Transcript Slide 1

New Treatment Strategies for
Type 2 Diabetes
Harold E. Lebovitz
August 14, 2005
New data that are changing our ideas about
the pathophysiology of type 2 diabetes
 Nature of beta cell apoptosis and regeneration
 Effects of troglitazone in preserving beta cell fuction
 Effects of PPARγ agonists on cardiovascular events
 Memory of vascular tissues for previous hyperglycemia
 Role of inflammation in vascular disease
 New targets for lipid treatment
Stages of Type 2 Diabetes
Insulin sensitizers
Insulin sensitizers Insulin sensitizers
+ insulin
+ Insulin
secretogogues
100
75
-Cell
Function 50
(%)
IGT
25
0
-12 -10
Postprandial Type 2
HyperglycemiaDiabetes
Phase I
-6
-2
0
Years From
Diagnosis
2
Type 2
Diabetes
Phase II
6
Type 2 Diabetes
Phase III
10
14
Lebovitz H, Diabetes Review 1999.
FIG. 7. Plot of {beta}-cell glucose sensitivity and insulin sensitivity against 2-h plasma
glucose concentration in obese NGT tertiles, IGT, and T2DM quartiles
Ferrannini, E. et al. J Clin Endocrinol Metab 2005;90:493-500
Copyright ©2005 The Endocrine Society
Reduction of beta cell mass in type 2 diabetes
Fig 2
Butler et al. Diabetes
2003;52:102
THIAZOLIDINEDIONES SLOW THE RATE
OF -cell LOSS IN PREDIABETES
1. Rosiglitazone preserves -cell function in
rodent models of insulin resistant diabetes
2. Troglitazone prevents type 2 diabetes and
preserves -cell function in women with
previous gestational diabetes—TRIPOD
STUDY
3. Troglitazone prevents progression from IGT to
type 2 diabetes in individuals with IGT---DPP
Fraction with Diabetes
TRIPOD: Diabetes Rates Post-trial
Off
Trial
On Trial
60%
Placebo
Troglitazone
21% per year
92% Risk
Masking
40%
Reduction
20%
3% per year
0%
ivGTT
0
20
40
60
Months after Randomization
Buchanan et al: Diabetes, in press
DPP: 4-Group Study, 1996 - 1998
Eligible participants
Randomized
Placebo
n = 582
Metformin Troglitazone ILS
n = 587
n = 585
n = 589
ILS = Intensive Life Style
Diabetes 54:1150-1156, 2005
Total n = 2,343
Cumulative Incidence (%)
Diabetes Cumulative Incidence
15
10
PLAC
MET
TROG
ILS
5
0
0.0
(2,343)
0.5
(1,568)
1.0
(739)
1.5
(237)
Years from Randomization (total no. of participants)
Diabetes 54:1150-1156, 2005
Diabetes Incidence Rates (95% C.I.)
Overall
TROG
P<0.001
v. PLAC
Incidence
(cases/100 pers-yr)
16
12
p<0.001
12.0
8
TROG
v. MET
P=0.02
TROG
v. ILS
P=0.18
6.7
5.1
4
3.0
0
PLAC
MET
TROG
ILS
Diabetes 54:1150-1156, 2005
Beta cell replication
and apoptosis in
type 2 diabetes
Fig 7
Butler et al. Diabetes
2003;52:102
DREAM = Diabetes Reduction Assessment
with Ramipril and Rosiglitazone Medication
Randomization
n=5269
Screening
n=24,872
Run-in
14-20 days
Ramipril 15 mg vs
placebo
AND
Rosiglitazone 8 mg
vs placebo
Washout
Regular
outcome
assessments
3-5 years
DESIGN
2X2 Factorial
Diabetologia 47:1519-1527, 2004
2-3
months
Final
Evaluation
Stages of Type 2 Diabetes
100
75
-Cell
Function 50
(%)
IGT
25
0
-12 -10
Postprandial Type 2
HyperglycemiaDiabetes
Phase I
-6
-2
0
Years From
Diagnosis
2
Type 2
Diabetes
Phase II
6
Type 2 Diabetes
Phase III
10
14
Lebovitz H, Diabetes Review 1999.
Metabolic Syndrome: Associated cardiovascular risk
factors
Endothelial Dysfunction
↑ Adhesion Molecules
↑ Cellular Proliferation
↓ Vasodilation
Dyslipidemia
↑ FFA
↓ Adiponectin
↓ HDL
↑ Triglycerides
↑Small dense LDL
Visceral Obesity
Insulin Resistance
Inflammation
↑ NFκB
↑ CRP
↑ IL-6
Procoagulant State
↑ PAI-1
↑ Fibrinogen
Modified from Lebovitz, Eur. J. Pharmacol. 2004
Relationship Coronary Heart
disease to Glucose Intolerance
4961 european patients with acute or chronic coronary
artery disease
31 % had known diabetes
69 % were not known to be glucose intolerant and
were tested with OGTT after they were stable
45 % had normal glucose tolerance
18 % were found to have diabetes
4 % had IFG
32 % had IGT
Only 31 % of patients with CAD
have normal glucose tolerance
EASD 2004
AbnormaI glucose regulation – CAD
100
Survival (%)
Normal
98
Newly
detected
AGR
96
94
92
Known
diabetes
NGR vs AGR p < 0.05
NGR vs DM p < 0.001
AGR vs DM p < 0.008
0
100
200
300
Follow up (days)
400
Rosiglitazone vs placebo on stent re-stenosis
P-control
P-Rx
R-control
R-Rx
9
8
7
6
5
4
3
Glucose
HbA1c
Insulin
Choi et al. Diabetes Care 2004;27:2654-2660
Rosiglitazone vs placebo on stent re-stenosis
P-control
R-control
P-Rx
R-Rx
7
6
5
4
3
2
1
0
TG
FFA
CRP
Choi et al. Diabetes Care 2004;27:2654-2660
Effect of rosiglitazone treatment on
stent re-stenosis
•
•
•
•
•
Characteristics
Number of patients
Number of lesions
In stent re-stenosis
Diameter stenosis
Control Rosiglitazone
45
55
38.2 %
40.9 %
38
51
17.6 % *
23.0 % ^
• p= 0.030
• ^ p < 0.004
Choi et al. Diabetes Care 2004;27:2654-2660
Effect of Rosiglitazone on Common
Carotid IMT Progression in Nondiabetic
Coronary Artery Disease Patients
Methods
• Consecutive subjects (n=92) with
clinically stable, angiographically
documented CAD and without diabetes
mellitus were randomized in a
double-blind manner to receive placebo
or rosiglitazone for 48 weeks
Sidhu JS et al., Arterioscler Thromb Vasc Biol March 4, 2004; Epub ahead of print.
Trial Profile
92 Patients Randomized
46 assigned placebo
1 diabetic
1 side effects
2 lost to follow-up
42 had scan at 24 weeks
1 lost to follow-up
41 completed study
46 assigned rosiglitazone
3 diabetic
2 side effects
1 lost to follow-up
40 had scan at 24 weeks
1 lost to follow-up
39 completed study
Sidhu JS et al., Arterioscler Thromb Vasc Biol March 4, 2004; Epub ahead of print.
Common Carotid IMT Progression
Progression rate=0.031mm/48 wks Progression rate=0.012 mm/48 wks
(0.0016, 0.0604)
(-0.0414, 0.0174)
Placebo
IMT change (mm)
0.04
Rosiglitazone 8 mg/day
0.03
0.02
0.01
0
-0.01
0
24
P=0.03 for difference
in progression slopes
0
48
Time (weeks)
24
48
Sidhu JS et al., Arterioscler Thromb Vasc Biol March 4, 2004; Epub ahead of print.
PROspective pioglitAzone Clinical
Trial In macroVascular Events
 Randomized, double blind outcome study of type 2 diabetic patients with a
history of previous macrovascular disease
 Diabetes managed with diet and/oral glucose lowering agents. Insulin
allowed. Randomized to placebo or pioglitazone. Pioglitazone force titrated 15
to 30 to 45 mg/day
 5,238 patients from 19 countries randomized. Approximately 61 % on
metformin or a sulfonylurea. Thirty 33 % using insulin
 Mean age 61.8 yrs, mean BMI 30.9 kg/m², mean duration type 2 diabetes
9.5 years
 Patients treated with lipid lowering, anti-hypertensive and anti-platlet drugs
as indicated
 End point----- time to first composite cardiovascular endpoint
RESULTS TO BE PRESENTED AT EASD in ATHENS
Sept. 12, 2005
Charbonnel B, Dormandy J, Erdmann E et al. Diabetes Care 2004;27:1647-1653
Prevalence of complications at the time of
diagnosis of type 2 diabetes: UKPDS
Complication
Prevalence (%)*
Any complication
Retinopathy
Abnormal ECG
Absent foot pulses (≥ 2) and/or ischemic feet
Impaired reflexes and/or decreased vibratory sensation
Myocardial infarction/angina/claudication
Stroke/transient ischemic attack
50
21
18
14
7
 2-3
~1
* UKPDS = United kingdom prospective diabetes study
Some patients had more than one complication at diagnosis
Adapted from Holman RR Consultant 1997; 37(suppl): S30-S36.
Epidemiology of Diabetes Interventions
and Complications (EDIC)
8-Year Follow-up of DCCT
• 1375 of patients completing the DCCT in 1993 were
followed for 7 years (688 from conventional group
and 687 from intensive group)
• Therapy provided by patient’s own physician
• Assessment of:
–HbA1c annually
–Retinopathy by fundus photography annually
–Renal function by urinary albumin excretion and
creatinine clearance during years 4 through 6
Distribution of HbA1c in the Former DCCT
Intensive and Conventional Groups During EDIC
14
Conventional
Intensive
HbA1c (%)
12
Mean HbA1c during EDIC
Conventional 8.2%
Intensive
8.0%
p = .0019
10
8
6
p < .0001 .0001 .0001 .002 .04
.08
2
3
4
5
DCCT 1
Closeout
EDIC year
.037
6
.59
7
.83
8
DCCT/EDIC
Further Retinopathy Progression Over 8 y of EDIC
From the Level at DCCT Closeout
Adjusted For DCCT Closeout Level
Cumulative incidence %
50
40
63% Risk Reduction with intensive therapy
p < .0001
30
Conventional
20
10
Intensive
0
0
1
2
3
4
5
EDIC YEAR
6
7
8
DCCT/EDIC
Cumulative Incidence (%)
Cumulative Incidence of
New Clinical Albuminuria > 300 mg/24 h
During EDIC
12
10
83% risk reduction
p < .0001
Conventional
8
6
4
Intensive
2
0
1-2
3-4
5-6
EDIC Year
7-8
DCCT/EDIC
Effect of DCCT Intensive vs. Conventional Treatment
on Prevalence of Hypertension in EDIC
50
Intensive
Conventional
Prevalence (%)
40
30
20
*
*
*
*
*
*
10
0
Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8
DCCT
Close-out
EDIC
* p < .05, intensive vs. conventional
Formation of Irreversible Advanced
Glycosylation End Products
Effect of Intensive Rx on Collagen Glycation
Products Primary Cohort
Conventional
%
Intensive
1,000
10
7.5
P Mole
per mg
Collagen
*
* p < .001
*
750
*
500
5
*
250
2.5
0
0
HbA1c
Furosine
Carboxymethyl Pentosidine x 10
lysine
Logistic Regression Analysis of Retinopathy Progression
During EDIC as Dependent Variable
Chi2
p
Mean DCCT HbA1c
41
<.0001
Skin collagen AGE’s
62
<.0001
Furosine, CML
55
<.0001
Furosine, CML
adjusted for HbA1c
16
.0004
Mean DCCT HbA1c
adjusted for furosine &
CML
2.3
NS
Independent Variables
UKPDS: Microvascular Endpoints
in Glucose Control Study
Cumulative: 346 of 3867 Patients (9%)
Patients with events
25%
Conventional (n=1138)
Intensive (n=2729)
20%
P=0.0099
15%
10%
5%
Risk reduction 25%
(95% CI: 7% to 40%)
0%
0
3
6
9
12
Years from randomization
15
Renal failure or death, vitreous hemorrhage, or photocoagulation.
UKPDS Group. Lancet. 1998;352:837-853.
Conclusions
• The benefit of intensive treatment in reducing
complications can be virtually all accounted for
by the reduction in hyperglycemia
• Tissue damage from any particular level of
glycemic exposure outlasts the period of
glycemic exposure and blunts the subsequent
response to intensive treatment
• The long lasting effects of glycemic exposure
may be explained by glycation of long-lived
molecules such as collagen
Stepwise treatment of
hyperglycaemia
BMI
<27
Diet
Gliclazide
Gliclazide
+
Metformin
BMI
≥27
Diet
Metformin
Gliclazide
+
NPH insulin
Metformin
+
NPH insulin
Time
Gaede P. et al., N Engl J Med 2003; 348:383-93.
Biochemical risk factors at year 7.8 in
conventional versus intensive groups
Conventional
• Haemoglobin A1c
Intensive
9.0%
7.9%
146 mm Hg
131 mm Hg
78 mm Hg
73 mm Hg
• Total-cholesterol
5.6 mmol/l
4.1 mmol/l
• LDL-cholesterol
3.3 mmol/l
2.1 mmol/l
• Triglycerides
3.0 mmol/l
1.7 mmol/l
126 mg/24h
26 mg/24h
• Systolic BP
• Diastolic BP
• Urinary albumin
Gaede P. et al., N Engl J Med 2003; 348:383-93.
Percentage of patients achieving
treatment goals set for the intensivetherapy group at 7.8 yr
%
HbA1c<6.5%
80
Cholesterol
<4.5 mmol/l
Triglycerides
<1.7 mmol/l
Systolic BP
<130 mm Hg
p<0.0001
Diastolic BP
<80 mm Hg
p=0.21
70
p=0.19
60
p=0.001
50
40
30
20
p=0.06
10
0
Int
Conv
Int
Conv
Int
1Conv
Int
Conv
Int
Conv
Gaede P. et al., N Engl J Med 2003; 348:383-93.
Despite the fact that management of
postprandial hyperglycemia
improves glycemic control and may
decrease macrovascular disease it is
rarely measured nor is it an
important target for glycemic control
Retinopathy During DCCT
Rate Per 100 Patient Years
Insulin
Twice a
Day
24
20
16
12
8
4
0
A
HbA1c
Insulin with
Each Meal and
Bedtime
1
8%
2
3
4
5
6
7
8
9
B
HbA1c
0
DCCT Research Group. Diabetes
1995;44:968-83.
9%
7%
0
24
20
16
12
8
4
0
11% 10%
1
2 3 4 5 6 7
Time During Study (yrs)
9%
8%
7%
8 9
25
Additional agents to control glycemia not
available to Steno 2
 PPARγ
agonists
 Exenatide
 Pramlintide
 Rapid-acting insulin secretogogues
 Basal insulins
 Bolus insulins
Exenatide Showed Durable
Effect on A1C
Blinded
Open-label
0.5
5 µg
BID
10 µg
BID
PBO
N=128
0.0
Change in
A1C From -0.5
Baseline (%)
5 µg BID
N=128
-1.0
10 µg BID
N=137
-1.5
0
10
20
30
40
50
Time (weeks)
Combined baseline A1C = 8.3%; Completer population (n=393) at 82 weeks
60
70
80
Exenatide Showed Durable
Effect on Weight
Blinded
0
Open-label
PBO
N=128
5 µg
BID
10 µg
BID
-2
5 µg BID
N=128
-4
Change in
Body Weight
From
-6
Baseline
(lbs)
10 µg BID
N=137
-8
-10
-12
0
10
20
30
40
50
Time (weeks)
Combined baseline body weight = 218.3 lbs; Completer population (n=393) at 82 weeks
60
70
80
Lipid management in type 2
diabetes
TNT Study: Diabetic Population
 1500 known diabetics
 5 years treatment
 753 Atorvastatin 10 mg/day; 748 Atorvastatin 80 mg/day
 Baseline: HbA1c 7.4 % ; BMI 30-31 kg/m² ; BP 135/77 mm Hg
 LDL cholesterol 98.6 vs 76.7 mg/dl
 Triglyceride
177.9 vs 145.1 mg/dl
 HDL cholesterol 44.9 vs 44.0 mg/dl
 Outcomes: Composite CV events 135 vs 103 (RRR = ↓ 25 %
Cerebrovascular events RRR = ↓ 31 %
ADA meeting 2005
Statin prevention of recurrent events involves both LDL
cholesterol lowering and anti-inflammatory effects
N Engl J Med 2005;352:20-28.