2 2

4
1. (Insulin secretagogues)
2
1.1 Sulfonylureas
sulfonylurea receptor

chlorpropamide, glibencamide, glipizide, gliclazide, gliquidone

glimepiride
1.2 Non-sulfonylurea insulin secretagogues


sulfonylurea repaglinide
nateglinide ( nateglinide )
2. (insulin sensitizer)
2.1 Metformin

2.2 Thiazolidinediones
peroxisome proliferator

activated receptor gamma
rosiglitazone
pioglitazone
3. alpha-glucosidase (alpha-glucosidase
inhibitors) acarbose
voglibose

4. Dipeptidyl Peptidase (DPP) IV inhibitors

glucagon-like peptide-1 (GLP-1) glucose-dependent insulinotropic polypeptide

(GIP) sitagliptin vildagliptin


1. Sulfonylureas


sulfonylurea receptor ATP-sensitive potassium channel
depolarization voltage-dependent
calcium channel
3 generations
First generation chlorpropamide
Second generation glibencamide glipizide
Third generation glimepiride gliclazide
1
chlorpropamide glibenclamide
chlorpropamide
ADH
gliclazide glimepiride sulfonylurea receptor
sulfonylureas sulfonylurea receptor

(Ischemic preconditioning)
2

sulfonylureas HbA1c 1.5-2%

HbA1c 2
HbA1c


repaglinide

1,
2

serum creatinine 2 /

2. non-sulfonylurea insulin secretagogue repaglinide nateglinide
repaglinide
1

15
HbA1c sulfonylureas
90

(creatinine clearance 30
/)
(mild to moderate renal insufficiency)

3. Metformin

AMP-activated protein kinase

HbA1c sulfonylureas


sulfonylureas
plasminogen activator inhibitor-1
United Kingdom Prospective Diabetes Study (UKPDS)
2
2

2-3
lactic acidosis
serum Cr 1.4 /
1.5 / lactic acidosis
48

radiocontrast agents

metformin
2
4. - glucosidase inhibitors
acarbose voglibose
alpha-glucosidase

complex carbohydrate oligosaccharide monosaccharide

50-70 / HbA1c 0.5-1.0
%
1
serum Cr > 2 /

5. Thiazolidinediones
rosiglitazone pioglitazone

nuclear receptor peroxisome

proliferator-activated receptor gamma (PPAR)

(adipocytokines)
TNF- adiponectin

HbA1c 1-1.5%

( 1 %)
inactive metabolites


(New York Heart Classification class 3 4)

sulfonylureas metformin
2

4. Dipeptidyl peptidase-4 inhibitors

glucagon-like peptide (GLP-1) glucose-dependent insulinotropic peptide (GIP)

2

GIP

K
cells GLP-1

L cells ileum
colon 2
glucosedependent
GLP-1

GLP-1
GLP-1 GIP
2 GLP-1
GIP

2 dipeptidyl

peptidase-4 (DPP-4) GLP-1 GIP

sitagliptin vildagliptin sitagliptin

HbA1c 0.8-1.0% sitagliptin
100 .
creatinine clearance 30-50 / 50 creatinine
clearance < 30 / 25

glucose-dependent

 1
class

Drug

Dose
mg/d

Half life
(.)

Metabolites and
excretion

Sulfonylurea
First generation

Chlorpropamide

250-500

24-48

Second generation

Glibenclamide

2.5-20

12

Glipizide

2.5-40

2-4

Gliclazide

80-320

12

Gliclazide MR

30-120

16

Glimepiride

1-8

Non-SU
secretagogues
Biguanides

Repaglinide

1-6

Metformin

500-2550

2-4

Thiazolidinediones

Pioglitazone

15-45

3-7

Rosiglitazone

4-8

3-4

Acarbose

75-300

12

Voglibose

0.6-0.9

12

Sitagliptin

100

8-14

Active/
urine 100%
Inactive/
urine 50%
Inactive/
urine 80%
Inactive/
urine 60%
Inactive/
urine 60%
Inactive/
urine 60%
Inactive/
bile 90%
-/
kidney 100%
Inactive/
urine 15%
Inactive/
urine 64%
active/
urine100%
active/
urine100%
-/
Urine 80%

Third generation

-Glucosidase
inhibitors

DPP4 inhibitors

HbA1c
reduction (%)
1.5-2

1-2
1.5-2
0.7-1.8
0.6-1.9
0.5-1.0
0.5-1.0
0.8-1.0

 2
2




1.

,


chlorpropamide glibenclamide 80
metformin creatinine clearance
50 / lactic acidosis metformin

glipizide repaglinide
repaglinide,
thiazolidinediones sitagliptin
creatinine clearance
15-30 /
thiazolidinediones
alpha-glucosidase
inhibitors, repaglinide DPP-4 inhibitors
lactic acidosis , ,
metformin
2.


HbA1c 6.5-7%
HbA1c <6%
HbA1c
sulfonylureas biguanides HbA1c
1.5-2 % ( 1)

3. (Extraglycemic effects)

UKPDS
metformin HbA1c


4.





metformin

sulfonylureas thiazolidinediones

5. (tolerability) (compliance)


2
2


Metformin
Sulfonylureas

Glinides

Thiazolidinediones

-glucosidase inhibitors
DPP-4 inhibitors

2-3

6.

Suggested Readings
1. Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, Zinman B.
Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation
and adjustment of therapy: a consensus statement from the American Diabetes Association
and the European Association for the Study of Diabetes. Diabetes Care 2006; 29: 1963-72.
2. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;
131: 281-303.
3. Nathan DM. Initial management of glycemia in type2 diabetes mellitus. N Engl J Med 2002;
347:1342-9.
4. Holmboe ES. Oral antihyperglycemic therapy for type 2 diabetes: clinical applications. JAMA
2002; 287: 373-6.
5. Campbell, R.K. Rationale for dipeptidyl peptidase 4 inhibitors: a new class of oral agents for
the treatment of type 2 diabetes mellitus. Ann Pharmacother 2007; 41: 51-60.