Why treat obesity? The entity of diabesity · 2019. 9. 24. · 6.7x. n=4369. 17.4x. Hu . et al. Arch Intern Med. 2004;164:892–6 *Prediabetes defined as fasting plasma glucose of

Why treat obesity?The entity of diabesity

Dr. Ann VerhaegenUZAZNA Jan Palfijn

Ann Verhaegen is a member of the Advisory Board and/or Speakers Bureau of:– Amgen– AstraZeneca– Boehringer Ingelheim– Eli Lilly & Co– Janssen-Cilag / J & J– Merck Sharp & Dohme– Novo Nordisk– Sanofi

Conflict of interest disclosures

Obesity is a complex and multifactorial disease

Badman MK & Flier JS. Science 2005;307:1909–14; US Department of Health and Human Services, 1998. NIH Publication No. 98-4083

Energy intake

Experienced palatability or

pleasure

Hedonic input

Energy expenditure

Environment

Inactive lifestyle, smoking cessation, psychosocial factors

and endocrine disruptors

Adipose tissue GutPancreas Genetics Medications

Obesity is associated with multiple complications

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

Physical functioning

Arthrosis

Sleep apnoea

IncontinenceCancers

Stroke

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

Type 2 diabetesPrediabetes

Thrombosis

Gout

Asthma

NAFLD

Gallstones

Infertility

Depression

Anxiety

Natural history of type 2 diabetes

Genetic susceptibility

Insulin resistance ↑

IGT

Type 2 diabetes

Obesity

Physicalinactivity

Early life events:Low birth weightFormula feeding

Compensatoryinsulin secretion

Reducedβ-cellfunction

Intrauterine nutritionInherited β-cell defectGlucotoxicityLipotoxicity

Impaired fasting glucose and glucose intolerance lead to an increased risk for T2DM

Gabir et al. Diabetes Care 2000;23:1108–12;

Individuals with obesity and prediabetes are at 17 times greater risk of type 2 diabetes

20Re

lativ

e ris

k fo

r T2D

vs

heal

thy

indi

vidu

als

0Obesity

5

10

15

Prediabetes* Obesity and prediabetes*

4.9x6.7x

17.4xn=4369

Hu et al. Arch Intern Med 2004;164:892–6

*Prediabetes defined as fasting plasma glucose of 110 mg/dL (6.1 mmol/L) and 2-h plasma glucose less than 140 mg/dL (7.8 mmol/L); impaired glucose regulation: fasting plasma glucose concentration 110–126 mg/dL (6.1–6.99 mmol/L) and/or 2-h plasma glucose concentration 140–200 mg/dL(7.8–11.09 mmol/L). RR, relative risk; T2D, type 2 diabetes

Excess weight is a risk factor for type 2 diabetes (Nurses Health Study)

0

20

40

60

100

Relative risk of type 2 diabetes

80

Relative risk for diabetes: weight at age 18 and weight gain till 32 years

BMI, body mass indexColditz GA et al. Ann Intern Med 1995;122:481–6

Rela

tive

risk

20

20

40

60

80

29.0

BMI at age 18

Weight gain 18–32 years (kg)

Environmental and lifestyle factorsin obesity and diabetes

Independent of age, exercise levels, sedentary behaviours, especially TV watching, were associated with significantly elevated risk of obesity and type 2 diabetes

Sedentary behaviours increase risk of obesity

Hu FB et al. JAMA 2003;289:1785–91

Each 2-hr/day increment in TV watching was associated with 23% increase in obesity and

14% increase in risk of diabetes

Pollutants and risk of diabetes, metabolic syndrome and obesity

Lim JS et al. Diabetes Care 2008;31:1802–7; Hectors TL et al. Diabetologia 2011;54:1273–90

Sleep restriction and risk of obesity

CI, confidence interval; OR, odds ratioWu Y et al. Sleep Med 2014;15:1456–62; Van Cauter E & Knutson KL. Eur J Endocrinol 2008;159 Suppl 1:S59–66

Chaput JP

Kobayashi D

Sayón-Orea C

Vgontzas AN

Stranges S (female)

Nagai M

Patel SR

Itani O

Itani O

Watanabe M (male)

Watanabe M (female)

Xiao Q (male)

Xiao Q (female)

Nishiura C (male)

Overall (I-squared = 66.3%, p=0.000

NOTE: Weights are from random effects analysis

Author Year

2010

2012

2013

2013

2008

2013

2006

2011

2011

2010

2010

2013

2013

2010

OR (95% CI)

2.97 (1.68, 4.34)

1.50 (1.10, 2.00)

1.94 (1.19, 3.18)

1.08 (0.48, 2.41)

1.05 (0.60, 1.82)

0.96 (0.59, 1.57)

1.15 (1.04, 1.27)

1.20 (1.09, 1.32)

1.71 (1.11, 2.87)

1.91 (1.36, 2.67)

0.35 (0.05, 2.69)

1.45 (1.06, 1.99)

1.37 (1.04, 1.79)

2.46 (1.41, 4.31)

1.45 (1.25, 1.67)

0.5 1 2 5

Sleep duration

Mechanisms linking obesity to diabetes, CVD and NASH

Prevalence of diabetes according to waist & BMI (worldwide IDEA study)

Circulation. 2007 Oct 23;116(17):1942-51

Nat Rev Dis Primers. 2017 Jun 15;3:17034.

A link between obesity, inflammation and cardiovascular disease: the role of ectopic fat

CRP, c-reactive protein; ICAM-1, intercellular adhesion molecule 1; IL-6, interleukin 6; LDL-ox, oxidised low-density lipoprotein; MCP-1, monocyte chemoattractant protein 1; NEFA, non-esterified fatty acids; PAI-1, plasminogen activator inhibitor-1; RBP-4, retinol binding protein 4; ROS, reactive oxygen species; TNF-α, tumor necrosis factor α; VLDL, very low-density lipoproteinVan Gaal LF et al. Nature 2006;444:875–80

Anstee QM et al Nat Rev Gastroenterol Hepatol 2013

From NAFLD or NASH to diabetes and CVD

Intestinal microbiota can alter human cardio-metabolism.

Sarah Vinjé et al. Eur Heart J 2014;35:883-887

Microbial Modification of Bile Acids and Its Metabolic Effect

Trends Endocrinol Metab. 2018 Jan;29(1):31-41

Excess adiposity leads to major risk factors and common chronic diseases

CHD, coronary heart disease; CHF, coronary heart failure; CKD, chronic kidney disease; GERD, gastroesophageal reflux disease; NAFLD, non-alcoholic fatty liver disease, NASH, non-alcoholic steatohepatitis; OSA, obstructive sleep apnoea; T2D, type 2 diabetesHeymsfield SB & Wadden TA. N Engl J Med 2017;376:254–66

Adiposity

Adipokine synthesis

Adipose tissue macrophages and other inflammatory cells

Pro-inflammatory cytokines

Impaired insulin signalling and insulin resistance

Insulin

T2D

Lipid production

Hydrolysis of triglycerides

NAFLDNASH

Cirrhosis

Release of fatty acids

Lipotoxicity Dyslipidaemia

CHD

CHFStrokeCKD

Activity of the sympathetic nervous

system

Activity of the renin-angiotensin-aldosterone

system

Mechanical stress

Systemic and pulmonary

hypertension

Pharyngeal soft tissue

Mechanical load on joints

Intra-abdominal pressure

Renal compression

GERDBarrett’s oesophagus

Oesophageal adenocarcinoma

OsteoarthritisOSA

Can weight loss prevent or even cure diabetes?

CV, cardiovascular; NAFLD, non-alcoholic fatty liver disease1. Van Gaal L et al. Int J Obes 1989;13 Suppl 2:47–9; 2. Knowler WC et al. N Engl J Med 2002;346:393–403; 3. Dattilo AM & Kris-Etherton PM. Am J Clin Nutr 1992;56:320–8; 4. Wing RR et al. Diabetes Care 2011;34:1481–6; 5. Dixon JB et al. Hepatology 2004;39:1647-54; 6. Patel AA et al. J Clin Gastroenterol 2009;43:970-4; 7. Warkentin LM et al. Obes Rev 2014;15:169–82; 8. Wright F et al. J Health Psychol2013;18:574–86; 9. Foster GD et al. Arch Intern Med 2009;169:1619–26; 10. Kuna ST et al. Sleep 2013;36:641–9; 11. Li G et al. Lancet Diabetes Endocrinol 2014;2:474–80

What are the effects of weight loss?

Benefits of 5–10% weight loss

Reduction in CV mortality11

Improvements in severity of

obstructive sleep apnoea9,10

Improvements in blood lipid profile3

Reduction in risk of type 2

diabetes1,2

Improvements in health-related quality of life7,8

Improvements in blood pressure4

Improvements in abnormal NAFLD liver histology5,6

Years are duration of trial or follow-up. Data are versus placebo and not directly comparable due to differences in study designDPP, Diabetes Prevention Programme; DPPOS, Diabetes Prevention Programme Outcomes Study; DPS, Diabetes Prevention Study; T2D, type 2 diabetes1. Tuomilehto et al. N Engl J Med 2001;344:1343–50; 2. Lindström et al. Lancet 2006;368:1673–9; 3. Knowler et al. N Engl J Med 2002;346:393–403; 4. Knowler et al. Lancet 2009;374:1677–86; 5. Li et al. Lancet 2008;371:1783–9

Weight loss can reduce progression to T2D

Lifestyle intervention trials% reduced risk of progression from prediabetes to T2D

Finnish DPS1,2

6 years

58%

10 years

34%

DPP/DPPOS3,4

4 years

58%

Da Qing5

6 years

51%

20 years

43%39%

13 years

Look AHEAD: NO cardiovascular benefit, unless …

Look AHEAD, NEJM, 2013

Look AHEAD Research Group. Lancet Diabetes Endocrinol. 2016. [Epub ahead of print]

Weight-loss responders have improved CV outcomesA post-hoc analysis of the Look AHEAD randomised clinical trial

Hazard ratio

Primary outcome - 21% lowerCV death, non-fatal acute MI, non-fatal stroke, or admission to hospital for angina

Secondary outcome - 24% lowerAs above plus CABG, carotid endartectomy, PCI,hospitalisation for CHF, peripheral vascular disease, or total mortality

p=0.034

p=0.003

Responder: lost at least 10% of their bodyweight in the 1st year of the study

Favors controlFavors responders

N=4406 participants with T2D to an intensive lifestyle intervention or diabetes support and education

Grafiek1

0.64

0.79

0.98

0.63

0.76

0.91

Y-Values

1.5

1.5

1.5

0.5

0.5

0.5

Sheet1

X-ValuesY-Values

0.641.5

0.791.5

0.981.5

0.630.5

0.760.5

0.910.5

1. Increase the number of patients responding to lifestyle modification

2. Increase the magnitude of the response

3. Increase the duration of the response

Pharmacotherapy helps with adherence to a lifestyle change

Adapted from Lau DCW et al. CMAJ 2007;176:S1–S13

OverweightBMI ≥25 kg/m2

Obese Class 1 BMI ≥30 kg/m2

Obese Class 2BMI ≥35 kg/m2

Liraglutide 3.0 mg: Weight loss and progression to T2DMSCALE Obesity and Prediabetes: 3 years

Full analysis set, fasting-visit data only. Line graphs are observed means (±SE).

le Roux CW, Van Gaal L et al. Lancet 2017 Apr 8;389(10077):1399-1409.

-2.1%

-5.2%

Chan

ge in

wei

ght (

%)

Off-drug follow-up Off-drug follow-upLiraglutide 3.0 mg Placebo

Week

-7.1%

-2.7%

Part

icip

ants

(%)

80% risk reduction 47

31

172

46

26

*Derived from the primary Weibull analysis. ETD, estimated treatment difference; LOCF, last observation carried forward; SCALE, Satiety and Clinical Adiposity – Liraglutide Evidence in individuals with and without diabetes; SE, standard error; T2D, type 2 diabetes; WL, weight loss.

Week

Full analysis set. Numbers in the figure correspond to the accumulated number of diagnosed participants.

-9.2%

-3.5%

Grafiek1

112

2.812.3

2.812.3

12.317.1

12.317.1

17.617.8

17.617.8

23.865.8

23.865.8

34.566.2

34.566.2

3577.7

3577.7

52.878.1

52.878.1

5379

5379

53.290.4

53.290.4

53.4103

53.4103

65.3113.4

65.3113.4

65.9113.7

65.9113.7

66.1113.9

66.1113.9

78114.9

78114.9

78.3124.8

78.3124.8

78.5126.4

78.5126.4

78.7137.8

78.7137.8

79.4139.3

79.4139.3

90149.6

90149.6

101.6149.9

101.6149.9

102.1158.1

102.1158.1

102.3158.3

102.3158.3

102.7158.7

102.7158.7

125.4161.7

125.4161.7

125.8162.8

125.8162.8

125.8170.1

125.8170.1

126.3170.5

126.3170.5

126.6172.5

126.6172.5

126.9

126.9

137.7

137.7

138.4

138.4

150.7

150.7

151.6

151.6

152.9

152.9

158

158

158.2

158.2

158.4

158.4

158.7

158.7

169.7

169.7

Placebo

Liraglutide 3.0 mg

0.12

0.08

0.12

0.08

0.26

0.15

0.26

0.15

0.41

0.22

0.41

0.22

0.56

0.29

0.56

0.29

1.06

0.39

1.06

0.39

1.22

0.48

1.22

0.48

1.41

0.58

1.41

0.58

1.6

0.79

1.6

0.79

2

0.89

2

0.89

2.18

1

2.18

1

2.37

1.12

2.37

1.12

2.58

1.22

2.58

1.22

2.82

1.35

2.82

1.35

3.22

1.45

3.22

1.45

3.66

1.57

3.66

1.57

4

1.69

4

1.69

4.12

1.92

4.12

1.92

4.33

2.04

4.33

2.04

4.56

2.16

4.56

2.16

5.06

2.29

5.06

2.29

5.25

2.42

5.25

2.42

5.6

2.54

5.6

2.54

6.1

2.67

6.1

2.67

6.36

2.79

6.36

2.79

6.64

2.93

6.64

2.93

6.94

3.03

6.94

3.03

7.2

3.18

7.2

3.18

7.48

3.3

7.48

3.3

7.8

3.72

7.8

8.04

8.04

8.32

8.32

8.62

8.62

8.92

8.92

9.22

9.22

9.51

9.51

9.82

9.82

10.2

10.2

10.42

10.42

10.73

10.73

11.02

Sheet1

X-ValuesY-Values

10.12

2.80.12

2.80.26

12.30.26

12.30.41

17.60.41

17.60.56

23.80.56

23.81.06

34.51.06

34.51.22

351.22

351.41

52.81.41

52.81.6

531.6

532

53.22

53.22.18

53.42.18

53.42.37

65.32.37

65.32.58

65.92.58

65.92.82

66.12.82

66.13.22

783.22

783.66

78.33.66

78.34

78.54

78.54.12

78.74.12

78.74.33

79.44.33

79.44.56

904.56

905.06

101.65.06

101.65.25

102.15.25

102.15.6

102.35.6

102.36.1

102.76.1

102.76.36

125.46.36

125.46.64

125.86.64

125.86.94

125.86.94

125.87.2

126.37.2

126.37.48

126.67.48

126.67.8

126.97.8

126.98.04

137.78.04

137.78.32

138.48.32

138.48.62

150.78.62

150.78.92

151.68.92

151.69.22

152.99.22

152.99.51

1589.51

1589.82

158.29.82

158.210.2

158.410.2

158.410.42

158.710.42

158.710.73

169.710.73

169.711.02

120.08

12.30.08

12.30.15

17.10.15

17.10.22

17.80.22

17.80.29

65.80.29

65.80.39

66.20.39

66.20.48

77.70.48

77.70.58

78.10.58

78.10.79

790.79

790.89

90.40.89

90.41

1031

1031.12

113.41.12

113.41.22

113.71.22

113.71.35

113.91.35

113.91.45

114.91.45

114.91.57

124.81.57

124.81.69

126.41.69

126.41.92

137.81.92

137.82.04

139.32.04

139.32.16

149.62.16

149.62.29

149.92.29

149.92.42

158.12.42

158.12.54

158.32.54

158.32.67

158.72.67

158.72.79

161.72.79

161.72.93

162.82.93

162.83.03

170.13.03

170.13.18

170.53.18

170.53.3

172.53.3

172.53.72

Grafiek1

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-1.96-0.790.03533111480.03533111480.05067128040.0506712804

-3.29-1.190.0477166620.0477166620.06838306150.0683830615

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68680.21904669890.21904669890.28705437650.2870543765

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-8.68-3.30.22860022860.22860022860.3035222970.303522297

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80800.22881258890.22881258890.30506767180.3050676718

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-8.69-3.350.23829918950.23829918950.31836788690.3183678869

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92920.24451030830.24451030830.32490638710.3249063871

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-8.65-3.520.24796619540.24796619540.33404888830.3340488883

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1041040.25110130310.25110130310.34443731890.3444373189

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-8.28-3.330.25881066670.25881066670.35082550170.3508255017

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1161160.26494971410.26494971410.35331114770.3533111477

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-7.79-3.010.27371877680.27371877680.35825280240.3582528024

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1401400.28689730240.28689730240.38951893410.3895189341

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1721720.29756941680.29756941680.40640535490.4064053549

Liraglutide 3.0 mg

Placebo

0

0

-6.87

-2.64

-8.23

-2.9

-9.06

-3.23

-9.21

-3.52

-8.94

-3.44

-8.61

-3.17

-8.63

-3.36

-8.53

-3.43

-8.05

-3.26

-7.6

-3

-7.41

-2.86

-7.24

-2.74

-7.09

-2.69

-5.24

-2.08

Sheet1

Liraglutide 3.0 mgPlaceboLira 3.0 mg LOCFPlacebo LOCFLira 3.0 SEMPlacebo SEM

000

-1.96-0.790.03533111480.0507

-3.29-1.190.0477166620.0684

-5.05-1.880.06976589970.1001

16-6.87-2.640.10420687770.1504

-7.44-2.760.12079892470.1683

28-8.23-2.90.14354579950.2013

40-9.06-3.230.17110095950.2367

-9.26-3.460.19315584390.2530

56-9.21-3.520.20050504410.2609

-9.02-3.640.21458009080.2806

68-8.94-3.440.21904669890.2871

-8.68-3.30.22860022860.3035

80-8.61-3.170.22881258890.3051

-8.69-3.350.23829918950.3184

92-8.63-3.360.24451030830.3249

-8.65-3.520.24796619540.3340

104-8.53-3.430.25110130310.3444

-8.28-3.330.25881066670.3508

116-8.05-3.260.26494971410.3533

-7.79-3.010.27371877680.3583

128-7.6-30.27386589810.3662

-7.49-2.940.28338034010.3726

140-7.41-2.860.28689730240.3895

152-7.24-2.740.29611350040.3865

160-7.09-2.69-6.14-1.890.30587640450.40010.19160.2314

-6.35-2.80.30246881460.3964

172-5.24-2.080.29756941680.4064

Caiazzo R and Patou F J Visc Surg 2013

Different surgical procedures?

Sjöström L et al N Engl J Med 2004

Reduction of incidence and remission from diabetes in SOS study

Effect of ‘metabolic’ surgery – a cure for diabetes?

74 %

30 %

Sjöström. JAMA. 2014;311(22):2297-2304.

Effect of ‘metabolic’ surgery by duration

Sjöström. JAMA. 2014;311(22):2297-2304.

Schauer P., et al. NEJM 2012

Reduction of diabetes medication

Long-Term Mortality After Gastric Bypass Surgery

% re

duce

d/10

,000

per

son-

yrs

40%56%

60%92%

All CauseMortality

CoronaryArtery

DiseaseCancer Diabetes

Adams TD, et al. NEJM 2007;357:753

Cumulative incidence of diabetic complications after bariatric surgery

Sjöström L., et al. JAMA. 2014;311(22):2297-2304.

Cumulative incidence of diabetic complications by disease duration

Sjöström L., et al. JAMA. 2014;311(22):2297-2304.

Bariatric surgery vs conventional therapy in Type 2 diabetesSTAMPEDE Trial

RCT: conventional ↔ Gastric bypass ↔ Sleeve gastrectomie

Schauer, et al. NEJM 2012;366:1567-76

Age: 49±8j BMI 36.4kg/m²

Duration 8.5±5j

HbA1c 9.2% ± 1.5Insulin use 43%

- 5 kg - 30 kg - 25 kg

34%: BMI

Schauer PR et al for the STAMPEDE Investigators NEJM 2014

Stampede: surgery vs medical therapy 3 y outcome data

J. Holst et al. Surg Obes Relat Dis. 2018 May; 14(5): 708–714.

Mechanisms in bariatric surgery: Gut hormones, diabetes resolution, and weight loss

J Intern Med. 2016 Nov; 280(5): 476–486.

Are there weight loss-independent therapeutic effects of upper gastrointestinal bypass?

Take home messages

• Obesity and diabetes are closely linked

– Common environmental and lifestyle triggers

– Pathogenetic mechanisms link “diabesity” with NASH, CVD and other common diseases

• Diabetes can be prevented by weight loss

• Diabetes remission can be attained through metabolic surgery

– Mechanisms involved give rise to possible future medical therapies

44Dank aan Prof. Van Gaal voor het ter beschikking stellen van zijn slides

Why treat obesity?�The entity of diabesityConflict of interest disclosuresObesity is a complex and multifactorial diseaseObesity is associated with multiple complicationsNatural history of type 2 diabetesImpaired fasting glucose and glucose intolerance lead to an increased risk for T2DMIndividuals with obesity and prediabetes are at �17 times greater risk of type 2 diabetesExcess weight is a risk factor for type 2 diabetes �(Nurses Health Study)Relative risk for diabetes: weight at age 18 and weight gain till 32 yearsEnvironmental and lifestyle factors�in obesity and diabetesSedentary behaviours increase risk of obesityPollutants and risk of diabetes, metabolic syndrome and obesitySlide Number 13Sleep restriction and risk of obesityMechanisms linking obesity to diabetes, CVD and NASHPrevalence of diabetes according to waist & BMI �(worldwide IDEA study)Slide Number 17A link between obesity, inflammation and cardiovascular disease: the role of ectopic fatSlide Number 19Slide Number 20Slide Number 21Excess adiposity leads to major risk factors and common chronic diseasesCan weight loss prevent or even cure diabetes? �What are the effects of weight loss?Weight loss can reduce progression to T2DLook AHEAD: NO cardiovascular benefit, unless …Weight-loss responders have improved CV outcomes�A post-hoc analysis of the Look AHEAD randomised clinical trialPharmacotherapy helps with adherence to a lifestyle changeLiraglutide 3.0 mg: Weight loss and progression to T2DM�SCALE Obesity and Prediabetes: 3 yearsSlide Number 30Slide Number 31Effect of ‘metabolic’ surgery – a cure for diabetes? Effect of ‘metabolic’ surgery by durationSlide Number 34Long-Term Mortality After Gastric Bypass SurgeryCumulative incidence of diabetic complications after bariatric surgeryCumulative incidence of diabetic complications by disease duration �Bariatric surgery vs conventional therapy in Type 2 diabetes�STAMPEDE TrialSlide Number 39Slide Number 40Slide Number 41Slide Number 42Take home messagesSlide Number 44