“Obesity and Chronic Diseases” Colorado Center for Health Wellness National Press Foundation April 29, 2013 Robert H. Eckel, M.D. Professor of Medicine Professor of Physiology and Biophysics Charles A. Boettcher II Chair in Atherosclerosis University of Colorado Anschutz Medical Campus
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“Obesity and Chronic Diseases” Colorado Center for Health Wellness National Press Foundation April 29, 2013 Robert H. Eckel, M.D. Professor of Medicine.
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“Obesity and Chronic Diseases”
Colorado Center for Health WellnessNational Press Foundation
April 29, 2013
Robert H. Eckel, M.D.Professor of Medicine
Professor of Physiology and BiophysicsCharles A. Boettcher II Chair in Atherosclerosis
Age-adjustedRR(%) ofDevelopingT2DM over 14 yr in women aged 30-55 in 1976
Overweight 34%
Obese 31%2007
Natural History of T2DM:A Critical Understanding
75
Insulin resistance
RelativeFunction
(%) 5025
0
Years of Diabetes-15 -10 -5 0 5 10 15 20 25
ß-cell
IGT
Diabetes
100125
Glucose (mg/dL)
350
250
100
-15 -10 -5 0 5 10 15 20 25
Fasting glucose
Post-meal glucose
300
200150
Weyer C et al. J Clin Invest 104: 787, 1999
500
400
300
200
100
00 1 2 3 4 5
Insu
lin S
ecre
tio
n (U
/mL
)
Insulin Action (mg/kg EMBS per minute)
Normal Glucose Tolerance
Insulin Resistance
-C
ell
Fai
lure
ImpairedGlucose
ToleranceType 2
Diabetes
Pathogenesis: ß-Cell Compensationand Decompensation and T2DM
DPP:Mean Weight Change from Baseline
-8
-7-6
-5
-4-3
-2
-10
1
Wei
gh
t C
han
ge
(Kg
)
0 6 12 18 24 30 36 42 48Months
Lifestyle
Metformin
+Placebo
N= 3051 2865 1500 3857.2%
4.2%
NEJM 2002;346: 393
0 1 2 3 4
0
10
20
30
40
Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Plac)Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )
All participants-2.8 years
Years from randomization
Cu
mu
lati
ve i
nci
den
ce (
%)
31% 58%
NEJM 346: 393, 2002
DPP: Diabetes Prevention
-10 -8 -6 -4 -2 0 2 4 6
6
11
16
metformin
placebo
Diabetes Risk by Weight Change in the DPP
Change from baseline weight (kg)
Dia
bet
es i
nci
den
ce /
100
per
s-yr
Diabetes 56:1153, 2007
Weight loss explained 64% of the risk reduction from metformin (a weight loss drug?)
Genetic Risk vs. Lifestyle in T2DM?Genetic Risk vs. Lifestyle in T2DM?(TCF7L2 SNP)
Genetic Risk vs. Lifestyle in T2DM?Genetic Risk vs. Lifestyle in T2DM?(TCF7L2 SNP)
Lifestyle intervention “trumps” genetic risk
Florez J et al, DPP Research Group, NEJM 355:241, 2006
Weight Loss in T2DM and Less CVD:Did Look AHEAD Answer All the
Questions?
• Primary Objective – To assess the long-term (11.5 yr) effects of an intensive weight
loss program over 4 years in overweight and obese subjects with type 2 diabetes.– n ~ 5000 men and women– age: 45-74 yr – BMI > 25 kg/m2– Primary outcome – time to a major CVD event– Secondary outcomes - many
Controlled Clin Trials 24:610, 2003
8%
Look AHEAD Research Group, 2011
Intensive Lifestyle Intervention (ILI)
Diabetes Support & Education (DSE)
0
10
20
30
40
50
60
70
80
90
100
> 0 % ≥ 10 % ≥ 5 % ≥ 7 %
74%
55%
46%
25%
35%
18%10%
23%
% o
f Par
ticip
ants
≥ 5 % ≥ 0%
18%
26%
45%
≥ 15 %
4%9%
Weight Gain Weight Loss
Percentage of Participants in ILI and DSE Groups Who Met Different Weight Loss
Criteria at Year 4
4-Year Weight Loss Outcomes
-6
-5
-4
-3
-2
-1
0
Overweight
Class I
Class II
Severe
Ch
ang
e in
bo
dy
we
igh
t (%
)
*
* Overweight significantly different from all other groups (p<0.001)
Look AHEAD Research Group, 2011
Revised NCEP ATP III LDL-C Goals
Circulation 2004; 110: 227
Moderately High
190* 0–1 RF’s
160*
2+ RF (10-20%/10 yr)
100* CHD or Risk Equivalent
(>20%/10 yr)
High(Very High)
ConsiderDrug Rx
CHD Risk Category
LDL-C Goal
<100(<70)
<130
<160
2+ RF (<10%/10 yr)
Moderate
Low
<130
130*
* Consider drug options if below goal, but above goal for next higher risk level
Metabolic Syndrome: Residual Risk
• April 2008– Known CHD
• On a statin
– LDL-C 67 mg/dl– TG 300 mg/dl– HDL-C 32 mg/dL– ETT – normal
• June 2008– AMI at work
• Resuscitation failed
• Could this have been avoided?Grady D. A Search for Answers in Russert’s Death. The New York
Times. June 17, 2008. Johnson A. NBC’s Tim Russert Dies of a Heart Attack at 58. NBC News and msnbc.com. June 14, 2008.
The New Definition of The Metabolic Syndrome (3 or more)
Approved by NHLBI, AHA, IDF, IAS, World Heart Federation
• Abdominal circumference (1 of 5)– men > 94 cm– women > 84 cm
• adjusted locally around the world• Triglycerides > 150 mg/dl• HDL cholesterol
– men < 40 mg/dl– women < 50 mg/dl
• Blood pressure > 130/85• Glucose > 100 mg/dl
Eckel RH et al, Lancet, 375:181, 2010
39
Metabolic Syndrome is Designed for Lifestyle Intervention
• An intervention that improves the quality of the diet, increases physical activity and produces weight reduction often – waist circumference (+ visceral fat)– triglycerides– HDL cholesterol– blood pressure– glucose– inflammatory markers
Fatty Liver (Foie Gras)
Normal goose liver
Goose liver after 3 months of overfeeding and inactivity
Definition: NAFLD & NASH
• NAFLD = Non-Alcoholic Fatty Liver Disease– Spectrum includes
• Steatosis• Steatohepatitis• Fibrosis and cirrhosis