Download Practicalities in the Use of Obesity Pharmacologic Agents

5/15/2015
Practicalities in the Use of
Obesity Pharmacologic Agents
Caroline M. Apovian, MD, FACN, FACP
Professor of Medicine and Pediatrics
Boston University School of Medicine
Director, Nutrition & Weight Management Center
Section of Endocrinology, Diabetes, and Nutrition
Boston Medical Center
May 14, 2015
2:15 pm-3:15 pm
Caroline M. Apovian, MD, FACN, FACP
Professor of Medicine and Pediatrics
Boston University School of Medicine
Director, Nutrition & Weight Management Center
Section of Endocrinology, Diabetes, and Nutrition
Boston Medical Center
Advisory Boards:
Research Funding:
• Amylin
• Lilly
• Merck
• Amylin
• Johnson & Johnson
• Arena
• Novo Nordisk
• Nutrisystem
• Zafgen
• Sanofi-Aventis
• Orexigen
• Aspire Bariatrics
• GI Dynamics
• Pfizer
• Sanofi-Aventis
• Orexigen
• Takeda
• MetaProteomics
• Dr. Robert C. and Veronica Atkins Foundation
• EnteroMedics
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U.S. Adult Overweight/Obesity by BMI
BMI:
<18.5
Underweight
U.S. Adult
Population
18.5-24.9
25.0-29.9
30.0-34.9
>35
>40
Normal
Overweight
Obesity I
Obesity II
Obesity III
31%
34%
20.6% 8.1%
6.4%
35.1% Obese
69% Overweight and Obese
More than two-thirds of Americans
Ogden CL, Carroll MD, Flegal KM. JAMA. 2014 Jul;312(2):189-90.
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3
Anti-obesity Drug Treatment Criteria by BMI
BMI:
<18.5
Underweight
U.S. Adult
Population
18.5-24.9
25.0-29.9
30.0-34.9
>35
>40
Normal
Overweight
Obesity I
Obesity II
Obesity III
31%
34%
20.6% 8.1%
BMI >27 kg/m2
with ≥1
comorbidity
Ogden CL, Carroll MD, Flegal KM. JAMA. 2014 Jul;312(2):189-90.
J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):2985-3023.
Apovian C, et al. J Clin Endocrinol Metab. 2015 Jan 15:jc20143415. [Epub ahead of print]
6.4%
BMI >30 kg/m2
with no comorbidities
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4
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Anti-obesity Medications
Role in Weight Loss
An adjunct to lifestyle modification
– not a substitute
Can increase chances of
meaningful weight loss
2013 AHA/ACC/TOS
Guideline for the
Management of
Overweight and
Obesity in Adults:
A Report of the American College
of Cardiology/ American Heart
Association Task Force on Practice
Guidelines and The Obesity Society
July 1, 2014
J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):2985-3023.
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PHARMACOLOGICAL
MANAGEMENT of
OBESITY:
An Endocrine Society Clinical
Practice Guideline
January 15, 2015
Apovian C, et al. J Clin Endocrinol Metab. 2015 Jan 15:jc20143415. [Epub ahead of print]
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First Guideline of its Kind: New MD Tool
PHARMACOLOGICAL MANAGEMENT of OBESITY: An Endocrine Society Clinical Practice Guideline
• Recommended medications and
•
•
•
•
dosage based on obesity-related
comorbidities
Specific recommendations for
transitioning patients off drugs
that cause weight gain
Shifts treatment paradigm from
treating weight last, to treating
weight first
Addresses drugs that cause
weight gain and alternative
drugs that promote weight
neutrality or weight loss
Lifestyle changes should be a
central part of any weight loss medications do not work on their
own
Bariatric
Surgery
Adjuncts
only
Pharmacotherapy
Diet
Exercise
Behavioral Modification
Fundamental
to all obesity
management
Roadmap for clinicians considering
anti-obesity drug treatment for
patients not finding success with
diet and exercise alone
Apovian C, et al. J Clin Endocrinol Metab. 2015 Jan 15:jc20143415. [Epub ahead of print]
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Frequent Patient Follow-up is Key
All patients prescribed weight loss medications:
JAN
FEB
MAR
APR
MAY
JUNE
JULY
At least monthly
for first 3 months
AUG
SEPT
OCT
NOV
DEC
Then at least
every 3 months
Best weight loss outcomes occur
with frequent face to face visits
16 visits per year average
Centers for Medicare & Medicaid Services
Coverage:
Month 1
Months 2-6
four visits (1 per week)
one visit per month
if 3 kg lost, then:
Month 7-12
one visit per month
www.cms.gov Intensive behavioral therapy for obesity; additional preventive services
Watch for new Guidelines on Endocrine Society website at:
http://www.endocrine.org/education-and-practice-management/clinical-practice-guidelines
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Initial Weight Loss Predicts
Ultimate Success
% reduction in initial weight
ILI participants who
lost ≥10% at year 1
(N=887)
ILI participants who
lost 5.0% to 9.9% at year 1
(N=702)
N=88
(9.9%)
4
0
N=174
(19.6%)
-4
N=177
(25.2%)
4
0
N=247
(35.2%)
N=177
(25.2%)
-8
-12
N=374
(42.2%)
1
2
3
N=101
(14.4%)
-16
4
1
Years
70% had >5% loss
at 4 years
0
N=245
(33.6%)
N=107
(14.7%)
-8
-12
-12
-16
N=325
(44.6%)
4
-4
-4
N=251
(28.3%)
-8
ILI participants who
lost <5% at year 1
(N=729)
2
3
4
Years
40% had >5% loss
at 4 years
-16
N=52
(7.1%)
1
2
3
4
Years
22% had >5% loss
at 4 years
Wadden TA, et al. Obesity. 2011;19(10):1987–1998.
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Interactions Among Hormonal and Neural Pathways1
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.
1. Apovian CM, Aronne, L, Bessesen, D al. J Clin Endocrinol Metab. 2015;100:342‐362.
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Expected Weight Loss with Approved
Anti-obesity Medications
Agent
Orlistat
60 mg
120 mg
Roche, GSK
Lorcaserin
10 mg
Arena
Phentermine plus
topiramate-ER
(3.75 mg/23 mg for 2
weeks, increased to
7.5 mg/46 mg,
escalating to a max of
15 mg/92 mg; 1×)d
Vivus
Bupropion/
naltrexone
Takeda and
Orexigen
Liraglutide
3.0 mg
Novo Nordisk
Mechanism of
Action
Cost
Pancreatic lipase
inhibitor causing
excretion of ~30% of
ingested triglycerides
in stool
60 mg, $45
120 mg, $207
wholesale
Highly selective
serotonergic
5-HT2C receptor
agonist causing
appetite suppression
$240
wholesale
Noradrenergic
+ GABA-receptor
activator, kainite
/AMPA glutamate
receptor
inhibitor causing
appetite suppression
$140-195
Inhibitor of dopamine
and
noradrenaline
reuptake +
µ opiate antagonist
$ 60-70 per
month
Glucagon-like peptide 1
(GLP-1) agonist
1 Year
Weight Loss
(kg)
60 mg, −2.5 kg
(−1.5 to −3.5)
120 mg, −3.4 kg
(−3.2 to −3.6)
−3.2 kg
(−2.7 to −3.8)
7.5 mg/46 mg
−6.7 kg
(−5.9 to −7.5)
15 mg/92 mg
−8.9 kg
(−8.3 to −9.4)
6.2 kg
48 weeks
6.2 kg
104 weeks
Common Adverse
Effects
FDA
Approval
Oily spotting, flatus with
discharge,
fecal urgency,
fatty oily stool, increased
defecation, fecal
incontinence
1999 orlistat
2007 OTC
Headache, dizziness, fatigue,
nausea, dry mouth, cough,
and constipation; and in
patients with type 2 DM: back
pain, cough, and
hypoglycemia
June 2012
Paresthesias dizziness,
taste alterations,
insomnia, constipation,
dry mouth, elevation in heart
rate, memory or cognitive
changes
July 2012
Nausea, constipation,
headache, vomiting, dizziness
trouble sleeping, dry mouth
diarrhea
September 2014
Pancreatitis
December 2014
Yanovski SZ and JA.JAMA. 2014;311(1):74-86.
Modified from Powell AG, Apovian CM, Aronne LJ. Clin Pharmacol Ther. 2011 Jul;90(1):40-51.
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Where
Obesity
Treatments
Work
Appetite
Suppressing Drugs
Hypothalamus
VBLOC Device
Vagus nerve
LAGB surgery
Stomach
Lipase Inhibitors (Orlistat)
Intestines
Source of photo: Gastrointestinal
peptides controlling body weight
homeostasis. Mendieta-Zero H, et
al. CIBER of Obesity and Nutrition
(ISCIII), Spain; accepted 12
November 2007; available online
21 November 2007.
Fat Metabolism Drugs
(Beloranib)
Adipose Tissue
Gastric Bypass,
BPD Gastric
Sleeve surgeries
Intestines
Antiobesity Agents and Their Mechanism of Action1
1. Apovian CM et al. J Clin Endocrinol Metab. 2015;100:342-362.
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Lorcaserin
FDA Approved June 27, 2012
Lorcaserin Phase 3 Trials
10 mg QD1
10 mg BID or 10 mg QD2
10 mg BID or 10 mg QD3
Arena Pharmaceuticals
1. Smith SR, et al. N Engl J Med 2010;363:245-56.
2. Fidler MC, et al. J Clin Endocrinol Metab, October 2011, 96(10):3067–3077.
3. O’Neil PM, et al. Obesity (16 March 2012) | doi:10.1038/oby.2012.66
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Lorcaserin: Weight Loss at Year 1
Smith S, et al. N Engl J Med 2010; 363:245-256.
Lorcaserin: Body Weight at Year 1
Smith S, et al. N Engl J Med 2010; 363:245-256.
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Lorcaserin: Body Weight at Year 1 and 2
Effects of lorcaserin on body weight during years 1 and 2 among only those patients who continued the study past year 1
Smith S, et al. N Engl J Med 2010; 363:245-256.
Lorcaserin: Adverse Events Reported
by >5% in Any Group
Lorcaserin
(N = 3195)
Placebo
(N = 3185)
Headache
537 (16.8)
321 (10.1)
Dizziness
270 (8.5)
122 (3.8)
Nausea
264 (8.3)
170 (5.3)
Constipation
186 (5.8)
125 (3.9)
Fatigue
229 (7.2)
114 (3.6)
Dry mouth
169 (5.3)
74 (2.3)
N (%)
Intention-to-Treat Analysis with LOCF Imputation
Smith SR, et al. NEJM. 2010;363:245-256.
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Lorcaserin ─ BLOOM Study:
Key Secondary Endpoints
Endpoint
Lorcaserin
Placebo
P value
Waist
circumference (cm)

−6.8
−3.9
<0.001
SBP/DBP (mm Hg)

−1.4 / −1.1
−0.8 / −0.6
0.04/0.01
Cholesterol (% ∆)
Total
LDL
HDL


−0.90
2.87
0.05
0.57
4.03
−0.21
0.001
0.049
0.72
Triglycerides (%)

−6.15
−0.14
<0.001
Safety
HR (beats/min)
Beck depression II

−2.0
−1.1
−1.6
−0.9
0.049
0.26
Intention-to-Treat Analysis with LOCF Imputation
Smith SR, et al. NEJM. 2010;363:245-256.
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Phentermine/Topiramate
FDA Approved July 2012
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Phentermine/Topiramate ER
Indications
and Dose
Mechanism of
Action
Phentermine
• Sympathomimetic
amine, NE release
Contraindications
and Warnings
Contraindications
• Approved by FDA,
July 2012, schedule IV
• Indication
• Blunts appetite
Weight loss in pts
with BMI ≥30 kg/m2
or BMI ≥27 kg/m2
with weight-related
co-morbid condition(s)
Topiramate
• Increases GABA
activity, antagonize
AMPA/ kainate
glutamate receptor,
carbonic anhydrase
inhibitor
• Treatment Dose Daily
phentermine 7.5 mg
topiramate ER 46 mg
• Max Dose Daily
phentermine 15 mg
topiramate ER 92 mg
• Prolongs satiety
 Pregnancy, glaucoma,
hyperthyroidism, MAOIs
Warnings
• Fetal toxicity
• Increased heart rate
• Suicide and mood and
sleep disorders
• Acute myopia and
glaucoma
• Cognitive impairment
• Metabolic acidosis
• Creatinine elevations
• Hypoglycemia with
diabetes meds
Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus; 2012.
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Phentermine/Topiramate ER
•
•
Once-a-day, oral, extended-release topiramate
Low doses of previously approved medications to minimize side effects
23 46
Maximum
Approved
Doses
92
Topiramate ER
0
50
10
0
150
200
250
300
350
400 mg
Phentermine
0
3.75
Low
5
7.5
Mid
10
15
Full
20
25
30mg
(free base)
DOSING
• Begin with low dose for 2 wks phentermine 3.75/ topiramate ER 23
• Advance to treatment dose phentermine 7.5/ topiramate ER 46
• If <3% weight loss after 12 wks, either discontinue or advance to full dose phentermine
15/ topiramate ER 92 (transition dose phentermine 11.25/ topiramate ER 69 for 2 wks)
• If <5% weight loss after 12 wks on full dose, discontinue (take every other day for 1 wk)
Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus; 2012.
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Percent Weight Loss with PHEN/TPM ER
7.5/46 and Individual Components
P<.05 vs. placebo at all time points except week 0 for all comparisons between PHEN/TPM ER
and placebo or the individual components except PHEN/TPM ER 7.5/46 vs. topiramate ER 92
at weeks 20, 24, and 28 in the mITT population
Aronne LJ, et al. Obesity (Silver Spring). 2013 Nov;21(11):2163-71.
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Percent Weight Loss with PHEN/TPM ER
7.5/46 and Phentermine 15 and Topiramate
P<.05 vs. placebo at all time points except week 0 for all comparisons between PHEN/TPM ER
and placebo or the individual components except PHEN/TPM ER 7.5/46 vs. topiramate ER 92
at weeks 20, 24, and 28 in the mITT population
Aronne LJ, et al. Obesity (Silver Spring). 2013 Nov;21(11):2163-71.
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Weight loss at 28 weeks with lifestyle intervention and
placebo, phentermine and phentermine/topiramate ER
0
N=103
N=104 N=106
N=103
-1
Weight Loss (%)
-2
-1.71
Placebo
-3
Phentermine 7.5 mg
-4
Phentermine 15 mg
-5
-5.45
-6
Phentermine/Topirmate
Topiramate
ER 7.5/46 mg
-6.06
-7
-8
-8.46
-9
Data shown are LS mean and all comparisons are statistically significant.
Treatment arms not shown are topiramate 46 mg, topiramate 92 mg and phentermine/topiramate ER 15/92 mg.
Aronne LJ, et al. Obesity (Silver Spring). 2013 Nov;21(11):2163-71.
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Randomized comparison of weight loss at 28 weeks
with lifestyle intervention and placebo, phentermine
7.5 mg or phentermine 15 mg
Aronne LJ, et al. Obesity 2013. 21, 1-9.
0
N=103 N=104
N=106 N=103
Weight Loss (%)
-1
-2
-1.71
Placebo
Phentermine 7.5 mg
Phentermine 15 mg
-3
-4
-5
-6
-5.45
-6.06
-7
Data shown are LS mean and all comparisons are statistically significant.
Treatment arms not shown are topiramate 46 mg and 92 mg and phentermine/topiramate ER 7.5/ 46 mg and 15/92 mg.
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Effect of Phentermine/Topiramate ER on Weight
Loss in Obese Adults Over 2 Years
SEQUEL Study
Placebo -1.8%
Phentermine/topiramate CR 7.5/46 -9.3%
-10.5%
Phentermine/topiramate CR 15/92
Data are shown with least squares mean (95% CI).
Garvey WT, et al. Am J Clin Nutr. 2012;95:297-308.
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Phentermine/Topiramate ER Improves Risk Factors and
Manifestations of Cardiometabolic Disease CONQUER Study
Changes from baseline to week 56 in secondary endpoints
Phentermine
7.5mg/
Topiramate
46 mg ER
Placebo
P value
Waist circumference (cm)

-7.6
-2.4
<0.0001
Systolic BP (mm Hg)

-4.7
-2.4
0.0008
-3.4
-2.7
0.1281
-8.6
4.7
<0.0001
-3.7
-4.1
0.7391
Variable
Diastolic BP (mm Hg)
Triglycerides (%)

LDL–C (%)
HDL–C (%)

5.2
1.2
<0.0001
CRP (mg/L)

-2.49
-0.79
<0.0001
Adiponectin (µg/mL)

1.40
0.33
<0.0001
Gadde KM, et al. Lancet. 2011;377(9774):1341-1352.
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Phentermine/Topiramate ER: EQUIP and CONQUER
Most Commonly Reported Treatment Emergent Adverse Events
Placebo
PHEN/TPM ER
3.75/23
PHEN/TPM ER
7.5/46
PHEN/TPM ER
15/92
Paresthesia
1.9
4.2
13.7
19.9
Dry mouth
2.8
6.7
13.5
19.1
Constipation
6.1
7.9
15.1
16.1
Upper respiratory
tract infection
12.8
15.8
12.2
13.5
Headache
9.3
10.4
7.0
10.6
Dysgeusia
1.1
1.3
7.4
9.4
Nasopharyngitis
8.0
12.5
10.6
9.4
Insomnia
4.7
5.0
5.8
9.4
Dizziness
3.4
2.9
7.2
8.6
Sinusitis
6.3
7.5
6.8
7.8
Nausea
4.4
5.8
3.6
7.2
Back pain
5.1
5.4
5.6
6.6
Fatigue
4.3
5.0
4.4
5.9
Blurred vision
3.5
6.3
4.0
5.4
Diarrhea
4.9
5.0
6.4
5.6
Adverse Event (%)
(N=3749)
Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus; 2012.
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Lorcaserin vs. Phentermine/topiramate
• Both lorcaserin (Belviq) and the phentermine/topiramate
ER combination (Qsymia) taken as adjuncts to diet and
exercise may be effective in increasing weight loss in the
first year of use, but much less so in the second year
• Qsymia appears to be more effective than lorcaserin, but
may cause more troublesome adverse effects
JAMA September 3, 2014 Volume 312, Number 9. Two Drugs for Weight Loss from:
The Medical Letter on Drugs and Therapeutics. September 3, 2012;54(1398):69-71.
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Naltrexone/Bupropion
FDA Approved
September 11, 2014
Naltrexone/Bupropion
• Mechanism of Action
–
Naltrexone ─ Opioid receptor antagonist
–
Bupropion ─ Dopamine/noradrenaline reuptake inhibitor
• Approved by FDA committee but FDA did not approve
until a CVD outcome study is performed due to concerns
about blood pressure and pulse in some patients
• The Light Study (CVD outcomes) is under way; estimated
completion: July 2017
Apovian C, et al. Obesity (Silver Spring). 2013 May;21(5):935-43.
Clinicaltrials.gov. Cardiovascular Outcomes Study of Naltrexone SR/Bupropion SR in Overweight and Obese
Subjects With Cardiovascular Risk Factors (The Light Study). 2012. http://clinicaltrials.gov/show/NCT01601704
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Naltrexone/Bupropion: Mechanism of Action
• Sustained-release combination of the
dopamine and norepinephrine reuptake
antagonist bupropion and the opioid
antagonist naltrexone
• Proposed dual mechanism of action involves
complementary stimulation of central
melanocortin pathways, resulting in increased
energy expenditure and reduced appetite
Padwal R. Curr Opin Investig Drugs. 2009 Oct;10(10):1117-25.
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Naltrexone/Bupropion: Dosages
NB32
• Sustained-release naltrexone 32 mg/day plus
sustained-release bupropion 360 mg/ day combined in
fixed-dose tablets
NB16
• Sustained-release naltrexone 16 mg/day plus
sustained-release bupropion 360 mg/day combined in
fixed-dose tablets
http://ir.vivus.com/releasedetail.cfm?ReleaseID=407933
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Naltrexone/Bupropion COR-I Phase 3
Mean Weight Loss
56 Weeks – Completer Population
Placebo
Naltrexone 16 mg + bupropion
Naltrexone 32 mg + bupropion
37
Greenway FL, et al. Lancet 2010 Aug 21; 376:595. DOI:10.1016/S0140-6736(10)60888-4.
COR-I and COR-II: Body Weight, Percent
Change from Baseline
Naltrexone/Bupropion
Observed
0
ITT‐LOCF
Observed#
0
(N=456)
-1.9%
-4
-1.3%
-5.0%*
-6
NB16 -6.8%*
(N=471)
-6.1%*
-8
Change from baseline (%)
Change from baseline (%)
(N=511)
-2
ITT‐LOCF
Placebo
Placebo
-1.4% -1.2%
-2
-4
-6
NB32
(N=702)
-8
-8.1%*
NB32 -8.2%*
-10
(N=471)
0
8
16
24
32
40
48
56
56
-10
0
8
16
24
Week
COR‐I
Completers
Placebo (N=290): ‐1.8%
NB16 (N=284): ‐6.7%*
NB32 (N=296): ‐8.1%*
-6.4%*
32
40
48
56
56
Week
COR‐II
Completers
Placebo (N=267): ‐1.4%
NB32 (N=434): ‐8.2%*
#COR‐II: NB observed data are NB32/NB48 pooled (N=825), no differences were observed for subjects re‐randomized to NB32 vs. NB48. LS mean ± SE; *P<0.001 vs Placebo at all time points. COR‐II: Week 56 data from subjects re‐randomized to NB32 is double‐weighted to account for the pre‐specified exclusion of subjects re‐randomized to NB48. ITT‐LOCF: 38
Subjects with a baseline and ≥1 post‐baseline weight measurement while on study drug. Data on file at Orexigen Therapeutics, Inc.
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Improvement in risk factors with use of
Naltrexone SR / Bupropion SR
Week 28
Measure
Placebo N = 456
Week 56
NB32 N = 825
P-value
Placebo N = 456
NB32 N = 702
P-value
108.9 ± 11.7
−2.7 ± 0.4
109.3 ± 11.9
−6.2 ± 0.3
<0.001
108.6 ± 11.8
−2.1 ± 0.5
109.0 ± 11.8
−6.7 ± 0.3
<0.001
113.4 ± 1.6
−1.4% (−5.0%,
+2.4%)
−7.3% (−9.8%, −4.8%)
0.007
112.8 ± 1.6
118.9 ± 1.6
51.4 ± 13.3
+1.2 ± 0.3
<0.001
51.6 ± 12.9
−0.9 ± 0.5
51.8 ± 13.6
+3.6 ± 0.4
<0.001
119.8 ± 30.2
−4.4 ± 0.9
0.004
116.8 ± 32.9
−2.1 ± 1.3
120.5 ± 30.2
−6.2 ± 0.9
0.008
94.8 ± 11.2
−2.1 ± 0.4
0.544
94.2 ± 10.4
−1.3 ± 0.6
95.0 ± 11.3
−2.8 ± 0.5
0.051
10.7 ± 1.9
+3.5% (−3.8%,
+11.2%)
11.4 ± 1.9
−11.4% (−15.9%,
−6.6%)
Waist circumference, cm
Baseline
Change
Triglycerides, mg/dL
Baseline
Percent change (95%
CI)
119.0 ± 1.6
−0.5% (−4.5%, +3.7%) −9.8% (−12.4%, −7.1%) <0.001
HDL-cholesterol, mg/dL
Baseline
Change
51.4 ± 13.1
−1.4 ± 0.4
LDL-cholesterol, mg/dL
Baseline
Change
117.1 ± 32.6
0.0 ± 1.3
Fasting blood glucose, mg/dL
Baseline
Change
94.2 ± 10.4
−1.7 ± 0.5
Fasting insulin, μIU/mL
Baseline
Percent change (95%
CI)
10.7 ± 1.9
−0.5% (−6.5%,
+5.9%)
11.4 ± 1.9
−14.1% (−17.9%,
−10.2%)
<0.001
<0.001
Systolic blood pressure, mm Hg
Baseline
Change
118.2 ± 10.5
−1.2 ± 0.4
118.1 ± 10.0
−0.9 ± 0.3
0.556
118.2 ± 10.5
−0.5 ± 0.4
117.9 ± 10.0
+0.6 ± 0.3
0.039
76.8 ± 7.0
+0.2 ± 0.2
0.017
76.8 ± 7.0
+0.3 ± 0.3
76.7 ± 7.0
+0.4 ± 0.2
0.847
Diastolic blood pressure, mm Hg
Baseline
Change
76.8 ± 7.0
−0.7 ± 0.3
Apovian CM, Aronne L, et al. Obesity (Silver Spring). 2013 May;21(5):935-43.
39
Naltrexone/Bupropion: Side Effects
Most frequent events:
• Nausea
• N=171 (29.8%) naltrexone 32 mg plus bupropion
• N=155 (27.2%) naltrexone 16 mg plus bupropion
• N=30 (5.3%) placebo
• Headache, constipation, dizziness, vomiting, and dry mouth
were also more frequent in the naltrexone plus bupropion
groups vs. placebo
• Transient increase of ~1·5 mm Hg in mean systolic and
diastolic blood pressure was followed by a reduction of around
1 mm Hg below baseline in the naltrexone plus bupropion
groups
• Combination treatment was not associated with increased
depression or suicides vs. placebo
Greenway FL, et al. Lancet. 2010 Aug 21;376(9741):595-605.PMID: 20673995.
40
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5/15/2015
Liraglutide
Approved December 2014
Liraglutide
• Glucagon-Like Peptide 1 (GLP-1) receptor agonist
approved in 2010 for treatment of type 2 diabetes (1.8
mg/day)
• Appetite effect mediated by both the activation of GLP-1
receptors expressed in the hypothalamus
• Affects appetite, food preference, and cardiovascular
biomarkers in patients with type 2 diabetes
• Phase III trials assessing effects of doses as high as 3.0
mg/day submitted to FDA
42
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Liraglutide Weight Loss: Two Years
Liraglutide 3.0 mg for 1 year (and then maintained on 2.4/3.0 mg for the second year)
maintained a mean weight loss of 10.3±7.1 kg from screening over 2 years
3.0 mg
10.3±7.1 kg
weight loss
Astrup A, et al. Int J Obes (Lond). Jun 2012; 36(6): 843–854.
43
Liraglutide: Adverse Events
• Generally well tolerated and improved quality of life
• Adverse events mostly mild or moderate
• Gastrointestinal events (particularly nausea and vomiting),
consistent with the known physiological effects of GLP-1,
were more frequent than with placebo
• At year 1, nausea and/or vomiting was associated with
greater weight loss with liraglutide 3.0 mg, but even those
who did not experience these events lost more weight
than those on placebo or orlistat
• Injection regimen did not impair adherence or cause
significant withdrawal during treatment or run-in
Astrup A, et al. Int J Obes (Lond). Jun 2012; 36(6): 843–854.
44
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Orlistat
FDA Approved
April 23, 1999
OTC
FDA Approved
April 23, 1999
Orlistat, Two Year Data
60 or 120 mg TID
Selective inhibitor of pancreatic lipase that reduces intestinal
digestion of fat; Side effects: initial gastrointestinal symptoms
Bray GA, Ryan DH. Ann N Y Acad Sci. 2014 Apr;1311(1):1-13. doi: 10.1111/nyas.12328.
46
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Orlistat, 4 Year Data
Weight loss (means ± SEM) during 4 years of treatment with orlistat plus lifestyle
changes or placebo plus lifestyle changes in obese patients (LOCF data)
3.0 kg
5.8 kg
120 mg
Torgerson J S, et al. Dia Care 2004;27:155-161.
47
Medications that Promote Weight
Loss/Weight Gain – On/Off Label
Type 2 DM and Obesity
• Metformin is the first line agent
• Exenatide and liraglutide
• SGLT-2 inhibitors
• Pramlintide
Depression and Obesity
• Bupropion is the first line agent
• Do not use Paxil (choose other SSRIs)
Hypertension and Obesity
• Do not use B –blockers
• Insomnia and Obesity
• Do not allow antihistamines
48
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Intermittent Versus Continuous
Phentermine for Weight Lossa
N=64
PBO
PHEN (30 mg)
PHEN and PBO (alternating every 4 weeks)
Mean weight loss, lb
0
-5
-10
-15
-20
-25
-30
-35
0
4
8
12
16
20
Time, weeks
24
28
32
36
Data for completer population (n = 64); patients received only initial instruction regarding diet (simple carbohydrate restriction,
≈ 1000 kcal/d) and reported for follow-up every 4 weeks.
a
49
Munro JF, et al. Brit Med J. 1968;1:352-354.
Off Label Use : Step Wise Approach
Phentermine
15-37.5 mg/d to clinical effect
Start at 15 mg or less
Topiramate
25-200 mg/d to clinical effect
Start at 25 mg afternoon/evening;
increase by 25 mg if needed
Metformin
500-2000 mg/d to clinical effect
Easy to use
Can be added to many drugs
Bupropion and
Naltrexone
Bupropion and
Zonisamide
Liraglutide
Exenatide
Pramlintide
SGLT2 inhibitors
ADD:
Topiramate
ADD:
Phentermine
ADD:
Phentermine
(25-200 mg/d to clinical effect)
Note: Side effects will be more pronounced
than brand name combo phen top
Side Effects: Insomnia, anxiety, palpitations
(phentermine) and paresthesias and
memory impairment (topiramate)
Phentermine contraindicated
or
Side effects from topiramate
phentermine and/or metformin
50
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On Label Use: Step Wise Approach
Phentermine
15-37.5 mg/d to clinical effect
Topiramate/phentermine
escalate to clinical effect
3.75/23 7/46 11.25/69 15/92 mg
Lorcaserin
10 mg BID
Bupropion and naltrexone
Tablet: 8 mg naltrexone HCl /90 mg bupropion HCl
ADD:
Phentermine
15 – 37.5 mg
Orlistat
120 mg TID
Exenatide Injectable
for Obese DM
Liraglutide Injectable
for Obese DM
SGLT 2 Inhibitors
for Obese DM
51
Summary
• New drugs: lorcaserin, phentermine/topiramate,
and naltrexone/bupropion
• Near approval: liraglutide PDUFA Oct-Dec 2014
• Off label: metformin, bupropion, naltrexone,
topiramate, zonisamide, pramlintide, exenatide,
liraglutide, SGLT-2 inhibitors
• ~5-15% weight loss with newer drugs
• Diet and exercise is the cornerstone
of weight loss- any diet will achieve weight loss if
calorie intake decreased; exercise most
important for weight maintenance
• Start slow with medications and switch or add if
weight loss < 5% in 12 weeks
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5/15/2015
Caroline M. Apovian, MD, FACN, FACP
Professor of Medicine and Pediatrics
Boston University School of Medicine
Director, Center for Nutrition and Weight
Management
Boston Medical Center
88 East Newton Street
Robinson Bldg. Suite 4400
Boston, MA 02118
tel: 617 638-8556
fax:617 638-8599
[email protected]
Summary of Randomized Placebo-Controlled
Antiobesity Drug Trials
Drug
1‐year Δ %WL (mean)
% with >5% WL (vs placebo)
Frequent
Side Effects
Uncommon
Side Effects
44.1
3.7%
45% vs 20%
Dry mouth
Fatigue
Nausea
Urinary tract infection
35.9
43.8
3.0%
47% vs 25%
Dizziness
Headache
Constipation
/diarrhea
Hypoglycemia (in pts with T2D)
604 (604)
36.0
52.4
3.5%
45% vs 16%
1267 (0)
42.2
42.6
9.4%
67% vs 17%
Paresthesia
Dry mouth
Palpitations
Disturbances in attention
Constipation
Headache
Dysgeusia
Insomnia
Dizziness
Alopecia
Diarrhea
Anxiety and irritability
Depression/fatigue
Blurred vision
Glaucoma
BMI Age (mean) (mean)
Reference
N (T2D)
Lorcaserin
[Smith et al. 2010] (BLOOM)
3182 (0)
36.2
Lorcaserin
[Fidler et al. 2011] (BLOSSOM)
4008 (0)
Phentermine/
topiramate
[O'Neil et al. 2012] (BLOOM‐DM)
[Allison et al. 2012] (EQUIP)
Phentermine/
topiramate
[Gadde et al. 2011] (CONQUER)
2487 (393)
36.6
51.1
8.6%
70% vs 21%
Liraglutide
[Astrup et al. 2012]
398 (21)
34.8
45.9
4.9%
73% vs 28%
Liraglutide
[Wadden et al. 2013]
422 (0)
35.6
46.2
6.1%
51% vs 21%
Lorcaserin
Nausea
Vomiting
Constipation
Diarrhea
Headache
Pancreatitis
BMI, body mass index; T2D, type 2 diabetes mellitus; WL, weight loss.
Manning S, et al. Ther Adv Chronic Dis. 2014;5(3):135-148.
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5/15/2015
Summary of Naltrexone/Bupropion Drug
Trials
56 Weeks of NB32 or Placebo
Trial
in overweight
and obese
adults
Description Randomized % Subjects in
subjects, N
completer
population(%)
Weight loss (%)
NB32
COR-I
COR-II
Subjects with ≥5% weight
loss (%)
Placebo
NB32
8.1 ± 0.5
*
1.8 ± 0.5
*
62%
23%
34%
54%
8.2 ± 0.4
*
1.4 ± 0.5
65%
*
22%
39%
793
51%
11.5 ± 0.6
7.3 ± 0.9
80%
*
60%
55%
505
54%
5.9 ± 0.5
2.2 ± 0.6
53%
*
24%
26%
Greenway
FL et al
Lancet
2010
1742
50%
Apovian CM
et al
Obesity
2013
1496
Wadden T
et al
Obesity
2011
Wadden T
et al
Obesity
2011
Placebo
Subjects with ≥10%
weight loss (%)
NB32
Placebo
*
11%
*
8%
*
30%
*
8%
CORBMOD
NB32 plus
intensive
lifestyle
modificatio
n
*
COR-DM
overweight
and obese
adults with
type 2
diabetes
*
Billes SK, et al. Pharmacol Res. 2014 Jun;84:1-11.
Anti-obesity Medications in Development
Kim GW, et al. Clin Pharmacol Ther. 2014 Jan;95(1):53-66.
28