Pharmacotherapy of Obesity: Practical Application for ... · Pharmacotherapy of Obesity: Practical...
Transcript of Pharmacotherapy of Obesity: Practical Application for ... · Pharmacotherapy of Obesity: Practical...
Pharmacotherapy of Obesity: Practical Application for Clinical Care
Caroline M. Apovian, MD, FACN, FACP, DABOMProfessor of Medicine and PediatricsBoston University School of MedicineDirector, Nutrition & Weight Management CenterSection of Endocrinology, Diabetes, and NutritionBoston Medical CenterBoston, Massachusetts
Scott Kahan, MD, MPH, FTOS, DABOMMedical Director, Strategies to Overcome and Prevent (STOP) Obesity AllianceGeorge Washington UniversityWashington, DC
Kimberly A. Gudzune, MD, MPHAssistant ProfessorJohns Hopkins University School of MedicineBaltimore, Maryland
2
Dr Apovian:
• Consultant: Merck; Nutrisystem; Zafgen; sanofi-aventis; Orexigen; EnteroMedics; Scientific Intake; Gelesis; Ferring; Takeda; Novo Nordisk
• Research funding: Aspire Bariatrics; GI Dynamics; Pfizer; Gelesis; Orexigen; MetaProteomics; Takeda; MYOS Corporation; The Dr. Robert C. and Veronica Atkins Foundation
• Stockholder: Science Smart, LLC
Dr Kahan:
• Consultant: Novo Nordisk; Takeda; Orexigen; Eisai
Dr Gudzune:
• Has no relevant financial relationships to disclose
Disclosures
3
Identify obesity as a disease, not a behavioral problem, and consider the implications of that paradigm shift on attitudes toward treating the condition
Identify indications that lifestyle interventions have not been sufficient to result in weight loss
Describe the pharmacology of, and indications for, the use of the currently available medications for chronic weight management
Describe ongoing management of people using anti-obesity medications, including means to gauge both therapeutic efficacy or the need to consider bariatric surgery
Learning Objectives
4
Case Study Introduction
The Disease of Obesity
Obesity Etiology
Caroline M. Apovian, MD, FACN, FACP, DABOM
Clinical Overview of Anti-Obesity Medications for Weight Management
Scott Kahan, MD, MPH, FTOS, DABOM
Barriers to the use of Pharmacotherapy
When to Consider Bariatric Surgery
Kimberly Gudzune, MD, MPH
Program
5
Public Health Crisis:69% of American Adults are Overweight or Obese
5
“The average American is now 23 pounds overweight.”~ Dr. Thomas R. Frieden, director of the U.S. Centers for Disease Control and Prevention
Ogden CL, et al. JAMA. 2014;312(2):189-190.
6
U.S. Adult Overweight/Obesity by BMI
BMI: <18.5 18.5-24.9 25.0-29.9 30.0-34.9 >35 >40
Underweight Normal Overweight Obesity I Obesity II Obesity III
6
U.S. Adult Population 31% 34% 20.6%
69% Overweight and ObeseMore than two-thirds
8.1% 6.4%
Ogden CL, et al. JAMA. 2014;312(2):189-190.
35.1% Obese
7
Extreme or Massive Obesity is Rapidly Expanding as a Subgroup BMI Increase by Category, 2001 to 2010
>10-fold increase
Sturn R, et al. Int J Obes (Lond). 2013;37(6):889-891.
Category BMI kg/m2
Underweight < 18.5
Normal weight 18.5–24.9
Overweight 25–29.9
Obese ≥ 30
Grade 1 30–34.9
Grade 2 35.0–39.9
Grade 3≥ 40 (severe, extreme,
or morbid obesity)
Grade 4 ≥ 50
Grade 5 ≥ 60
Poirier P, et al. Circulation 2009;120:86-95.
8
Case: 52-year-old female
• CC: “I can’t lose weight.”
• Family history: type 2 diabetes and CAD
• Tried multiple diets; lifestyle interventions are not
currently achieving weight loss goals.
Current medications
• Multivitamin, calcium, vitamin B12, vitamin D
Vital statistics and laboratory results for this visit
• Height: 5’7”
• Weight: 190 lb
• BMI: 29 kg/m2 (overweight)
• Blood pressure: 145/95 mm Hg
• Fasting blood glucose: 97 mg/dl
• HbA1C: 5.9
• Vitals and labs: patient is hypertensive and
dyslipidemic, but no dysglycemia
9
Q: What would you recommend for this patient?
A. Dietary and exercise lifestyle recommendations
B. Medication including off-label use of metformin
C.On-label use of Belviq (lorcaserin), Contrave (Bupropion/naltrexone), Qsymia (phentermine/topiramate), or Saxenda (liraglutide)
D. Off-label use of GLP-1 or SGLT-2 inhibitor
• BMI 29 with prediabetes and probably HTN • Family history positive for CAD and DM
10
Designation of Obesity as a Disease
1. ASMBS, TOS, ASBP, AACE Joint Statement. Obesity is a disease: leading obesity groups agree. June 19, 2013.
http://asmbs.org/2013/06/obesity-is-a-disease-leading-obesity-groups-agree/. Accessed September 11, 2013.
2. American Medical Association. AMA Resolution No. 420 (A-13). June 19, 2013.
www.ama-assn.org/assets/meeting/2013a/a13-addendum-refcomm-d.pdf.
Medical Associations and Societies1
World / National Health Organizations1,2
• American Association of Clinical Endocrinologists
• American Academy of Family Physicians
• American College of Cardiology
• American College of Surgeons
• American Medical Association
• American Society for Reproductive Medicine
• American Urological Association
• The Endocrine Society
• The Obesity Society
• The Society for Cardiovascular Angiography and Interventions
• World Health Organization
• Food and Drug Administration
• National Institutes of Health
Obesity is a disease: leading obesity groups agree
June 19
2013
11
Obesity: A Major Contributor to Disease
CHF=congestive heart failure; GERD=gastroesophageal reflux disease; PCOS=polycystic ovarian syndrome.
1. Catenacci VA, et al. Clin Chest Med. 2009;30(3):415-444. 2. Wang C, et al. Diabetes Care. 2011;34(7):1669-1675.
3. Lauby-Secretan B, et al. N Engl J Med. 2016;375(8):794-798.
Neurologic1
Stroke
Intracranial hypertension
Dementia
Gastrointestinal1
Nonalcoholic fatty liver disease
Gall bladder disease
GERD
Hernia
Cardiovascular1
Atherosclerosis
Hypertension
Dyslipidemia
CHF
Genitourinary1,2
PCOS
Abnormal menses
Infertility
Urinary incontinence
Low testosterone
Psychological1
Depression
Poor self-image
Poor quality of life
Eating disorder
Pulmonary1
Obstructive sleep apnea
Hypoventilation syndrome
Asthma
Pulmonary hypertension
Dyspnea
Cancer3
Esophagus
Stomach
Colorectal
Liver
Gallbladder
Pancreas
Breast
Musculoskeletal1
Low back pain
Osteoarthritis
Restrictive mobility
Metabolic1
Type 2 diabetes
Gout
Insulin resistance
Metabolic syndromeDermatologic1
Venous stasis
Cellulitis
Corpus uteri
Ovary
Kidney
Meningioma
Thyroid
Multiple myeloma
12
How Obesity Causes Disease
13
Ectopic Fat Deposits Associated with Metabolic Disorders
FFA = free fatty acid; IL = interleukin; MCP-1 = monocyte chemoattractant protein 1; RAS = renin angiotensin
system; TG = triglyceride; TNF- = tumor necrosis factor ; VLDL = very low density lipoprotein;
Gustafson B, et al. Atherosclerosis. 2015;241(1):27-35.
Systemic
effects
Increased
metabolic
risk factors
Local
effects
Increased
risk for
vascular
diseases
Pancreatic fat
Intramuscular fat
Fatty liver
Visceral fat
Perivascular fatEpi/pericardial
fatMyocardial steatosis
Renal sinus fat
-cell dysfunction, insulin resistance, impaired
glucose metabolism, inflammation, lipotoxicity
Hepatic insulin resistance, oxidative stress,
inflammation, lipogenic transcription factors,
VLDL-TG
Inflammation, macrophage infiltration, insulin
resistance, altered release of adipokines, altered
FFA metabolites, RAS activation, oxidative stress
Inflammation, TNF-, IL-6, leptin, MCP-1,
cell adhesion molecules, calcification,
decreased diastolic function, coagulation
defectsHypertension, vascular resistance,
glumerosclerosis, proteinuria, intra-renal
pressure
Systemic and intramuscular insulin resistance,
mitochondrial dysfunction, impaired lipid and
glucose metabolism
Meta
bo
lic
syn
dro
me
Ca
rdio
vas
cu
lar d
ise
as
e, ty
pe 2
dia
bete
s
14
Pathogenesis of the Metabolic Syndrome Trait Complex
Central Adiposity
Dyslipidemia• Increased large VLDL• Increased small LDL• Decreased large HDL
Endothelial Dysfunction• Vascular reactivity• Dysfibrinolysis• Inflammation• Foam cell proliferation
Insulin Resistance• Glucose intolerance
Metabolic Consequences
• Adiponectin
• Leptin
• Resistin
• Free fatty acids
• PAI-1
• IL-6
• TNFα
• Angiotensinogen
• CETP
Secreted Adipocyte Factors:
CETP = cholesteryl ester transfer protein; HDL = high-density lipoprotein; IL-6 = interleukin 6; LDL = low-
density lipoprotein; PAI-1 = plasminogen activator inhibitor 1; TNF- = tumor necrosis factor ; VLDL = very-
low-density lipoprotein.
WT Garvey, 2013.
15
Association Between Visceral Fat and Insulin Resistance
CT scans courtesy of Wilfred Y. Fujimoto, MD.
Carey DG, et al. Diabetes.1996;45(5):633-638.
Ins
uli
n S
en
sit
ivit
y(
mo
l/m
in p
er
kg
le
an
ma
ss
)
% Visceral Abdominal Fat
20
110
25 30 35 40 45 50
100
90
80
70
60
50
40
30
20
BMI <25 kg/m2
BMI 25 kg/m2
16
Annual Prevalence of Obesity-Related Comorbidities, 2004-2013
Li Q, et al. J Med Econ. 2015 Sep 4:1-9. Li Q, et al. J Med Econ. 2015;4:1-9.
Three most prevalent
and expensive annually
17
Possible Causes of Poor Weight Loss Maintenance
Ebbling CB, et al. JAMA. 2012;307(24):2627-2634.
One explanation for the poor long-term outcome of weight-loss diets relates to behavior:
Motivation to adhere to restrictive regimens typically diminishes with time
Adherence
Weight loss elicits biological adaptations that promote weight regain:
Specifically, a decline in energy expenditure (adaptive thermogenesis)
and an increase in hunger
Hypothalamic Injury
18
Biological AdaptationHow long do these biological adaptations persist w/ calorie restriction?
Evidence suggests often indefinitely1
Biological pressure to restore bodyweight to the highest-sustained lifetime level gets stronger as weight loss increases.2
Then is a patient ever truly “recovered” from obesity?
Few individuals ever fully recover from obesity1,2
Individuals with obesity who lose weight are essentially in “remission” and biologically very different than their counterparts1,2,3
1. Ochner CN., et al. Physiol Behav 2013;120:106-113.
2. Rosenbaum M, et al. Int J Obes (London). 2010;34 (suppl 1) S47–S55.
3. Ochner CN, et al. Lancet. 2015;3(4):232-234.
19
Obesity Associated with Hypothalamic Injury in Rodents and Humans
• Rodent models of obesity, induced by consuming high-fat diet (HFD), are characterized by inflammation both in peripheral tissues and hypothalamic areas critical for energy homeostasis
• Unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain
• Both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding
• Evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI
Thaler JP, et al. J Clin Invest. 2012;122(1):153-162.
Findings suggest obesity is associated with neuronal injury
in a brain area crucial for body weight control
in both humans and rodent models
20
Hypothalamus is a Regulation Center of Appetite and Energy Expenditure
• Integrates peripheral and CNS signals that collectively modulate feeding behavior and energy balance1-3
• A primary regulation center is the arcuate nucleus (ARC)1
ARC of the
Hypothalamus
1. Yu JH et al. Diabetes Metab J. 2012;36:391-398.
2. Morton GJ et al. Nature. 2006; 443:289-295.
3. Cone RD. Nat Neurosci. 2005; 8:571-578.
4. NetterImages. http://www.netterimages.com/image/4742.htm. Accessed October 2, 2013.
CNS, central nervous system
ARC, arcuate nucleus
Primarily based on data from animal studies.
21
Hypothalamic Injury Diminishes Signaling to Cortex and NTS*, Leading to Greater Weight Gain
AGRP: agouti-related peptide; α-MSH: α-melanocyte-stimulating hormone; GHSR: growth hormone secretagogue receptor; INSR: insulin receptor;
LepR: leptin receptor; MC4R: melanocortin-4 receptor; NPY: neuropeptide Y; POMC: proopiomelanocortin; PYY: peptide YY; Y1R; neuropeptide Y1 receptor;
Y2R: neuropeptide Y2 receptor.
Apovian CM, et al. J Clin Endocrinol Metab. 2015;100(2):342-362. *NTS: nucleus tractus solitarius
22
The Fat Trap
22Sumithran P, et al. N Engl J Med. 2011;365(17):1597-1604.
Body continues to fight against weight loss long after dieting has stopped
• 2009, 50 obese men and women
• Men 233 lbs/average; women 200 lbs/average
• Extreme low-calorie diet
• Optifast shakes + 2 cups of low-starch vegetables
• Total 500-550 kcal/d for eight weeks
• Reported feeling more hungry and preoccupied with food than before the weight loss
30-lb LOSS
11-lb GAIN
10 week weight-loss program
23
14% Weight Loss Produced Changes in 8 Hormones That Encourage Weight Regain
15% Weight Loss
Reduced: Increased:
Leptin - 65%
Peptide YY
Cholecystokinin
Insulin
Amylin
Ghrelin
Pancreatic polypeptide
Gastric inhibitory polypeptide
Measures of appetite
10-week, lifestyle-based weight loss intervention in healthy overweight and obese adults (n=34) led to sustained elevations in appetite stimulating hormone(s) and decreases in appetite suppressing hormones
Mean fasting and postprandial levels of some peripheral signals at baseline and 62 weeks
NET RESULT OF THESE HORMONAL CHANGES is WEIGHT GAIN!
Sumithran P, et al. N Engl J Med. 2011;365(17):1597-1604.
24
Sustained Changes in Peripheral Signals for Up to One Year Following Weight LossMean fasting and postprandial levels of some peripheral signals at baseline and 62 weeks
10-week, lifestyle-based weight loss intervention in healthy overweight and obese adults (n=34) led to sustained elevations in appetite stimulating hormone(s) and decreases in appetite suppressing hormones
Appetite Stimulating
Hormone was Higher
Appetite Suppressing Hormone was Lower
Appetite Suppressing Hormone was Lower
Gh
relin
, p
g/m
L
0 180 24030 60 120
200
100
0
Postprandial Time, min Pep
tid
e Y
Y, p
g/m
L
0 180 24030 60 120
60
20
0
Postprandial Time, min
CC
K,
fmo
l/m
L
Postprandial Time, min
Week 62
BaselineWeek 62
Baseline
0 180 24030 60 120
4
2
0
1
3
Week 62
Baseline
Am
yli
n,
pg
/mL
Postprandial Time, min
0 180 24030 60 120
200
100
0Week 62
Baseline
Appetite Suppressing Hormone was Lower
(chole
cysto
kin
in)
Sumithran P, et al. N Engl J Med. 2011;365(17):1597-1604.
25
Sustained Changes in Peripheral Signals for Up to One Year Following Weight Loss
Mean fasting and postprandial ratings of hunger and desire to eat at baseline and weeks 10 and 62
Changes were accompanied by significant increases in appetite
based on self-reported ratings (P<0.001)
Hunger Desire to Eat
Sumithran P, et al. N Engl J Med. 2011;365(17):1597-1604.
26
Obesity is an epidemic with massive obesity being the fastest growing subgroup
Obesity was designated a disease by multiple medical organizations in 2013
– Increased expression of some hormones, suppression of others, leads to inflammation and disease
Neurological injury in the brain and hormonal changes account for weight regain, not lack of willpower
Summary
27
Case Study Introduction
The Disease of Obesity
Obesity Etiology
Caroline M Apovian, MD, FACN, FACP, DABOM
Clinical Overview of Anti-Obesity Medications for Weight Management
Scott Kahan, MD, MPH, FTOS, DABOM
Barriers to the use of Pharmacotherapy
When to Consider Bariatric Surgery
Kimberly Gudzune, MD, MPH
Program
28
Q: When do you prescribe obesity pharmacotherapy in your practice?
A. I prescribe obesity medications in all my patients
B. I do not prescribe obesity medications in my practice
C. I prescribe only in patients who have severe obesity
D. I prescribe only in patients who have obesity comorbidities
E. I am not sure what are appropriate guidelines for prescribing
29
Intensive Behavioral Therapy for Obesity
Look AHEAD Research Group. Obesity. 2014;22(1):5-13.
92.8
68.0
37.7
15.6
73.6
50.3
26.9
11.0
0
20
40
60
80
100
% o
f Pa
rtic
ipan
ts
YEAR 1 YEAR 8
>0% ≥5% ≥10% ≥15% >0% ≥5% ≥10% ≥15%
30
Pharmacotherapy Increases Magnitude and Likelihood of Weight Loss
Wadden TA, et al. Obesity. 2011;19(1):110-120.
31
Pharmacotherapy Increases Magnitude and Likelihood of Weight Loss
Pucci A, et al. Can J Cardiol. 2015;31(2):142-152.
Astrup A, et al. Int J Obes (Lond). 2012;36(6):843-854.
PBO ORL LOR PHEN/TPM ER BN LIRA
45
2025
16 1721
30
16 17
41
1922
27 28
72
45 47 45
6770
75
48
67
54
44
50
64
73
0
20
40
60
80
XEN
DO
S
BLO
OM
BLO
SSO
M
BLO
OM
-DM
EQU
IP
CO
NQ
UER
SEQ
UEL
*
CO
R I
CO
R-I
I
CO
R-B
MO
D
CO
R-D
SCA
LE M
ain
tain
SCA
LE O
bes
ity
Ast
rup
et
al (
20
12
)
Pati
ents
wit
h ≥
5%
WL
32
Pharmacotherapy Increases Magnitude and Likelihood of Weight Loss
le Roux C, et al. Poster presented at: TOS 2015; November 2-7, 2015; Los Angeles, CA. Poster T-P-LB-3843.
33
Pharmacotherapy Improves Weight Maintenance
Wadden TA, et al. Intl J Obes (London). 2013;37(11):1443-1451.
34
Key Obesity Pharmacotherapy Guidelines
Use pharmacotherapy as adjunct to diet, exercise, and behavioral counseling for individuals…• with BMI 30+; or 27+ with comorbidity• who are unable to lose and successfully maintain weight• who meet label indications
Use medications to promote long-term weight loss maintenance
Assess efficacy and safety monthly for the first 3 months, then every 3 months thereafter
At 3 months, if loss is 5% or more, continue; if not, discontinue and seek alternative approaches
Pharmacological Management of Obesity: An Endocrine Society
Clinical Practice Guideline. J Clin Endocrinol Metab, 2015.
35
Outcomes by Responder Status
Smith SR, et al. Obesity (Silver Spring). 2014;22(10):2137-2146.
36
• 5 FDA-approved medications for long-term use
• Orlistat (Xenical/Alli)
• Phentermine/topiramate ER (Qsymia)
• Lorcaserin (Belviq)
• Naltrexone/Bupropion SR (Contrave)
• Liraglutide 3.0 mg (Saxenda)
• Phentermine (Lomaira/Adipex) approved for short-term use
Obesity Pharmacotherapy
37
Mechanism of action (MOA): Sympathomimetic amine, norepinephrine (NE) release
Blunts appetite
Approved in 1959 for short-term use, schedule IV
Dosing: 8 mg to 37.5 mg qAM; use lowest effective dose
Contraindications: pregnancy, nursing, MAOIs, glaucoma, drug abuse history, hyperthyroidism
Relative contraindications: uncontrolled hypertension, tachycardia, CAD, CHF, stroke, arrhythmia
Warnings: primary pulmonary hypertension, valvular heart disease, tolerance, risk of abuse, alcohol use
Phentermine
Phentermine [package insert]. Sellersville, PA: Teva Pharmaceuticals USA; 2009
38
MOA: Lipase inhibitor, decreases fat absorption
Approved 1999; long-term use
Not scheduled
Dosing: 120 mg TID with meals (Rx) or 60 mg TID (OTC)
Use multivitamin supplement (MVI) with fat-soluble vitamins at bedtime
Contraindications: pregnancy, chronic malabsorption syndrome, cholestasis
Possible gastrointestinal adverse events
Orlistat
Xenical [package insert]. Nutley, NJ: Roche Laboratories, Inc.; 2009.
39
MOA: Selective 5-HT2C receptor agonist; increases satiety
Approved in 2012 for long-term use; schedule IV
Single dose: 10 mg BID
Discontinue if less than 5% weight loss after 12 weeks of use
Contraindications: pregnancy
Warnings: co-administration with serotonergic agents, valvular heart disease, psychiatric disorders (euphoria, suicidal thoughts, depression), priapism
Lorcaserin
Belviq [package insert]. Woodcliff Lake, NJ: Eisai, Inc.; 2012.
40
Phentermine MOA: sympathomimetic amine; blunts appetite
Topiramate MOA: increases GABA activity, carbonic anhydrase inhibitor, and other actions; prolongs satiety
Approved in 2012 for long-term use; schedule IV
“Recommended” dose: 7.5/46 mg; max: 15/92 mg
Discontinue if less than 3% weight loss after 12 weeks
Contraindications: pregnancy, glaucoma, MAOIs, hyperthyroidism
Phentermine/ Topiramate Extended Release
Qysmia. [package insert]. Mountain View, CA: Vivus; 2012.
41
Bupropion MOA: dopamine/noradrenaline reuptake inhibitor
Naltrexone MOA: opioid receptor antagonist
Not a controlled substance
Standard dose: 32/360 mg (2 tablets BID)
Consider discontinuation if <5% weight loss after 16 weeks
Black box warning for suicidal thoughts in adolescents
Contraindications: pregnancy, uncontrolled hypertension, seizure disorders, chronic opioid use, MAOIs
Naltrexone/Bupropion Extended Release
Contrave [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2014.
42
MOA: Glucagon-like peptide 1 (GLP-1) receptor agonist
Multiple actions; effect on weight is primarily via hypothalamus neurons
Liraglutide 1.8 mg approved for T2DM in 2010
Liraglutide 3.0 mg approved for obesity in 2014
Not a controlled substance
Dosing: weekly escalation by 0.6 mg SC
Discontinue if <4% weight loss at 16 weeks
REMs: medullary thyroid carcinoma, acute pancreatitis
Liraglutide 3.0 mg
Saxenda [package insert]. Plainsboro, NJ: Novo Nordisk, Inc.; 2016.
43
Improvements in Risk Factors and Comorbidities
Orlistat Lorcaserin Phentermine/topiramate ER
Naltrexone/bupropion SR
Liraglutide3.0 mg
WC
BP
LDL
HDL
TG
A1C
HR 0
Diabetes
44
Case Study Introduction
The Disease of Obesity
Obesity Etiology
Caroline M Apovian, MD, FACN, FACP, DABOM
Clinical Overview of Anti-Obesity Medications for Weight Management
Scott Kahan, MD, MPH, FTOS, DABOM
Barriers to the use of Pharmacotherapy
When to Consider Bariatric Surgery
Kimberly Gudzune, MD, MPH
Program
45
Weight-Favorable Medications for Management of Other Conditions (1)
ConditionPromoteWeight Gain
Weight-NeutralPromote Weight Loss
Diabetes mellitus Insulin*SulfonylureasTZDsMetiglinides
DPP-4 Inhibitors MetforminPramlintideGLP-1 AgonistsSGLT2 InhibitorsAcarboseMiglitol
Cardiovascular disease β Blockers**α Blockers
ACE InhibitorsARBsCCBs
--
*Weight gain differs by type of insulin regimen used. Basal insulin only typically has less weight gain than premixed or combination therapy. **If needed, certain agents may have less weight gain effects including carvedilol, nebivolol, and bisoprolol.
Apovian C, et al. J Clin Endocrinol Metab. 2015;100(2):342-362.
46
Weight-Favorable Medications for Management of Other Conditions (2)
ConditionPromoteWeight Gain
Weight-NeutralPromote Weight Loss
Contraception Medroxyprogesteroneinjection
Combination OCPsBarrier methods IUDs
--
Allergies Antihistamines* Decongestants Steroid inhalers
--
Chronic inflammatorydisease (e.g., RA)
Corticosteroids NSAIDs --
*Most common with sedating anti-histamines.
Apovian C, et al. J Clin Endocrinol Metab. 2015;100(2):342-362.
47
Weight-Favorable Medications for Management of Other Conditions (3)
ConditionPromoteWeight Gain
Weight-NeutralPromote Weight Loss
Depression ParoxetineFluvoxamineAmytriptylineDoxepinImipramineNortriptylineTrimipramineMirtazapineLithium
Fluoxetine*Sertraline*
Bupropion
*Weight loss may occur with short-term use.
Apovian C, et al. J Clin Endocrinol Metab. 2015;100(2):342-362.
48
Weight-Favorable Medications for Management of Other Conditions (4)
ConditionPromoteWeight Gain
Weight-NeutralPromote Weight Loss
Serious mental illness ClozapineRisperidoneOlanzapineQuetiapineHaloperidol PerphenazineQuetiapine
ZiprasidoneAripiprazole
--
Epilepsy CarbamazepineGabapentinValproate
Lamotrigine TopiramateZonisamide
Apovian C, et al. J Clin Endocrinol Metab. 2015;100(2):342-362.
49
Q: What has prevented you from prescribing weight loss medications?
A.I have concerns about the long-term safety of these medications
B. The side effects and risks of these medications are too great
C.Patients have been dissatisfied with the weight loss results with these medications
D.Patients should have the will power to lose weight without medications
E.Patients don’t stick with taking the medications and just regain weight
50
Few patients with obesity prescribed a weight loss medication• Range 1-2% in large cohorts of insured patients
More likely to pursue nonprescription options• 4-18% report using herbs, supplements or OTC
meds
• OTC products have no association with clinically significant weight loss
• Safety data often unknown and reports of previous serious adverse effects
Prescribing Habits for Weight-Loss Medications
Bolen SD, et al., Obesity 2010; 18:206-9. Samaranayake NR et al., Ann Epidemiol. 2012;22:349-53. Xia Y, et al. Obesity.
2015;23:1721-1728. Nicklas JM, et al. Am J Prev Med. 2012;42:481-485. Bertisch SM, et al. Obesity (Silver Spring).
2008;16(7):1610-1615. Bray GA. Obesity (Silver Spring). 2008;16(3):509-514.
51
80% of providers in a 2016 NEJM poll voted against prescribing an FDA-approved medication • Preferred maximizing lifestyle modification first
• “Short-sighted to simply treat obesity with a prescription medication”
Past history may be influencing current perceptions• Amphetamine “diet pills,” fenfluramine, sibutramine
• Prompt us to look carefully at the safety profile of anti-obesity drugs
– Inappropriate to generalize and think that any potential anti-obesity drug is unacceptably harmful
Prescriber Perceptions of Pharmacotherapy
Yeh JS, et al. N Engl J Med. 2016;375(12):1187-1189.
Halpern B, Halpern A. Expert Opin Drug Saf. 2015;14(2):185-189.
52
Weight bias and stigma may also play a role
• Majority of physicians report limited efficacy in weight management
• Many feel unprepared with respect to training, in addition to limited time and reimbursement for services
• Weight management considered unrewarding or futile
• Avoid discussing weight and weight loss entirely when trying to balance multiple priorities during the visit
Prescriber Perceptions of Pharmacotherapy
Kristeller JL, et al. Prev Med.1997;26(4):542-549; Foster GD, et al. Obes Res. 2003;11(10):1168-1177;
Fogelman Y, et al. Int J Obes Relat Metab Disord. 2002;26(10):1393-1397; Kushner RF, et al. Prev Med.
1995;23:546-552; Gudzune KA, et al. Patient Educ Couns. 2012;89(1):152-157.
53
Barriers to Pharmacotherapy
Yeh JS, et al. N Engl J Med. 2016;375(12):1187-1189.
Halpern B, Halpern A. Expert Opin Drug Saf. 2015;14(2):185-189.
Fujioka K. Obesity (Silver Spring). 2015;23(Suppl 1):S7-S11.
Lack of long-term data efficacy and safety data• Clinicians want to wait for
definitive long-term data for weight-loss pharmacotherapy – Not economically feasible for
manufacturers– Delays potentially useful options
for decades
• Other chronic diseases the long-term use of medications is well accepted – why is obesity different?– Long-term surveillance necessary
with any chronic medication– Apply stopping rules if no benefit
at ~12 weeks
Concern about adverse effects
• Benefits do not outweigh the possible side effects– Weight loss achieved highly
variable between individuals• Some may have substantial
benefit
• Side effects an issue for any medication– Counseling about side effects
and risks important component of medication discussion to guide selection
• Shared decision-making process with patient
54
Barriers to Pharmacotherapy
Nicklas JM, et al. Am J Prev Med. 2012;42(5):481-485.; Risser JA, et al. Obes Res. 2005;13(1):86-92.; Wee
CC, et al. J Gen Intern Med. 2004;19(12):1206-1211.; Bray GA. Obesity (Silver Spring). 2008;16(3):509-514.
Patient Non-adherence
• Patients are more likely to achieve clinically significant weight loss if they use prescription meds– Medication persistence tends
to be low
• Medications can be costly & few have insurance coverage– Costs drives non-adherence for
many patients
– Insurance coverage improves adherence and weight loss
Patient Dissatisfaction with Results
• Most patients do not value modest weight loss– Many misperceive the
amount of weight loss that they are likely to achieve with medications
– Counseling on weight loss that may be achieved along with other health benefits may help manage expectations
55
When to Consider Bariatric Surgery
Approved for use in patients with:
• BMI ≥40 kg/m2
• BMI ≥35 kg/m2 + obesity-related condition such as CVD, OSA, uncontrolled T2DM or severe OA
Surgery Mechanism Mean Weight Loss - 1 Year Mean Weight Loss - 3 Years
Adjustable Gastric Banding
Restriction 30.2 kg 34.8 kg
Sleeve Gastrectomy Restriction 40.4 kg 37.2 kg
Roux-en-Y GastricBypass
Restriction + Malabsorption
43.5 kg 41.5 kg
BiliopancreaticDiversion
Malabsorption 51.9 kg 53.1 kg
Mechanick JI, et al. Obesity (Silver Spring). 2009;17 Suppl 1:S1-S70.; Maggard MA, et al. Ann Intern Med.
2005;142(7):547-559.; Carlin AM, et al. Ann Surg. 2013;257(5):791-797.
56
Bariatric Surgery Pros & Cons
Benefits
• Improved obesity-related comorbidities– T2DM – up to 77% resolve
– HTN – up to 62% resolve
– OSA – up to 84% resolve
• Improved quality of life
• Reduce mortality– 40% in overall mortality
– 50% in CVD deaths
Complications
• Risk of death from procedures low– <5%
• Variable by procedure type– GI symptoms 7-38%
– Nutrition/electrolyte imbalances 3-17%
– Reoperation 2-12%
– Weight regain 9-25%
Buchwald H, et al. JAMA. 2004;292(14):1724-1737.; Levy P, et al. Obes Surg. 2007;17(9):1248-1256.;
Sjostrom L, et al. N Engl J Med. 2004;351(26):2683-2693.; Sjostrom L, et al. JAMA. 2012;307(1):56-
65.; Chang SH, et al. JAMA Surg. 2014;149(3):275-287.
57
Summary
Obesity was designated a disease by multiple medical organizations in 2013
Causes of poor long-term weight loss include both behavioral and physiologic factors
Several obesity pharmacotherapy options are approved for use, including long-term use, and have strong data on efficacy and safety
Examining patients’ current medication lists is critical to identify weight-gain promoting medications and discuss weight-favorable alternatives
For patients who fail lifestyle modifications +/- weight loss medications, bariatric surgery should be considered
Q&A
Thank You
BACKUP SLIDES
61
Effects of Phentermine Plus Topiramate on Bodyweight
Gadde KM et al. Lancet. 2011;377:1341-52.
62
Effects of Sustained-Release Naltrexone/Bupropion on Bodyweight
Greenway FL et al. Lancet. 2010; 376:595-605.
63
Weight Loss Observed with Liraglutide
Pi-Sunyer X et al., N Engl J Med. 2015; 373:11-22.
64
Impact of Liraglutide on Plasma Glucose, and Prevalence of Prediabetes
Pi-Sunyer X et al., N Engl J Med. 2015; 373:11-22.
65
Rate of T2DM Development
Pi-Sunyer X et al., N Engl J Med. 2015; 373:11-22.
66
Drug Common AE Contraindication Safety Consideration Tolerability
Phentermine InsomniaDry mouthAgitationConstipation
CVD, CHF, arrhythmiasUncontrolled hypertensionMAOI useHyperthyroidismGlaucomaPregnancy
Primary pulmonary hypertension Discontinuation (CNS):Phentermine – 17%Placebo – 3%
Orlistat GI complaints Chronic malabsorptionGallbladder disease
May increase cyclosporine exposure; Liver failureMultivitamin administration
Discontinuation:Orlistat – 8.8%Placebo – 5%
Phentermine/topiramate ER
Dry mouthParesthesiasHeadacheInsomnia
GlaucomaHyperthyroidismMAOI usePregnancy
TeratogenicityMetabolic acidosisGlaucoma
Discontinuation:Top dose – 17% Low doses – 12%Placebo – 8%
Lorcaserin HeadacheDizzinessFatigueDry mouth
MAOI useUse with caution with serotonergic drugsPregnancy
Serotonin syndromeValvular heart diseaseDepressionPriapism
Discontinuation:Lorcaserin – 8.6%Placebo – 6.7%
Naltrexone/bupropion SR
NauseaGI complaintsHeadacheInsomnia
Seizure disorderUncontrolled hypertensionChronic opioid useMAOI usePregnancy
Suicidality in adolescentsElevated blood pressure, pulseGlaucomaHepatotoxicity
Discontinuation: Naltrexone/bupropion –24% Placebo – 12%
Liraglutide 3.0 NauseaGI complaints
Personal/family history of medullary thyroid carcinoma or MEN2History of pancreatitisPregnancy
Thyroid c-cell tumors (rodents)Acute pancreatitisGallbladder diseaseHypoglycemiaTachycardiaRenal impairmentSuicidal behavior
Discontinuation: Liraglutide – 9.8%Placebo – 4.3%