陽明大學附設醫院

內分泌暨新陳代謝科

林冠宏 醫師

1

2

Eyes (retinopathy,

glaucoma, cataracts)

Brain and Cerebral Circulation (stroke, TIA)

Heart and Coronary Circulation (angina, MI, CHF)

Kidneys (nephropathy,

ESRD)

Peripheral Nervous System

(peripheral neuropathy)

Peripheral Vascular Tree (peripheral vascular disease, gangrene, amputation)

CHF=congestive heart failure; ESRD=end-stage renal disease; MI=myocardial infarction; TIA=transient ischemic attack; T2DM=type 2 diabetes mellitus. Adapted from International Diabetes Federation. Complications. Available at: http://www.eatlas.idf.org/complications. Accessed April 14, 2006. 3

Serious long-term complications in T2DM

For every 1% reduction in mean HbA1c there was a reduction in risk (%) of complications

Lowering HbA1c can reduce the risk of

complications associated with T2DM

-37%

-14%

-21%

Microvascular complications

Retinopathy, neuropathy, nephropathy

Myocardial infarction

Fatal and nonfatal MI

Deaths related to diabetes

MI = myocardial infarction Stratton IM, et al. BMJ. 2000;321:405-412.

Benefits of lowering HbA1c

4

Aggregate endpoint 1997 2007

Any diabetes-related endpoint RRR =

P =

12%

0.029

9%

0.040

Microvascular disease RRR =

P =

25%

0.0099

24%

0.001

MI RRR =

P =

16%

0.052

15%

0.014

All-cause mortality RRR =

P =

6%

0.44

13%

0.007

After median 8.5 years’ post-trial follow-up

MI=myocardial infarction; RRR=relative risk reduction; P=log rank. Diabetes Trials Unit. UKPDS Post Trial Monitoring. UKPDS 80 Slide Set. Available at: http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/. Accessed 12 September, 2008; Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589; UKPDS 33. Lancet. 1998; 352: 837–853.

5

Early glucose control not only reduces complications but has a long term legacy

http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/

Source: CODE-2 Study. Williams R et al. Diabetologia 2002; 45: S13-S17.

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Microvascular & Macrovascular

3.5x

Macrovascular

2.0x

Microvascular

1.7x

No Complications

1.0x

Effect of Complications on Average Cost per Patient

Co

st I

mp

ac

t Fa

cto

r

Costs were assessed retrospectively for 6 months

Incremental cost due to complications Base cost without complications

6

Micro- and macro-vascular complications are the key divers of the costs associated with T2DM

7

Tahrani AA et al, Lancet 2011;378:182-197 8

Addressing impaired incretin action as a third core defect in

T2DM has important clinical implications

Impaired Incretin Action

Insulin Resistance

Beta cell dysfunction

Type 2 diabetes mellitus

Incretin action: Emerging as a core defect in T2DM

Adapted from: Kendall DM. Am J Med. 2009;122:S37-S50. 9

(% R

ela

tiv

e F

un

ctio

n

of

no

rma

l)

0

50

100 150

200

300

-10 -5 0 5 10 15 20 25 30

50

100

150

200

250

300

350

Insulin Resistance

Insulin Level

Fasting BG

Incretin action

Postprandial BG

Glu

cose

(m

g/d

L) Prediabetes Diabetes

250

Normal

Normal BG Range

Time (Years)

Natural progression of T2DM

BG = blood glucose Adapted from: Mazze R, et al. Part two: The treatment of diabetes. In: Mazze R, Strock ES,

Simonson G, Bergenstal RM, eds. Staged Diabetes Management: A Systematic Approach.

2nd ed. rev. 2006:78-154.. 10

↑ Glucose

Fewer -cells

-cells Hypertrophy

Insufficient Insulin

Excessive Glucagon

– +

↓ Glucose Uptake

↑ HGO

+

HGO=hepatic glucose output. Adapted from Ohneda A, et al. J Clin Endocrinol Metab. 1978; 46: 504–510; Gomis R, et al. Diabetes Res Clin Pract. 1989; 6: 191–198. 11

Pancreatic islet dysfunction leads to hyperglycemia

Glucagon

25

30

35

40

45

pm

ol/

L

Time (min) -60 0 60 120 180 240 300

NGT

IGT

0

Insulin

200

400

600

pm

ol/

L

Glucose

Glucose

50

100

150

200

250

mg

/dL

NGT

IGT

NGT

IGT

Elevated glucagon in T2DM and IGT (↓ insulin / glucagon ratio)

IGT T2DM

CHO=carbohydrate; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus. Adapted from Müller WA, et al. N Engl J Med. 1970; 283: 109–115.

IGT=impaired glucose tolerance; NGT=normal glucose tolerance. Adapted from Mitrakou A, et al. N Engl J Med. 1992; 326: 22–29.

CHO meal

0

NGT

T2DM

-60

Time (min)

0 60 120 180 240

Glucose 100

200

300

400

mg

/dL

0

Insulin 50

100

150

μU

/mL

NGT

T2DM

Glucagon

75

100

125

150

pg

/mL

NGT

T2DM

12

13

IV=intravenous. Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986; 63: 492–498.

Oral Glucose Tolerance Test and Matched IV Infusion

Pla

sma

Glu

co

se (

mg

/dL

)

0

50

100

150

200

–30 0 30 60 90 120 150 180 210

Time (min)

Pla

sma

In

suli

n (

pm

ol/

L)

0

100

200

300

400

–30 0 30 60 90 120 150 180 210

Time (min)

Oral IV

50 g Glucose

N=6

14

L-cell

(ileum)

Proglucagon

GLP-1 [7–37]

GLP-1 [7–36 NH2]

K-cell

( jejunum)

ProGIP

GIP [1–42]

GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1. Adapted from Drucker DJ. Diabetes Care. 2003; 26: 2929–2940. 15

16 Girard J. Diabetes Metab. 2008 34: 550–559.

17 Girard J. Diabetes Metab. 2008 34: 550–559.

GIP

GLP-1

* * * * *

* *

20

15

10

5

0 0 60 120 180 240

Time (min)

Meal

GL

P-1

† (

pm

ol/L

)

Mean ± SE; N=102; *p

Postprandial

19

20

GLP-1 inactive

(>80% of pool)

Active GLP-1

Meal

DPP-4

Intestinal GLP-1 release

GLP-1 t½=1–2 min

DPP-4 inhibitor

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1. Adapted from Rothenberg P, et al. Diabetes. 2000; 49 (Suppl 1): A39. Abstract 160-OR. Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126–1131. 21

Meal

*

*

*

*

*

* * * *

* *

*

Vildagliptin 100 mg (n=16)

Placebo (n=16)

GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus. *P

See accompanying Prescribing Information and safety information included in this presentation 23

Mean (SE); N=25. Fehse F, et al. J Clin Endocrinol Metab. 2005;90:5991-5997. Copyright 2005, The Endocrine Society.

Healthy Subjects, Placebo

Insu

lin

Se

cre

tio

n

(pm

ol•

kg

-1•m

in-1

)

Time (min)

Exenatide versus Healthy

Exenatide versus Placebo p=.0002 p=.0002

p=.0029

T2D, Placebo

T2D, Exenatide

24

Madsbad S, Lancet 2009;373:438-439 25

26

27

28

D = duct Tourrel C, et al. Diabetes. 2002;51:1443-1452. Copyright © 2002 American Diabetes Association. From Diabetes, Vol 51, 2002; 1443-1452. Reprinted with permission from The American Diabetes Association.

Untreated Diabetic Rats Diabetic Rats Treated With GLP-1

Double immunostaining for BrdU and insulin (A and B) and indirect

immunoperoxidase staining for insulin (C and D) in 7-day-old Rats

29

Control GLP-1

Day 1

Day 3

Day 5

♦ Pancreatic islets cultured in the absence of GLP-1 lost organisation after 5 days

♦ By Day 5, 45% of islets in control cultures had lost their 3-D structure

♦ Only 15% of GLP-1– treated islets lost their 3-D structure in 5 days (p

0

2

4

6

8

10

165 180 190 210 240 260 270 290

Time (min)

C-p

ep

tid

e (

nm

ol/

L)

4 weeks off-drug

Pre-treatment 52 weeks on-drug

0

2

4

6

8

10

165 180 190 210 240 260 270 290

Time (min)

C-p

ep

tid

e (

nm

ol/

L)

C-Peptide Concentrations During Hyperglycemic Clamp: Exenatide vs. Glargine

Exenatide Insulin Glargine

Data represent mean ± SE

Phase: 1st 2nd

AIRarg Phase: 1st 2nd

AIRarg

Bunck et al. Diabetes Care 2009;32:762-8.

31

Patients with T2D; Evaluable population, n=61 for both treatment groups; Geometric LS mean ± SE Standard meals administered at t = 0 min; Geometric mean baseline insulinogenic index2: 0.4 1. Adapted from DeFronzo RA, et al. Curr Med Res Opin. 2008;24:2943-2952.; 2. Data on file, Amylin Pharmaceuticals, Inc.

Insu

lin

og

en

ic I

nd

ex1

BYETTA Sitagliptin

p=.02

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.55

0.82

*Increment was defined as the post-meal minus the pre-meal levels at the time of peak glucose concentration

Insulinogenic index = increment in plasma insulin*

increment in plasma glucose*

32

Patients with T2D; Evaluable population, n=61 for all treatment groups; Mean ± SE Adapted from DeFronzo RA, et al. Curr Med Res Opin. 2008;24:2943-2952.

Pla

sma

Glu

cag

on

(p

g/m

L)

Time (min) Standard Meal

-30 0 30 60 90 120 150 180 210 240 70

80

90

100

110

120

Baseline Exenatide Sitagliptin

33

Exenatide Placebo

ITT patient sample, LS Mean ± SE, *p

PP

G (

mm

ol/

L)

Time (min) Standard Meal

Patients with T2D; Evaluable population, n=61 for all treatment groups; Mean ± SE; * least square (LS) mean ± SE, p

-5 -4 -3 -2 -1 0 1 2 3 4 5 -30

-25

-20

-15

-10

-5

0

5

10

15

10%

68%

6%

16%

HbA1c Change from Baseline (%)

We

igh

t C

ha

ng

e F

rom

Ba

seli

ne

(k

g)

N=217 Adapted from Klonoff DC, et al. Curr Med Res Opin 2008;24:275-286.

36

Placebo-controlled/Open-label Extension (Combined)1

1. Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286. 2. Exenatide Clinical Data Analysis Shows No Increased Risk of Cardiovascular Events [press release]. San Diego, CA, Indianapolis, IN, and Cambridge, MA; March 26, 2009.

Me

an

Ch

an

ge

(%

)

N=151 *p

*In three 30-week placebo-controlled trials. Adapted from Byetta [prescribing information]. San Diego, CA: Amylin Pharmaceuticals Inc, 2005.

18%

4% 6%

44%

13% 13%

0

5

10

15

20

25

30

35

40

45

50

Nausea Vomiting Diarrhea

Pro

po

rtio

n o

f P

ati

en

ts (

%) Placebo (n=483)

Exenatide (n=963)

38

39 Drunker DJ et al. Dabetes Care. 2010; 33(2): 428-433.

40

-glucosidase inhibitors Delay intestinal carbohydrate absorption

Thiazolidinediones Decrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle and decrease glucose production in liver

Sulfonylureas Glinides Increase insulin secretion from pancreatic -cells

GLP-1 analogs Improve pancreatic islet glucose sensing, slow gastric emptying, improve satiety

DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus. Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226. Ahrén B, Foley JE. Int J Clin Pract. 2008; 62: 8–14.

DPP-4 inhibitors Prolong GLP-1 action leading to improved pancreatic islet glucose sensing, increase glucose uptake

41

Biguanides Increased glucose uptake and decreases hepatic glucose production

42

Change from baseline in HbA1c

McIntosh B et al. Open Medicine. 2011; 5(1): E35

43

Odds of at least 1 event of overall hypoglycemia

McIntosh B et al. Open Medicine. 2011; 5(1): E35

Pancreatic cell

Adapted from: Cheng AYY, et al CMAJ. 2005; 172: 213–216. * Levy AR et al. Health and Quality of Life Outcomes 2008, 6:73

• Increased secretion of insulin independently of glucose level

• Increased risk of hypoglycemia

• Chronic effect: weight gain due to defensive eating*

SU

K+ X

Release of insulin

Pancreas Insulin

44

Sulphonylureas do not work in glucose-dependent manner increasing risk of hypoglycemia

45

Change from baseline in body weight

McIntosh B et al. Open Medicine. 2011; 5(1): E35

21.6

13.0

0

5

10

15

20

25 3.6

-0.4-1

0

1

2

3

4

% of Edema without HF Weight Gain (kg)

Placebo

Pioglitazone

CI=confidence interval; CV=cardiovascular. Adapted from Nissen SE, Wolski K. N Engl J Med. 2007; 356: 2457–2471.

Myocardial infarction

Small trials combined

DREAM

ADOPT

Overall

Death from CV causes

Small trials combined

DREAM

ADOPT

Overall

2.0 4.0 1.0

Log Odds Ratio (95% CI)

0.5

1.43 (1.03–1.98) P=0.03

1.45; P=0.15

1.65; P=0.22

1.33; P=0.27

2.40; P=0.02

1.20; P=0.67

0.80; P=0.78

1.64 (0.98–2.74) P=0.06

47

Aubert RE, et al. Diabetes Obes Metab. 2010;12(8):716-721 Colin R. Arch Intern Med. 2009;169(15):1395-1402.

48

49 Voelker R. JAMA. 2012; 307(24): 2577.

50 Mamtani R et al. J Natl Cancer Intst. 2012; 104(18): 1411-21.

51 Mamtani R et al. J Natl Cancer Intst. 2012; 104(18): 1411-21.

52

53

54

Adapted from Inzucchi SE et al. Diabetologia. 2012; 55(6): 1577-1596. 55

56

57

58 58

59

60

61

62

Lifestyle modification

Drug of choice Efficacious

Low risk for hypoglycemia

Weight neutral/loss

Less adverse effects (CV, osteoporosis, cancer, etc.)

Good adherence (once daily)

63

Personalized/individualized care should be the

cornerstone of modern diabetes management.