Obesity is a Chronic Disease

Not Just a Lifestyle Choice10th Aug 2019Dr Hilton Kaplan MB BCH (Rand), FCPSA M.Med (UCT)

Specialist Physician and Endocrinologist

Disclosures & Disclaimer

Honoraria

•Novo Nordisk

Speaker 

•Novo Nordisk

Product Advisory Board 

•Novo Nordisk

• THIS IS A NOVONORDISK SPONSORED EVENT TO SUPPORT THE SCIENTIFIC COMMUNITY WITH CONTINUOUS MEDICAL EDUCATION.

• NOVO NORDISK SOUTH AFRICA DOES NOT ADVOCATE THE USE OF THEIR PRODUCTS OTHER THAN DESCRIBED IN THE LOCALLY APPROVED PACKAGE INSERT

• ALL PRESENTERS ARE INDEPENDENT HEALTHCARE PRACTITIONERS AND THEIR VIEWS DO NOT NECESSARILY REFLECT THOSE OF NOVO NORDISK SOUTH AFRICA

• LIRAGLUTIDE 3.0 MG IS NOT APPROVED FOR WEIGHT MANAGEMENT IN SOUTH AFRICA

INTRODUCTION:OBESITY• AN OVERWEIGHT PATIENT WALKS INTO YOUR CONSULTING ROOMS AND YOU LOOK AT THE PATIENT AND THINK:

”Perhaps this is your fault?” (BLAME)

“Has it been due to SLOTH AND GLUTTONY?

“IS YOUR PROBLEM DUE TO AN UNHEALTHY LIFESTYLE?””

(“What am I going to do now”? (How am I going to manage?//////Frustration@@@@@!!!)

The doctor feels helpless…AND THE PATIENT OFTEN FEELS GUILTY AND SELF CONSCIOUS

But is this a LIFESTYLE CHOICE or a DISEASE?

Obesity-Lifestyle choice or Disease?

• Obesity has been around for a long time

• It is a fallacy to assume that this is only a

modern lifestyle condition

• It was almost certainly something that was

evident thousands of years ago

• Was it a lifestyle condition then? Or is there

something more fundamental to the understanding

Venus of Willendorf (25 000 BCE)

Early Israelites, Christians and the Talmud 

Hippocrates (460BC‐370BC)

Writings in ancient Greece, India and Egypt

South Pacific Islands Jamaica, Kuwait and Afghanistan 

Early 19th and 20th Century

Post World War II ‐Physicians

History of Obesity

“Fertility, an idolization of beauty or desirability, object of worship or a totem for good fortune”

“Obesity was then stamped as shameful and undesirable”

“Obesity led to infertility, illness and early mortality”

“Suggested obesity as being an impediment to health”

“Girls were fattened up and then presented to the chief for his admiration as an example of beauty and fertility”

“Saw obesity as a societal rather than a medical problem”

“Obesity often a sign of success, sometimes an object of ridicule”

Obesity in Art

Definition and classification of obesity:

• Obesity is defined as abnormal or excessive fat accumulation that may impair health

• Body mass index (BMI) provides the most convenient population-level measure of overweight and obesity currently available

Classification BMI (kg/m2)

Underweight <18.5

Normal range ≥18.5 and <25

Overweight ≥25 and <30

Obesity ≥30

Obesity class I ≥30 and <35

Obesity class II ≥35 and <40

Obesity class III ≥40BMI =

weight (kg)height (m2)

Quetelet (1796‐1874)

“weight increases as a function of weight in kg divided by the square of the height in meters‐QUETELET INDEX”

Obesity is driving the type 2 diabetes pandemicAge standardised global prevalence of obesity and diabetes

1. Adapted from NCD Risk Factor Collaboration (NCD-RisC). Lancet 2017:390;2627–42 2. Adapted from NCD Risk Factor Collaboration (NCD-RisC). Lancet 2016:387;1513–30

Obesity1

1980 2000 2016

1980 2000 2014

Diabetes2

Prevalence, % <5 5–<10 10–<15 15–<20 20–<25 25–<30 30–<35 ≥35

East and South East AsiaHigh-income Asia PacificOceania

Latin America and CaribbeanHigh-income English speaking countries and Western EuropeCentral and Eastern Europe

Sub-Saharan AfricaCentral Asia, Middle East and North AfricaSouth Asia

1975 1980 1985 1990 1995 2000 2005 2010 2015

50M

100M

150M

200M

250M

300M

350M

1975 1980 1985 1990 1995 2000 2005 2010 2015

50M

100M

150M

200M

250M

300M

350M

Num

ber of people

Num

ber of people

Men BMI ≥30 kg/m2 Women BMI ≥30 kg/m2

Obesity rates worldwide are increasing

Adapted from NCD Risk Factor Collaboration (NCD‐RisC). Lancet 2017:390;2627–42

Obesity in South Africa

49.3

59.4

42

27

38

4

40

74.6

66

56.4

35.5

0 10 20 30 40 50 60 70 80

African Males

African Females

Coloured Males

Coloured Females

Caucasian Males

Caucasian Females

Indian Males

Indian Females

% Percent population

Popu

latio

n Ca

tegorie

s

South African 2015 Obesity & Overweight statistics

Obese & Overweight

Obese

South Africa has the 43rd highest average BMI in the world1.H. S. Kruger et al. Obesity in South Africa: Challenges for Government and Health Professionals. Article in Public Health Nutrition: September 2005;  2. A. Cois,  C. Day. Obesity trends and risk factors in the South African adult population. BMC Obes. 2015;2:42

Urbanization and Globalization

Coca‐Cola epidemic

Socio‐economic factors

Cultural Factors

Dietary practices

Physical activity

Broad causes of obesity in different socio-economic groups

• Take‐outs, fries, fats

• More TV and computer time, less sport, office‐based  jobs

• Perceptions and beliefs about body weight

• South Africa is one of the  largest markets for Coca Cola in the world 

• Obesity associated with age, level of education, ethnicity, area of residence

• Shift away from traditional foods

Bray et al. Obes Rev 2017;18:715–23; 2. AMA resolutions. June 2012. Available here; 3. Food and Drug Administration. Guidance for Industry Developing Products for Weight Management 2007 Available here; 4. Obesity Canada. Available here; 5. EASO: 2015 Milan Declaration: A Call to Action on Obesity. Available here; 6. EMA Draft Guideline on clinical evaluation of medicinal products used in weight control EMA/CHMP/311805/2014. Available here.

“Obesity is a chronic relapsing health risk defined by excess body fat”3FDA

“American Medical Association recognizes obesity and overweight as a chronic medical condition (de facto disease state) and urgent public health problem…and work towards the recognition of obesity intervention as an essential medical service…”2

AMA

American Medical Association

The US Food and Drug Administration

“Obesity is characterized by excess body fat that can threaten or affect your health. Many organizations including Obesity Canada, now consider obesity to be a chronic disease.”4

OC

Obesity Canada

“The World Obesity Federation takes the position that obesity is a chronic, relapsing, progressive disease process and emphasizes the need for immediate action for prevention and control of this global epidemic”1

WOF

World Obesity Federation

“A progressive disease, impacting severely on individuals and society alike, it is widely acknowledged that obesity is the gateway to many other disease areas…”5

EASO

European Association for the Study of Obesity

“Obesity is recognised as a chronic clinical condition and is considered to be the result of interactions of genetic, metabolic, environmental and behavioural factors, and is associated with increases in both morbidity and mortality”6

EMA

European Medicines Agency

Obesityis recognised as a disease and health issue

Obesity meets common criteria of a disease

• An impairment of the normal functioning of some aspect of the body• Characteristic signs or symptoms• Harm or morbidity

AMA

American Medical Association Resolution: 420 (A‐13). Available at: http://www.npr.org/documents/2013/jun/ama‐resolution‐obesity.pdf.

AMA, American Medical Association, NAFLD, non‐alcoholic fatty liver disease

• Appetite dysregulation• Abnormal energy balance• Endocrine dysfunction

• Increased body fat• Symptoms associated with increased body fat 

including:• Joint pain• Immobility

• Sleep apnoea• Infertility• NAFLD• Dyslipidaemia

• Type 2 diabetes• Cardiovascular disease• Cancer• Osteoporosis• Polycystic ovary syndrome

Obesity is associated with multiple comorbidities and complicationsMetabolic, mechanical and mental

Adapted from Sharma AM. Obes Rev. 2010;11:808‐9; Guh et al. BMC Public Health 2009;9:88; Luppino et al. Arch Gen Psychiatry 2010;67:220–9; Simon et al. Arch Gen Psychiatry 2006;63:824–30; Church et al. Gastroenterology 2006;130:2023–30; Li et al. Prev Med 2010;51:18–23; Hosler. Prev Chronic Dis 2009;6:A48

Metabolic

Type 2 diabetesPrediabetes

CVD and risk factors• Stroke• Dyslipidaemia• Hypertension• Coronary artery disease• Congestive heart failure• Pulmonary embolism

Infertility

NAFLD

Cancers*

Gout

Thrombosis

Asthma

Gallstones

Mental

Depression

Physical functioning

Mechanical

Sleep apnoea

Incontinence

Arthrosis

Chronic back pain

CVD, cardiovascular disease; NAFLD, non-alcoholic fatty liver disease*Including breast, colorectal, endometrial, esophageal, kidney, ovarian, pancreatic and prostate

Anxiety

Obesity is associated with more than 195 Complications

Prospective Studies Collaboration. Lancet 2009;373:1083–96

Data are based on male subjects; n=541,452

Life expectancy decreases as BMI increases

1000

20

40

60

80

100

35 40 50 60 70 80 90

BMI range (kg/m2)22.5–2525–3030–3535–4040–50

Normal BMI =almost 80% chance of reaching age 70

BMI 35–40 =~60% chance of reaching age 70

BMI 40–50 =~50% chance of reaching age 70

Prop

ortio

n still alive (%

)

Age (years)

020 25 35 5030 40 45

Body‐mass index

Deaths (in millions)

Deaths in 20150.4

0.3

0.2

0.1

Increasing BMI contributes to death and disability

GBD 2015 Obesity Collaborators N Engl J Med 2017;377:13–27

10

8

6

4

2

020 25 35 5030 40 45

Body‐mass indexDisability‐adjusted

 life‐years (in 

millions)

Disability‐adjusted life‐years in 2015

Musculoskeletal disorders Cardiovascular diseases Cancers Chronic kidney disease Diabetes mellitusCVD, cardiovascular disease, DALYs, disability‐adjusted life‐years

CVD, related to a high BMI, accounted for 2.7 million 

deaths 

34% of DALYs were the result of CVD in people with 

obesity

1. Knowler et al. N Engl J Med 2002;346:393–403; 2. Li et al. Lancet Diabetes Endocrinol 2014;2:474–80; 3. Datillo et al. Am J Clin Nutr 1992;56:320–8; 4. Wing et al. Diabetes Care 2011;34:1481–6; 5. Foster et al. Arch Intern Med 2009;169:1619–26; 6. Kuna et al. Sleep 2013;36:641–9; 7. Warkentin et al. Obes Rev 2014;15:169–82; 8. Wright et al. J Health Psychol 2013;18:574–86

Weight loss may improve obesity related comorbidities

Improvements in blood lipid profile3

Benefits of a 10% weight loss

Reduction in risk of type 2 diabetes1

Reduction in CV mortality2

Improvements in severity of 

obstructive sleep apnoea5,6

Improvements in health‐related quality 

of life7,8

Improvements in blood pressure4

15 20 25 30 35 40 45

Cawley et al. Pharmacoeconomics 2015;33:707–22

CI, confidence interval; US, United States

Obesity is associated with significant healthcare costsUS annual medical expenditure

Tota

l ann

ual m

edic

al

expe

nditu

res

per

pers

on (

$)

30k

25k

20k

15k

10k

5k

0

Healthyweight

Overweight Obesity

Population distribution Medical expenditure ± 95% CI

BMI (kg/m2)

8

6

4

2

0

Prevalence (% of population)

‐20,000

‐15,000

‐10,000

‐5,000

0

5,000

*Estimated costs are based on 2010 data for non-institutionalised US adults aged ≥18 years. Figure drawn based on data available in the reference

Adapted from Cawley et al. Pharmacoeconomics 2015;33:707–22

Change in expen

diture ($

)

5% weight loss10% weight loss15% weight loss20% weight loss

Baseline BMI (kg/m2)

Medical costs decrease with weight lossGreater savings with higher baseline BMI

Endocrine and childhood causes of obesity

Hormonal imbalance or illness as a direct cause of obesity is uncommon (<5%)

• Hypothyroidism • Cushing’s syndrome• Hypogonadism• Menopause: the role of FSH • PCO? – cause or effect? • Genetic and developmental diseases causing obesity in childhood

FUNDAMENTAL TO THE CONTROL OF APPETITE

•Obesity has long been misunderstood, trivialized, and stigmatized as a simple “lifestyle” issue that can be effectively be addressed by the mantra of “eat‐less‐move‐more”. 

•This simplistic view of obesity disregards both the lived experience of persons with obesity as well as the vast body of scientific evidence showing that, like other chronic diseases, obesity is a rather heterogeneous condition resulting from the complex interaction of a multitude of socio‐psycho‐biological factors that promote excessive weight gain and ultimately impair health.

•Most importantly, once established, powerful neuro‐hormonal factors effectively defend our bodies against weight loss, thereby often making obesity a life‐long problem, where weight regain (or relapse) is the rule 

Obesity is not just a lifestyle problem

•Obesity is associated with a prolonged imbalance between energy intake and expenditure, both of which are regulated by multiple feedback processes, each with associated internal and external factors. 

•These processes constitute three hierarchical control systems – homeostatic, hedonic, and cognitive – with extensive interaction between them

Obesity is the result of an interaction between the modern environment and our biology

Economic factors

Cognitive

Genetics/Epigenetics

Homeostatic

Social factors

Hedonic

Environmental factors

Hall et al. Am J Public Health 2014;104:1169‐75; Blundell et al. Obes Rev 2010;11:251–270

Social factors

Social factorsCognitive

CognitiveSocial factorsGenetics/epigenetics

Components of appetite

•Hunger

•Satiation

•Satiety

•Fullness

•PFC

Components of appetite

•Wanting

•Liking

•Reward 

PFC, prospective food consumption

External factors

Internal factors

Homeostatic regulation of appetite

ARC PVN

DMN

VMNLHA

Gut hormone system• The gut, adipose tissue and pancreas produce several 

hormones that promote satiety or hunger • These may influence central appetite control centres either 

directly via vagal afferents and the brainstem 

GutGhrelinPYYOXMGLP‐1CCK

Adipose tissue

Leptin

Hypothalamus

Simpson et al. Expert Rev Endocrinol Metab 2008;3:577–92; Cooke, Bloom. Nat Rev Drug Discov 2006;5:919–31; Berthoud. Curr Opin Neurobiol 2011;21:888–96

Homeostatic regulation• Biological systems act to maintain body weight,

including regulation via peptide hormones that can induce hunger/satiety

AP, area postrema; ARC, arcuate nucleus; AgRP, agouti‐related peptide; CART, cocaine and amphetamine regulated transcript; CCK, cholecystokinin; DMN, dorsomedial hypothalamic  nucleus; GLP‐1, glucagon‐like peptide‐1; NPY, neuropeptide Y; OXM, oxyntomodulin; LHA, lateral hypothalamic area; PP, pancreatic polypeptide; PYY, peptide‐YY; POMC, pro‐opiomelanocortin; PVN, paraventricular hypothalamic nucleus; NTS, nucleus tractus solitarius; VMN, ventromedial hypothalamic nucleus

Amylin

PancreasBrainstem

NTS

AP

Hedonic regulation of appetite

ARC PVN

DMN

VMNLHA

Hedonic control systems• Appetite is influenced by homeostatic (metabolic) and hedonic 

(pleasure, emotional) factors• Hedonic appetite systems comprise external sensory 

information processing, reward processing, and cognition and executive functions

• Multiple different areas are involved including the amygdala and the cortex

Prefrontalcortex

Cortex

Hypothalamus

Amygdala

Nucleus accumbens

Simpson et al. Expert Rev Endocrinol Metab 2008;3:577–92; Cooke, Bloom. Nat Rev Drug Discov 2006;5:919–31; Berthoud. Curr Opin Neurobiol 2011;21:888–96

Hedonic regulation• Reward of survival behaviours through pleasure• Operates even in the presence of satiety signals• Leads to food consumption beyond homeostatic

need• Link between hedonic attraction to food and

obesity

AP, area postrema; ARC, arcuate nucleus; DMN, dorsomedial hypothalamic; LHA, lateral hypothalamic area; PVN, paraventricular hypothalamic nucleus;NTS, nucleus tractus solitarius; VMN, ventromedial hypothalamic nucleus

Brainstem

NTS

AP

Hypothalamic regulation of appetite

ARC PVN

DMN

VMNLHA

Prefrontalcortex

Cortex

Hypothalamus

GutGhrelinPYYOXMGLP‐1CCK

Adipose tissue

Leptin

Nucleus accumbens

Hypothalamic regulation• The hypothalamus integrates signals from several different 

systems• Multiple hypothalamic nuclei are involved such as the ARC 

and PVN• Two main opposing neuronal types:

• AgRP/NPY neurons (hunger)• CART/POMC neurons (satiety)

Amygdala

Simpson et al. Expert Rev Endocrinol Metab 2008;3:577–92; Cooke, Bloom. Nat Rev Drug Discov 2006;5:919–31; Berthoud. Curr Opin Neurobiol 2011;21:888–96

AP, area postrema; ARC, arcuate nucleus; AgRP, agouti‐related peptide; CART, cocaine and amphetamine regulated transcript; CCK, cholecystokinin; DMN, dorsomedial hypothalamic  nucleus; GLP‐1, glucagon‐like peptide‐1; NPY, neuropeptide Y; OXM, oxyntomodulin; LHA, lateral hypothalamic area; PP, pancreatic polypeptide; PYY, peptide‐YY; POMC, pro‐opiomelanocortin; PVN, paraventricular hypothalamic nucleus; NTS, nucleus tractus solitarius; VMN, ventromedial hypothalamic nucleus

Amylin

PancreasBrainstem

NTS

AP

AppetiteEffectorsFeedingGastric emptyingMetabolic rate

Appetite

Hypothalamic regulation of appetite Peripheral signals modulate appetite and energy expenditure via hypothalamic neurons

Hypothalamus Hindbrain

Vagal afferents

Nucleus tractus solitarius

HungerSatietySecond order neurons

Arcuate nucleusNPY/AgRP

POMC/CART

Leptin     Insulin

Adiposity signals

Badman et al. Science 2005;307:1909–14; Seo et al. Endocr J 2008;55:867–74; Secher et al. J Clin Invest 2014;124:4473–88; Boyle et al. Mol Metab 2018;8:203–10

α-MSH, α-melanocyte stimulating hormone; AgRP, Agouti-related protein; CART, cocaine and amphetamine regulated transcript; GLP-1, glucagon-like peptide-1; NPY, neuropeptide Y; OXM, oxyntomodulin; POMC, pro-opiomelanocortin; PP, pancreatic polypeptide; PYY, peptide YY

Ghrelin

Hunger signals

PYY         GLP‐1PP             OXM Satiety 

signals

GLP‐1    Amylin

Satiety peptide

Area postrema

Other factors contributing to the pathogenesis of obesity

Other factors contributing to the pathogenesis of obesity

• >600 loci for obesity-related traits found in the last decade, but these

explain a small portion of total variance (approx. 3% of BMI)

• SNPs(single nucleotide polymorphisms) are not useful yet in predicting who will develop obesity

• Individual loci have small effects, but with sizable effects in combination

Can genes explain Obesity?

• Many other loci are involved in adipocyte metabolism- sexual dimorphism

• Key benefit of gene identification is elucidation of the pathophysiology of obesity which may one day lead to new therapies

• Requires detailed knowledge of causal SNP and genes affected

• So far, only known for FTO

Can genes explain Obesity

FTO Gene in Obesity

• So far, only known for FTO: individuals with 1 of the FTO obesity risk alleles reported increased food intake, especially high-energy foods, as well as impaired satiety.

• FTO variants mediate obesity by increasing energy output.

• People who are homozygous for the at-risk allele of r9939609 have approximately 1.7-fold increased risk of obesity and are about 3 kg heavier than average.

• Diet and lifestyle changes blunt the effects of a genetic predisposition toward obesity due to the FTO risk allele so allele carriers could be

TREATMENT

BARRIERS TO OBESITY TREATMENT: Obesity disease recognition

Results from the US ACTION study

65% of PwOrecognise obesity as a disease

65% of PwOrecognise obesity as a disease

80% of HCPsrecognise obesity as a disease

80% of HCPsrecognise obesity as a disease

Kaplan et al. Obesity (Silver Spring). 2018;26:61‐69

HCP: healthcare provider; PwO: people with obesity

Gaps in obesity careResults from the US ACTION study

PwO (n=3008) HCPs (n=606)

82% consider weight loss to be completely their own responsibility82% consider weight loss to be completely their own responsibility

Only 55% have received a formal diagnosis from their HCPOnly 55% have received a formal diagnosis from their HCP

Of those receiving a diagnosis, only 24% have a follow‐up appointmentOf those receiving a diagnosis, only 24% have a follow‐up appointment

Most HCPs down‐prioritise weight loss discussions due to lack of time or more important matters 

Most HCPs down‐prioritise weight loss discussions due to lack of time or more important matters 

HCPs set unrealistic weight loss targets with their patients (mean target of 19%)HCPs set unrealistic weight loss targets with their patients (mean target of 19%)

Little belief in the efficacy of weight loss medications and concerns about side‐effectsLittle belief in the efficacy of weight loss medications and concerns about side‐effects

Kaplan et al. Obesity (Silver Spring). 2018;26:61‐69

HCP, healthcare provider; PwO, people with obesity

Current obesity treatment guidelines

1. Jensen et al. Circulation 2014;129(25 Suppl 2):S102–38; 2. Garvey et al. Endocr Pract 2016;22(Suppl 3):1–203; 3. Yumuk et al. Obes Facts 2015;8:402–424; 4. Apovian et al. J Clin Endocrinol Metab 2015;100:342–62

ENDO Pharma Management 

20154

AACE Clinical Practice Guidelines 20162

ObesityACC/AHA/TOS 

20141

EASO Guidelines for Obesity Management 

20153

Guidelines describe obesity treatment pathway

Diet and exercise

Pharmacotherapy

Surgery

Three‐tiertreatment pathway

Available guidelines

AACE Clinical Practice 20163

Model

1. Jensen et al. Circulation 2014;129(25 Suppl 2):S102–38; 2. Yumuk et al. Obes Facts 2015;8:402–424; 3. Garvey et al. Endocr Pract 2016;22(Suppl 3):1–203

BMI‐centric

Complication‐centric

Diagnosis of obesity

BMI

Other anthropomorphic  measures*

EASO 20152

ACC/AHA/TOS 20141

Staging†

*Other measures include waist circumference and body composition assessments. †Optional step 

DIETS AND DIETING

LIFESTYLE MODIFICATION-Diet & Exercise

Individual Plan

Regular Follow‐Up Visits

Simple Sugars

Low GISnacking

Alcohol

Smaller Plate size

Ideal diet plan

0 5 10 15 20 25 30

Lifestyle intervention1

Very‐low calorie diet2,3

IBT4,5

Pharmaco‐therapy6

Gastric band7

Gastric sleeve8

Gastric bypass7

Efficacy of existing weight loss interventions

Weight loss (%)

3–5%

3–10%

4–6%

6–10%

24–38%

7–23%

9–38%

1. le Roux et al. Lancet 2017;389:1399–409 2. Lean et al. Lancet 2018;391:541–51; 3. Tsai & Wadden. Obesity 2006;14:1283–1293; 4. Wadden et al. Obesity 2011;19:1987–1998; 5. Wadden et al. Obesity 2018; doi:10.1002/oby.22359; 6. Patel. Metabolism 2015;64:1376–85; 7. Courcoulas et al. JAMA 2013;310:2416–25; 8. Berry et al. Obes Surg 2018;28:649–655

Diets (Pros and Cons)

Diet Type Cons

Paleo dietLimits whole grains, legumes and dairy which are healthy and nutritious

Vegetarian

Low in certain vitamins including B12, D, and other nutrients like Iron, zinc, calcium, iodine and omega‐3 acids

HCG with low calorie diet in phases

Many side effects. May be dangerous. FDA disapproves of this diet labeling it dangerous, illegal and fraudulent

The Zone DietLimits consumption of some healthy carb sources

Intermittent fastingDoes not suit everyone

Challenges in Weight-loss strategies

The Economist April/May 2019

• Calorie counting inaccurate

• Labeling of food inaccurate

• The way different people metabolize food differs depending on many complex factors

• Not all calories are equal

• Energy absorbed is influenced by food preparation

• Chilling and reheating influences the amount of calories absorbed

Weight-Loss & Maintenance strategiesChallenges and Obstacles

• Most successful dieters have 3% more protein, 5% more fat and 8% less carbohydrate

• No sugar• Exercise• Persistence• Patience• Encouragement

• Difference managing a person with a BMI 0f<30 and >30

• While lifestyle modification is essential in both situations the chances for successful weight loss to target (whatever that is) will decrease as the BMI increases

• Why is this SOOOO difficult?

Failed Diet

Hormonal

Environment

Neuronal Signalling Chemical

Body weight set‐point

Adherence

REASONS WHY DIETS FAIL

Brain serotonin, carbohydrate‐craving, obesity and depression. Wurtman RJ, Wurtman JJ. Obes Res 1995 Nov;Suppl 4:477S‐480S; Carbohydrate craving, obesity and brain serotonin. Richard J. Wurtman, Judith J. Wurtman. Elsevier.  Appetite. Volume 7, Supplement, 1986, Pages 99‐103; Traci Mann. Why do dieters regain weight. Psychological Science Agenda. May 2018

Physiological responses to weight loss favour weight regain1,2

Hunger Desire to eat

Gut

GLP‐1 CCK  PYY Ghrelin

Adipose tissue

Leptin

Energy expenditure

Energy intake

1. Schwartz et al. Obes Rev 2010;11:531–47; 2. Sumithran et al. N Engl J Med 2011;365:1597–604

CCK, cholecystokinin; GLP-1, glucagon-like peptide-1; PYY, peptide YY

Weight management interventions are often followed by weight rebound

Wadden et al. Ann Intern Med 1993;119:688–93

Wei

ght

chan

ge (

kg)

Very low-calorie dietModified diet + behaviour therapy

Very low-calorie diet + behaviour therapy

0

–5

–10

–15

–20

5

Intervention

1 2 3 4 50

Years post‐intervention

Data are from diet and behavioural interventions

*p<0.001, §p=0.008, †p=0.09 vs mean at baseline (week 0)

Sumithran et al. N Engl J Med 2011;365:1597–604

Hunger increases in response to weight loss

• 50 individuals with overweight/obesity lost weight on a 10‐week VLCD 

• Appetite was measured using VAS scores at 0, 10 and 62 weeks

95

90

85

80

00 8 10 18 26 36 44 52 62

Week

Weight (kg) All patients (ITT)

Completers40

20

00 30 60 120 180 240

Postprandial time (min)

Desire to eat (m

m)

40

20

00 30 60 120 180 240

Hunger (m

m)

Week 0 Week 10 Week 62

*

*

*

*

*

*

†

§

James et al. Lancet 2000;356:2119–25

A long-term approach to obesity management is required for maintaining weight loss104

102

100

98

96

94

92

90

88

Control

Medication

0 122 4 6 8 10 14 16 18 20 22 24

Body

 weight (kg)

Month

Weight loss Weight maintenance

*Approved for short‐term use. FDA Drugs: http://www.fda.gov/Drugs/default.htm; EMA Medicines: http://www.ema.europa.eu/

Pharmacological options for weight management

Orlistat Energy wastage

Mode of action Indications

Phentermine/topiramate Appetite suppression

Phentermine* Appetite suppression

Lorcaserin Appetite suppression

Naltrexone/bupropion Appetite suppression

Liraglutide 3.0 mg  Appetite suppression

Adjunct to diet and physical activity for chronic weight management in 

a) obesity BMI ≥30 kg/m2

b) overweight BMI ≥27 kg/m2

with comorbidity

Sibutramine Appetite suppression n/a Liraglutide 3.0 mg is not approved for weight management in South Africa

*Approved for short‐term use. FDA Drugs: http://www.fda.gov/Drugs/default.htm; EMA Medicines: http://www.ema.europa.eu/

Pharmacological options for weight management

Orlistat Energy wastage

Mode of action Indications

Phentermine/topiramate Appetite suppression

Appetite suppression

Naltrexone/bupropion Appetite suppression

Liraglutide 3.0 mg  Appetite suppression

Adjunct to diet and physical activity for chronic weight management in 

a) obesity BMI ≥30 kg/m2

b) overweight BMI ≥27 kg/m2

with comorbidity

Liraglutide 3.0 mg is not approved for weight management in South Africa

Many new pharmacological options in development

Trials are in progress

Watch this space……………………………….

Merchenthaler et al. J Comp Neurol 1999;403:261–80; Baggio, Drucker. Gastroenterology 2007;132:2131–57; Ducker, Nauck. Lancet 2006;368:1696–705

DPP‐4, dipeptidyl peptidase‐4; GLP‐1, glucagon‐like peptide‐1; t½, half‐life

What is GLP-1?

• GLP-1 is a peptide comprised of 31 amino acids• Member of incretin family• Secreted predominantly from L-cells in the gut, but also the brain (nucleus tractus solitarius)

t½=1.5–2 min

Enzymatic degradation by DPP‐4

Human endogenous GLP‐1

Lys

His Ala Thr Thr SerPheGlu Gly AspVal

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly Arg

Adapted from: Orskov et al. Scand J Gastroenterol 1996;31:665–70

GLP-1 is released in response to food intake

GLP-1Meal Meal Mealn=6

Plas

ma

GLP

-1

conc

entr

atio

n (p

mol

/L)

9 13 19 22Time (h)

0

10

20

30

40

50

24

Merchenthaler et al. J Comp Neurol 1999;403:261–80; Baggio, Drucker. Gastroenterology 2007;132:2131–57; Ban et al. Circulation 2008;117:2340–50; Vrang et al. Prog Neurobiol 2010;92:442–62; Pyke et al. Endocrinology 2014;155:1280–90

GLP-1 secretion and receptor expression

GLP‐1 is secreted by: GLP‐1R is expressed in:

AV, atrioventricular; GI, gastrointestinal; GLP-1R, glucagon-like peptide-1 receptor

Pancreas

GI tract

Kidney

Brain

Lung

Heart (AV node)

L‐cells ofthe gut

Neurons inhindbrain

*At an ad libitum lunch during GLP‐1 or saline infusion in 19 healthy normal‐weight male subjects. Data are mean ± SEM. GLP‐1, glucagon‐like peptide‐1; SEM, standard error of mean

Adapted from: Flint et al. J Clin Invest 1998;101:515–20 

GLP-1 increases satiety and reduces hunger In normal weight subjects

• Infusion increased plasma GLP-1 from 10 pmol/L to 60–90 pmol/L

Ad libitum lunchGLP-1 infusion 50 pmol/kg/h OR salineMeal

Time (min)

0

20

40

60

80

100H

unge

r (m

m)

360300240180120600

p=0.012

GLP-1 (n=19)Saline (n=19)

0

20

40

60

80

100

Time (min)

360300240180120600

p=0.013

Satie

ty (m

m)

Spontaneous ad libitum energy intake*

01

34

6

7

Ener

gy in

take

(M

J)

GLP-1Saline

5

2Mean: 4.2 MJ Mean: 3.7 MJ

p=0.002

Liraglutide 3.0 mg is not approved for weight management in South Africa

Liraglutide 3.0 mg influences all dimensions of appetite

0

20

40

60

80

100

Satiety Fullness Hunger PFC

* *

**

Adapted from: van Can et al. Int J Obes 2014;38:784–93

5 weeks treatment including 0.6 mg weekly dose escalation. Ratings are AUC15-300 min/285 min reported as FAS LS-means.*Statistical significance p≤0.01 vs. placebo. Data for overall includes 100 minus scores for hunger and PFC.AUC, area-under-the-curve; FAS, full analysis set; LS, least squares; PFC, prospective food consumption

Mean ratin

g (m

m)

Anorexigenic Orexigenic

Liraglutide 3.0 mg Placebo

Liraglutide 3.0 mg is not approved for weight management in South Africa

Secher et al. J Clin Invest 2014;124:4473–88; van Can et al. Int J Obes (Lond) 2014;38:784–93

Arcuatenucleus

POMC/ CART

NPY/ AgRP

Appetite

Liraglutide

Liraglutide increases satiety and reduces hunger Via neurons in the arcuate nucleus

AgRP, Agouti-related peptide; CART, cocaine- and amphetamine-regulated transcript; NPY, neuropeptide Y; POMC, pro-opiomelanocortin

HungerSatiety

Liraglutide 3.0 mg is not approved for weight management in South Africa

Persistence with obesity pharmacothery is low

0 3 6 9 12 15

0

20

40

60

80

100

Ganguly et al. Diabetes Res Clin Pract 2018;143:348–356

Persisten

ce ra

te (%

)

Follow up months

Persistence rate at 6 months

• Liraglutide 3.0 mg : 41.8%• Phentermine/topiramate: 27.3%*• Naltrexone/bupropion: 18.1%*• Lorcaserin: 15.9%*

*P<0.0001

Liraglutide 3.0 mg Phentermine/topiramate Naltrexone/bupropion Lorcaserin

Persistence rate at 12 months

• Liraglutide 3.0 mg : 33.0%• Phentermine/topiramate: 16.8%*• Naltrexone/bupropion: 12.7%*• Lorcaserin: 10.3%*

*P<0.0001

Kaplan–Meier plot

• Bariatric surgery: indications and outcomes

• Bariatric surgery is currently the most efficacious long-term treatment option, with the degree of weight loss depending on the type of surgical procedure performed

•However, due to the complexity and cost of this intervention, it is typically only used in individuals with a BMI ≥40 kg/m2 or a ≥35 kg/m2 with comorbidities, and is therefore only available to a limited number of individuals

How to manage the very obese?

Bariatric surgery is associated with sustained weight loss over 20 years

Sjöström L et al. JAMA 2012;307:56–65

Data are mean ±95% confidence interval

Weight change (%

)

Control

Banding

Vertical-banded gastroplasty

Gastric bypass

Years

0

–10

–20

–30

1 2 3 4 6 8 10 150 20

−1%(control)

−18%(mean, surgical interventions)

Mean weight loss from baseline:

SUMMARY:OBESITY

• There are complex multifactorial interactions between

• external environment• genetic, • metabolic and neurophysiological factors

• “adiposity-based chronic disease or ABCD” is a better term than obesity to more accurately represent the condition as a disease and focusing on the distribution and abnormal function of adipose tissue and not only on the BMI”-AACE 2017

• 10% Body Mass weight loss = improved outcomes

Summary

• Treatment is difficult- higher dose GLP-1 analogues might be an answer

• Bariatric surgery is still the most effective way to treat severe obesity

• Cost considerations for surgery is still a problem

Summary

ObesityComplex interactions

Pathognomicsymptoms

AACE201710% Body Mass drop

GLP‐1 Dose increase

Bariatric Surgery & 

Cost

Thank You

Thank You