Obesity medications: understanding the impact on appetite, hunger and

behaviors

Carl Roberts

Disclosures• Carl declares grant support from Unilever

Pharmacotherapy• Pharmacotherapy provides an aid to behaviour modification in the

management of weight-loss.

• Each drug/combination acts differently. So can we assume they affect eating behaviour in different ways?

Personalised medicine• Standardised personalised medicine approach is to target

key genes

• Standardised PM approach not appropriate for weight-loss (too polygenic)

In order to personalise pharmacotherapy for weight-loss we need to target behaviour

Behaviour associated with adiposity – underpinned by our (neuro)biology

Inadequate impact of food

• Increased eating rate and a failure to develop normal satiation during the course of a meal

• weakened satiety signals after a meal (feel hungrier quicker)

Less control over eating

• Greater responsiveness to food cues (sights and smell of food)

• Heightened hedonic responses to palatable food (eating is pleasurable)

• Experiences of uncontrolled hunger and greater disinhibition of eating behaviour

Diet vs DrugsPharmacotherapy could reduce –ive

psychological and biological consequences of dieting

Aiding behaviour change

Improving self-efficacy

Personalised approach not possible without guidance from patient experience

Hunger

Pre-occupation with food

Food grabbing your attention

Exert control over eating behaviour

Measures to assess drug action on behavior

• Experimental procedures do exist to answer how drugs can modify satiety, food reward (wanting and liking), and control over eating behaviour

• so we should know how these drugs affect behaviour right?

Drug action on behaviour should be assessed prior to regulatory approval

So what do we know?

• Proposed mechanisms of action

• Efficacy for producing 5% weight loss in phase III clinical trials

• How the drugs produce weight loss – effects on the brain and behavior

• Can successful responders be characterised from these data?

Liraglutide: boost satiety, reduce “liking”

Bupropion naltrexone: boost satiety, reduce “liking”, improve control

Lorcaserin: boost satiety, without adverse cardiovascular profile

Phentermine/Topiramate: boost satiety, improve control

Proposed mechanisms of action

• The ability/inability to stop, change or delay an inappropriate response, in the environment (Logan et al, 1986)

Inhibitory control and food• Exposure to high-calorific food cues reduces ability to inhibit

behaviour in people regardless of weight status• Ability to resist cravings

What is inhibitory control?

Liraglutide (Saxenda)

• GLP-1 receptor agonist (A satiety hormone)

• FDA and EMA approved for weight loss at 3.0mg injectable dose

• Acts on hypothalamus to increase satiety. Also acts on reward-related areas of the brain

• 63% of participants achieved 5% weight-loss in phase 3 trials (Khera et al., 2016) 2921 participants (3 studies)

• Only 1 study on behaviour with the 3.0mg dose: Decreased ad lib food intake (lasagne), increased satiety and fullness (post-meal), reduced prospective consumption (post-breakfast). No increase in Energy expenditure

Efficacy: Liraglutide

Conclusion?

Produces weight loss through homeostatic mechanisms that boost satiety, leading to reduced intake.

More data is needed with the 3.0mg dose in non-T2DM samples

Bupropion/Naltrexone (Contrave) • Bupropion = anti-depressant used to reduce craving

in smoking cessation.

• Naltrexone = opioid antagonist, reduces reward sensitivity to palatable food

• Proposed to boost satiety, dampen reward, and improve control of eating

Efficacy: Bupropion/naltrexone• 55% of people achieved 5% weight loss (n=2044, over 4 studies)

• Some self report data on fullness/hunger (satiety effects), desire for sweet foods (reward effects), ability to control eating and resist food cravings (craving control).

• Wang et al. (2014): increased activation in brain areas associated with control over eating

No clinical experimental data available for effects on eating behaviour

Without behavioural data, the suggestion of improved control from fMRI remains speculative

Lorcaserin (Belviq)

• Reduced food intake by stimulating serotonin receptors–however selective for 5HT2c receptor subtype – limiting psychological and cardiovascular side effects observed with non-selective serotonergic drugs

• Proposed to increase satiety

• 49% of people achieved 5% weight loss (n=3350 over 3 studies).

• Martin et al. (2010): Reduced energy intake at ad-lib lunch and dinner, reduced appetite and hunger.

• Farr, et al. (2016b):Decreased amygdala at baseline predicts weight loss. – first study to try and predict responders from baseline brain activity

Efficacy: Lorcaserin

Phentermine/Topiramate (Qsymia) • Phentermine = amphetamine derivative• Topiramate = anticonvulsant with weight loss

properties

• Combination of lower doses of each drug to reduce undesired cardiovascular effects whilst having a synergistic effect on weight loss.

• Exact mechanism of action unclear

• Impressive weight loss data at phase 3

• No mechanistic/behavioural or neuroimaging data

• Behavioural specificity of phentermine/topiramate remains unknown

• Without clear data on how the drug effects eating behaviour it is difficult to suggest which individuals may benefit from taking this drug and to assess its tailoring potential.

Efficacy: Phentermine/topiramate

Drugs for weight-loss – what we know

• What we do know: Drugs can be effective in achieving 5% weight loss

• Each drug will have a large portion of non-responders

• Developing tailored weight management plans to meet individual needs is the gold standard in specialist weight management services

• Pharmacotherapy as an aid to reduced calorie diets and behaviour modification may provide additional benefit for achieving and maintaining clinically meaningful weight loss.

• Which drugs will benefit which patients (little data to enable the link between pharmacology and real world therapeutic benefits i.e. proof of concept)

• There are not enough data for clinicians to make informed decisions about the pharmacotherapeutic tools at their disposal.

• Without appropriately designed, well-powered mechanistic studies detailing drug effects on the substrates of eating behaviour, the tailoring potential of these drugs remains speculative.

Drugs for obesity – what we don’t know

What needs to be done? • In order to deliver personalised treatment it is necessary to characterise drug effects on

behaviors associated with increased energy intake.

• Clinical response to pharmacotherapy can vary greatly, sub-populations of people who respond to drug treatment successfully need characterising

• Ultimately patients understand their own needs and behaviour better than anyone. Personalised treatment requires input from the patient.

• If we know more about how the drugs work on behaviour, then clinicians and patients together will be able to make informed decisions about the most appropriate drugs to target specific barriers to weight-loss goals

Take home• Pharmacotherapy has the potential to be very helpful in aiding behaviour modification.

• E.g. Reducing hunger for those with weak satiety signalling, or reducing cravings for problem foods, or dampening reward sensitivity so foods are not so attention grabbing, reducing temptations, or helping with emotional eating.

• Or offset increases in the above as a result of dieting

• Try to identify problematic eating behaviours that you have difficulty modifying (may be entrenched habits)

• Think about whether drug therapy may be helpful to make that behaviour change – what evidence is there that a drug might help you with your specific challenges (personalise your plan)

Thank you for listening

• Questions?

• Email: Carl.Roberts@Liverpool.ac.uk• Twitter: @Carl_A_Roberts

What is the medication - habit connection?

Robert Kushner, MD.Professor of Medicine

Northwestern University Feinberg School of MedicineDirector, Center for Lifestyle Medicine

Northwestern MedicineChicago, IL, USA

rkushner@northwestern.edu

Inside the person Outside the person

Increased intake

Increased intake

Intake & expenditure

(or unknown)

Intake & expenditure

(or unknown)

Decreased expenditure

Decreased expenditure

Contributors to energy storage

Disordered eating • Hyperreactivity to Environmental

food cues• Delayed satiety• Heightened hunger responsesEmotional

coping

• Age-related changes• Pathological sources of endocrine dysregulation• Central & peripheral regulators of appetite and

adipose tissue• Chronic inflammation• Genetic and epigenetic factors

• Self regulatory & coping deficits• Trauma history• Mood disturbance• Mental disabilities

Gestational diabetes

• Thermogenesis• Gut microbiota• Pain sensitivity• Physical disabilities

Social anxiety

• Maternal employment• Breast feeding and/or related

factors• Maternal stress• Maternal smoking• Delayed prenatal care• Birth order• Having children (women)• Non-parental childcare• Maternal over-nutrition during

pregnancy• Birth by c-section

• Stress• Child mistreatment• Weight cycling

• Family conflict• Social networks• Weight bias and stigma• Entering into a romantic

relationship• Lack of employer preparedness to

assist with obesity• Lack of health care provider

support/knowledge & inadequate access to care

• Westernisation & economic development• Low SES & nutrition support Living in crime-prone area

• Infection• Weight gain inducing drugs• Smoking cessation• Sleep deficits

• Consistent temperature• Increased sedentary time• Built environment• Decreased opportunity for

non-exercised based physical activity

• Labour-saving devices

Prenatal air pollution

Environmental/chemical toxins

• Increased availability of energy dense, nutrient poor foods and beverages

• Larger portion sizes• Eating as recreation, snacking, special occasions• Lack of nutritional education• Skipping meals• Food insecurity• Diet patterns• Eating away from home• Lack of family meals

• Market economy• Food surplus• Pervasive food advertising

Adapted from www.obesity.org/obesity/resources/facts-about-obesity/infographics/potential-contributors-to-obesity (Accessed 27 March 2018)

Environmental Pressures on Physical activity Biological/Medical Maternal/Developmental Economic Food and Beverage Behaviour/Environment Psychological Social

POTENTIAL CONTRIBUTORS TO OBESITY

Medications work “inside the person” to alter appetite

Sensory Factors:TasteSmell

TextureSight

Effects of varietySensory-specific satiety

PalatabilityFood concentrationReady availability

Brain mechanisms: Modulate sensory factors by

satiety signals to produce reward value and appetite

Satiety/hunger signals:Fat cell hormones

Gut hormonesGastric distention

Cognitive factors:Conscious rational control

Beliefs about the foodAdvertising

Eating

Eating Triggers

Adapted from Rolls. Obesity Rev 2007

Family & social influences

Weight Loss Requires Translation of Brain Signaling into Change in Eating Behavior

2. Reduced appetite (neurochemical)

3. Reduce eating (behavioral)

4. Cognitive learning & cueing(behavioral)1. Take drug

Prefrontal Cortex

Nucleus AccumbensStriatum

Hypothalamus

Substantia Nigra

Ventral Tegmental Area

Amygdala

Weight Loss Requires Translation of Brain Signaling into Change in Eating Behavior

2. Reduced appetite (neurochemical)

3. Reduce eating (behavioral)

4. Cognitive learning & cueing(behavioral)1. Take drug

Prefrontal Cortex

Nucleus AccumbensStriatum

Hypothalamus

Substantia Nigra

Ventral Tegmental Area

Amygdala

Weight Loss Requires Translation of Brain Signaling into Change in Eating Behavior

2. Reduced appetite (neurochemical)

3. Reduce eating (behavioral)

4. Cognitive learning & cueing(behavioral)1. Take drug

Prefrontal Cortex

Nucleus AccumbensStriatum

Hypothalamus

Substantia Nigra

Ventral Tegmental Area

Amygdala

Weight Loss Requires Translation of Brain Signaling into Change in Eating Behavior

2. Reduced appetite (neurochemical)

3. Reduce eating (behavioral)

4. Cognitive learning & cueing(behavioral)1. Take drug

Prefrontal Cortex

Nucleus AccumbensStriatum

Hypothalamus

Substantia Nigra

Ventral Tegmental Area

Amygdala

Blundell et al. Obes Rev 2010;11:251–270; van Can et al. Int J Obes 2014;38:784–93

Components of appetite

HungerDrive to consume

WantingMotivation to

consume a specific food (craving)

Liking (hedonic)Sensory pleasure elicited

by contact with food

SatiationNegative feedback, leading

to meal termination (within-meal inhibition)

SatietyEnd state of satisfaction

(between-meal inhibition)

Fullness Physical feeling

experienced in the gut

Prospective food consumption

How much an individual feels they would like to eat

Difficulty controlling diet: What does it sound like?• “I’m on the ‘see food diet’—I see

food, and I eat it.”• “If I have sweet treats in the house,

I just can’t stop thinking about them.”

• “For me, eating just begets more eating.”

• “I have always turned to food for comfort.”

• “Ice cream is my best friend when I’m lonely.”

• “I love to eat. It is one of my greatest pleasures.”

• “The amount of food I eat is similar to how much my friends and coworkers eat, so it’s hard to know if my portions are too large.”

• “I don’t get a red stop signal that tells me when to stop eating.”

• “I was always a ‘clean-your-plate’ kind of person.”

15. How difficult has it been to resist eating this food during the last 7 days?14. How often have you had cravings for savoury foods?

13. How often have you had cravings for fruit or fruit juice?12. How often have you had cravings for other sweets?

11. How often have you had cravings for chocolate-flavoured foods?10. How pleasant have your meals been?

9. How often have you had thoughts of food?8. How full have you felt after meals?

7. How hungry have you felt?6. How difficult has it been to control your meal portion sizes?

5. How often have you eaten in response to food cravings?4. How difficult has it been to resist any food cravings?

3. Overall, how difficult has it been to control your eating?2. How strong have any food cravings been on average?

1. How often have you had food cravings?

-40 -20 0 20

Blundell J et al. Diabetes Obes Metab 2017;19:1242-1251

Effect of semaglutide on multiple parameters of appetite

ETD (semaglutide 1.0 mg – placebo), mm

Weight Change Over 104 Weeks With Lorcaserin(Belviq) Therapy

Smith SR, et al. NEJM 2010;363:245-56

Smith SR, et al. NEJM 2010;363:245-56

Weight Change Over 104 Weeks With Lorcaserin(Belviq) Therapy

Data availableLiraglutide 3.0 mg 1467 1295 1223 1161 1100 1030 971 911 885 849 830 805 780 747 778Placebo 734 635 576 544 508 465 436 399 375 365 354 336 327 322 320

Off-drugfollow-up

period

le Roux CW, et al. Lancet 2017;389:1399-1409

3 years of liraglutide (Saxenda) versus placeboLiraglutide 3.0 mgPlacebo

LOCFLOCF

–3.5% –3.4%

–8.5%–9.2%

–2.7%

–7.1%

–1.9%

–6.1%

0 16 28 40 56 68 80 92 104 116 128 140 152 160 172-12

-10

-8

-6

-4

-2

0

Chan

ge in

wei

ght (

%)

Weeks

Why do people regain weight? Are they less motivated?• People are motivated because…

• they value a particular activity (internal/intrinsic motivation), or• there is strong external coercion (external motivation)

• People will be internally motivated only when a change holds personal interest for them, such as enjoyment, satisfaction, and intrinsic reward

• However, intrinsic motivation requires supportive conditions (people and environment)

Importance of reducing simple carbohydrates for diabetes

Environmental factors at workBill is motivated to change his diet since he wants to control his diabetes. He understands the link between diabetes and diet.

Food AvailabilityAbundanceSnackingConvenience StoresVending MachinesProcessed FoodsCooking LessEating Out MoreLarge PortionsFast Food ChoicesValue MealsFood CourtsAll You Can Eat Buffets

Should Eat Healthy FoodsShould Watch Portion SizesShould Cook MoreShould Eat Only When Hungry

What determines a patient’s eating habits?

Healthy Choices

Unhealthy Environment

Importance of reducing calories for weight loss

“We like you just the way you are.”

Rose is motivated to lose weight since her mother died of obesity-related complications. She understands that losing weight now will help her avoid getting those complications.

Wadden et al. Arch Intern Med 2001;161:218

Its not just the medication – it’s what you do with the medication that makes the difference!

0

5

10

15

20

0 2 4 6 8 10 12Time (months)

Wei

ght L

oss (

%)

*

*Medication, behavior modification and meal replacements

Medication and behavior modification

Medication* alone

*P < 0.05 vs medication alone

*sibutramine

Cognitive Behavioral Therapy

Wadden TA, Foster GD. Med Clin North Am. 2000;84:441-461.

Problem solvingSelf monitoring

Cognitive restructuring

Social support

Stress management

Stimulus control

Contingency managementHealth

Behavior

Cognitive Behavioral Therapy

Wadden TA, Foster GD. Med Clin North Am. 2000;84:441-461.

Problem solvingSelf monitoring

Cognitive restructuring

Social support

Stress management

Stimulus control

Contingency managementHealth

Behavior

Stimulus Control: Take Control Action Steps

• Make your home a safe haven.• Make healthy options the easiest choice.• Keep portions in check.• Tame hunger with the right foods.• Tackle eating temptations head on.• Develop an emotional-eating action plan.• Control intense cravings and eating impulses.

Cognitive Behavioral Therapy

Wadden TA, Foster GD. Med Clin North Am. 2000;84:441-461.

Problem solvingSelf monitoring

Cognitive restructuring

Social support

Stress management

Stimulus control

Contingency managementHealth

Behavior

Simply Monitoring Often Changes Behavior• Heisenberg Principle

• The very act of observing a phenomenon alters that phenomenon in some way

• Hawthorne Effect• The tendency of some people to work harder and

perform better when they are observed.• Individuals may change their behavior due to the

attention they are receiving

The Power of Monitoring and Accountability

How to Change BehaviorInformation and Reasonable Expectations

Self-Monitoring

Weight (obesity)

Blood Pressure (hypertension)

Blood Sugar (diabetes)

Electronic Programs

27

Tracking Physical Activity

JawBone smartphoneNike FUEL

Fitbug FitbitBodyMedia

Cognitive Behavioral Therapy

Wadden TA, Foster GD. Med Clin North Am. 2000;84:441-461.

Problem solvingSelf monitoring

Cognitive restructuring

Social support

Stress management

Stimulus control

Contingency managementHealth

Behavior

Depletion of self-regulatory resources leads to lose of self-control

Sleep deprivation Stress

Changing eating habits is hard

• Executive function• Controlling thoughts, emotions,

and actions toward achieving a new behavior

• Managing temptation techniques• Environment & stimulus control• Urge surfing• Problem solving• Acceptance-based therapy

• Techniques for developing and sustaining healthy habits and lifestyle patterns

• Context-dependent repetition• Self-regulation strategies (self-

monitoring & planning)• Coping planning• Accountability & positive feedback• Social support• Behavioral flexibility

• Pharmacotherapy (anti-obesity medication) is an effective adjunct to obesity care through its impact on multiple processes of appetite regulation

• Long-term weight management depends on habit formation, executive function and control of temptations

• Stress and sleep deprivation deplete self-regulatory resources leading to lose of self-control

• By reducing appetite, it is easier to control food intake and make healthier behavioral changes

Summary