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 PPAR γ agonists on cardiovascular events
 Memory of vascular tissues for previous hyperglycemia
 Role of inflammation in vascular disease
 New targets for lipid treatment

Insulin sensitizers Insulin sensitizers Insulin sensitizers
+ insulin secretogogues
+ Insulin
100
75

-Cell
Function
(%)
50
25
IGT Postprandial Type 2
Hyperglycemia Diabetes
Phase I
Type 2
Diabetes
Phase II
0
-12 -10 6 -6 -2 0 2
Years From
Diagnosis
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

On Trial
Off
Trial
60%
Placebo
Troglitazone
21% per year
40%
20%
0%
3% per year ivGTT
0
Buchanan et al: Diabetes, in press
20 40 60
Months after Randomization

DPP: 4-Group Study, 1996 - 1998
Eligible participants
Randomized
Placebo Metformin Troglitazone ILS n = 582 n = 587 n = 585 n = 589
ILS = Intensive Life Style
Diabetes 54:1150-1156, 2005
Total n = 2,343

15
10
PLAC
MET
TROG
ILS
5
0
0.0
0.5
1.0
1.5
(2,343) (1,568) (739) (237)
Years from Randomization (total no. of participants)
Diabetes 54:1150-1156, 2005

Overall p<0.001
16
12
12.0
TROG v. PLAC
TROG v. MET
TROG v. ILS
P<0.001
P=0.02
P=0.18
8
6.7
5.1
4 3.0
0
PLAC MET TROG ILS
Diabetes 54:1150-1156, 2005

Fig 7
Beta cell replication and apoptosis in type 2 diabetes
Butler et al. Diabetes
2003;52:102

DREAM = Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication
Screening n=24,872
Run-in
14-20 days
Randomization n=5269
Ramipril 15 mg vs placebo
AND
Rosiglitazone 8 mg vs placebo
Regular outcome assessments
3-5 years
Washout
2-3 months
DESIGN
2X2 Factorial
Diabetologia 47:1519-1527, 2004
Final
Evaluation

100
75

-Cell
Function
(%)
50
25
IGT Postprandial Type 2
Hyperglycemia Diabetes
Phase I
Type 2
Diabetes
Phase II
0
-12 -10 6 -6 -2 0 2
Years From
Diagnosis
Type 2 Diabetes
Phase III
10 14
Lebovitz H, Diabetes Review 1999.

Metabolic Syndrome: Associated cardiovascular risk factors
Dyslipidemia
↑ FFA
↓ Adiponectin
Endothelial Dysfunction
↑ Adhesion Molecules
↑ Cellular Proliferation
↓ Vasodilation
Visceral Obesity
↓ HDL
↑ Triglycerides
↑Small dense LDL
Insulin Resistance
Procoagulant State
↑ PAI-1
↑ Fibrinogen
Inflammation
↑ NFκB
↑ CRP
↑ IL-6
Modified from Lebovitz, Eur. J. Pharmacol. 2004

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
EASD 2004

100
98
96
94
92
0
NGR vs AGR p < 0.05
NGR vs DM p < 0.001
AGR vs DM p < 0.008
100 200 300
Follow up (days)
Normal
Newly detected
AGR
400
Known diabetes

Rosiglitazone vs placebo on stent re-stenosis
P-control P-Rx R-control R-Rx
4
3
6
5
9
8
7
Glucose HbA1c Insulin
Choi et al. Diabetes Care 2004;27:2654-2660

Rosiglitazone vs placebo on stent re-stenosis
P-control P-Rx R-control R-Rx
7
6
5
4
3
2
1
0
TG FFA CRP
Choi et al. Diabetes Care 2004;27:2654-2660

• Characteristics
• Number of patients
• Number of lesions
• In stent re-stenosis
• Diameter stenosis
• p= 0.030
• ^ p < 0.004
Control Rosiglitazone
45
55
38.2 %
40.9 %
38
51
17.6 % *
23.0 % ^
Choi et al. Diabetes Care 2004;27:2654-2660

Effect of Rosiglitazone on Common
Carotid IMT Progression in Nondiabetic
Coronary Artery Disease Patients
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.

92 Patients Randomized
46 assigned placebo
1 diabetic
1 side effects
2 lost to follow-up
46 assigned rosiglitazone
3 diabetic
2 side effects
1 lost to follow-up
42 had scan at 24 weeks
1 lost to follow-up
40 had scan at 24 weeks
1 lost to follow-up
41 completed study 39 completed study
Sidhu JS et al., Arterioscler Thromb Vasc Biol March 4, 2004; Epub ahead of print.

0.04
Progression rate=0.031mm/48 wks
(0.0016, 0.0604)
Progression rate=0.012 mm/48 wks
(-0.0414, 0.0174)
Placebo Rosiglitazone 8 mg/day
0.03
0.02
0.01
0
-0.01
0 24 48
Time (weeks)
0 24 48
P=0.03 for difference in progression slopes
Sidhu JS et al., Arterioscler Thromb Vasc Biol March 4, 2004; Epub ahead of print.

 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.

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:
– HbA
1c 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
12
Conventional
Intensive
Mean HbA
1c during EDIC
Conventional 8.2%
Intensive 8.0%
p = .0019
10
8
6 p < .0001 .0001 .0001 .002
.04
.08
.037
.59
.83
DCCT
Closeout
1 2 3 4 5
EDIC year
6 7 8
DCCT/EDIC

Further Retinopathy Progression Over 8 y of EDIC
From the Level at DCCT Closeout
Adjusted For DCCT Closeout Level
50
40
30
63% Risk Reduction with intensive therapy
p < .0001
Conventional
20
10
Intensive
0
0 1 2 3 4
EDIC YEAR
5 6 7 8
DCCT/EDIC

4
2
0
Cumulative Incidence of
New Clinical Albuminuria > 300 mg/24 h
During EDIC
12
10
83% risk reduction
p < .0001
Conventional
8
6
Intensive
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
40
*
30
*
*
*
20
*
*
10
0
DCCT
Close-out
Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8
EDIC
* p < .05, intensive vs. conventional

%
10
Effect of Intensive Rx on Collagen Glycation
Products Primary Cohort P Mole per mg
Collagen
Conventional Intensive
1,000
* p < .001
*
*
7.5
750
*
500
5
*
250
2.5
0
0
HbA
1c Furosine Carboxymethyl lysine
Pentosidine x 10

Logistic Regression Analysis of Retinopathy Progression
During EDIC as Dependent Variable
Independent Variables Chi 2 p
Mean DCCT HbA
1c
Skin collagen AGE’s
Furosine, CML
Furosine, CML adjusted for HbA
1c
Mean DCCT HbA
1c adjusted for furosine &
CML
41
62
55
16
2.3
<.0001
<.0001
<.0001
.0004
NS

Cumulative: 346 of 3867 Patients (9%)
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
Years from randomization
12 15
Renal failure or death, vitreous hemorrhage, or photocoagulation.
UKPDS Group. Lancet . 1998;352:837-853.

• 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

BMI
<27
Diet
BMI
≥27
Diet
Gliclazide
Metformin
Gliclazide
+
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
• Haemoglobin A
1c
• Systolic BP
• Diastolic BP
• Total-cholesterol
• LDL-cholesterol
• Triglycerides
• Urinary albumin
Conventional
9.0%
146 mm Hg
78 mm Hg
5.6 mmol/l
3.3 mmol/l
3.0 mmol/l
126 mg/24h
Intensive
7.9%
131 mm Hg
73 mm Hg
4.1 mmol/l
2.1 mmol/l
1.7 mmol/l
26 mg/24h
Gaede P. et al., N Engl J Med 2003; 348:383-93.

30
20
10
0
%
80
Percentage of patients achieving treatment goals set for the intensivetherapy group at 7.8 yr
HbA
1c
<6.5% Cholesterol
<4.5 mmol/l
Triglycerides
<1.7 mmol/l
Systolic BP
<130 mm Hg
Diastolic BP
<80 mm Hg p<0.0001
p=0.21
70 p=0.19
60
50 p=0.001
40 p=0.06
Int Conv Int Conv 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

Insulin
Twice a
Day
24
20
16
12
8
4
0
A
HbA
1c
11% 10%
9%
8%
7%
0 1 2 3 4 5 6 7 8 9
Insulin with
Each Meal and
Bedtime
24
20
16
12
8
4
0
B
HbA
1c
9%
0 1 2 3 4 5 6 7 8 9
Time During Study (yrs)
8%
7%
DCCT Research Group. Diabetes
1995;44:968-83.
25

Additional agents to control glycemia not available to Steno 2
 PPAR γ agonists
 Exenatide
 Pramlintide
 Rapid-acting insulin secretogogues
 Basal insulins
 Bolus insulins

Blinded Open-label
0.5
5 µg
BID
10 µg
BID
PBO
N=128 0.0
Change in
A1C From
Baseline (%)
-0.5
5 µg BID
N=128
-1.0
10 µg BID
N=137
-1.5
0 10 20 30 40
Time (weeks)
50
Combined baseline A1C = 8.3%; Completer population (n=393) at 82 weeks
60 70 80

Blinded Open-label
0 PBO
N=128
5 µg
BID
10 µg
BID
-2
Change in
Body Weight
-4
From
Baseline
(lbs)
-6
-8
5 µg BID
N=128
10 µg BID
N=137
-10
-12
0 10 20 30 40
Time (weeks)
50
Combined baseline body weight = 218.3 lbs; Completer population (n=393) at 82 weeks
60 70 80

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 3031 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.