OBESITY TREATMENT: THE CUTTING EDGE

Holly Wyatt, M.D.

Associate Professor of Medicine Division of Endocrinology, Metabolism and Diabetes Associate Director Anschutz Health and Wellness Center

DISCLOSURE SUMMARY

Dr. Wyatt has served as an advisor for Orexigen Pharmaceuticals, Arena Pharmaceuticals, Wellspring Camps, Retrofit Inc. and Eisai Inc. She receives royalties from Up to Date and has received grant funding from the NIH, Orexigen, Norvo Nordisk and GI Dynamics. She has ownership interests in Active Planet LLC and has co-ownership on a patent for a weight loss maintenance strategy.

GAME PLAN

Current Treatment Guidelines Advances in Diet Advances in PA New Medications Surgery New Areas- ahead of the curve

CURRENT APPROACH TO OBESITY TREATMENT

TREATMENT OPTIONS BMI Range Diet, Exercise and Behavioral Therapy Current Patient Risk LOW → 25-26.9

27-29.9

30-34.9

Patient Risk HIGH 35-39.9

Potential Treatment Risk LOW

+ + + +

>40

+

↓ Pharmacotherapy Surgery Treatment Risk HIGH

+ + + with a comorbidity with a comorbidity Wyatt HR . Accepted for Publication JCEM 2013.

+

NEW OBESITY GUIDELINES IN 2013

• • The NHLBI has announced that new Guidelines for Obesity, Hypertension and Lipids will be released jointly in 2013 Guidelines for Lifestyle and for Risk Assessment will be released concomitantly. These new treatment guidelines will replace the older 1998 Guidelines and provide evidenced based approaches for obesity treatment for the practicing clinician.

TREATMENT GAP

HOW SHOULD WE THINK ABOUT OBESITY TREATMENT?

Acute Weight Loss Strategy Chronic Weight Loss Strategy Weight Loss Strategy 1 4-6 months Transition Strategy 1.5

Weight Maintenance Strategy 2 Years/Forever?

DIFFERENCES BETWEEN WEIGHT LOSS AND WEIGHT LOSS MAINTENANCE Weight Loss

• Time limited • Physiological State: fuel negative energy balance; obligatory decreased RQ; negative fat balance; burn more fat as • Best Strategy for Success: Reduced caloric intake • Physical activity not required for success • Macronutrient composition of diet not as important • Common • Relatively easy • Multiple strategies have success • Exciting!

Maintenance of Weight Loss

• Life-long • Physiological State: energy balance at a reduced body weight; RQ=FQ; need to be in fat balance; burn less fat as fuel • Best Strategy for Success: Physical activity “required” for success • Macronutrient composition of the Diet is more important (ie. Fat balance is important) • Rare • Harder/More elusive • Less strategies?

• Longer-term health risk becomes an issue • Boring!

WHAT IS THE BEST APPROACH FOR WEIGHT LOSS AND WEIGHT LOSS MAINTENANCE?

Diet Restriction

Increased Activity

Over Time

Slide Source: James Hill and Holly Wyatt

DIETS DON’T WORK? OR DO THEY ?

WHAT IS THE BEST DIET FOR WEIGHT LOSS?

WHAT IS THE BEST MACRONUTRIENT COMPOSITION OF A DIET FOR WEIGHT LOSS?

• • Wadden et al presented a comprehensive review highlighting the randomized, controlled trials that have compared diets with varying macronutrient composition No single diet emerged as a clear winner despite a very robust number of clinical studies in this area • TAKE AWAY: Impact of the caloric restriction that a diet produces outweighs the impact of the macronutrient composition of the calories consumed in that diet Wadden TA, Webb VL, Moran CH, Bailer BA 2012 Lifestyle modification for obesity: new developments in diet, physical activity, and behavior therapy. Circulation 125:1157-1170

COMPARISON OF WEIGHT LOSS DIETS WITH DIFFERENT COMPOSITIONS OF CARBOHYDRATE/ PROTEIN/ FAT (N=811)

Sacks FS et al.

NEJM

. 2009;360(9):859-873.

WHAT DOES PREDICT DIETARY WEIGHT LOSS SUCCESS?

IT IS NOT WHAT YOU EAT BUT HOW LONG YOU CAN EAT IT Dansinger, M. L. et al. JAMA 2005;293:43-53

SELF-REPORTED DIETARY ADHERENCE DECLINES RAPIDLY

Dansinger, M. L. et al. JAMA 2005;293:43-53.

Copyright restrictions may apply.

WHAT ARE THE BEST STRATEGIES TO MAXIMIZE WEIGHT LOSS ?

• • • • • • Your physiology and environment can be overpowered by cognitive eating control strategies (diets) There are many diet strategies to reduce calories short-term Caloric restriction trumps macronutrient composition Adherence is the key Matching individuals to the “best” diet Should the goal be too get off as much weight as possible?

HOW MUCH PA DO WE PRESCRIBE TO PREVENT WEIGT REGAIN?

• • • • The data consistently shows that for the majority of patients 60 minutes of moderate intensity activity most days of the week is an amount required to prevent or mitigate weight loss regain. A recent review of randomized trials and observational data by Donnelly et al in 2009 highlighted and confirmed this PA rec This high level of PA is also supported by self-reports and objective measures of individuals in the National Weight Control Registry (NWCR) As well as a recent prospective analysis in the Nurses’ Health Study published in 2010 Donnelly JE et al. 2009. Medicine and science in sports and exercise 41:459-471 Mekary RA et al. 2010. Obesity 18:167-174

WE DO KNOW A LOT ABOUT WHAT WILL WORK ! BUT HOW DO WE GET OUR PEOPLE TO DO IT ?

MOST EXCITING RECENT ADVANCES IN OBESITY TREATMENT IN 2013 ARE IN DRUG THERAPY

PREVIOUSLY AVAILABLE PHARMACOTHERAPIES

Agent

Mechanism Approval Cost Common Adverse Effects

PHENTERMINE

Phentermine Prescribing Information, 2011. Orlistat Prescribing Information, 2009.

ORLISTAT

• • • • Central Noradrenergic Short-term use Class IV $ Restlessness Insomnia ? Increase in pulse ? Increase in blood pressure • • Peripheral Pancreatic lipase inhibitor Long-term use Not scheduled $$ GI symptoms including oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, and others less frequently Increase in urinary oxalate

RECENTLY EVALUATED OR APPROVED PHARMACOTHERAPY

Obesity Drug Lorcaserin Trade Name

Belviq

Mechanism

Selective Serotonergic 2C receptor agonist

Proposed Dosage

10 mg po BID

Phase 3 Clinical Trials

BLOSSOM BLOOM BLOOM- DM

Average Expected % Weight Loss

Drug:5-6% Placebo:2-3 %

Most Common Adverse Events Safety Concern Raised by the FDA

Headache Nausea Dizziness Fatigue Carcinogenicity Valvulopathy Cardiovascular risk

Phentermine/ Topiramate

Qsymia Sympathomimetic amine and anticonvulsant agent Low:3.75mg/23mg Mid:7.5 mg/46mg High:15mg/92mg po q day EQUATE EQUIP CONQUER SEQUEL Drug:5-11% Placebo:1-2% Headache Paresthesia Dry Mouth Altered taste Dizziness

Bupropion SR/Naltrexone SR

Contrave Dopamine and norepinephrine reuptake inhibitor and opioid receptor antagonist Sustained release 360 mg/ 32mg po q day COR I COR-II COR-BMOD COR-Diabetes Drug:5-6% Placebo:1-2% Nausea Headache Insomnia Constipation Tremor Depression Cognitive Issues Cardiovascular Risk from increased heart rate Birth Defects Cardiovascular risk from increased blood pressure and heart rate Wyatt HR . Accepted for Publication JCEM 2013

LORCASERIN

• • • • • Selective serotonin 2C receptor agonist that works by decreasing food intake. Mechanism of action is similar to fenfluramine and dexfenfluramine except it is specific for the 2C serotonin receptor that is not found on the heart or heart valves. The result is a compound with a desirable increased satiety effect and no heart valve damage. Echo studies showed no increased incidence of FDA-defined cardiac valvulopathy. There is some concern the studies were not powered adequately for complete confidence because of a lower than expected event rate. The FDA advisory panel voted in favor of approval 18-4 in May 2012 and locaserin was officially approved by the FDA in June 2012. It should be available in 2013.

CATEGORICAL WEIGHT CHANGE OVER WITH LORCASERIN THERAPY- BLOOM

47.5% 20.3% 22.6% 7.7% Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, Bays H, Shanahan WR 2010 Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 363:245-256

LORCASERIN SAFETY DATA

Headache Back pain Nasopharyngitis Nausea Urinary tract infection Cough Symptomatic hypoglycemia Fatigue Gastroenteritis, viral Dizziness Influenza Procedural pain Hypertension Gastroenteritis Depression O’Neil PM, et al.

Obesity

. 2012;20:1426-1436.

Lorcaserin 10 mg BID, n=256 37 (14.5) 30 (11.7) 29 (11.3) 24 (9.4) 23 (9.0) 21 (8.2) 19 (7.4) 19 (7.4) 18 (7.0) 18 (7.0) 15 (5.9) 13 (5.1) 13 (5.1) 8 (3.1) 6 (2.3)

Safety Population N (% of patients)

Lorcaserin 10 mg QD, n=95 16 (16.8) 8 (8.4) 22 (23.2) 8 (8.4) 9 (9.5) 5 (5.3) 10 (10.5) 5 (5.3) 5 (5.3) 11 (11.16) 8 (8.4) 0 6 (6.3) 5 (5.3) 5 (5.3) Placebo, n=252 18 (7.1) 20 (7.9) 25 (9.9) 20 (7.9) 15 (6.0) 11 (4.4) 16 (6.3) 10 (4.0) 11 (4.4) 16 (6.3) 13 (5.2) 5 (2.0) 8 (3.2) 5 (2.0) 5 (2.0)

• • • • •

HOW I SEE THE FUTURE ROLE OF LOCASERIN

While locaserin meets FDA weight loss criteria, the efficacy is modest, but the risk profile is also low. For this drug, it is important for clinicians to realize that certain individuals may respond more (have a significantly greater weight loss) than other individuals. This drug may be one that eventually will be helpful in a smaller subset of obese “responders” Locaserin’s reduction in HbA1c levels appears more substantial than the weight loss reduction in the BLOOM-DM study and therefore diabetics may also prove to be a subset that may have greater benefit Locaserin has not been studied in combination with other drugs such as phentermine. While combining the two drugs (phentermine and locaserin) may increase weight loss, the safety of the combination has not been evaluated

• • • •

PHENTERMINE AND TOPIRAMATE (PHEN/TPM)

Phentermine induces central NE release and promotes weight loss by decreasing food intake. It is currently approved as a monotherapy for only short-term use.

Topiramate monotherapy (200-400 mg/day) was approved in 1996 for the treatment of seizures and in 2004 for migraine prophylaxis (100mg/day) and is currently not approved as a monotherapy for weight management. Topiramate exhibits a combination of properties such as effects on sodium channels, enhancements of GABA-activated chloride channels, and inhibition of carbonic anhydrase isoenzymes, but the specific mechanism promoting weight loss is unclear.

In combination the drugs have shown greater weight reduction than either agent alone.

PHENTERMINE AND TOPIRAMATE (PHEN/TPM)

• • • Higher dose topiramate trials as a monotherapy were halted because of the cognitive and depressive side effects. The combination of PHEN/TPM allows a lower dose of controlled release topiramate to be used and therefore a more acceptable adverse events profile. The drug combination of phentermine and topiramate received a 20-2 in favor vote from the February 2012 FDA advisory panel and was FDA approved in July of 2012. It became available for use in late 2012.

EFFECT OF PHENTERMINE/TOPIRAMATE ER ON WEIGHT LOSS IN OBESE ADULTS AFTER 1 YEAR- CONQUER

Gadde KM, et al.

Lancet

. 2011;377:1341-1352

PHENTERMINE/TOPIRAMATE ER SAFETY DATA

% Adverse Events Dry mouth Paraesthesia Constipation URI Nasopharyngitis Dysgeusia Insomnia Headache Dizziness Sinusitis Back pain Nausea Fatigue Diarrhoea Blurred vision UTI Arthralgia Placebo (n=993) 2 2 6 13 9 1 5 9 3 7 5 4 5 5 4 4 5 Bronchitis 4 4

GADDE KM, ET AL.

LANCET

. 2011;377:1341-1352.

INFECTION; UTI, URINARY TRACT INFECTION

PHEN/TPM ER 7.5/46 (n=498) 13 14 15 12 11 7 6 7 7 7 6 4 4 6 4 5 5

P

Value <0.0001

<0.0001

<0.0001

0.7422

0.2204

<0.0001

0.3832

0.1983

0.0005

1.0000

0.6199

0.6754

0.7010

0.2229

0.7729

0.1753

0.5373

PHEN/TPM ER 15/92 (n=994) 21 21 17 13 10 10 10 10 10 9 7 7 7 6 6 5 4 1.0000

5

URI, UPPER RESPIRATORY

0.4004

P

Value <0.0001

<0.0001

<0.0001

0.7906

0.3947

<0.0001

<0.0001

0.4467

<0.0001

0.1511

0.0386

0.0139

0.1270

0.3690

0.0157

0.0855

0.3025

HOW I SEE THE FUTURE ROLE OF PHEN/TPM

• • • • Weight loss with the combination of PHEN/TPM is better than any of the obesity drugs in the pipeline at this time.

Along with this increase in efficacy however comes a more troublesome risk profile that clinicians need to understand and actively address with their patients. Depression and cognitive issues have not been major issues in the more recent controlled release trials. Cardiovascular events and birth defects appear to be the issues that will need to be monitored closely.

EMERGING PHARMACOTHERAPY

Agent

Approval Status

Naltrexone/BupSR 1 Liraglutide 2,3

FDA requested additional Phase 3 data In Phase 3 clinical trials Mechanism Naltrexone, opioid receptor antagonist; Bup, norepinephrine-dopamine reuptake inhibitor Glucagonlike peptide-1 analogue Follow-up Duration 56 weeks 56 weeks Common AEs • • • • • • Nausea Headache Constipation Dizziness Vomiting Dry mouth • • • Nausea Vomiting Gastro-intestinal effects 1 2 Astrup A, et al.

Lancet

. 2009;374:1606-1616. 3 Greenway FL, et al.

Lancet

. 2010;376:595-605. Lean ME, et al.

Obesity

. 2010;18(suppl 2) Abst# 484-P:S153.

NALTREXONE AND BUPROPION (NAL/BUP)

• • • • The Naltrexone SR/Bupropion SR combination functions as an opioid receptor antagonist combined with a norepinephrine and dopamine receptor reuptake inhibitor. Bupropion has neuronal effects that lead to reduced energy intake and increased energy expenditure. Naltrexone was chosen as a complement to bupropion in order to block compensating mechanisms that attempt to prevent long-term, sustained weight loss. The FDA advisory panel voted in favor of approval (13-7) of this combination in December of 2010 however the FDA declined to approve the drug in early 2011 going against the advisory panel recommendation

NALTREXONE AND BUPROPION (NAL/BUP)

• • • The FDA is requiring large scale safety study evaluating cardiovascular events. This was an interesting decision by the FDA given buproprion which is the drug potentially associated with the increase in cardiovascular risks, is currently available and used by millions of Americans for the treatment of mild depression or to stop smoking.

Blood pressure and pulse were slightly increased indicating the potential for an increased cardiovascular events. Increased risk of seizures as well as syncope in the treatment group was also a safety concern that was noted. A study of this size and scope will take tremendous resources and time to complete. The earliest this drug could be approved is late 2014 or early 2015.-

WEIGHT LOSS WITH NALTREXONE SR/BUPROPION SR COMBINATION THERAPY AS AN ADJUNCT TO BEHAVIOR MODIFICATION: THE COR-BMOD TRIAL

Wadden et al Obesity (2011) 19, 110–120.

SURGICAL TREATMENT OF OBESITY

• • • The use of bariatric surgery as a treatment for obesity has grown dramatically over the last several years. The International Diabetes Federation recommended consideration of bariatric surgery as an accepted treatment option in patients with a BMI 30 to 35 when DM cannot be adequately controlled by traditional medical management In 2011 the FDA expanded approval of the LAP-BAND adjustable gastric banding system to be used in patients with a BMI of 30-34 with an existing condition related to their obesity.

WHAT IS NEW FOR THE FUTURE?

ENDO BARRIER

HOW DO WE GET PEOPLE TO DO IT?

• • • •

Motivation/Priorities

•

Carrot or Stick

•

Purpose/Mindset Skill Building Rituals and Routines Create New Environments

MAKE HEALTHY DECISIONS AUTOMATIC

• In todays world healthy behaviors takes planning and choices • • It’s not the default Sticking to your intentions requires willpower

BUILDING YOUR WILLPOWER MUSCLE

• • • • • Willpower is like a muscle It fatigues over the day You use it all day long Finite resource make it strong and use it wisely Examples of ways to use it efficiently • Planning ahead • Morning exercise

HABITS, ROUTINES AND RITUAL

•

Patterns of behavior that are subconscious

•

Regular courses of action

•

Routines that have a deeper meaning

•

Make the behaviors more likely to happen

• • • • • • •

HEALTHY DIET ROUTINES AND RITUALS

• • •

Never go down the chip aisle in the grocery store Eat Starbucks oatmeal for breakfast when traveling Only buy single serving snacks Never bring ice cream home- always go out for it Prepare food on Sunday afternoon for the week Buy precut prewashed veggies Always order Grilled Teriyaki chicken, sauce of the side, only half the brown rice at my favorite Chinese restaurant Decline bread basket Always order dressing or sauce on the side Start with a veggies at dinner

HIGH ACTIVITY ROUTINES AND RITUALS

• Only watch TV after exercise • • Always stand or walk on the cell phone Sleep by 10pm • • Prepack Gym bag Schedule working out on Sunday • • Meet friends Sign up for events • Walk for 10 minutes at noon

CREATE A SUPPORTIVE ENVIRONMENT

• You want your relationships and surroundings to work for you not against your efforts • Reengineer your environment • Physical • Social • • Make healthy the default when possible Push back against the environment

THE IMPORTANCE OF YOUR SOCIAL NETWORK

• The people you interact with at work, home and in your community have a tremendous influence over your behavior • Join a group or develop new circles of friends that are doing the behavior you want to do