704 138
(Incretin) 2
Incretin ( )
-1 ( glucagon-like peptide-1 GLP-1 ) GLP-1
G L P - 1
( dipeptidyl peptidase IV DPP IV ) GLP-1
DPP IV GLP-1 exenatide liraglutide
DPP IV GLP-1
FDA 2
2 2
2 ( Type 2 diabetes mellitus )
-1 ( Glucagon-like peptide-1, GLP-1) ( Incretin )
( Dipeptidyl peptidase IV )
( United Kingdom P r o s p e c t i v e D i a b e t e s S t u d y
UKPDS )
2 1
2
( 1 )
2
thia- zolidinediones ( TZDs )
alpha-glucosidase inhibitors meglitinides
( 2 ) 1
TZDs
3,4
2
( en- teroinsular axis )
( incretin )
50%
( 1 )
( glucose dependent insulinotropic polypeptide ) ( gastric inhibitory polypeptide ) GIP ( 2 ) -1 ( Glucagon-like
peptide-1 GLP-1 )5 2
GLP-1 2
6 2
- - -
GLP-1
( Extrapancreatic effect ) 2
G L P - 1
GLP-1 ( 1 ) GLP-1
( 2 ) GLP-1 B ( apoptosis )7 ( 3 ) GLP-1
G L P - 1
8,9 ( 4 ) GLP-1 10
GLP-1
11 ( 1 ) GLP-1
( 2 )
GLP-1 GLP-1
( 3 ) G L P - 1 1 2
13 14
( ischemia/ reperfusion ) 15
16 GLP-1
2
2
GLP-1 GIP
G L P - 1
G L P - 1
( endovascular serine protease ) dipeptidyl pep-
tidase IV ( DPP IV ) N N
GLP-1 ( 9-36 amide )
17
G L P - 1 G L P - 1
G L P - 1
DPP IV Exenatide
DPP IV GLP-1
peptide ( fatty
acid chain ) peptide GLP-1
DPP IV DPP IV G L P - 1
vildagliptin ( LAF-237 ) sitagliptin ( MK-0431 ) D P P I V
DPP IV GLP-1
Exenatide ( Byetta®)
FDA 2005 Exenatide ( Byetta ® )
2 3
3 3 0
( Sulfonylureas ) 18
metformin 19
20 HbA1c 7.0% 2
( placebo ) exenatide 5 g twice daily exenatide 10 g twice daily
Exenatide
30 HbA1c 10 g 5 g
placebo 0.86 0.11% 0.46
0.12% 0.12 0.09% HbA1c 7%
41% ( 10 g ) 33%
( 5 g ) 9% ( placebo ) ( P 0.001 ) 10 g exenatide
1.6 0.3 kg ( P <0.05 vs. placebo )17 m e t f o r m i n
Exenatide 30 HbA1c 10 g
5 g placebo 0.78
0.10% 0.40 0.11% 0.08 0.10%
( p 0.002 ) HbA1c 7%
46% ( 10 g ) 32% ( 5 g )
13% ( placebo ) ( P 0.01 vs. placebo ) p l a c e b o e x e n a t i d e 1 0 g
5 g 2.8 0.5 kg 1.6 0.4
kg( P 0.001 vs. placebo )18
exe-
natide 30 HbA1c 10 g 5
g placebo 0.8 0.1%
0.6 0.1% 0.2 0.1% ( placebo ) ( P 0.0001 vs. placebo ) HbA1c 7%
34% 27% 9% ( P
0 . 0 0 0 1 ) e x e -
natide 1.6 0.2 kg place-
bo 0.9 0.2 kg ( P 0.01 )19
exenatide
5 2
4 exenatide 5 g twice daily exenatide 10 g twice daily
52 82
2006 21
82 HbA1c 7%
51% [10 g ] 49% [5 g ]
47% [placebo ]
4.5 kg 0.5 kg 146
2 HbA1c
1 . 2 % 0 . 1 %
5.5 0.5 kg 265 82
8 2
HbA1c 1.2% 0.1%
4.6 kg 0.3kg triglyceride
36.94 mg/dl ( 95% CI 55.96 to 17.91 ) Total cholesterol 2.52 mg/dl ( 95%CI 6.43 to 1.39 )
HDL C 4.46 mg/dl ( 95% CI 3.64 to
5.27 ) 1.48mmHg ( 95% CI
3.46 to 0.51 ) 3.24 mmHg ( 95% CI 4.37 to 2.10 )
2
exenatide insulin glargine 22 283 exenatide 10 g twice daily 268 insulin glargine once daily 26
exenatide insulin glargine A1C 7% ( 48%
vs.46% ) A1C 6.5% ( 32% vs.25% )
exenatide 2.3 kg
0.2 kg insulin glargine 1.8 0.2kg ( p 0.001 )
Liraglutide ( NN2211 )
F D A
2
23
Liraglutide
0.045 0.225 0.45 0.6 0.75 mg metformin 1000 mg bid Liraglutide
metformin 0.045 mg 0.225 mg
HbA1c 1.28%
0.86% 0.22% 0.16% 0.30% and
0.09% [metformin ]
24
DPP IV ( DPP IV inhibitors )
Sitagliptin ( Januvia ®)
2006 10 FDA 2
Merck 25
2 Sitagliptin
24 ( n=473 ) 18 ( n=296 ) ( HbA1c 7.0% to 10.0% ( 8.0% ) 2
Sitagliptin HbA1c
2 ( HbA1c 8.0%,
n=441 ) ( HbA1c 8.0% 9.0%, n=
239 ) ( HbA1c 9.0%, n=119 ) 18
0.6% 0.7%
1.4% ( p 0.001 )
1 24 Sitagliptin 100 mg once daily ( add-on therapy )
metformin
pioglitazone 2
Sitagliptin placebo met- formin HbA1c 0.7% ( p 0.001 ) piogli- tazone HbA1c 0.7% ( p 0.01 )
HbA1c 7% metformin
Sitagliptin 47% placebo 9% ( P 0.001 ) pi- oglitazone Sitagliptin 45% placebo 23% ( P 0.001 )
24 metformin
Sitagliptin 100 mg
qd 25 mg/dL 51
mg/dL ( p 0.001 ) 24 Sitagliptin
0.2 kg ( vs. 1.1 kg in placebo ) metformin add-on therapy
0.7 kg ( vs. 0.6 kg in placebo ) place-
bo Sitagliptin
placebo
placebo Vildagliptin ( Galvus ®)
Vildagliptin 2006 3 NDA F D A
1 1 2
26 279 2
5 m g t w i c e d a i l y 2 5 m g 50mg 100 mg once daily vildagliptin p l a c e b o H b A1 c
placebo vildagliptin 50 mg qd and 1 0 0 m g q d H b A 1 c
vildagliptin 50 mg qd 4
vildagliptin 100 mg qd 4 B
HOMA-B vildagliptin 100 mg qd vildagliptin 100 mg qd
placebo
1 12 Vildagliptin 25 mg bid
( n=70 ) 2
Vildagliptin (
HbA1c 8.0 % ) HbA1c ( 0.6% ) H b A 1 c 8 . 0 - 9 . 5 %
HbA1c 1.2 % Vildagliptin
20 7 mg/dL ( p= 0.0043 ) 34 9 mg/dL ( p 0.0001 ) Vildagliptin
placebo 27
2
GLP-1 DPP IV
2 DPP IV
GLP-1 exenatide
DPP IV
exenatide DPP
I V
2
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Clinical Evidence of GLP-1 Receptor Agonists and DPP VI Inhibitors in the Treatment
of Type 2 Diabetes
Shu-Hwa Hsiao, Horng-Yih Ou1, and Ta-Jen Wu1
Incretin plays an import role in postprandial insulin secretion. Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide have well been known to have properties of incretin effect. Patients with type 2 diabetes are noted to be with lost or severely impaired incretin effect. Therefore, the patients also have decresed post- prandial insulin secretion. The major cause of impaired incretin effect in patients with type 2 diabetes is decrease in GLP-1 secretion. GLP-1 also has some effects on promotion of cell growth and differentiation, decreasing cell apoptosis, and glucagon suppression effect. In addition, some beneficial extrapancreatic effects, such as decreasing food intake by acting on central nervous system and direct action on cardiovascular system are also noted. Due to its glucose-dependent insulin secretion effect, the risk of hypoglycemia is low. The incretins are rapidly inactivated by dipeptidyl peptidase IV (DPP VI). Recently, two different approaches are developed to re- tard DPP VI action. One is to use GLP-1 receptor agonists that are resistant to degradation by DPP VI. These GLP-1 mimetics include exenatide and liraglutide. Another approach is to inhibit the activity of DPP VI so that half-life of endogenously released GLP-1 can be prolonged. These DPP VI inhibitors include sitagliptin and vildagliptin. The beneficial effects of these preparations on clinical parameters in patients with type 2 diabetes mellitus have recently been reported in some evidence-based studies. ( J Intern Med Taiwan 2007; 18: 189-194 )
Department of Pharmacy, 1Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan
