Appetite suppressants in weight management: How and When to Choose Meera Shah, M.B.,Ch.B - AACE Education
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Appetite suppressants in
weight management:
How and When to Choose
Meera Shah, M.B.,Ch.B.
Assistant Professor of Medicine
Division of Endocrinology, Diabetes and Nutrition
Mayo Clinic Rochester
©2015 MFMER | slide-1
Learning Objectives
• Understand the mechanisms of action of
pharmaceutical agents for obesity, and their
efficacy at weight loss
• Determine when to start an appetite
suppressant in an obese patient
• Review data related to diabetes prevention with
these agents
• Learn the most common adverse effects of
these agents
©2015 MFMER | slide-2
Appetite regulation is complex
Harvard-Oxford cortical and subcortical structural atlas
©2015 MFMER | slide-4
Obesity: Faulty reward circuitry?
• Dopamine released in the brain in response to caloric
intake. Negatively associated with BMI
• Neural pathway similar to processes in addiction and
compulsion over-eating
• Substances that increase dopaminergic activity (e.g.
MAOi) decrease hunger and intake
• Natural targets for pharmacotherapy
Schlögl, Lancet Diabetes and Endocrinology 2016
©2015 MFMER | slide-5
FDA approved weight loss medications
Name Trade name Year approved
Orlistat XenicalTM 1999
AlliTM (over-the-counter)
Lorcaserin Belviq® 2012
Phentermine/topiramate-ER Qsymia® 2012
Naltrexone-SR/bupropion-SR Contrave® 2014
Liraglutide 3mg Saxenda® 2014
©2015 MFMER | slide-6
When to add appetite suppressant?
AHA/ACC/TOS 2013 (expert opinion)
For individuals with BMI ≥30 or BMI ≥27 with at
least 1 obesity-associated comorbid condition
who are motivated to lose weight,
pharmacotherapy can be considered as an
adjunct to comprehensive lifestyle intervention to
help achieve targeted weight loss and health
goals. Medications work to reinforce lifestyle
change.
©2015 MFMER | slide-7
When to add appetite suppressant?
AACE/ACE 2016
Initiate weight loss medication as adjunct to
lifestyle therapy in these circumstances:
1. If BMI 27–29.9 kg/m2 and presence of
comorbidities
2. If BMI ≥ 30 kg/m2 and failure of lifestyle
therapy alone.
©2015 MFMER | slide-8
Lorcaserin
Belviq®
• Highly specific activator of the 5HT2C receptor
on pro-opiomelanocortin neurons of the
hypothalamus.
• POMC is cleaved into α-melanocyte-stimulating
hormone, which then binds melanocortin 4
receptors within the hypothalamus, leading to
decreased food intake.
• Binds 5HT2C receptors with 100× more affinity
than the 5HT2B receptors on cardiac valves
Thomsen et al. J Pharmacol Exp Ther 2008
©2015 MFMER | slide-9
BLOOM Trial: Lorcaserin weight loss at 2-yrs
≥ 5% weight loss: ~50% vs. 20% in placebo arm
Weight loss
from baseline
2.2 kg
5.8 kg
Smith SR, et al. N Engl J Med 2010
©2015 MFMER | slide-10
Adverse events
• Headache, dizziness, nausea, URTI symptoms
• No difference in rate of FDA-defined
valvulopathy
Smith SR, et al. N Engl J Med 2010
©2015 MFMER | slide-11Lorcaserin- 3 year data
Bohula et al. N Engl J Med 2018
©2015 MFMER | slide-12Phentermine/topiramate-ER
Qsymia®
• Phentermine: releases catecholamines in the
hypothalamus
• Topiramate: appetite suppression and satiety
enhancement:
i) augments GABA
ii) modulates voltage-gated ion channels
Iii) inhibits AMPA/kainite excitatory glutamate receptors
iv) inhibits carbonic anhydrase
Rothman. Am J Ther 2009
Shin et al. Diabetes Metab Synd Obes 2013
©2015 MFMER | slide-13SEQUEL: Phentermine/topiramate-ER effect
on weight loss at 2 years
52 week extension study (108 wks); n=676, 84% completion rate
Weight loss
from baseline
1.8%
9.3%
10.5%
Garvey WT, et al. Am J Clin Nutr. 2012
©2015 MFMER | slide-14SEQUEL: Phentermine/topiramate-ER effect
on weight loss
Subjects achieving >5% weight loss from baseline to week 108
Garvey WT, et al. Am J Clin Nutr. 2012
©2015 MFMER | slide-15Phentermine/Topiramate ER Effect on
Risk Factors: CONQUER Study
Variable Phentermine- Placebo P
Topiramate ER value
7.5/46 mg
Waist (cm) -7.6 -2.4Phentermine/Topiramate ER and the Prevention of
Diabetes in Patients With Metabolic Syndrome
and/or Prediabetes: SEQUEL Study
12
Placebo
11
PHEN/TPM ER 7.54/46
10
PHEN/TPM ER 15/92
Cumulative Incidence
9
Rate of Type 2
8
Diabetes
7
6
5
4
3
2
1
0
0 4 12 20 28 36 44 52 60 68 76 84 92 100 108
Weeks
Garvey WT et al. Diabetes Care. 2014
©2015 MFMER | slide-17Adverse events
• Dry mouth, paresthesia, constipation, URTI
symptoms, dysgeusia
• Reported anxiety-related adverse events was
dose-dependent:
3.1% for placebo
6.5% for 7.5/46
9.5% for 15/92
Garvey WT, et al. Am J Clin Nutr. 2012
©2015 MFMER | slide-18Naltrexone-SR/bupropion-SR
Contrave®
POMC
Bupropion Naltrexone
α-MSH β-endorphin
Anorexia
May also regulate the mesolimbic reward pathways by modulating
reward values and goal-oriented behaviors.
©2015 MFMER | slide-19(COR I): Naltrexone-SR/bupropion-SR on
weight loss
1741 subjects randomized in 1:1:1 fashion; 83% included in final analysis
Weight loss
Weeks from baseline
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
0
-1
1.3%
Weight Change From Baseline (%)
*
-2
* Placebo
-3 *
Naltrexone SR 16
*
-4 * mg/bupropion SR 180 mg
* Naltrexone SR 32
-5 * * mg/bupropion SR 360 mg
*
-6 * * *
* *
* * * * 5.6%
-7 *
*
-8 * * 6.1%
* * * *
-9 * *
-10
Greenway F, et al. Lancet 2010
©2015 MFMER | slide-20(COR I): Naltrexone-SR/bupropion-SR on
weight loss
48
39
25
20
16 12
9
7
2
Greenway F, et al. Lancet 2010
©2015 MFMER | slide-21Adverse events
• Nausea, dizziness, headache, constipation
• 20-25% discontinued drug vs.10% placebo arm
due to side effects (Greenway)
• Transient rise in SBP by 1.5 mmHg in first 12
weeks, followed by gradual reduction, in line
with weight loss
Greenway F, et al. Lancet 2010
Wadden, et al, Obesity 2011
©2015 MFMER | slide-22Liraglutide 3mg
Saxenda®
• GLP-1 receptor agonist
• GLP-1 is synthesized by L-cells and a small
population of neurons in the brainstem
• GLP-1 receptors present in the hypothalamus
and hindbrain
• Synergistic actions of GLP-1 in the gut and
brain responsible for the effects on satiety
©2015 MFMER | slide-23Liraglutide vs Orlistat
Effect on body weight over 2-years
Astrup A, et al. Int J Obes. 2012
©2015 MFMER | slide-24Treatment of Patients with Prediabetes with Liraglutide 3 mg/day
Cumulative Diabetes
Incidence (%)
Glucose Insulin
Le Roux CW et al. Lancet 2017
©2015 MFMER | slide-25Adverse effects
• Nausea, vomiting
• 9% withdrew from trial mostly due to GI s/e
• Higher risk of pancreatitis seen in patients with
T2DM
• Increased incidence of thyroid c-cell tumors in
rodents
Astrup A, et al. Int J Obes. 2012
©2015 MFMER | slide-26FDA “Off-Ramp” for Obesity Pharmacotherapy If patient has not lost at least: 5% (lorcaserin, naltrexone ER/bupropion ER, phentermine/topiramate ER) or 4% (liraglutide 3 mg) of baseline weight by week 12 on full maintenance dose, then discontinue • Lorcaserin: Begin treatment with full dose, 10 mg bid • Naltrexone ER/bupropion ER: Begin one pill 8 mg/90 mg po q AM for week 1, then one bid for week 2, two q AM one q PM week 3, and 2 po bid week 4 • Phentermine/topiramate ER: one pill 3.75 mg/23 mg po q AM for 2 weeks, then treatment dose 7.5 mg/46 mg po q AM. If
Early Response Predicts Long-term Efficacy
No Diabetes Liraglutide 3 mg Diabetes
No Diabetes Lorcaserin Diabetes
Fujioka K et al. Obesity 2016; Smith SR et al. Obesity 2014
©2015 MFMER | slide-28What is lifestyle modification?
All participants advised daily calorie deficit of
between 500 and 600 calories
• BLOOM: Assessments at 2 and 4 weeks, then monthly with
standardized nutritional and exercise counselling(15- 60 mins)
• SEQUEL: Monthly study meetings to advise calorie deficit and
lifestyle modification
• COR1: Patient assessments at 12, 24, 36 and 48 weeks with
instruction on CR and advice on lifestyle modification
• Liraglutide: 2 week run in period, then randomization. CR,
pedometers, 3 day food diary x 4
©2015 MFMER | slide-29Summary: Weight-loss Drug Efficacy
All data placebo-subtracted,
% weight loss from baseline after 1-year
maximal dose, ITT-LOCF,
unless otherwise indicated.
Phentermine/ Liraglutide Naltrexone/ Lorcaserin Orlistat Phentermine
Topiramate 3 mg Bupropion
Garvey WT. Endocr Pract. 2013
Wadden TA et al. Int J Obes (Lond). 2013
Courtesy of Dr D Hurley
©2015 MFMER | slide-30Therapeutic Weight Loss Reduces Complications
(courtesy Dr. T Garvey)
OBESITY COMPLICATION % weight loss required for
therapeutic benefit Notes References
Diabetes Prevention 3% to 10% Maximum benefit 10% DPP (Lancet, 2009)
SEQUEL (Garvey et al, 2013)
BP still decreasing >15% Look AHEAD (Wing, 2011)
Hypertension 5% to >15%
TG still decreasing at Look AHEAD (Wing, 2011)
Dyslipidemia 3% to >15% >15%
HbA1c still decreasing at Look AHEAD (Wing, 2011)
HbA1c 3% to >15% >15%
Improves steatosis, Assy et al, 2007;
NAFLD 10% inflammation, mild fibrosis Dixon et at, 2004;
Anish et al, 2009
Little benefit at ≤ 5% Sleep AHEAD (Foster, 2009)
Sleep Apnea (AHI) 10% Winslow et al, 2012
Improves symptoms and Christensen et al, 2007
Osteoarthritis 5-10% joint stress mechanics Felson et al, 1992;
Aaboe et al, 2011
Burgio et al, 2007
Stress Incontinence 5-10% Leslee et al, 2009
Singh et al, 2013
5-10% women
GERD Tutujian R, 2011
10% men
Lowers androgens, Panidis D et al, 2008
5-15% (>10% improves ovulation, Norman et al, 2002
PCOS Moran et al, 2013
optimal) increases insulin
sensitivity
©2015 MFMER | slide-31Phentermine
• Approved by FDA for short-term use (generally < 12
weeks)
• Common practice to prescribe for longer
• Retrospective study in 269 patients on phentermine (15-
75 mg) for up to 7 years (65% retention at 1 year) At 1
year, from baseline:
• Lower systolic and diastolic BP (incl. baseline HTN)
• No change in pulse rate
• Improved weight loss vs. no rx
• Same group report no addiction potential
Hendricks et al, Obesity 2011
Hendricks et al, Int J.Obes 2014
©2015 MFMER | slide-32Pharmacological Treatments for Obesity:
Weight Loss and Adverse Events
A Systematic Review and Meta-analysis
28 RCTS
29,000 patients
Higher SUCRA scores reflect
higher associated
weight loss and a lower rate
of adverse events
Khera et al. JAMA 2016
©2015 MFMER | slide-33Limitations
Name Trade name Retail cost/month
• $$
Lorcaserin Belviq® $ 258
Phentermine/topiramate-ER Qsymia® $ 198
Naltrexone-SR/bupropion-SR Contrave® $ 255
Liraglutide 3mg Saxenda® $ 1196
• Side effects
• Potentially teratogenic
• Duration of therapy and durability of results
• No outcomes data
©2015 MFMER | slide-34Conclusion
• Centrally-acting drugs for weight loss primarily
work as appetite suppressants
• Efficacy reported in clinical trials is concurrent
with a lifestyle modification program
• Consider use in patients who have established
a lifestyle modification program but are
struggling
• Side effects, drug-drug interactions and cost
limit generalized usage
• Weight gain may occur when drug is
discontinued
©2015 MFMER | slide-35Questions & Discussion
shah.meera@mayo.edu
©2015 MFMER | slide-36You can also read
