Treatment Options for Obesity: Lifestyle and Pharmacotherapy

Daniel Bessesen, MD Professor of Medicine

University of Colorado, School of Medicine Denver, Colorado USA

Daniel.Bessesen@ucdenver.edu

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