review of therapies in relation to key drivers - kendall

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


Associate Professor of Medicine

University of Minnesota

Minneapolis, MN


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


Park Nicollet

The Pathophysiology of Type 2 Diabetes

Impaired Incretin Effect

Relative Insulin Deficiency

Insulin Resistance

© 2008 International Diabetes Center. All rights reserved


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


Park Nicollet

Diabetes Disease Progression: β cell Dysfunction and Early Hyperglycemia

Ferrannini E. J Clin Endocrinol Metab 90: 493–500, 2005


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


Park Nicollet

Clinical Impact of Diabetes Therapy

Diabetes Prevention and Disease Progression


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


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%


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


Park Nicollet

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


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 (%

)


Park Nicollet

Diabetes Disease Progression: Impact of Specific Therapies

Insulin



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)




Park Nicollet

Thiazolidinediones

A Closer Look at β Cell Function and Diabetes Disease Progression


Park Nicollet

Effect of Early TZD Use on A1C


Park Nicollet

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


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


Park Nicollet

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)


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


Park Nicollet

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


Park Nicollet

Exenatide Improves Phasic Insulin Secretion in Type 2 Diabetes


Park Nicollet

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


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


Park Nicollet

Weight HbA1c

The Temporal Pattern of Weight Loss with Exenatide Therapy

Kendall DM et al. Diabetes 2008. ADA Annual Scientific Sessions


Park Nicollet

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


Park Nicollet

Impact of Type 2 Diabetes Therapy on Disease Progression: A Checklist

No No No No Insulin

No

No

No

No


Yes

Yes

No

No


Incretin based Rx Yes

Yes

Yes

No

? ?

Yes Yes TZD

No Yes AGI

No No Sulfonylurea

No Yes Metformin

No Yes Lifestyle (MNT)




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


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?

review of therapies in relation to key drivers - kendall

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