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Obesity and the Continuum of Dysglycemia, Prediabetes and Diabetes

Sam Dagogo-Jack, MD, DM, FRCP

A. C. Mullins Endowed Chair in Translational Research

Professor of Medicine & Director

Division of Endocrinology, Diabetes, and Metabolism

Director, General Clinical Research Center

University of Tennessee Health Science Center

Memphis, Tennessee

DisclosuresSam Dagogo-Jack, MD

Research Grants: NIH/NIDDK

Clinical Trial Contracts (UTHSC):AstraZenecaNovo NordiskBoehringer Ingelheim

Consultant/Advisory Board: Merck, Novo Nordisk, Boehringer Ingelheim, Janssen, Sanofi, Amgen

• Review lifestyle and multimodality interventions for reversal of dysglycemia

• Discuss the integrated pathophysiology of obesity and dysglycemia

• Understand the principles of obesity pharmacotherapy and future directions in early intervention

OUTLINE

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Interplay of Genes and the Environment

Adapted from Dagogo-Jack S. Diabetes Care, 2011

Genes Environment

Insulin Resistance

Type 2 Diabetes

beta-Cell Dysfunction

+

OBESITY

Energy Expenditure

Energy Intake

GeneticPredisposition

Twin studies show ~50% concordance of obesity

Obesity: Chronic Disequilibrium Between Intake and Output

Energy Intake

EnergyExpenditure

Appetite, Satiety,Food Choices

• REE• EEE• TEF• NEAT

DiBaise JK et al. Mayo Clin Proc 83:460-469, 2008

The Human Gastrointestinal Microbiome

a- Prokaryotic phyla were identified by using an alignment of an 18,348-sequence datasetb- Not related to any known genera.

• The human microbial gene load (microbiome) contains approximately 100 times as many genes as does the human genome.

• Metagenomics focuses on the role of human and commensal microbial genes in health and disease.

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• a, Gas-chromatography mass-spectrometry quantification of short-chain fatty acids in the caeca of lean and obese C57BL/6J mice• b, Bomb calorimetry of faecal gross energy content (kcal/ g) of lean (+/+, ob/+; n=9) and obese (ob/ob; n=13) C57BL/6J mice• c, Colonization of germ-free wild-type C57BL/6J mice with a caecal microbiota from obese donors results in increased wt.

Total body fat content was measured before and after a 2-week colonization, using DEXA. *P<0.05, **P=0.01, ***P=0.001)

Turnbaugh PJ, et al. Nature 2006; 444, 1027-131

Fecal Transplantation Experiments

Energy Weight Change

Incr

ease

in b

ody

fat (

%)

Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Nature 2006;444:1022-1023

• Relative abundance of Bacteroidetes and Firmicutes

• Lean controls include 4 stool samples taken 1 yr apart(Mean + SE)

Intestinal Flora Associated with Weight Loss in Humans

• Abundance of Bacteroidetesfollowing weight loss

• > 2% weight loss for the CARB-R diet and > 6% for the FAT-R diet.

Cha

nge

in b

acte

roid

etes

abun

danc

e (%

)Pe

rcen

tage

of

tota

l se

quen

ces

Obesity and Diabetes

Colditz et al. Am J Epidemiol. 1990;132:504. (Nurses HS)

Diabetes

Body Mass Index (kg/m2)

0

10

20

30

40

50

60

Rel

ativ

e R

isk

<22 22– 23– 24– 25– 27– 29– 31– 33– 35+

22.9 23.9 24.9 26.9 28.9 30.9 32.9 34.9

Waaler HT. Acta Med Scand. 1984;679

Mortality

Nurses Health Study

4

Insulin resistance

Increased hepatic glucose production

Hyperglycemia

Incr

ease

d gl

ucos

ere

abso

rptio

n

Incr

ease

d lipol

ysis

Pathophysiological Defects in T2DM

Dagogo-Jack S, Askari H, Tykodi G. JCEM 94:2031-2036, 2009.

<90 90-99 100-125100-125FPG2-H PG <140 <140 <140 >140

0

.02

.04

.06

.08

.10

.12

.14

.16

ISI-

clam

p(m

ol/k

g.m

in-1

/pM

)

**

0

2

4

6

8

10

12

HO

MA

-IR

*

**

***

*

IFG IFG-IGT

Insulin Sensitivity

Insulin Resistance

Insulin Action and Secretion in Normal vs. Prediabetic Subjects

IFG IFG-IGT 2-H PG

FPG <90 90-99 100-125100-125<140 <140 <140 >140

Dis

po

siti

on

Ind

ex

0

.02

.04

.06

.08

.1

.12

.14

.16

# #

Disposition Index

*P=0.04. **0.002, ***P<0.0001, #P=0.02

Insu

lin S

ecre

tio

n (

pM

)

Cavaghan et al. J Clin Invest 1997;100:530-37

5

Insulin resistance

Increased hepatic glucose production

Hyperglycemia

Incr

ease

d gl

ucos

ere

abso

rptio

n

Incr

ease

d lip

olys

is

Pathophysiological Defects in T2DM and Prediabetes

✓ ✓

✓

✓

✓

✓Present in prediabetes

The Continuum of Dysglycemia

The Continuum of Dysglycemia

DPP Research Group. Diabet Med 24:137-144, 2007; Haffner SM, et al. Diabetologia 36:1002-1006, 1993; Papanas N, et al.Nat Rev Endocrinol 7:682-690, 2011

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Population Prevalence (%) of CKD Stages 1 – 4 by Diabetes and Prediabetes Status, NHANES 1999-2006

Plantinga L, et al. Clin J Am Soc Nephrol 5: 673–682, 2010

CKD diagnosed with eGFR by MDRD equation

Dagogo-Jack S, et al. J Clin Endocrinol Metab 99:1078-87, 2014

?

Question

Pathobiology of Prediabetes in A Bi-racial Cohort(POP-ABC)

Pathobiology of Prediabetes in A Bi-racial Cohort(POP-ABC)

Dagogo-Jack S, et al. J Clin Endocrinol Metab 98:120-128, 2013.

Baseline/ repeated assessments every 3 months x 5 years

OGTT in

African-Americans

Caucasians

with parental T2DM

Age: 18-65 yr

IFG

NFGNGT

T2DM

IGT

IFG/IGT

Baseline assessment

Baseline assessment

Baseline assessment

Progressors

IGT

NFGNGT

T2DM

IFG/IGT

IFG

Baseline

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Dagogo-Jack S, et al. J Clin Endocrinol Metab 99(6):E1078-87, 2014

Progression from Normoglycemia to Prediabetes

(P=0.7855)

All subjects

White

Black

Developed Prediabetes:

• 101 (29.5%)

Developed T2DM:

• 10 (2.9%)

Maintained NGR:

• 232 (67.6%)

0

10

20

30

40

50

60

Pe

rce

nt

of

Su

bje

cts

-40 -20 0 20 40 60 80Change in FPG from Enrollment (mg/dl)

White Offspring

0

10

20

30

40

50

60

-40 -20 0 20 40 60 80

Black Offspring

Pe

rce

nt

of

Su

bje

cts

0

10

20

30

40

50

60

-40 -20 0 20 40 60 80Change in FPG from Enrollment (mg/dl)

White Offspring

Glycemic Excursions Among Black and White Offspring of T2DM Parents

Predictors of Incident Prediabetes

Dagogo-Jack S, et al. J Clin Endocrinol Metab 99:1078-87, 2014; Boucher A, et al. Metabolism 64:1060-1067, 2015

• Age

• Male gender

• Behavioral

• Adiposity

• 2hrPG

• Adiponectin

• C-reactive protein

• Insulin sensitivity

• Insulin secretion

• Lipid profile

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Behavioral PredictorsA

1.0

2.0

3.0

4.0

15 25 35 45 55 65

(r = 0.14, P=0.01)

Body Mass Index (kg/m2)

FH

Q

Sco

re

B

-20

0

20

40

60

80

100

15 25 35 45 55 65

(r = -0.12, P=0.03)

Body Mass Index (kg/m2)

MA

Q (

ME

T-h

rs/w

eek)

DC

MA

Q/F

HQ

Metabolic Syndrome Components0 1 2 >3

0

2

4

6

8

10

12

***

Pro

gre

ssio

n (

%)

100

10

20

30

40

50

0

MAQ/FHQ Quartiles1 2 3 4

38.6% 38.1%31.0%

28.4%

• Review lifestyle and multimodality interventions for reversal of dysglycemia

• Discuss the integrated pathophysiology of obesity and dysglycemia

• Understand the principles of obesity pharmacotherapy and future directions in early intervention

OUTLINE

0

4

8

12

Caucasian AfricanAmerican

Hispanic AmericanIndian

Asian

Lifestyle Metformin Placebo

Diabetes Incidence Rates (per 100 pers-yr)

Screen

Randomize (IGT)

Lifestyle(n = 1079)

Metformin(n = 1073)

Placebo(n = 1082)

DPP Study Design

DPP Research Group. NEJM 346:393-403, 2002; Diabetes Care 28:888-894,2005

Diabetes Prevention Program (DPP)

% R

isk

Red

uct

ion

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Primary T2DM Prevention TrialsYear Study Follow-up Intervention Outcome

1982 Bedford 10 yr Diet + SU Decrease

1991 Malmo 10 yr Diet + exercise Decrease

1997 Da Quing 6 yr Diet + exercise Decrease, 51%

2001 DPS, Finland 3 yr Diet + exercise Decrease, 58%

2002 DPP 2.8 yr Diet+Ex vs. Met Decrease, 58%

2002 TRIPOD 2.6 yr Troglitazone Decrease, 59%

2002 STOP-NIDDM 3.3 yr Acarbose + Diet Decrease, 25%

2004 XENdos 4 yr Orlistat + Diet Decrease, 37%

2006 DREAM 3 yr Rosiglitazone Decrease, 60%

2008 ACT NOW 2-4 yr Pioglitazone Decrease, 72%

2006 IDPP-1 3 yr L/S + Met Decrease, 26-28%

2009 IDPP-2 3 yr L/S + Pio Pio not additive to L/S

2010 Navigator 5 yr Nateglinide No effect

Valsartan Decrease, 14%

2010 CANOE 4 yr Rosi+Met Decrease 69%

Echouffo-Tcheugui JB, Dagogo-Jack S. Nat Rev Endocrinol 8:557-562, 2012

DPP: Regression from Prediabetes to Normal Glucose Regulation

Freq

uenc

y (%

)

Lifestyle Metformin Placebo

Normal Diabetes

NEJM 346:393-403, 2002

Look AHEAD: Effects of ILI on Metabolic Endpoints

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

0 1 2 3 4

Year

DSE

ILI

% W

eig

ht

chan

ge

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0 1 2 3 4Year

DSE

ILI

A1

c (%

)

0

1

2

3

4

5

0 1 2 3 4

Year

DSE

ILI

HD

L (

mg

/dl)

-40

-30

-20

-10

0

0 1 2 3 4

Year

DSE

ILI

Trig

lyce

rid

es (

mg

/dl)

p<0.0001p<0.0001

p<0.0001

P=0.001

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

Year

Year Year

Year

10

Prevalence of remission Duration of remission

Continuous Remission (Partial/Complete)Number of Years

>1 >2 >3 4

20

16

12

8

4

0

Estim

ate,

%

Prev

alen

ce, %

Year1 2 3 4

16

12

8

4

0

Intensive lifestyle intervention

Diabetes support and education

Gregg EW, et al; Look AHEAD Research Group. JAMA. 308:2489-2496, 2012

Intensive lifestyle intervention

Diabetes support and education

Transition from meeting diabetes criteria to a prediabetes or nondiabetic level of glycemia (FPG <126 mg/dL and HbA1c <6.5%) on no DM meds

• Review lifestyle and multimodality interventions for reversal of dysglycemia

• Discuss the integrated pathophysiology of obesity and dysglycemia

• Understand the principles of obesity pharmacotherapy and future directions in early intervention

OUTLINE

Antidiabetes Medications, 1922-2016

Choices:

DegludecDegludecDulaglutideDulaglutide

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Weight Gain & Hypoglycemia: Common Features

Weight gain

• Majority of type 2 diabetes patients overweight/obese

• Exacerbated by insulin, TZDs and sulfonylureas

Preventive Approach• Lifestyle counseling

• DPP-4 inhibitors

• Metformin

• GLP-1 receptor agonists

• SGLT-2 inhibitors

Hypoglycemia

• Many diabetes patients have had hypoglycemia

• Exacerbated by insulin and sulfonylureas

Preventive Approach• Diabetes education

• DPP-4 inhibitors

• Metformin

• GLP-1 receptor agonists

• SGLT-2 inhibitors

Garvey WT, et al. AACE/ACE CPG … Care of Patients with Obesity. Endocr Pract. 2016 Jul;22 Suppl 3:1-203.

• R76. Pharmacotherapy for overweight and obesity should be used only as an adjunct to lifestyle therapy and not alone.

• R77. The addition of pharmacotherapy produces greater weight loss and weight loss maintenance compared with lifestyle therapy alone.

• R78. The concurrent initiation of lifestyle therapy and pharmacotherapy should be considered in patients with weight-related complications that can be ameliorated by weight loss.

• R79. Pharmacotherapy should be offered to patients with obesity, when potential benefits outweigh the risks, for the chronic treatment of their disease. Short-term treatment (3-6 months) using weight-loss medications has not been demonstrated to produce longer-term health benefits and cannot be generally recommended based on scientific evidence.

Principles of Obesity Pharmacotherapy

Pharmacological Management of Obesity: An Endocrine Society Clinical Practice Guideline

Caroline M. Apovian, Louis J. Aronne, Daniel H. Bessesen, Marie E. McDonnell, M. Hassan Murad, Uberto Pagotto, Donna H. Ryan, and Christopher D. Still

Who should be considered for drug treatment of obesity?

BMI ≥ 27 kg/m2 with ≥1 comorbidities

BMI ≥ 30 kg/m2 with no comorbidities

Apovian CM, et al. JCEM100:342-362 , 2015

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CCK1R, CCK1 receptor; GLP1R, GLP-1 receptor; CTR, calcitonin receptor; DAT, dopamine active transporter; DVC, dorsal vagal complex; GHSR, GH secretagogue receptor; MCH1R, melanin-concentrating hormone 1 receptor; Y1/Y5R, Y1/Y5 receptor; Y2R, Y2 receptor; Y4R, Y4 receptor; OR, -opioid receptor. [Adapted from G. W. Kim et al: Clin Pharmacol Ther. 2014;95:53–66], Apovian C, et al. JCEM 100: 342–362, 2015

Weight loss with Orlistat at 4 year

Torgerson JS, et al. Diabetes Care 2004, 27: 155-161

3.0 kg

5.8 kg

120mg 3 time/day with each main meal containing fat

Effects of Lorcaserin on Body Weight

Smith, S. R., New England Journal of Medicine 2010 363(3): 245-256.

Adverse EventsHeadache:18% vs. 11%, Yr 1

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Effects of Phentermine/Topiramate on Body Weight

Gadde et .al The Lancet 2011, 377(9774): 1341-1352.

Cha

nge

from

bas

elin

e (%

)

Adverse Events(7-15% v 2-9%)

Dry mouthParesthesiaConstipationInsomniaDizzinessDysgeusia

Effect of Naltrexone/Buproprion on Body Weight

Greenway, F. L., The Lancet 2010, 376(9741): 595-605.

Cha

nge

from

bas

elin

e (%

)

Adverse Events(6-27% v 3-9%)

NauseaHeadacheConstipationInsomniaDizzinessVomiting

Pi-Sunyer X, et al. NEJM 2015;373:11-22

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Khera R, et a. JAMA. 2016;315:2424-2434

SUCRA- surface under the cumulative ranking probabilities

Network Metaanalysis: SUCRAs for Weight Loss and Adverse Event Outcomes

SUC

RA

Pro

babi

lity

of H

avin

gFe

wes

t Adv

erse

Eve

nts

SUCRA Probability of Being Highest Ranked in Achieving >5% Weight Loss

Garvey WT, et al. AACE/ACE CPG … Care of Patients with Obesity. Endocr Pract. 2016 Jul;22 Suppl 3:1-203.

Practice of Obesity Pharmacotherapy

Women of reproductive potential• R112. Weight-loss medications must not be use in pregnancy (Grade A; BEL 2,upgraded due to high relevance).

• R113. All weight-loss medications should be used in conjunction with appropriate forms of contraception in women of reproductive potential (Grade A; BEL 1).

• R114. Weight-loss medications should not be used in women who are lactating and breast-feeding (Grade D).

Addiction/alcoholism• R118. In patients with obesity and alcohol or other addictions, consider using orlistat or liraglutide 3 mg (Grade A; BEL 1). Lorcaserin (abuse potential due to euphoria at supra-pharmacological doses) and naltrexone ER/bupropion ER (lowers seizure threshold) should be avoided in patients with alcohol abuse, and naltrexone ER/bupropion ER is contraindicated during alcohol withdrawal (Grade A; BEL 1).

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Garvey WT, et al. AACE/ACE CPG … Care of Patients with Obesity. Endocr Pract. 2016 Jul;22 Suppl 3:1-203.

Practice of Obesity Pharmacotherapy

Cardiovascular disease and cardiac arrhythmia• R94. In patients with established atherosclerotic CVD, orlistat and lorcaserin are preferred weight-loss medications (Grade A).

• Liraglutide 3 mg, phentermine/topiramate ER, and naltrexone ER/bupropion ER are reasonable to use with caution, and to continue if weight-loss goals are met, with careful monitoring of heart rate and blood pressure (Grade A; BEL 1).

• R95. Orlistat and lorcaserin are preferred weight-loss medications in patients with a history or risk of cardiac arrhythmia (Grade B).

• Naltrexone ER/bupropion ER, liraglutide 3 mg, and phentermine/topiramate ER are not contraindicated but should be used cautiously with careful monitoring of heart rate and rhythm (Grade A).

CVOTs are planned or ongoing for all weight-loss medications except orlistat.

Future Directions

Energy Intake

EnergyExpenditure

Appetite, Satiety,Food Choices

• REE• EEE• TEF• NEAT

Central Pathways

Substances That Promote Negative Energy Balance (Weight Loss)

C

• bBDNF

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Farooqi et al. J Clin Invest 110:1093-1103, 2002

Leptin Therapy In Humans

Model of Homeostatic Circuit Regulating Energy Balance through the Melanocortin 4 Receptor (MC4R).Increased adiposity leads to increased leptin production in fat tissue. Leptin stimulates neurons in the arcuate that coexpress the anorexigenichormones a-MSH and CART. Leptin also inhibits neurons in the arcuate that coexpress the orexigenic hormones AGRP and NPY. The neurons in the arcuate project to other regions of the hypothalamus where a-MSH binds to its receptor, MC4R, resulting in an up-regulation of anorexigeniceffectors such as CRH and TRH and a down-regulation oforexigenic effectors such as melanin concentrating hormone (MCH) and orexin. AGRP acts as an antagonist of MC4R. Adapted from List JF, Habener JF. NEJM 348:1160-1163, 2003.

Leptin

-MSH

MC4R

CARTPOMC

Weight Loss Surgery

Sleeve GastrectomyRoux-en-Y Gastric Bypass Gastroplasty

Gastric Banding

BiliopancreaticDiversion

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SOS Study: Weight Changes over a 10-Yr Period

Sjöström L, Lindroos A-K, Peltonen M, et al. N Engl J Med 351:2683-2693, 2004

0 0.5 1 2 3 4 6 8 10

Wei

gh

t C

han

ge

(%)

Years of Follow-upN= 4047 for 2 yr cohortN= 1703 for 10 yr cohort

Sjöström L, Peltonen M, Jacobson P, et al. JAMA 311:2297-2304, 2014.

American Diabetes Association 2016• Bariatric surgery: Adults with BMI >35 kg/m2 and T2DM, esp. if

associated comorbidities and failing lifestyle and drugs

• Patients with T2DM who have undergone bariatric surgery needlifelong lifestyle support and medical monitoring.

• Insufficient evidence to recommend surgery for BMI < 35kg/m2

ADA. Diabetes Care 2016;39:S49-S51; Garvey WT, et al. AACE/ACE CPG. Endocr Pract. 2016 Jul;22 Suppl 3:1-203; Keating CL, et al. Diabetes Care 2009;32:580-584; Courcoulas AP, et al. JAMA Surg 2014;149:708-715.

Current Recommendations

AACE/ACE 2016: • R120. Patients with BMI of ≥40 kg/m2 without coexisting medical

problems if procedure would not be associated with excessive risk (A)

• R121. BMI ≥35 kg/m2 and 1 or more comorbidities (Grade A)

• BMI ≥30 kg/m2 (Grade B-C evidence for weight and CVD risk)

target of weight control

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Thank You