Understanding the science of incretin biology and ...
Transcript of Understanding the science of incretin biology and ...
Understanding the science of incretin biology and implications on cardiovascular risk and diabetes
Sanjay Rajagopalan, MD FACC FAHA Melvin Sharoky Professorship in Medicine Chief, Division of Cardiovascular Medicine The University of Maryland School of Medicine Baltimore, MD
Slides prepared and presented during CDMC in Almaty, Kazakhstan on Saturday April 12 , 2014
Adapted from Monnier L. Eur J Clin Invest. 2000;30(suppl 2):3-11.
Patients With Type 2 Diabetes May Spend
12 Hours Per Day in the Postprandial State
Postprandial Postabsorptive Fasting
Duration of Postprandial State
Breakfast Lunch Dinner Midnight 4AM Breakfast
8 AM 11 AM 2 PM 5 PM
Relationship Between Post-Prandial State
and CV Disease
• CM and CM remnants induce
atherosclerosis (1)
• RLP-C correlates with CIMT (2)
• Higher fasting RLP-C predicts CAD
events (Honolulu Heart Study) (3)
• RLP-C predicts CAD incidence
independent of TC/HDL-C/LDL-C
(Honolulu HS) (4)
• RLP-C strongest causal predictor of
CV events in Copenhagen Heart
Study
• DECODE reported that 2 h glucose
concentrations after OGTT are better
predictors of CV events and all-cause
mortality than fasting blood glucose
The Framingham Offspring Study, 2-h
blood glucose predicted CV events
better than A1C
• A meta-analysis of 38 prospective
studies in non-diabetics confirmed a
strong association between 2-h blood
glucose with fatal and nonfatal
cardiovascular events
3
Post-Prandial Lipemia
1. Zilversmit DB. Atherosclerosis a Post-Prandial Phenomenon. Circulation. 1979
Sep;60(3):473-85.
2. Karpe et al. RLPs are related to IMT of carotid artery independent of LDL-C and plasma
TG. J Lipid Res 2001; 42; 17-21
3. Kugiyama et al Remnant Lipoprotein Levels in Fasting Serum Predict Coronary Events in
patients with CAD. Circulation 1999; 99; 2858-60
4. Imke C and Rodriguez et al. Honolulu Heart Study. Arterioscl Thromb Vasc Biol 2005; 25;
1718-1722
5. Varbo A et al. Circulation. 2013 Sep 17;128(12):1298-30
Post-Prandial Hyperglycemia
1. DECODE Study Group. Glucose tolerance and CV mortality: comparison of fasting
and 2-hour criteria. Arch Intern Med 2001;161:397–405
2. Meigs JB,et al. Framingham Offspring Study. Fasting and postchallenge glycemia
and cardiovascular risk: the Framingham Offspring Study. Diabetes Care
2002;25:1845–1850
3. Levitan EB et al. Is nondiabetic hyperglycemia a risk factor for cardiovascular
disease? A meta-analysis of prospective studies. Arch Intern Med 2004;164:2147–
2155 .
0
10
20
30
40
50
60
70
80
NGT T2DMC
ontr
ibutions o
f In
cre
tin F
acto
rs (
%)
Oral glucose load
Intravenous glucose infusion
Time (min)
Insulin
(m
U/l)
80
60
40
20
0
180 60 120 0
Incretin
effect
Control subjects (n=8) People with Type 2 diabetes (n=14)
Insulin
(m
U/l)
Time (min)
80
60
40
20
0
180 60 120 0
Nauck M, et al. Diabetologia. 1986;29(1):46-52. Kreymann B, et al. Lancet. 1987;2(8571):1300-1304.
1964: Plasma insulin higher with oral than IV glucose
1969: A factor from porcine intestine by Brown et al termed GIP
1. Brown J, Dryburgh JR 1971 A gastric inhibitory polypeptide. The complete sequence. Can J Biochem 49:867-72.
2. Dupre J, Ross SA, Brown JC 1973 Stimulation of insulin secretion by GIP in man. JCEM 37:826–828
GLP-1 and GIP Are the Two
Major Incretins ProGIP
GIP[1-42]
K-cell
GLP-1 GIP
• Produced by L cells in distal gut • Produced by K cells in the proximal gut
• Half life 1 minute • Half life 10 minutes
• Suppresses glucagon secretion • Stimulates glucagon secretion
• Inhibition of gastric emptying • Minimal effect on gastric emptying;
• Reduces Apo 48, CM and VLDL Production • Increases Lipoprotein Production
• Insulinotropic Activity in DM Preserved • Insulinotropic Activity in DM/IR Attenuated
GLP, glucagon-like peptide; GIP, glucose-dependent insulinotropic polypeptide.
GIP
[1-42]
GIP
[3-42]
INACTIVE
DPP-IV
GLP-1
[7-36NH2]
DPP-IV GLP-1
[9-36NH2]
INACTIVE
Proglucagon
GLP-1[1-37]
GLP-1[1-36NH2]
L-cell
GLP-1[7-36NH2]
5
Complexity of GLP-1 Peptide Biology
7
GLP-1 (7-36)
DPP-IV
GLP-1R
GLP-1 (28-36)
NEP 24.11
GLP-1R Mediated Effects GLP-1R Independent Effects
?Receptor
GLP-1 (9-36)
SDF-1 (1-68) GLP-1 (7-36) BNP(1-32) SP (1-11) NPY (1-36) PYY (1-36) GLP-2 (1-33) GIP (1-42)
BNP (3-32) GLP-1 (9-36) NPY (3-36) PYY (3-36)
Progenitor
cell Blood vessel
Kidney
Heart
Brain
DPP-4
Adipose tissue
Ussher JR, and Drucker DJ. Endocrine Reviews 2012;33:187-215
Diversity of DPP4 Substrates
9
Summary of Pharmacological Incretin action
on Different Target Tissues
Pancreas
GI tract
Insulin biosynthesis
Glucagon Release
Beta-cell proliferation
Beta-cell apoptosis
INCRETINS
Brain Neuroprotection
Appetite
Insulin secretion
Glucagon secretion
Gastric emptying
Stomach
Cardioprotection
Cardiac output
Liver
Insulin sensitivity Glucose production
VLDL Production
Muscle
Apo 48 production
CM Production
Heart
Inflammation
Vasodilation
Endothelial function
Vasculature
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Location and Impact of GLP-1/Receptors in
the Cardiovascular System
• Atrial Tissue in the heart
• Endocardium
• Endothelium
• Smooth Muscle Cells
• T Lymphocytes/Macrophages
Koska J, et al. Diabetes Care. 2010;33(5):1028-30.
Basu A, et al. Am J Physiol Endocrinol Metab 2007;293(5);1289-1296.
Zhao T, et al. J Pharmacol Exp Ther. 2006;317(3):1106–1113.
Nikolaidis, et al. Circulation. 2004;110(8):955–961.
Nikolaidis LA, et al. Am J Physiol Heart Circ Physiol. 2005;289(6):H2401–H2408.
Nikolaidis LA, et al. Circulation. 2004;109(8):962–965.
Sokos GG, et al. J Card Fail. 2006;12(9):694–699.
Watts GF, Chan DC. Diabetes 2013;62(2);336-338.
• GLP-1 agonists improve endothelial function
• GLP-1 agonists reduce BP
• Improve function in post-MI LV dysfunction and CHF
12
GLP-1 Agonists Lower Blood Pressure: Results
of a Meta-regression Analysis
Using Random effect models
−3.42 mm Hg decrease in SBP (95% CI −3.54 to −3.31)
−2.56 kg loss of weight (95% CI = −3.12 to −2.00)
Increase in HR of 1.30 bpm (95% CI = 0.26–2.33
31 trials; >1500 patients;
Random-Effects Meta-analysis
and Meta-regression analysis
Am J Hypertens 2014;27:130-139
Mechanisms of GLP-1 Induced Reduction in
Blood Pressure and Natriuresis
14 Kim M et al. Nat Med. 2013 May;19(5):567-75. doi: 10.1038/nm.3128. Epub 2013 Mar 31.
Increased expression of DPP4 (CD26) in Acute
Coronary Syndrome
CD26 CD40L CD69
30
20
10
0
* * *
*
Group 1: Stable angina
Group 2: USA on treatment
Group 3: Refractory USA
Group 4: Acute MI
Hosono M, et al. Atherosclerosis. 2003;168 :73-80. 16
Sell H et al. Dia Care 2013;36:4083-4090
DPP4 Expression and Activity is Increased in
Obesity/IR
Effect of DPP4 Inhibition in Atherosclerosis
• Alogliptin reduces atherosclerosis and
Adipose inflammation in High-Fat Fed
Insulin Resistant LDLR–/–
• PKF275-055 reduces
atherosclerosis in ApoE–/–
NV
ND
HV
HD
70,000
60,000
50,000
40,000
30,000
20,000
10,000
0 Ath
ero
scle
roti
c a
rea (
μm
2)
NV ND HV HD
^^
##
**
Shah Z, et al. Circulation. 2011;124(21):2338-2349. Terasaki M, et al. Metabolism. 2012;61(7):974-977.
NV=Normal diet vehicle
ND=Normal diet Alogliptin
HV=High fat diet Vehicle
HD=High fat diet Alogliptin
Visceral Adipose Aortic Plaque
Lipid Accumulation
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Alogliptin Reduces Plaque Inflammation and
Improves Vascular Function
Plaque Inflammation/Fibrosis Vascular Function
CD
11
b c
ell
s in
%
75
50
25
0
**
#
CD
11
b/C
D2
06
ce
lls
in
%
75
50
25
0
**
##
^^
F4
/80
+ c
ell
s
15
10
5
0
% C
oll
ag
en
of
pla
qu
e
70
60
50
40
30
20
10
*
#
0
Rela
xa
tio
n (
% o
f p
re-c
on
str
uctio
n)
0
-25
-50
-100
-75
-8 -7 -6 -5
Log [Ach]
-8 -7 -6 -5
Log [PE]
Co
ns
tric
tio
n (
% o
f K
Cl1
20
)
500
400
300
0
100
200
NV=Normal diet vehicle
ND=Normal diet Alogliptin
HV=High fat diet Vehicle
HD=High fat diet Alogliptin Shah Z, et al. Circulation. 2011;124(21):2338-2349. 21
Liver
↑ GLP-1R
signaling in Gut
Adipocytes
↓ Lipolysis
Pancreas
↓ Plasma FFAs
↓ Competition for
CM Clearance?
Effects of GLP-1R Signaling on Lipoprotein Metabolism
Direct
Sympathetic enteric neurons?
↓ Gastric
emptying?
↓ TG
absorption
Enterocytes
↑ Insulin
↓ Apo B100
↑ FA β-oxidation
↓ Apo48
↓ CM Biogenesis
↓ Plasma
FFAs
↓ VLDL
DECREASED POST-PRANDIAL
TG, VLDL AND CM REMNANTS 22
* *
**
**
** ** *
*
**
*** *** ***
***
***
*** *** ***
*** *** ***
*** **
Alogliptin Reduces Post-Prandial Lipoproteins
5
4
0
Tri
ac
ylg
lyc
ero
ls
(mm
ol/
l)
–1 0 1 2 3 4 5 6 7 8
Time (h)
2
5
4
2 Ch
ylo
mic
ron
Ap
oB
-48
(mg
/l)
0 2 4 6 8
Time (h)
3
16
14
4
Ch
ylo
mic
ron
tria
cylg
lyc
ero
ls (
mm
ol/
l)
0 2 4 6 8
Time (h)
6
0.7
0.5
0.2 VL
DL
1 A
po
B-4
8 (
mg
/l)
0 2 4 6 8
Time (h)
0.4
8
10
12
0.6
0.3
*
1
3
***
**
*
**
***
*** *** ***
***
Eliasson B et al. Diabetologia. 2012;55(4):915-925.
Alogliptin
*p<0.5
**p<0.01
***p<0.001
16 week double-blind placebo controlled trial in Type II DM
Mixed Meal Challenge at end of treatment (n=71)
VLDL Apo B100 ↓ with Alo but not Alo/Pio 23
Communication Between Heart and
Bone Marrow Signals in Repair
SDF-1
Bone Bone marrow
MI
Zaruba M, et al. Cell Stem Cell. 2009;4(4):313–323.
Zhang D, et al. Am J Physiol Heart Circ Physiol. 2010;299(5):H1339–H1347.
Theiss HD, et al. Int J Cardiol. 2010;145(2):282–284.
DPP4
DPP4
In Peri-MI tissue Degradation
of SDF-1 Homing of CXCR4
Progenitor Cells Healing of MI
DPP4 Inhibitor
CXCR4
DPP4i
Stem/progenitor cell
GLP-1 Reduces MI Size in Patients with STEMI
n Exenatide n Placebo P-value
Salvage index 0.71 ± 0.13 51 0.62 ± 0.16 0.003
Infarct size (g)/area at risk (g) 0.30 ± 0.15 51 0.39 ± 0.15 0.003
Lønborg J et al. Eur Heart J. 2012;33(12):1491-1499.
Double-blind placebo controlled trial of Exenatide (25 mg) vs. Placebo in STEMI with
TIMI 0/1 Flow (n=172) Infarct Size and Salvage Index at 90 days by CMR
No change in 30-day clinical outcomes or LV function 25
A suggested working model.
Shigeta T et al. Circulation 2012;126:1838-1851
Copyright © American Heart Association
A Role for DPP-4 in LV Remodeling:
Implications for Diabetic Cardiomyopathy
26 Shigeta T, Murohara T et al. Circulation. 2012 Oct 9;126(15):1838-51
Incretin Based Therapies: Summary
• Incretins such as GLP-1 have complex and
pleiotropic effects on the cardiovascular system
beyond glycemic control
• DPP-4 (CD26) is up regulated in tissues such as the
vessel wall, visceral adipose and inflammatory cells
• Enzymatic inhibition of DPP-4 reduces
inflammation, atherosclerosis, chylomicron/VLDL
biosynthesis and LV remodeling and may be
cardioprotective
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