(Overweight) III
BMI Tertiles
III
0.5
II
0.5
I
(Lean)
BMI = body mass index
Reprinted from Ohlson LO, et al. Diabetes. 1985;34:10551058, with permission from the American Diabetes Association.
Copyright © 1985 American Diabetes Association.
II
I
Waist/Hip
Ratio Tertiles
Obesity and prevalence of type 2
diabetes mellitus
Gregg. Preventive Medicine, 2007. NHANES 1999-2004.
Risk estimates by cancer site
Men
Women
Renehan. Lancet 2008;371:569.
30–35 kg/m²,
median survival
reduced by 2–4
years
40–45 kg/m²,
median survival
reduced by 8–10
years (comparable
to effects of
smoking).
Lancet. 2009.
Yearly deaths per 1000
All-cause mortality vs BMI
Baseline BMI (kg/m2)
Cause of Death (U.S., 2007)
1.
2.
3.
4.
5.
6.
7.
8.
9.
Heart disease: 616,067
Cancer: 562,875
Stroke (cerebrovascular diseases): 135,952
Chronic lower respiratory diseases: 127,924
Accidents (unintentional injuries): 123,706
Alzheimer's disease: 74,632
Diabetes: 71,382
Influenza and Pneumonia: 52,717
Nephritis, nephrotic syndrome, and nephrosis:
46,448
10. Septicemia: 34,828
Obesity Is Caused by Long-Term Positive
Energy Balance
Sight
Fat
stores
Smell
Emotions
Basal metabolic
rate
Energy
expenditure
Energy
intake
GI flora?
Learned behavior
Learned behavior
Genes/adipostat
Metabostat?
Access
Access
NEAT
Relationship Between Adoptee Weight and Weight
of Biological or Adoptive Parents
BMI of Parents (kg/m2)
27
Biological Parents
Adoptive Parents
26
25
24
23
Fathers
Mothers
22
21
Thin
Median Overweight Obese
Thin
Median Overweight Obese
Weight Classification of Adoptees
Stunkard et al. N Engl J Med 1986;314:193.
Copyright © 1986 Massachusetts Medical Society. All rights reserved.
Precision of food intake
Age-related increase in weight = 0.5 lb/year
(males age 20-60)
0.5 lb adipose tissue = 1560 kcal
900,000 kcal/year
Excess energy consumption = 1560/900,000 = 0.17%
Weigle. FASEB J 1994;8:302.
Friedman. Science 2003;299:856.
FTO and obesity
Genome-wide association study
Each allele= 0.4-0.66 kg/m2 in BMI or
1.3-2.1 kg
European descent 63% heterozygous,
16% homozygous
Population attributable risk
– Obesity 20%
– Overweight 13%
Nucleic acid demethylase
Abundant in hypothalamus/arcuate
nucleus
Frayling. Science 2007;316:889.
Inactivation of the Fto gene
protects from obesity
Fischer. Nature, 2009.
Neuroendocrine control of energy balance
+Neuropeptide Y
+Agouti-related Protein
-α-MSH
-CART
-Insulin
-Pancreatic Polypeptide
-Leptin
Glucocorticoids
Endocannabinoids
+Ghrelin
-CCK
-Peptide YY
-GLP-1
-Oxyntomodulin
Hypothalamic “adipostat”
Higher
Centers
CRF
TRH
MCH
Second-order
neurons (PVN, LHA)
Alteration of food intake/
energy expenditure
Brainstem
Food
Intake
AgRP/
NPY
First-order neurons
(arcuate nucleus)
+
Ghrelin
Food
Intake
POMC/
CART
_
+
Leptin
Insulin
PYY
Gene-Environment Interaction in the
Pathogenesis of Obesity
Body Mass Index (kg/m2)
50
40
P <0.0001
Pima Indians
30
20
10
0
Maycoba, Mexico
Arizona
Ravussin E et al. Diabetes Care 1994;17:1067-1074.
Environmental Factors
Availability of highly processed, calorie-dense foods
Increasing portion sizes
Decreasing physical activity
Disrupted meal patterns
Disordered and inadequate sleep
High levels of stress
Social isolation
Medications that promote weight gain
Impact of Weight Loss on Risk Factors
~5%
Weight Loss
HbA1c
Blood Pressure
Total Cholesterol
HDL Cholesterol
5%-10%
Weight Loss
1
1
2
2
3
3
3
3
Triglycerides
1. Wing RR et al. Arch Intern Med. 1987;147:1749-1753.
2. Mertens IL, Van Gaal LF. Obes Res. 2000;8:270-278.
3. Blackburn G. Obes Res. 1995;3 (Suppl 2):211S-216S.
4. Ditschunheit HH et al. Eur J Clin Nutr. 2002;56:264-270.
4
Weight loss and mortality
(bariatric surgery)
Bariatric surgery
results in 24%
decreased risk
of death
HR= 0.76
#deaths= 129 control, 101 surgery
Sjostrom. NEJM 2007;357(8):741.
Management of obesity
Assess/treat secondary causes
Set realistic weight loss goal
Diet therapy
Exercise/physical therapy
Behavioral therapy
Pharmacotherapy
Bariatric surgery
Is it worth your effort?
≥5%
36.6
Percent with long-term weight loss
≥ 10%
≥ 15%
≥ 20%
17.3
8.5
4.4
NHANES 1999-2006 (adults who ever had a BMI ≥25, N=14,306)
Kraschnewski. Int J Obes. 2010.
Arch Intern Med, 2010.
Look AHEAD
Multicenter (16), randomized
N= 5145 with DM2
Mean age 58.7
BMI >25 kg/m2 (mean 36)
1.1%
4.7%
8.6%
Year
Bariatric/Metabolic Surgery
~15-20% total body weight loss
~25-30% total body weight loss
~30-35% total body weight loss
Adjustable gastric band
Sleeve gastrectomy
Roux-en-Y gastric bypass
Complications of Bariatric Surgery
All procedures:
Atelectasis and pneumonia
Deep vein thrombosis
Pulmonary embolism
Wound infection
Gastrointestinal bleeding
Gallstones
Inadequate weight loss (15%)
Intractable vomiting/kwashiorkor (B1)
Mortality (0.1%–2%)
Gastric bypass:
Anastomotic leak with peritonitis (2.5%)
Stomal stenosis (15%)
Marginal ulcers (13%)
Staple line disruption (1-5%)
Nutrient deficiencies (iron, calcium, folic
acid, vitamin B12, thiamine)
Dumping syndrome
Small bowel obstruction
– Internal hernia
– Adhesions
Gastric banding procedure:
Band slippage
Reoperation 5-20%
Band erosion
Esophageal dilatation
Band or port infections
Port disconnection
Port displacement
Biliopancreatic diversion:
Anastomotic leak with peritonitis
Protein-calorie malnutrition (15%)
Calcium, iron, folic acid, thiamine,
fat soluble vitamin (A,D,E,K)
deficiencies
Dehydration
Steatorrhea
Small bowel obstruction
– Internal hernia
– Adhesions
Obesity “treatment gap”
Pharmacotherapy
FDA approved medications
– Orlistat/Alli
– Phentermine
FDA reviewed medications
– Phentermine plus topiramate
– Bupropion plus naltrexone
– Lorcaserin
Non-FDA approved medications
– Exenatide
– Pramlintide
Future approaches
– Metreleptin plus pramlintide
– Ghrelin vaccine
2007 criteria for effectiveness of weight
loss medication
1 Mean efficacy criterion - The difference in mean weight loss
between the active-product and placebo-treated groups is at
least 5 percent and the difference is statistically significant.
OR
2 Categorical efficacy criterion - The proportion of subjects who
lose greater than or equal to 5 percent of baseline body weight in
the active-product group is at least 35 percent, is approximately
double the proportion in the placebo-treated group, and the
difference between groups is statistically significant.
Pharmacotherapy
FDA approved for:
– BMI of 27 to 29.9 kg/m2 with comorbidity
– All patients with BMI ≥30 kg/m2
FDA approved medications:
– Long-term use
Orlistat (Xenical, Alli)
Sibutramine (Meridia)
– Short-term use (12 weeks)
Phentermine
Diethylpropion
Benzphetamine
Phendimetrazine
Orlistat
Prevents Fat Digestion and Absorption by
Binding to Gastrointestinal Lipases
Intestinal Lumen
Orlistat
Mucosal Cell
TG
FA
MG
Bile Acids
TG=triglyceride; MG=monoglyceride; FA=fatty acid.
Micelle
Orlistat (Xenical, Alli)
FDA approved 1999
60-120 mg t.i.d. meals
Contraindications
– Cholestasis
– Malabsorption
Adverse effects
– Diarrhea
– Ft soluble vitamin loss
– AKI (oxalate stones)
– Liver injury?
Advise taking MVI before bedtime
Orlistat
688 patients
BMI 28-47 kg/m2 (36)
6.1%
Age 18-77 (45)
120 mg tid or placebo
↓Total cholesterol, LDL, glucose,
insulin
Adverse effects
– Gastrointestinal symptoms (3-5%)
Sjostrom. Lancet 1998;352:167.
10.2%
XENical in the Prevention of Diabetes in
Obese Subjects (XENDOS) Study
Torgerson. Diabetes Care 2004;27:155.
Phentermine
Amphetamine-related; Schedule IV
37.5 mg daily or divided b.i.d
FDA approved 1959 for short-term use (12 weeks)
Contraindicated
– Known vascular disease
– Hypertension
– Hypothyroidism
– Glaucoma
– MAO-I
Adverse effects
– Dry mouth
– Constipation
– Insomnia
– Nervousness, irritability
– Increased pulse
Amphetamine: mechanism of action
1.
↑ release of monoamines
(norepinephrine, 5-HT and dopamine)
from vesicular storage sites.
2.
Competes with monoamines for
reuptake via DAT, NET or SERT.
3.
Facilitates the release of cytoplasmic
presynaptic monoamines by inducing
“reverse” transporter exchange (e.g.
exchange of intracellular monoamines
for extracelluar amphetamine - a
symport mechanism).
4.
Weakly inhibits MAO, causing a rise in
presynaptic monoamine levels.
5.
Amphetamines may have some direct
receptor agonist actions (e.g. 5-HT) in
some areas of the CNS (Westfall,
2006).
Presynaptic nerve terminal
Phentermine
Age 35, mostly female
Phentermine 30 mg daily
Side effects included dry mouth, palpitations, sleep difficulties,
nervousness, depression, fatigue, and increased dreaming
Dropout rate approx 50% all groups
Weintraub. Arch Intern Med 1984;144:1143-1148.
Topiramate
2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulphamate
Intermediate during synthesis of analog of fructose-1,6-diphosphate to
inhibit fructose 1,6-bisphosphatase thereby inhibiting gluconeogenesis
Insulin secretagogue? Insulin sensitiser? Increase adiponectin? AMPK
activation?
Structural resemblence to sulfonamide moiety in acetazolamide prompted
evaluation of possible anticonvulsant effects
Potentiates GABA receptors; inhibits glutamate, sodium, and calcium
channels; inhibits carbonic anhydrase enzymes
Seizure disorders, migraine prophylaxis, neuropathic pain, essential tremor,
bipolar disorder, bulimia, PTSD, schizophrenia
Phentermine plus topiramate (Qnexa)
CONQUER: phentermine plus topiramate
Phase 3
Randomized
56 week
Age 18-70 (51)
70% female
N
– 994 placebo
– 498 low dose
– 995 high dose
BMI 27-45 kg/m2
(36.6)
100 kg
A1c= 5.9%
HTN 50%
IGT or DM2 70%
38% dropout
(greatest in placebo)
-1.6%
-9.6%
-12.4%
Gadde. Lancet 2011;377:1341-1352.
CONQUER: phentermine plus topiramate
Gadde. Lancet 2011;377:1341-1352.
CONQUER: phentermine plus topiramate
Gadde. Lancet 2011;377:1341-1352.
CONQUER: phentermine plus topiramate
Adverse effects (p<0.05)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Dry mouth (2 vs 21%)
Paresthesia (2 vs 21%)
Constipation (6 vs 17%)
Dysgeusia (1 vs 10%)
Insomnia (5 vs 10%)
Dizziness (3 vs 10%)
Nausea (4 vs 7%)
Blurred vision (4 vs 6%)
Anxiety (2 vs 4%)
Irritability (<1 vs 3%)
Disturbance in attention (<1 vs 4%)
Serum bicarbonate decreased 1
Nephrolithiasis (<1 vs 1%; 3 events)
Pulse increased 1.7
Gadde. Lancet 2011;377:1341-1352.
FDA advisory panel: July, 2010
Votes 10 to 6 against approval
– Psychiatric and cognitive issues
– Lack of long-term data to rule out
cardiovascular risks
– Potential for birth defects in women
34 women became pregnant, 13 gave birth, no
birth defects
FDA rejects petition November, 2010
Bupropion plus naltrexone (Contrave)
Bupropion blocks dopamine and norepinephrine
reuptake
– Stimulate POMC neurons
– FDA approved for depression and smoking cessation
Naltrexone blocks opioid receptors
– Block beta-endorphin-mediated inhibition of POMC neurons
– FDA approved for alcohol and opioid dependence
Modulate mesolibmic reward pathways?
Bupropion
Naltrexone
COR-I: bupropion plus naltrexone
Phase 3
Randomized, double
blind
56 week
34 sites
N= 1742
Age 18-65 (44)
85% female
BMI 27-45 kg/m2 (36)
Bupropion 180 mg BID
– Naltrexone 8 mg BID
– Naltrexone 16 mg BID
Greenway. Lancet 2010;376:595-605.
-1.8%
-6.7%
-8.1%
P<0.05
–
–
–
–
–
–
↓Trig
↑HDL
↓ LDL
↓ hsCRP
↓ Insulin
↓ Glucose
Wt loss 5% or more
COR-I: bupropion plus naltrexone
Adverse Effects
–
–
–
–
–
–
–
–
Nausea (5.3 vs 29.8)
Headache (9.3 vs 13.8)
Constipation (5.6 vs 15.7)
Dizziness (2.6 vs 9.4)
Vomiting (2.5 vs 9.8)
Dry mouth (1.9 vs 7.5)
Blood pressure: ↑1.5 mm Hg then ↓1 mm Hg
Pulse: ↑1.5-2.5 bpm
Dropout 50%
FDA advisory panel: Dec, 2010
Votes 13 to 7 in favor of approval
FDA rejects petition January, 2011
– Concern for long-term cardiovascular risks
Lorcaserin (Lorqess)
BLOOM: lorcaserin
N= 3182
98 centers
18-65 y/o (44)
BMI 27-45 kg/m2 (36)
83% female
HgbA1c 5.6%
Lorcaserin dose 10 mg BID
Modest ↓ systolic and
diastolic BP, pulse, LDL,
trig, fasting glucose, insulin,
A1c, and hsCRP
2.6%
5.8%
47.5%
20.3%
Smith. NEJM 2010;363:245-256.
BLOOM: lorcaserin
Headache
Nausea
Dizziness
45-55% dropout
Smith. NEJM 2010;363:245-256.
FDA advisory panel: Sept, 2010
Votes 9 to 5 against approval
– Valvular heart disease
– Neuro-psychiatric and cognitive-related
adverse events
– Preclinical tumor development (breast)
FDA rejects petition October, 2010
Glucagon-like peptide-1 (GLP-1)
Exenatide in obese non-diabetic patients
BMI >30 kg/m2 without DM2
N= 152
N= 38 with IGT or IFG
BMI= 39.6 kg/m2
10 µg BID
Structured diet and activity
IGT or IFG resolved 77% vs
56%
Nausea (No difference in wt
loss)
Dropout 33%
Δ3.3%
Rosenstock. Diabetes Care 2010;33:1173-1175.
Liraglutide in obese non-diabetic patients
Randomized
N= 70-80 per group
BMI 30-40 kg/m2 (34)
Mean wt 97 kg
~30% prediabetes
↓BP, ↓ prediabetes
(84-96%)
Nausea/vomiting
(liraglutide)
Diarrhea (orlistat)
Astrup. Lancet 2009;374:1606-1616.
kg
-2.8
-4.1
-4.8
-5.5
-6.3
-7.2
Amylin
37 amino acid peptide
Co-secreted with insulin
Discovered in 1987
Deficient DM1 and DM2
Suppresses postprandial glucagon
production
Slows gastric emptying
Centrally mediated induction of satiety
Reduction in postprandial glucose
levels
Pramlintide FDA approved for DM1 and
DM2
Pramlintide
Pramlintide in obese non-diabetic patients
Randomized
N= 349
BMI 30-50 kg/m2
(37)
Mean wt 105 kg
73% female
Nausea 2%
placebo; 9-29%
pramlintide
30-40% dropout
kg
0.8
8.0
Smith. Diabetes Care 2008;4(4):176.
Metreleptin plus pramlintide
12 US sites
BMI 27-35 (mean= 32)
177 enrolled
Subjects who lost 2-8% wt randomized (n=139)
Mean age 38-40 y/o
63% female
30-34% dropout
Ravussin. Obesity 2009;17:1736-1743.
Metreleptin plus pramlintide
Ravussin. Obesity 2009;17:1736-1743.
-8.2%
-8.4%
-12.7%
Metreleptin plus pramlintide
Metreleptin plus pramlintide
Press release, July 9, 2009
Phase 2, 28-week, randomized, double-blind,
placebo-controlled multi-center study
randomized study
608 patients with BMI of 27-45 kg/m2
Weight loss
– Placebo: 1.8%
– Pramlintide 360 mcg/metreleptin 5 mg BID: 11%
Metreleptin plus pramlintide
Press release, March 16, 2011
Amylin and Takeda Voluntarily Suspend Clinical Activities in Obesity Trial
“suspended clinical activities in an ongoing Phase 2 study examining the
safety and effectiveness of the investigational combination therapy
pramlintide/metreleptin for the treatment of obesity. The clinical study was
voluntarily halted to investigate a new antibody-related laboratory finding with
metreleptin treatment in two patients who participated in a previously
completed clinical study of obesity.”
"This decision was based on results….suggesting potential neutralizing
activity to metreleptin (and leptin) may have occurred. At this time, the
clinical significance of these laboratory findings is not well understood, and
we are working to investigate them further."
Summary of weight loss
(“placebo” subtracted)
Metformin
Orlistat
Phentermine
Phentermine plus topiramate
Bupropion plus naltrexone
Lorcaserin
Exenatide
Liraglutide
Pramlintide
Metreleptin plus pramlintide
1-2%
3-4%
5-6%
10-11%
5-6%
3-4%
3-4%
3-4%
5-7%
9-10%
Pre-Pro-Ghrelin
MPSPGTVCSLLLLGMLWLDLAMAGSSFLSPEHQRVQQRKESKKPPAKLQPRALAGWLRPEDGGQAEGAEDELEVRFNAPFDVGIKLSGVQYQQHSQALGKFLQDILWEEAKEAPADK
Prohormone Cleavage
Des-Acyl Ghrelin
GSSFLSPEHQRVQQRKESKKPPAKLQPR
Acylated on Serine 3
O=C-(CH
2)6-CH3
ı
Oı
GSSFLSPEHQRVQQRKESKKPPAKLQPR
Ghrelin
X/A (ghrelin cells)
Mouse stomach 20x
Ghrelin and Appetite
Active Plasma Ghrelin
7M+5F Fed
7M+5F Fasted
Average of 12 Subjects
Night
50
Lunch
Dinner
Bkfast
40
30
20
10
am
10
am
8
am
6
am
4
am
2
m
id
12
pm
10
pm
8
pm
6
pm
4
pm
2
am
no
on
12
10
am
0
8
Ghrelin (pg/ml)
Bkfast
Gaylinn et al. Unpublished.
Vaccination against weight gain
Zorrilla. PNAS, 2006.
Ghrelin vaccine
Zorrilla. PNAS, 2006.
Clinical case
HPI: 39 y/o female with obesity and metabolic syndrome
– “Always heavy”
– Family overweight or obese
– Slow progressive weight gain, worse after high school and pregnancies x3
– Tried many diets, exercise trainer
PMH: Migraine headaches, metabolic syndrome, knee OA, tubal ligation
SH: no tobacco; 1 EtOH/week; works desk job
FH: CAD (MI in father 52 y/o), DM2
Medications: HCTZ, fish oil, sumatriptan prn, ibuprofen prn
PE: BP 135/85, P 81, BMI 39; Euthyroid, no features of Cushings
syndrome or acromegaly, no edema
Labs: TSH 3.2, Hgb A1c 6.0%, Trig 189, HDL 38, LDL 110, LFTs wnl
Clinical case
If lifestyle changes (diet, exercise, behavioral
modification) are unsuccessful, what would
you offer this patient?
A.
B.
C.
D.
E.
F.
G.
Nothing, she is weak willed and lazy.
Straight to bariatric surgery.
Metformin.
Orlistat.
Phentermine.
Exenatide or liraglutide.
Phentermine plus topiramate.