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Treatment Options for Obesity: Lifestyle and Pharmacotherapy
Daniel Bessesen, MD Professor of Medicine
University of Colorado, School of Medicine Denver, Colorado USA
Question 1
A patient comes to see you wanting to know your opinion
about the best diet to use to help with weight loss. She has
pre-diabetes and a positive family history of diabetes. Your
goal is to help her avoid the development of diabetes. Which
of the following diets would you suggest?
A. A low carbohydrate diet
B. A Mediterranean diet
C. A low fat calorie restricted diet
D. A meal replacement program
Question 2
A man comes to see you wanting to lose weight. He has a
BMI=32 kg/m2. He used to play soccer in his youth and he
thinks that he will exercise to lose weight. You tell him that
engaging in a structured exercise program will likely produce
what change in his body weight?
A. He will likely gain weight
B. He will likely lose about 2% of his baseline weight
C. He will likely lose about 5% of his baseline weight
D. He will likely lose 8% of his baseline weight.
Question 3
A patient comes to see you frustrated about the limited weight
loss that she has achieved with lifestyle changes alone. She
asks your opinion about weight loss medications, specifically
wondering which of the available medications is likely to
produce the most weight loss. Which of the following do you
tell her is likely to produce the most weight loss?
A. Lorcasarin
B. Phentermine/Topiramate ER
C. Liraglutide 3 mg
D. Naltrexone/bupropion
What do we mean by ‘Best Diet’? (400,000 articles on diet)
►Tastes good, convenient, inexpensive: The Western Diet
►Produces the most weight loss
►The diet you can adhere to long term
►Weight loss with maintained functional capacity without sarcopenia
►Randomized trials demonstrate decreased disease incidence, or mortality
Low Carb, Low Fat: No Difference
in Weight Loss at 2 Years
Foster GD. Ann Intern Med. 2010;153:147-157.
• 19 adults, two 2 week periods of dietary restriction of 800 kcal/d of either fat or carbohydrate
• Measured nutrient balance and fat mass
Hall et al., 2015, Cell Metabolism 22, 427–436
Hall et al., 2015, Cell Metabolism 22, 427–436
Copyright restrictions may apply.
Dansinger, M. L. et al. JAMA 2005;293:43-53.
It’s not the diet, it’s adherence
Modeling Weight Loss: The importance of adherence
J Biol Dynamics; 5 (6) 2011, 579–599 Thomas, Heymsfield,
Model of weight change over 5 years in a 44 year old 77 kg man consuming 2200 Kcal/d with age held constant (dashed line) or age allowed Progress (solid line).
Modeling Weight Loss: The importance of adherence
C Martin et al. Obesity (2015) 23, 935–942.
Meal Replacements
►Provides adequate nutrition at a very reduced calorie intake (800-1000 kcal)
►Adherence is better
►Weight loss is better (best of all diets over the short run)
►Cost is high, taste is well….
►Long term weight loss is hard to maintain
A Tsai et al, Obesity (Silver Spring). 2006 Aug;14(8):1283-93.
Meal Replacements + Meds
D Ryan et al, Arch Intern Med. 2010;170(2):146-154.
Sarcopenic Obesity in the Elderly
J Am Geriatr Soc 62:253–260, 2014.
4,200 men age 60-79 followed for 11 years. 1,300 deaths
Traditional Mediterranean Diet ► Abundance of plant foods
► Minimally processed, locally grown foods
► Fresh fruit as typical dessert, limited sugar
► Olive oil as the principal source of fat
► Cheese and yogurt daily, limited amounts
► Fish and poultry in low to mod amounts
► Zero to four eggs/week
► Red meat in low amounts
► Wine daily with meals
Cardiovascular Events in the Lyon Heart Study
de Lorgeril, M. et al, Circulation 99:779, 1999
P=0.0002
Finnish Diabetes Prevention Study
►522 subjects randomized to lifestyle intervention or control
►Goals
Weight reduction >5%
Fat intake <30% of energy
Saturated fat <10% of energy
Fiber >15 g/1000 kcal
Exercise > 4hr/wk
NEJM 344:1343-50, 2001
Finnish Diabetes Prevention Study
NEJM 344:1343-50, 2001
All Cause Mortality after Lifestyle
Intervention: Da Qing Trial
Lancet Diabetes Endocrinol 2014; 2: 474–80
DPP-like
Intervention trial
conducted in China.
23 yr follow up.
Significant reduction
In all-cause and
CVD mortality
(p=0.049)
Conclusions/Opinions ►Low carb/low fat debate is over. Diet composition
does not matter for weight loss.
►Weight loss is greatest with a meal replacement diet, but there is no long term data on this strategy
►DPP diet (group behavioral weight loss that is low fat calorie restricted) and Mediterranean diets have the best outcome data for diabetes prevention and cardiovascular disease prevention.
►Probably lots of inter-individual variability
►Adherence is the key feature in any diet. Has to be convenient, inexpensive and taste good.
Physical Activity and Weight Loss
• Most studies suggest a reasonable amount of physical activity does not produce much weight loss, about 2% on average
• May produce slight improvements in body composition during weight loss (higher percent fat loss then lean tissue loss)
• Does promote weight loss maintenance.
• Does have proven health benefits independent of weight loss.
Rela
tive R
isk o
f C
VD
M
ort
alit
y
1
2
3
4
5
6
7
8
Lean Normal Obese
Body Fat Category (% Weight as Fat)
<16.7% 16.7%–24.9% 25%
Fatness, Fitness, and Cardiovascular Disease
Mortality
Lee et al. Am J Clin Nutr 1999;69:373.
Aerobically fit
Unfit
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
PharmacologicalTreatment of
Obesity
• Current medications 5-12% wt loss
• Benefits only last as long as patient takes the
medication. Chronic treatment likely needed.
• Drugs probably not paid for by insurance so
cost is a big issue for patients.
• Issues of FDA approval, long term safety, and
efficacy.
• Choice of mechanisms, OTC versus
prescription, combinations?
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 LJ Bessesen D et al. J Clin Endocrinol Metab. 2015;100:342-362.
Phentermine
• Increases NE content in the brain
• Chemically related to amphetamine, ‘not
addictive’
• Dose: 15-37.5 mg/d,
• Cheapest
• 5% weight loss
• Side effects: hypertension, headache,
nervousness
Zhaoping L et al. Ann Int Med, 2005
Orlistat (Xenical)
• Pancreatic Lipase inhibitor
• Inhibits fat absorption by 30%
• 120 mg three times per day
• 3-5% weight loss
• Safest weight loss medication
• GI side effects: oily stools, urgency
• MVI to prevent fat soluble vitamin
deficiency
Placebo
Orlistat
-10
Week
-8.1%
0 15 30 45 60 75 90 104
0
Eucaloric diet
-4.5%
-6.0%
Hypocaloric diet
- 5
Weight loss
(%)
-7.9%
Effect of Orlistat on Body Weight
Sjostrom et al. Lancet 352:167, 1998
Lorcasarin (Belviq)
• Serotonin 2C receptor agonist
• Previous serotonin agonists caused cardiac valve disease, removed from market
• 2C receptor only in the brain not in heart
• Studies in 1-2,000 people for up to 2 years do not show evidence if valvulopathy with lorcasarin.
Lorcasarin (Belviq)
• Weight loss: 4-5%
• Least side effects: minimal headache, dizziness and nausea
• May ultimately prove to be more effective when combined with phentermine (no data on safety or efficacy)
Lorcasarin: Weight Effects
N Engl J Med. 2010 Jul 15;363(3):245-56
Lorcasarin: Weight Effects
N Engl J Med. 2010 Jul 15;363(3):245-56
Phentermine/Topiramate
• Combination gives greater efficacy with fewer side effects
• Doses 7.5/46 mg and 15/92 mg phentermine/topiramate
• Side effects: dry mouth, paraesthesias, insomnia, dizziness, anxiety, irritability and disturbance in attention
• Stop if clinically significant increase in BP or pulse
Lancet. 2011 Apr 16;377(9774):1341-52
Topiramate/Phentermine
(Qsymia) Effects on Weight
Topiramate/Phentermine
(Qsymia) Effects on Weight
Lancet. 2011 Apr 16;377(9774):1341-52
Phentermine/Topiramate
• 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 10-12% weight loss.
Naltrexone SR/Bupropion SR
• Combination of Naltrexone SR 32 mg/d and Bupropion SR 360 mg/d (NB32) or Naltrexone. (8/90 tablets, 2 BID)
• Bupropion stimulates hypothalamic pro-opiomelanocortin (POMC) neurons reduces food intake.
• Naltrexone blocks opioid receptor-mediated POMC auto-inhibition, augmenting POMC firing in a synergistic manner. Alters reward pathways.
• Intermediate in effectiveness and side effects
Naltrexone SR/Bupropion SR
• Worrisome Side Effects: increased blood pressure and pulse, lowers seizure threshold, suicidal ideation (black box).
• Common side effects: Nausea, constipation, diarrhea, headache, dry mouth
• Category X in pregnancy
• Stop if clinically significant increase in BP or pulse
• Stop if <5% weight loss at 3 months
Naltrexone SR/Bupropion SR: Diabetes Trial
Diabetes Care 36:4022–4029, 2013.
Liraglutide 3mg
• GLP-1 agonist, on the market already for diabetes treatment
• Works centrally to reduce appetite
• Side effects: Nausea, vomiting
• Contraindications: Pancreatitis, medullary carcinoma of the thyroid, history of MEN2
• Intermediate in side effects and efficacy
Liraglutide: Weight Loss Over 2 Years1
1. Astrup A et al. Int J Obes (Lond). 2012;36:843-854.
All patients on liraglutide/placebo switched to liraglutide 2.4 mg at week 52, and then to
3.0 mg between weeks 70 and 96
Patients: BMI 30-40
Weight loss: 104 weeks
Some final thoughts on weight
loss medications
• Medications that cause weight gain
• Marked variability in response, some
lose a lot, some don’t
– Stop if doesn’t lose 5% in 3 months
• Diet plus medications better than either
alone.
• Likely useful in weight regain following
bariatric surgery.
• Are these part of type 2 diabetes care?
Questions:
Question 1
A patient comes to see you wanting to know your opinion
about the best diet to use to help with weight loss. She has
pre-diabetes and a positive family history of diabetes. Your
goal is to help her avoid the development of diabetes. Which
of the following diets would you suggest?
A. A low carbohydrate diet
B. A Mediterranean diet
C. A low fat calorie restricted diet
D. A meal replacement program
Question 2
A man comes to see you wanting to lose weight. He has a
BMI=32 kg/m2. He used to play soccer in his youth and he
thinks that he will exercise to lose weight. You tell him that
engaging in a structured exercise program will likely produce
what change in his body weight?
A. He will likely gain weight
B. He will likely lose about 2% of his baseline weight
C. He will likely lose about 5% of his baseline weight
D. He will likely lose 8% of his baseline weight.
Question 3
A patient comes to see you frustrated about the limited weight
loss that she has achieved with lifestyle changes alone. She
asks your opinion about weight loss medications, specifically
wondering which of the available medications is likely to
produce the most weight loss. Which of the following do you
tell her is likely to produce the most weight loss?
A. Lorcasarin
B. Phentermine/Topiramate ER
C. Liraglutide 3 mg
D. Naltrexone/bupropion
BMI and Waist Circumference
Cutpoints for Asian Indians
International Journal of Obesity (2011) 35, 167–187
Trial of Mediterranean Diet for CVD
►Multicenter trial conducted in Spain
►7447 subjects studied for 4.8 years
►Randomized to Mediterranean diet with extra olive oil (1 l/week) or extra nuts (30 g/d mixed nuts).
►Control condition given information on a ‘low fat diet’
N Engl J Med 2013;368:1279-90
Mediterranean Diet and CVD
N Engl J Med 2013;368:1279-90
Mediterranean Diet and Mortality
N Engl J Med 2013;368:1279-90
Diabetes Prevention Program
►3234 subjects randomized to metformin, lifestyle or control
►Lifestyle
Fat gram budget 25% of calories from fat
7% weight loss, with caloric restriction -500 kcal
150 min/wk physical activity
individualized program
Diabetes Prevention Program Research Group.
40
30
20
10
0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Placebo
Metformin
Lifestyle
Cum
ula
tive I
ncid
ence
of D
iabete
s (
%)
Year
Knowler WC et al. N Engl J Med 2002;346:393-403.
Diabetes Prevention Program
A Guide to Selecting
Treatment
Treatment
BMI category
25-26.9 27-29.9 30-34.9 35-39.9 40
Diet, physical activity,
and behavior therapy
Pharmacotherapy
Surgery
With
co-morbidity
With
co-morbidity
With
co-morbidity
+ + + +
+
+
+ +
The Practical Guide. 2000
Antiobesity Agents and Their Mechanism of Action1
1. Apovian CM Aronne LJ Bessesen D et al. J Clin Endocrinol Metab. 2015;100:342-362.
N Engl J Med 2015;373:11-22.
Wadden, NEJM
353:2111-2120,
2005
Combining Diet and
Medications is Better
Than Either Alone
Panel A:
Intention to Treat
Panel B:
Last observation carried
Forward
Variability in Response to a Weight loss
Medication: example pramlintide
Ravussin E; Obesity (Silver Spring). 2009 Sep;17(9):1736-43
New Medications on the Horizon
• FGF21 mimetics
• MC4R Agonists
• methionine aminopeptidase 2 (MetAP2 ) inhibition
• ‘Triple agonist’ GLP-1, GIP and glucagon
• Challenges with uptake/low prescribing rates and safety trials
Nat Med. 2015 Jan;21(1):27-36 Monomeric peptide that is simultaneously an agonist of GLP-1, GIP and glucagon
Pharmacotherapy for Obesity: ENDO Society Guidelines1
a Mean weight loss in excess of placebo as percentage of initial body weight or mean kg weight loss over placebo. GABA: gamma-aminobutyric acid; GLP-1: glucagon-like peptide-1. 1. Apovian CM et al. J Clin Endocrinol Metab. 2015;100:342-362.
Drug Mechanism of Action Mean Weight Lossa Study Duration
Phentermine resin
Norepinephrine-releasing agent 3.6 kg 2 to 24 weeks
Diethylpropion Norepinephrine-releasing agents 3.0 kg 6 to 52 weeks
Orlistat Pancreatic and gastric lipase
inhibitor 2.9 to 3.4 kg, 2.9% to 3.4%
1 year
Lorcaserin 5HT2C receptor agonist 3.6 kg, 3.6% 1 year
Phentermine/
topiramate
GABA receptor modulation (topiramate) plus
norepinephrine-releasing agent (phentermine)
6.6 kg (recommended
dose), 6.6%; 8.6 kg (high dose), 8.6%
1 year
Naltrexone bupropion
Reuptake inhibitor of dopamine and norepinephrine (bupropion)
and opioid antagonist (naltrexone)
4.8% 1 year
Liraglutide GLP-1 agonist 5.8 kg 1 year
ENDO Society Guidelines: common side effects
Key Point: Side Effects Guide Treatment
Drug Common Side Effects
Phentermine resin Headache, elevated BP, elevated heart rate, insomnia, dry
mouth, constipation, anxiety; palpitation, tachycardia, Diethylpropion
Orlistat Decreased absorption of fat-soluble vitamins, steatorrhea, oily spotting, fecal urgency, oily evacuation, increased defecation
Lorcaserin Headache, nausea, dry mouth, dizziness, fatigue, constipation
Phentermine/ topiramate
Insomnia, dry mouth, constipation, paresthesia, dizziness, dysgeusia
Naltrexone bupropion
Nausea, constipation, headache, vomiting, dizziness
Liraglutide Nausea, vomiting
1. Apovian CM et al. J Clin Endocrinol Metab. 2015;100:342-362.
MAOI: monoamine oxidase inhibitor; SSRI: selective serotonin reuptake inhibitor. 1. Apovian CM et al. J Clin Endocrinol Metab. 2015;100:342-362.
Category Drug Class Weight Gain Alternatives
Psychiatric agents
Antipsychotic Clozapine, risperidone, olanzapine, quetiapine,
haloperidol, perphenazine Ziprasidone, aripiprazole
Antidepressants/mood stabilizers: tricyclic
antidepressants
Amytriptyline, doxepin, imipramine, nortriptyline, trimipramine, mirtazapine
Bupropiona, nefazodone, fluoxetine (short term),
sertraline (<1 year)
Antidepressants/mood stabilizers: SSRIs
Fluoxetine?, sertraline?, paroxetine, fluvoxamine
Antidepressants/mood stabilizers: MAOIs
Phenylzine, tranylcypromine
Lithium —
Neurologic agents
Anticonvulsants Carbamazepine, gabapentin,
valproate Lamotrigine?,
topiramatea, zonisamidea
Endocrinologic agents
Diabetes drugs
Insulin (weight gain differs with type and regimen used),
sulfonylureas, thiazolidinediones, sitagliptin?, metiglinide
Metformina, acarbosea, miglitola, pramlintidea, edenatidea, liraglutidea
a Weight-reducing.
Drugs Associated With Weight Gain and Suggested Alternatives1
Category Drug Class Weight Gain Alternatives
Gynecologic agents
Oral contraceptives
Progestational steroids, hormonal contraceptives containing progestational
steroids
Barrier methods, IUDs
Endometriosis treatment Depot leuprolide acetate Surgical methods
Cardiologic agents
Antihypertensives α-blocker?, β-blocker?
ACE inhibitors?, calcium channel blockers?,
angiotensin-2 receptor antagonists
Infectious disease agents
Antiretroviral therapy Protease inhibitors —
General
Steroid hormones Corticosteroids, progestational
steroids NSAIDs
Antihistamines/ anticholinergics
Diphenhydramine?, doxepin?, cyproheptadine?
Decongestants, steroid inhalers
IUD: intrauterine device. 1. Apovian CM et al. J Clin Endocrinol Metab. 2015;100:342-362.
Drugs Associated With Weight Gain and Suggested Alternatives (Cont’d)1