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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
2
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.
3
• 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
6
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
7
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
8
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
9
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
11
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
12
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
13
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
14
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).
15
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
16
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
17
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
18
Thank You