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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.