TREATMENT UPDATES FOR BESITY FROM “MAGIC …c.ymcdn.com/sites/ UPDATES FOR OBESITY: FROM...

TREATMENT UPDATES FOR OBESITY:

FROM “MAGIC” PILLS TO FAD DIETS

Tara Storjohann, PharmD, CGP, FASCP

Assistant Professor

Midwestern University College of

Pharmacy-Glendale

Elizabeth Pogge, PharmD, MPH, BCPS,

FASCP

Assistant Professor

Midwestern University College of

Pharmacy-Glendale

OBJECTIVES Upon conclusion of this program, participants should be able

to…

Describe the current obesity epidemic and how it impacts

healthcare.

Compare and contrast dietary approaches for treating

obesity.

List counseling tips for patients’ who are attempting weight

loss.

Compare and contrast the current FDA approved

pharmacotherapy for treating obesity.

Describe key aspects of the large randomized controlled

trials studying lorcaserin and phentermine/topiramate CR

CONFLICT OF INTEREST STATEMENTS

Dr. Pogge does not have an affiliation with any of

the agencies or companies funding this study, nor

has she received any grants or honorariums from

said companies.

Dr. Storjohann does not have an affiliation with

any of the agencies or companies funding this

study, nor has she received any grants or

honorariums from said companies.

BACKGROUND

In 2007-2008 NHANES1 34.2% of United States (US) adults over 20 are

overweight (BMI 25-30 kg/m2)

33.8% are obese (BMI > 30 kg/m2)

Healthy People 2020 goal2 Promote health and reduce chronic disease risk

through the consumption of healthful diet and achievement and maintenance of healthy body weight

US total cost of overweight and obesity3 $147 billion

1. http://www.cdc.gov/NCHS/data/hestat/obesity_adult_07_08/obesity_adult_07_08.pdf. Accessed Nov. 19, 2012.

2. http://www.healthypeople.gov/2020/topicsobjectives2020/overview.aspx?topicid=29. Accessed Nov. 19, 2012.

3. Finkelstein EA et al. Health Affairs. 2009; 28(5): w822-w831

Obesity Hypertension

Hyperlipidemia

Type 2 diabetes

Coronary artery

disease Stroke

Gallbladder disease

Osteoarthritis

Sleep apnea

DISEASES ASSOCIATED WITH OBESITY

Expert Panel on the Identification, Evaluation, and Treatment of Overweight in Adults. Am J Clin Nutr, 68, 899-917.

Dietary Therapy

• Create caloric deficit of 500-1000 kcal/day

Increase Physical Activity

• Build up to at least 30 minutes most days of the week

Behavioral Therapy

• Principles that provide tools for overcoming barriers

TREATMENT OF OBESITY

Clinical Guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. NIH publication. No. 98-4083. September 1998. NICE guidelines. 2006

DIETARY MANAGEMENT FOR

THE TREATMENT OF OBESITY

ESTABLISHING GOALS

Goal of Dietary Therapy: Decrease energy intake

from food.

Be Realistic!

Keep current weight stable

Set initial weight loss goal of 5-7% of current body

weight

Weight loss of >5% can reduce risk factors for

cardiovascular disease

BMI between 20 and 25 kg/m2 puts the subject in

the lowest risk category

1. Up To Date: Dietary Therapy for Obesity. Bray et al. Accessed 4/19/13

RATE OF WEIGHT LOSS

The rate of weight loss is directly related to the

difference between the subject's energy intake and

energy requirements.

Calculating energy intake:

Food Records

Calculating energy expenditure:

Gender

Age

Genetic Factors

1. Heymsfield SB, Harp JB, Reitman ML, Beetsch JW, Schoeller DA, Erondu N, Pietrobelli A. Why

do obese patients not lose more weight when treated with low-calorie diets? A mechanistic

perspective. Am J Clin Nutr. 2007;85(2):346


MAINTENANCE OF WEIGHT LOSS

Weight loss causes a reduction in energy

expenditure.

For example: 42 year-old female that is sedentary:

@200 lbs (91 kg)= TEE= ~2075 kcal/day

@150 lbs (68 kg)= TEE =~1829 kcal/day

Therefore this female has to reduce her caloric intake

by 246 cal/day to MAINTAIN weight loss and not gain

it back.


TYPES OF DIETS

Conventional diets are defined as those below

energy requirements but above 800 kcal/day

These diets fall into five groups:

Balanced low-calorie diets/portion-controlled diets

Low-fat diets

Low-carbohydrate diets

Mediterranean diet

Fad diets (diets involving unusual combinations of

foods or eating sequences)

1. Freedman MR, King J, Kennedy E. Popular diets: a scientific review.

Obes Res. 2001;9 Suppl 1:1S.


BALANCED LOW-CALORIE DIETS

Select the desired caloric intake

Choose foods with adequate nutrients in addition

to protein, carbohydrate, and essential fatty acids

Eliminate:

Alcohol

Sugar-containing beverages

Highly concentrated sweets


PORTION-CONTROLLED DIETS

Use individually packaged foods

Formula diet drinks- Not recommended alone due to

lack of nutritional variety

Nutrition bars

Frozen low-calorie meals (250-350 kcal/package)

Pre-packaged meals

Example plan for 1000-1500 kcal/day diet:

Breakfast: Formula drink or breakfast bar

Lunch: Formula drink or frozen lunch entrée

Dinner: Frozen calorie-controlled entrée with

additional vegetables

1. Flechtner-Mors M, Ditschuneit HH, Johnson TD, Suchard MA, Adler G. Metabolic and weight loss

effects of long-term dietary intervention in obese patients: four-year results. Obes Res. 2000;8(5):399.


LOW-FAT DIETS

Reduce daily fat intake to less than 30% of energy intake

Approx 30 g of fat for every 1000 calories in a diet 1500 calorie = 45 grams of fat

WHI Study: A low-fat dietary pattern with healthy carbohydrates is associated with weight loss.

Weight loss was greatest in women who decreased their percentage of energy from fat the most.

Implementation Strategies:

Follow a specific menu plan of low-fat foods

Count fat grams utilizing information on food labels

1. Howard BV, Manson JE, Stefanick ML, Beresford SA, Frank G, Jones B, Rodabough RJ, Snetselaar

L, Thomson C, Tinker L, Vitolins M, Prentice R. Low-fat dietary pattern and weight change over 7

years: the Women's Health Initiative Dietary Modification Trial. JAMA. 2006;295(1):39.

LOW-CARBOHYDRATE DIETS Low Carb Diet= 60-130 g carbohydrates/day

Very Low Carb Diet= 0 to 60 g/day

Ketosis:

Occurs if carbohydrate intake is <50 g/day- Due to glycogen mobilization

Rapid weight-loss occurs due to glycogen breakdown and fluid loss (not fat loss)

Effective for short-term weight loss but not for long-term

Encourage healthy choices for fat and protein

Implementation:

Follow a specific menu plan of low-carb foods

Count carbohydrate grams utilizing information on food labels

1. Nordmann AJ, Nordmann A, Briel M, Keller U, Yancy WS Jr, Brehm BJ, Bucher HC. Effects of low-

carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized

controlled trials. Arch Intern Med. 2006;166(3):285.

2. Fung TT, van Dam RM, Hankinson SE, Stampfer M, Willett WC, Hu FB. Low-carbohydrate diets and all-

cause and cause-specific mortality: two cohort studies. Ann Intern Med. 2010;153(5):289.

HIGH-PROTEIN DIETS

May work better in the short-term for weight loss

than the low-fat diet

May improve weight maintenance

Increases urinary calcium excretion

Potential↑ risk for bone loss and calcium stone formation

Long-term risk of nephrolithiasis


MEDITERRANEAN DIET

Typically high in: Fruits

Vegetables

Whole grains

Beans, nuts, and seeds

Olive oil as an important source of fat.

Typically low to moderate amounts of: Fish and poultry

Dairy products

Limited red meat

Health benefits: Shown to reduce cardiovascular risk April 2013: NEJM: 1776 persons at high CV Risk

Found that an energy un-restricted Mediterranean diet supplemented with EVOO or nuts resulted in a substantial reduction of major CV events among high-risk persons.

1. Estruch E. N Engl J Med April 2013; 368:14. p1279-90.


VERY LOW-CALORIE DIETS/FAD DIETS

Diets with energy levels between 200 and 800 kcal/day Below 200 kcal/day= Starvation Diets

The basis: The lower the calorie intake the more rapid the weight loss Energy withdrawn from body fat stores is a function of the

energy deficit.

Have not been shown to be superior to conventional diets for long-term weight loss1

Physiologic Effects within the first week: ↓↓ in BP

↓ BG concentrations

Hair loss, thinning of skin, and coldness

↑ Cholesterol mobilization from fat stores= ↑ Gallstone Risk

Generally not recommended

1. Tsai AG, Wadden TA. The evolution of very-low-calorie diets: an update and meta-analysis. Obesity

(Silver Spring). 2006;14(8):1283.


WHICH DIET IS THE BEST?

The impact of specific dietary composition on weight

change remains uncertain

When energy from carbohydrates ↓: Energy from fat sources ↑

When energy from fat sources ↓: Energy from carbohydrates ↑

The short answer is that all of the diets discussed work

to induce modest weight loss —if the patient will

adhere to the diet long-term

Strategies for success:

Have the patient choose a diet based on preferences

Behavioral modification has the greatest impact on long-

term weight loss


2. Up To Date: Behavioral strategies in the treatment of obesity. Bray et al. Accessed 5/16/13

2011: CMS DECISION MEMO FOR INTENSIVE

BEHAVIORAL THERAPY FOR OBESITY

CMS will cover intensive behavioral

therapy for the treatment of obesity

Minimum duration of coverage: 6 months

After 6 months, if the patient has lost at

least 3 kg (6.6 lbs), CMS will cover an

additional 6 months

Note: Pharmacists are not currently

recognized as providers in the decision

memo

21

PHARMACOTHERAPY

PHARMACOTHERAPY

Indication

Used adjunctively for patients with BMI greater than

30 or BMI greater than 27 with concomitant obesity

related disease or risk factors

Always should be implemented with dietary therapy

and physical activity

NHLBI and NIDDKD. Obesity Research. 1998;6(2):51S-210S.

PHARMACOTHERAPY Orlistat

Over-the-counter 60 mg (Alli®)

Prescription 120 mg (Xenical®)

Blocks the digestion and absorption of about 30% of dietary

fat

Oily spotting, flatus with discharge, fecal urgency, oily stools, oily

evacuation, increased defecation

Decreased absorption of fat soluble vitamins

Efficacy: 2.7-3.19 kg weight loss over 1-2 years

Vetter et al, 2010. Kushner RF. Pediatr Blood Cancer. 2012;58:140-43.

PHARMACOTHERAPY

Sympathomimetic amines

Examples: Phentermine, diethylpropion,

phendimetrazine, benzfetamine

Schedule III or IV

Only approved for short term, up to 12 weeks

Increased heart rate, increased blood pressure,

nervousness, insomnia, dry mouth, constipation

Efficacy: 5-6 kg over 12 weeks

Efficacy decreases with time

Kushner RF. Pediatr Blood Cancer. 2012;58:140-43.

HISTORY OF OBESITY MEDICATIONS

Thyroid hormone

DNP (Dinitrophenol) Amphentamines

Fenfluramine/phentermine

(Fen-Phen)

Dexfenfluramine

Ephedra

Withdrawn from the market

FDA NEWS RELEASE: OCT. 2010

Increased risk of heart attack and stroke

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2010/ucm228812.htm

WHAT ARE YOUR THOUGHTS?

What is your biggest concern with using

pharmacotherapy for weight loss in clinical practice?

a. Lack of efficacy

b. Lack of safety

c. Lack of available clinical agents

d. I commonly recommend pharmacotherapy for weight

loss

CONQUER1

A combination of phentermine and controlled release topiramate (PHEN/TPM CR) as an adjunct to lifestyle modification was shown to reduce body weight through 56 weeks of treatment

SEQUEL was an extension study to assess the long-term efficacy and safety for an additional 52 weeks2

EQUIP3

A 56 week randomized controlled trial in severely obese (BMI > 35 kg/m2) adults

NOTE: The low dose in EQUIP was 3.75/23 mg while the low dose in CONQUER was 7.5/46 mg- The high dose in both studies was 15/92 mg

1. Gadde et al. Lancet 2011;377:1341-52.

2. Garvey et al. Am J Clin Nutr 2012;95:297-308.

3. Allison et al. Obesity 2011;20:330-42.

QSYMIA® (PHENTERMINE/TOPIRAMATE CR)

STUDY CHARACTERISTICS

Study design- All studies

Randomized Controlled Trials

All patients received lifestyle and dietary counseling

that included dietary calorie restriction (500 kcal) as

well as increased physical activity

Do we do this in practice?

Cardiovascular co-morbidities

Diabetes, hypertension, hyperlipidemia




RESULTS: EQUIP

-1.6%

-5.1%

-10.9%

P< 0.0001 compared to placebo Allison et al. Obesity 2011;20:330-42.

Mean baseline weight = 115 kg = 12.5 kg loss

RESULTS: EQUIP

0 20 40 60 80

>5%

> 10%

> 15%

17.3

7.4

3.4

44.9

18.8

7.3

66.7

47.2

32.3

PHEN/TPM CR 15/92

PHEN/TPM CR 3.75/23

Placebo

Percentage of subjects

P < 0.0001 compared to placebo for all values except (+) +P=0.0234 compared to placebo

+

Allison et al. Obesity 2011;20:330-42.

RESULTS: CONQUER/SEQUEL -1.8%

-9.3%

-10.5%

P< 0.0001 compared to placebo Garvey et al. Am J Clin Nutr 2012;95:297-308.

Mean baseline weight = 103 kg = 11 kg loss

RESULTS: CONQUER/SEQUEL

Percentage of subjects

P < 0.0001 compared to placebo for all values except (+) +P=0.0072 compared to placebo

+

Garvey et al. Am J Clin Nutr 2012;95:297-308.

RESULTS: CO-MORBIDITIES

Each study, had a dose dependent decrease in the

measured comorbidities compared to placebo

Waist circumference, systolic and diastolic blood

pressure, fasting glucose, triglycerides, total

cholesterol, LDL, and HDL

Results were not always statistically significant




RESULTS: SAFETY Most common treatment emergent adverse

events (AEs)

Upper respiratory tract infection

Constipation

Paraesthesia

Sinusitis

Dry mouth

Insomnia

The incidence of serious AEs was similar

between treatment groups




RESULTS: SAFETY

0.4

3.1

-0.2

1.21.3

6.5

0.3

2.9

1.7

9.5

1.2

3.7

-2

0

2

4

6

8

10

HR (BPM) Anxiety (%) HR (BPM) Anxiety (%)

Placebo

PHEN/TPM CR 7.5/46 (3.75/23)

PHEN/TPM CR 15/92

Mean increase in heart rate (BPM) Anxiety related AE (%)

SEQUEL EQUIP

+

+= statistically significant

+ +

+

+

1. Gadde et al. Lancet 2011;377:1341-52. 2. Garvey et al. Am J Clin Nutr 2012;95:297-308. 3. Allison et al. Obesity 2011;20:330-42.

WHAT ARE YOUR THOUGHTS?

Do you think the increase in heart rate seen

in these clinical trials is clinically

significant?

a. Yes

b. No

DISCUSSION

PHEN/TPM CR, in addition to lifestyle modification,

shows significant weight loss up to 2 years

~10% weight loss (11-12 kg)

>50% of patients were able to sustain 10% weight loss for

2 years

Reduced most comorbidities

Discontinuation rates were similar across all

treatment groups

TAKE HOME POINTS

Important information about PHEN/TPM CR

Requires dosage titration (all give once daily)

Initial dose: 3.75mg PHEN/23mg TPM CR X 14 days

Maintenance dose: 7.5mg PHEN/46mg TPM CR X 12 weeks

If 3% weight loss has not been achieved, discontinue or increase dosage to 15mg PHEN/92mg TPM CR X 12 weeks

If 5% weight loss is not seen after an additional 12 weeks then gradually discontinue the medications Taper for at least 1 week to prevent withdrawal seizures

Qsymia®(phentermine/topiramate) full prescription information. Vivus Inc. 4/2013.

TAKE HOME POINTS

Safety information- C IV1

REMS- Must dispense with medication guide

Increased risk of birth defects associated with first

trimester exposure (Category X)

Decreases efficacy of oral contraceptives

Increased heart rate

Vivus® will be required to do 10 postmarketing

studies, including long-term CV outcome trials2

1. Qsymia®(phentermine/topiramate) full prescription information. Vivus Inc. 4/2013.

2. FDA News Release. FDA approves weight-management drug Qsymia. July 17, 2012. Available at:

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312468.htm

TAKE HOME POINTS

Why the combination product over currently

available phentermine and/or topiramate?

Pill burden- 1 tablet daily

Dosing is slightly lower than currently available

topiramate and phentermine

Is this significant?

Both agents are generic

Topiramate has been studied alone in clinical trials

Similar results but agent was never granted FDA approval

for this indication

Steddering et al. Eur J Endocrinol. 2012;167(6):839-45.

WHAT ARE YOUR THOUGHTS? Image you are a 52 year old female, BMI = 35 kg/m2

with hypertension and diabetes. Would you take

PHEN/TPM CR for weight loss?

a. Yes

b. No

LORCASERIN (BELVIQ®)

MOA: 5-HT2C receptor agonist

Meta-analysis of available studies

3 studies meet inclusion criteria

All patients received lorcaserin 10 mg once or twice daily verses placebo

Co-intervention: 600 calorie per day deficit diet along with nutritional and exercise counseling

Average age: 45-55

Baseline BMI: ~35 kg/m2

Weight: ~100 kg

Length: 1-2 years

Chan et al. Obes Rev. 2013;14(5):383-92.

RESULTS

• Pooled mean weight loss: 3.23 kg


RESULTS

• Pooled mean BMI reduction = 1.16 kg/m2


OTHER CO-MORBIDITIES

Items circled are not statistically significant


SAFETY

1 trial enrolled only diabetic patients and in this trial, symptomatic hypoglycemia occurred in more patients taking lorcaserin vs. placebo (8.3% vs. 6.3%) 2

1. Chan et al. Obes Rev. 2013;14(5):383-92. 2. O’Neil et al. Obesity 2012;20:1426-36.

1

DISCUSSION

~3 kg weight loss over 1 year

100 kg patient ~ 3% weight loss in 1 year

Risk vs. benefit

A modest reduction was also seen in co-

morbidities


TAKE HOME POINTS

Dosing: 10 mg twice daily; evaluate response in 12

weeks and if patient has not lost >5% of baseline

body weight, DC agent

Renally eliminated; use caution in CrCL< 50

mL/min (not recommended CrCL<30 mL/min)

Pregnancy Category X

Approved in June 2012 and became available June

2013

Schedule IV controlled substance

Belviq®(lorcaserin) full prescription information. Eisai Inc. 6/2012.

TAKE HOME POINTS

Interactions Serotonergic medications = ↑ risk of serotonin syndrome

CYP 2D6 inhibitor

Warnings/Precautions (most due to SE seen rarely in trials) Valvular heart disease (potential due to affect on 5-HT2B)

Cognitive impairment

Psychiatric disorders

Hypoglycemia in diabetic adults

Priapism

Heart rate decrease

Decrease in white blood cell count

Prolactin elevation

Pulmonary hypertension

Belviq®(lorcaserin) full prescription information. Eisai Inc. 6/2012.

TAKE HOME POINTS

As part of the approval, the company will conduct

post-marketing studies

Pediatrics

Long-term efficacy

Long-term safety (ECG)

FDA News Release. FDA Belviq to treat some overweight or obese adults. June 27, 2012. Available at:

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm309993.htm

SUMMARY

Orlistat Phentermine/

topiramate

Lorcaserin

Weight loss with

max dose

~3 kg ~11 kg (10%) ~3 kg (3%)

Major side effects Oily spotting,

flatus with

discharge, fecal

urgency, oily

stools, increased

defecation

Increased heart

rate,

paraesthesia, dry

mouth,

constipation,

insomnia,

anxiety, infection

Headache,

nausea, dizziness,

fatigue, UTI,

constipation, dry

mouth

Dose 60-120 mg up to

three times a day

3.75 /25mg up to

15/92 mg once

daily

10 mg twice daily

Longest study 2 years 2 years 2 years

Garvey et al. Am J Clin Nutr 2012;95:297-308. Gadde et al. Lancet 2011;377:1341-52.

Allison et al. Obesity 2011;20:330-42. Kushner et al. Pediatr Blood Cancer 2012;58:140-43.


WHAT ARE YOUR THOUGHTS? Image you are a 52 year old female, BMI = 35 kg/m2 with

hypertension and diabetes. Would you take lorcaserin for

weight loss?

a. Yes

b. No

Discussion: What issues do you see with these medications

that will make it difficult for prescribers to use?

QUESTIONS

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