review of therapies in relation to key drivers - kendall
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International Diabetes Center
Park Nicollet
Review of Diabetes Therapies: Key Drivers of Disease Progression
David M. Kendall, MD
Medical Director and Chief of Clinical and Professional Services
International Diabetes Center
Associate Professor of Medicine
University of Minnesota
Minneapolis, MN
International Diabetes Center
Park Nicollet
Diabetes Therapies and Disease Progression: Discussion Outline
• Disease progression in Type 2 diabetes – The role of beta cell function and insulin resistance
– Clinical consequences of disease progression
Glycemic control and treatment “failure”
• Specific therapies – effect on diabetes progression – Diabetes prevention vs. disease progression
• A Glimpse of the Future – Implications for Treatment – Early intervention and diabetes treatment response
– Impact on the risk of complications
International Diabetes Center
Park Nicollet
The Pathophysiology of Type 2 Diabetes
Impaired Incretin Effect
Relative Insulin Deficiency
Insulin Resistance
© 2008 International Diabetes Center. All rights reserved
International Diabetes Center
Park Nicollet
Glu
cose
(m
g/dL
)
Diabetes diagnosis
50 100 150 200 250 300 350
Fasting glucose
Kendall DM, Cuddihy, RM, Bergenstal RM © 2008 International Diabetes Center. All rights reserved
Years
Rel
ativ
e am
ount
-10 -5 0 5 10 15 20 25 30
Insulin resistance
Insulin level
Onset Diabetes
0
50
100
150
200
250
-15
Natural History of Type 2 Diabetes
Postmeal Glucose
Incretin effect β cell function
International Diabetes Center
Park Nicollet
Diabetes Disease Progression: β cell Dysfunction and Early Hyperglycemia
Ferrannini E. J Clin Endocrinol Metab 90: 493–500, 2005
International Diabetes Center
Park Nicollet
Diabetes Disease Progression: Clinical Consequences
• Implications of disease progression – Progressive deterioration in glycemic control (UKPDS)
Increasing risk of complications
– Stepped, failure-based therapeutic approach – delay in Rx
0
5
10
15
20
25
Metformin only (n = 513)
Sulfonylurea only (n = 3394)
14.5
20.5
Brown JB, et al. Diabetes Care. 2004;27:1535-1540.
Inte
rval
Bef
ore
Rx
Cha
nge
6
7
8
9
0 3 6 9 12 15
HbA
1c (%
)
Years from randomization
Conventional (7.9%)
Intensive therapy (7.0%)
UKPDS 33. Lancet 352: 837–53, 1998
International Diabetes Center
Park Nicollet
Clinical Impact of Diabetes Therapy
Diabetes Prevention and Disease Progression
International Diabetes Center
Park Nicollet
Diabetes Disease Progression: Impact of Specific Therapies
Insulin
Increased β cell mass
Improved Insulin Secretion
Incretin based Rx
TZD
AGI
Sulfonylurea
Metformin
Lifestyle (MNT)
Disease Modification
Diabetes Prevention Therapy
• Measures of fasting insulin
• Stimulated insulin response
• Beta cell mass
• Insulin content and mRNA
• Stimulated (maximal) insulin secretion
• Prevent increase in FPG
• Maintain or restore normal glucose response
• Diabetes prevention
• Stability of glycemic control
• Limit need for added therapies
International Diabetes Center
Park Nicollet
↓ 31%
Placebo (n=1082) Metformin (n=1073, p<0.001 vs. PBO) Lifestyle (n=1079, p<0.001 vs. Met and PBO)
Diabetes Prevention Program (DPP) Prevention of Diabetes
The DPP Research Group, NEJM 346:393-403, 2002
↓ 58%
International Diabetes Center
Park Nicollet
The STOP-NIDDM Study: Effect of Acarbose Therapy
Placebo
200 400 600 800 1000 1200
Cum
ulat
ive
Prob
abili
ty (%
)
Days After Randomization
Acarbose
Placebo
25% Relative Risk Reduction
100
0.90
0.80
0.70
0.60
0.50
0.40 0 200 400 600 800 1000 1200
Chiasson JL et al. Lancet 2002;359:2072 and JAMA 2003;290:486
International Diabetes Center
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Hanefeld (n=500)
Charbonnel (n=630)
CHICAGO (n=462)
ADOPT (n=2897)
UKPDS (n=1573)
-2
-1
0
1
Cha
nge
in A
1C (%
)
Time (yrs) 0 1 2 3 4 5 6 10
Glimepiride Glyburide
Glyburide
Glyburide
Gliclazide
Mazzone T. JAMA. 2006;296:2572-2581. Hanefeldd M. Cur Med Res Opin. 2006;22:1211-1215. Nissen SE. JAMA. 2008;299:1567-1573. UKPDS Study Group. Lancet.1998;352:837-853 Charbonnel B. Diabetoogia. 2005;48(6):1093-1104.
Durability of Glycemic Control with Sulfonylurea Therapy
International Diabetes Center
Park Nicollet
6
7
8
9
0 3 6 9 12 15
HbA
1c (%
)
Years from randomization
Intensive Treatment of Type 2 Diabetes: UKPDS
UKPDS 33. Lancet 352: 837–53, 1998 UKPDS 16. Diabetes 44:1249–1258, 1995
Conventional (7.9%)
Intensive therapy (7.0%) SU or insulin
Metformin
0
20
40
60
80
HO
MA β-
Cel
l Fun
ctio
n (%
)
International Diabetes Center
Park Nicollet
Diabetes Disease Progression: Impact of Specific Therapies
Insulin
Increased β cell mass
Improved Insulin Secretion
Incretin based Rx
TZD
AGI
Sulfonylurea
Metformin
No No No No
No No No Yes
No
No
No
Yes
No
Yes
No No
No Yes
No Yes Lifestyle (MNT)
Disease Modification
Diabetes Prevention Therapy
International Diabetes Center
Park Nicollet
Thiazolidinediones
A Closer Look at β Cell Function and Diabetes Disease Progression
International Diabetes Center
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Effect of Early TZD Use on A1C
International Diabetes Center
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DREAM: Investigation of Diabetes Prevention or Delay
No. at risk Placebo Rosiglitazone
DREAM Trial Investigators. Lancet 368(9541):1096-105, 2006
2634 2635
2470 2538
2150 2414
1148 1310
177 217
0.6
0.5
0 1 2 3 4 Follow-up (years)
0.4
0.3
0.2
0.1
0.0
Rosiglitazone
Placebo 60% RRR
HR 0.40 (0.35–0.46) P < 0.0001
Rat
e of
ne
w-o
nset
di
abet
es o
r dea
th
International Diabetes Center
Park Nicollet
ADOPT Cumulative Incidence of Treatment Failure
Kahn SE, et al. N Engl J Med 2006;355:2427–2443.
Years
40
20
1 2 3 4 5
30
0
10
0
Cum
ulat
ive
Inci
denc
e of
M
onot
hera
py F
ailu
re (%
)
No. at risk Rosiglitazone 1393 1207 1078 957 844 324 Metformin 1397 1205 1076 950 818 311 Glyburide 1337 1114 958 781 617 218
Glyburide
Metformin
Rosiglitazone
Rosi vs metformin, 32% RRR P<0.001
Rosi vs glyburide, 63% RRR P<0.001
Improved estimates of β cell function
International Diabetes Center
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ADOPT Impact of Initial Therapy on A1C
*Significant difference rosiglitazone vs other treatment groups with Hochberg adjustment. Kahn SE, et al. N Engl J Med 2006;355:2427–2443.
Years
6.0
7.6
8.0
6.8
0 1 2 3 4 5
Gly
cate
d H
emog
lobi
n (%
)
7.2
0
Rosiglitazone, 0.07 (0.06 to 0.09) Metformin, 0.14 (0.13 to 0.16)* Glyburide, 0.24 (0.23 to 0.26)*
6.4
No. of Patients 4012 3308 2991 2583 2197 822
Rosiglitazone vs metformin, -0.13% P=0.002 Rosiglitazone vs glyburide, -0.42% P<0.001
Annualized slope (95% CI)
International Diabetes Center
Park Nicollet
Kahn SE. N Engl J Med. 2006;355:2427-2443. Mazzone T. JAMA. 2006;296:2572-2581 Hanefeld M. Cur Med Res Opin. 2006;22:1211-1215. Tan MH. Diabetes Care. 2005;28:544-550 Nissen SE, et al. JAMA. 2008;299:1567-1573.
-2
-1
0
1 C
hang
e in
A1C
(%)
Time (yrs)
0 1 2 3 4 5 6
PIO
PIO
Rosiglitazone
Hanefeld (n=250)
Tan (n=270)
Chicago (n=232)
ADOPT (n=1456)
PIO
PERISCOPE (n=178)
PIO
Durability of Glycemic Control with Thiazolidindiones
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Incretin Based Therapy with GLP-1 Potential Impact on Disease Progression
Flint A et al. J Clin Invest. 1998;101:515-520. Larsson H et al. Acta Physiol Scand. 1997;160:413-422 Nauck MA et al., Diabetologia. 1996;39:1546-1553. Drucker DJ. Diabetes. 1998;47:159–169.
Stomach: regulates gastric emptying
CNS: promotes satiety and reduction of appetite
Liver: ↓ glucagon reduces
hepatic glucose output
Alpha cell: ↓ glucagon secretion
post-meal
Beta cell: enhances glucose-dependent insulin secretion and β cell mass
Impaired β-cell function
Excess food intake
Rapid substrate delivery
Glucagon excess
Excess glucose production
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Exenatide Improves Phasic Insulin Secretion in Type 2 Diabetes
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Incretin Based Therapies and Disease Progression Impact of Exenatide Over 3 Years
0 26 52 78 104 130 156 -7 -6 -5 -4 -3 -2 -1 0 1
Treatment (wk) Baseline Weight: 99 kg
-5.3 ± 0.4 kg
Change in Body Weight (kg) Change in A1c (%)
0 26 52 78 104 130 156 4 5 6 7 8 9
10
Treatment (wk)
-1.0 ± 0.1% -1.1 ± 0.1%
46% 54% % achieving A1C ≤ 7%
N = 217; Mean ± SE Klonoff DC, et al. Curr Med Res Opin 2008; 24:275-286
International Diabetes Center
Park Nicollet
Exenatide vs Glargine Over 1 Year Impact on C-peptide Secretion During Hyperglycaemic Clamp
Arginine Bolus Glucose Bolus Exenatide
AIRarg
Mean (SE)
Glucose 15 mM
165 180 190 210 240 260 270 290 0 1 2 3 4 5 6 7 8 9
10
Time (min)
C-p
eptid
e (n
mol
/L)
P< 0.0001
0
1 2 3
4
Rat
io to
bas
elin
e
3.19 1.31
Bunck M. Diabetologia. EASD 2007/2008
International Diabetes Center
Park Nicollet
Weight HbA1c
The Temporal Pattern of Weight Loss with Exenatide Therapy
Kendall DM et al. Diabetes 2008. ADA Annual Scientific Sessions
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Impact of DPP-4 Inhibitor on Glycemic Control and Beta Cell Function
Nauck M. Diabetes Obes Metab, 2007; 9:195-205 Xu L, et al. Diabetes Obes Metab. 2008;10:1212-20
Week
0 6 12 18 24 30 38 46 52
LS M
ean
Cha
nge
in A
1C (%
)
–1.5
–1.2
–0.9
–0.6
–0.3
0.0
Glipizide
Sitagliptin 100 mg
Baseline A1C 7.7%
Placebo Sitagliptin 100 mg
Baseline (dashed)
End-treatment period
200
400
600
800
1000
1200
1400
160 180 200 220 240 260
Glucose concentration (mg/dL)
Insu
lin S
ecre
tion
(pm
ol/m
in)
Pooled monotherapy studies
International Diabetes Center
Park Nicollet
Impact of Type 2 Diabetes Therapy on Disease Progression: A Checklist
No No No No Insulin
No
No
No
No
Increased β cell mass
Yes
Yes
No
No
Improved Insulin Secretion
Incretin based Rx Yes
Yes
Yes
No
? ?
Yes Yes TZD
No Yes AGI
No No Sulfonylurea
No Yes Metformin
No Yes Lifestyle (MNT)
Disease Modification
Diabetes Prevention Therapy
International Diabetes Center
Park Nicollet
A Glimpse of the Future: Implications for Clinical Care
• Early intervention and diabetes treatment response – Achieve and sustain glucose control
– Legacy effect on risk of complications
• Therapeutic Options – Disease modification – targeting pathophysiologic defects
– Sustain beta-cell responsiveness
– Early combination therapy
• Limit factors that negatively impact treatment response ? Hypoglycemia
? Weight gain
? Treatment tolerability and concordance
International Diabetes Center
Park Nicollet
Clinical Implications of Disease Progression: The “Natural History” of Type 2 Diabetes
TIME (yrs since diagnosis)
A1C
(%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5 Early deterioration in
glycemic control Drives the risk for
complications
Adapted from Prof. Stefano del Prato. EASD Commentary, Rome ITALY, 2008. With permission
May limit later efforts at intensive glucose control?
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