2 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 glucose-
dependent 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

class Drug Dose Half life Metabolites and HbA1c

mg/d (.) excretion reduction (%)
Sulfonylurea 1.5-2
First generation Chlorpropamide 250-500 24-48 Active/
urine 100%
Second generation Glibenclamide 2.5-20 12 Inactive/
urine 50%
Glipizide 2.5-40 2-4 Inactive/
urine 80%
Third generation Gliclazide 80-320 12 Inactive/
urine 60%
Gliclazide MR 30-120 16 Inactive/
urine 60%
Glimepiride 1-8 9 Inactive/
urine 60%
Non-SU Repaglinide 1-6 1 Inactive/ 1-2
secretagogues bile 90%
Biguanides Metformin 500-2550 2-4 -/ 1.5-2
kidney 100%
Thiazolidinediones Pioglitazone 15-45 3-7 Inactive/ 0.7-1.8
urine 15%
Rosiglitazone 4-8 3-4 Inactive/ 0.6-1.9
urine 64%
-Glucosidase Acarbose 75-300 12 active/ 0.5-1.0
inhibitors urine100%
Voglibose 0.6-0.9 12 active/ 0.5-1.0
urine100%
DPP4 inhibitors Sitagliptin 100 8-14 -/ 0.8-1.0
Urine 80%
 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

2-3
Metformin X X
Sulfonylureas X
Glinides X X
Thiazolidinediones X
-glucosidase inhibitors X X
DPP-4 inhibitors
 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.