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Effects of troglitazone on coagulation—fibrinolysis abnormalities in patients with type II diabetes mellitus
CURRENT THEXAPEUTIC RESEARCH” VOL. 59, NO. 8, AUGUST
EFFECTS
1998
OF TROGLITAZONE ON COAGUIATION-FIBRINOLYSIS ABNORMALITIES IN PATIENTS WITH TYPE II DIABETES MELLITUS KEXJI KUF30
Department
of Endocrinology,
Hiroshima
Prefectural
Hospital, Hiroshima,
Japan
AlWlRACT Type II diabetes mellitus is frequently complicated by arteriosclerotic disease and by coagulation-fibrinolysis abnormalities, which may be essentially responsible for the development and progression of arteriosclerosis and are positively correlated with insulin resistance. Troglitazone, a drug that improves insulin resistance, was administered to patients with type II diabetes. The effect of troglitazone on coagulation-fibrinolysis abnormalities was observed and compared with that of gliclazide, a sulfonylurea. Twenty-one patients were included in the It-week study; 12 received troglitazone 400 mg/d, and 9 received gliclazide 40 mg/d. Of the 12 patients given troglitazone, 7 were treated with troglitazone only, and 5 received troglltazone and concomitant sulfonylureas. Fasting blood samples were collected before study initiation and after completion of treatment, and variables were measured. After 12 weeks of troglitazone therapy, fastlug plasma glucose and hemoglobin A,, levels showed a signlflcant decrease, as did levels of immunoreactive insulin, plasminogen activator inhibitor-1 (PA&l), and fibrinogen. After gliclazide therapy, fasting plasma glucose and hemoglobin A,, levels showed reductions similar to those produced by troglitazone with a significant increase of immunoreactive insulin, but levels of PAI- and fibrinogen showed no decrease. Thus the use of troglitazone in the treatment of patients with type II diabetes produced improvement in increased PAL1 level and hyperfibrinogenemia as well as in glycemic control. This improvement in glycemic control, hyperlnsulinemia, and coagulation-fibrinolysis abnormalities may result in the prevention of vascular complications in these patients. It ls also concluded that improvement of glycemic control by gliclazide has little effect on coagulation-fibrinolysis abnormalities. Key words: fibrinogen, insulin resistance, plasminogen activator inhibitor-l, troglitazone. INTRODUCTION
Type II diabetes mellitus is frequently complicated by arteriosclerotic disease and by abnormalities of the coagulation-fibrinolysis system,’ which Address correspondence to: Dr. Keiji K&o, Department of Endocrinology, l-5-54, Ujina-Kanda, Minami-ku, Hiroshima, 734-8530, Japan. Received for publication on March 16, 1998. Printed in the USA. Reproduction in whole or part is not permitted.
537
Hiroshima Prefectural Hospital,
0011.393xm/$19.00
EFFECTS
OF TROGLITAZONE
IN TYF’E II DIABETES
MELLITUS
may be essentially responsible for the development and progression of arteriosclerosis. An association between insulin resistance and abnormalities of the coagulation-fibrinolysis system has been reported.’ Troglitazone is a new thiazolidinedione derivative that appears to lower blood glucose concentrations primarily by enhancing insulin action rather than by altering insulin secretion.3p4 Because of its effect on lowering insulin resistance, troglitazone is proposed to have a beneficial effect on coagulation-fibrinolysis abnormalities. Sulfonylureas have been shown to cause an increase in insulin secretion by enhancing the release of insulin; however, their effect on coagulation-fibrinolysis abnormalities is unclear. In the present study, troglitazone, a drug that improves insulin resistance, was administered to patients with type II diabetes. The effect of troglitazone on coagulation-fibrinolysis abnormalities was observed and compared with that of gliclazide, a sulfonylurea. PATIENTS AND METHODS
The study was composed of 21 patients with type II diabetes and stable glycemic control who were attending the outpatient clinic of Hiroshima Prefectural Hospital, Hiroshima, Japan. Patients were allocated randomly to receive either troglitazone or gliclazide for 12 weeks. Twelve patients (3 men and 9 women) received troglitazone 400 mg/d (200 mg twice daily, morning and after dinner), and 9 patients (5 men and 4 women> received gliclazide 40 mg/d. Of the 12 patients given troglitazone, 7 (2 men and 5 women) were treated with troglitazone only and 5 (1 man and 4 women) received troglitazone and concomitant gliclazide. Diet and exercise therapy remained unchanged throughout the study, as well as sulfonylurea dosage. Patients with diabetic retinopathy, nephropathy, neuropathy, or arteriosclerotic disease were excluded. The study protocol was approved by the ethics committee of Hiroshima Prefectural Hospital. Written informed consent was obtained from all patients. Blood samples were collected from fasting patients both before and after treatment, and levels of plasma glucose, hemoglobin A,, (Hb A,,), insulin, C peptide, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, free fatty acids, fibrinogen, and plasminogen activator inhibitor-l (PAI-1) were measured. Blood pressure and body-mass index (BMI) were also determined before and after treatment. Plasma glucose, total cholesterol, triglyceride, and free fatty acid levels were measured by enzymatic methods; Hb A,, level, by high-performance liquid chromatography; and insulin and C peptide levels, by radioimmunoassay. Selective inhibition, thrombin clotting time, and enzyme-linked immunosorbent assay were used to determine levels of HDL cholesterol, fibrinogen, and PAI-1, respectively. 538
K. Km0
Statistical Analysis Results are given as mean * SD for normally distributed data or as median I interquartile range for non-normally distributed data. The Wilcoxon signed-rank test was used for paired data, and the Mann-Whitney U test was used for unpaired data. P < 0.05 was considered statistically significant. RESULTS
Table I shows the clinical and biochemical characteristics of patients before treatment. Between-group differences in PAI- and fibrinogen levels were not statistically significant before treatment. Likewise, the degrees of glycemic control and BMI were similar, but the levels of insulin and C peptide were significantly higher in the troglitazone group than in the sulfonylurea group (P < 0.01 and P < 0.05, respectively). Table II shows the data obtained before and after treatment with troglitazone. After treatment, fasting plasma glucose, II% A,, and triglyceride levels all decreased significantly (P < 0.01, P < 0.01, and P c 0.05, respectively). Insulin and C peptide levels also showed a significant decrease (P < 0.01 and P < 0.01, respectively), but there was no significant change in BMI. As shown in Figure 1, levels of PAI- and fibrinogen decreased significantly (P < 0.01 and P < 0.01, respectively) after troglitazone therapy.
Table I. Clinical and biochemical characteristics of all patients before treatment Values are given as mean * SD unless otherwise noted.
Troglitazone (n= 12) A e(Y)
B
F G (mg/dL)
PAI- (ng/mL) Fibrinogen (mg/dL)
i f f f
=
P
63.1 zt6.7
62.3 * 9.0
162.6 a.2 7.5 2.5
Gliilaziie
(N = 21).
174.4 a.9 4.6 1.6
25.5 1.3 4.8 0.5
* f * i
20.6 0.6 3.2 0.5
<0.05 to.01
101.3 f*37.9 208.2 23.9 61.9 zt 10.5 529.3 f i 79.8
149.6 i 67.6 229.9 33.6 57.0 f 10.1 577.0 * 207.9
!E
1;f5; I ;;5
134.4 85.8 24.9 al.9 273.5
kE
27.1 : 3:5 113.5241.3 296.1 f 60.6
f* * f *
16.9 9.8 3.4 32.9 26.6
E
K NS
FPG = fasting plasma glucose; Hb A,, = hemoglobin A,,;,IRI = immunoreactive insulin; CP = C peptide; TC = total cholesterol; TG = triglyceride; HDL-C = high-density lipoprotein cholesterol; WA = free fatly acids; SBP = systolic blood pressure; DBP = chastolic blood pressure; BMI = body-mass index; PAI- = plasminogen activator inhibitor-l. * Values are given as median f interquartile range. 539
EFFECTS
OF TROGLITAZONE
IN TYPE II DIABETES
MELLITUS
T a b l e II. Clinical a n d b i o c h e m i c a l c h a r a c t e r i s t i c s of p a t i e n t s before a n d a f t e r t r o g l i t a z o n e t r e a t m e n t (n = 12). V a l u e s a r e g i v e n a s m e a n ± SD u n l e s s o t h e r w i s e noted.
FPG ( IldL Hb A. O,ro) IRI (IJ "nL)* CP (n nL)* TC (n ;IL) TG (n dL) HDL-, mg/dL) FFA t nEq/L) SBP mm Hg) DBP mm Hg) BMI ~(g/mz)
Before Treatmenl
After Treatment
162.6 + 25.5
117.8 + 21.3
8.2
7.1
1.3
7.5 + 4.8 2.5 ± 0.5 208.2 ± 23.9 101.3 ± 37.9 61.9 ± 10.5 529.3 ± 179.8 145.7 ± 15.5 87.3 + 6.6 27.1 + 3.5
P <0.01
<0.Ol
1.2
4.5 ± 4.1 1.8 ± 0.7 207.7 ± 32.2 79.9 + 24.2 62.2 ± 12.7 515.6 ± 200.6 145.7 ± 11.1 87.0 ± 6.9 27.6 ± 3.6
<0.01 <0.01 NS <0.05 NS NS NS NS NS
FPG = fasting plasma glucose; Hb Ale = hemoglobin Alc; IRI = immunoreactive insulin; CP = C peptide; TC = total cholesterol; TG = triglyceride; HDL-C = high-density lipoprotein cholesterol; FFA = free fatty acids; SBP = systolic blood pressure; DBP = diastolic blood pressure; BMI = body-mass index. * Values are given as median ~ interquartile range.
After administration of gliclazide, fasting plasma glucose and Hb Ale levels decreased significantly (P < 0.01 and P < 0.01, respectively); differences were similar to those seen in the troglitazone group (Table III). Insulin levels showed a significant increase (P < 0.05), whereas C peptide and triglyceride levels and BMI did not change significantly. There were no changes in PAI-1 or fibrinogen (Figure 2).
P
200 ~,150-
I
400
T
~lOO~r t
I
P
I
113.5 ± 41.3
]
[
E
~'200
50-
Before Treatment
-
-
¢g
m
o loo"~__.
.-g IL
0
i
i
Before
After Treatment
Treatment
296.1 ± 60.8
67.3 ± 29.9
!I
i
After
Treatment 246.3
± 44.1
F i g u r e 1. C h a n g e s in p l a s m i n o g e n a c t i v a t o r inhibitor-1 (PAI-1) a n d fibrinogen w i t h troglitazone t r e a t m e n t (n = 12). V a l u e s a r e g i v e n a s m e a n ± SD. 540
K.
KUBO
Table III. Clinical and biochemical characteristics of patients before and after gliclazide treatment (n = 9). Values are given as mean * SD unless otherwise noted. Before Treatment
After Treatment
P
174.4 f 20.6 ::: : !I
130.8 i 11.0 ::; i r+:
1.6kO.5 229.9 f 33.6 149.6 i 67.8 57.0 f 10.1 577.0 f 207.9 134.4 * 16.9 85.8 * 9.8 24.9 f 3.5
2.1 213.8 127.1 57.3 525.4 132.9 86.9 25.1
* 0:6 i 21.2 2 49.0 i 8.9 i 158.1 i 16.3 f 7.7 2 3.3
E
FPG = fasting plasma $ lucose. A - hemoglobin A,,; IRI = immunoreactive insulin; CP = C peptide; ,’ Hb .1cTC = total cholesterol; G = tnglycende; HDL-C = high-density lipoprotein cholesterol; FFA = free fatty acids; SBP = systolic blood pressure; DBP = diastolic blood pressure; BMI = body-mass index. Values are given as median + interquartile range. l
DISCUSSION
with type II diabetes frequently have coagulation-fibrinolysis abnormalities’-specifically, hyperfibrinogenemia5 and increased PAI- activity6-which are involved in the development and progression of arteriosclerosis. An association between insulin resistance and increased PAIactivity,7 as well as between insulin resistance and hyperfibrinogenemia,8 has been reported. Patients
NS
NS I
I
I
400 1
g300g 5 200F ; loo-
Before
Treatment 81.9 f 32.9
After Treatment
Before Treatment
76.0 f 22.4
273.5
f 26.6
After Treatment 298.3 f 60.4
Figure 2. Changes in plasminogen activator inhibitor-l (PAL1) and fibrinogen with gliclazide treatment (n = 9). Values are given as mean * SD. 541
EFFECTS
OF TROGLITAZONE
IN TYPE II DL4BETES
MELLITUS
Insulin Resistance and Increased Plasminogen Activator Inhibitor-l Activity Vague et al7 observed a positive correlation between fasting insulin levels and PAI- levels in patients with type II diabetes. Furthermore, insulin has been reported to stimulate the synthesis of PAI- in cultured human hepatocytes.g Persistent hyperinsulinemia in the presence of insulin resistance is presumed to enhance hepatic PAI-1 synthesis, leading to elevated PAI- levels. In the present study, administration of troglitazone alone or in combination with sulfonylurea caused a significant decrease in PAI- levels, as well as in fasting insulin and C peptide levels. These results suggest that troglitazone first improved insulin resistance and then improved hyperinsulinemia. As a result of the improvement in hyperinsulinemia, hepatic PAI- synthesis may have declined, reducing the circulating PAI- level. Metformin has also been reported to reduce PAI- levels.” This decrease in PAI- may occur as a result of a mechanism similar to that proposed for troglitazone. One in vitro study” indicated that hyperglycemia augments expression of PAI- messenger ribonucleic acid by cultured human endothelial cells, suggesting another possible influence of hyperglycemia on PAI-1 levels. In our study, however, the level of PAI- was unchanged when glycemic control was improved by gliclazide, so PAIlevel appears to be more strongly influenced by insulin level and insulin resistance than by plasma glucose. Fat cells have been reported to generate PAI-1.12,13In patients with type II diabetes, PAI- is likely to be synthesized and secreted directly from fat cells, and troglitazone may inhibit PAI- release from fat cells by some mechanism. Insulin Resistance and Hgperfibrinogenemia Some data suggest a negative association between insulin resistance and fibrinogen level,* whereas insulin and proinsulin levels are positively correlated with fibrinogen level in healthy subjects. Furthermore, reduced fibrinogen levels have been shown to be effective in preventing the progression of coronary artery disease. ‘* Although insulin does not directly influence fibrinogen synthesis by the liver,g in the presence of insulin resistance, elevated free fatty acid levels stimulate hepatic fibrinogen synthesis.8 In the present study, administration of troglitazone alone or in combination with sulfonylurea significantly decreased fibrinogen levels as well as fasting insulin and fasting C peptide levels. In contrast, improvement of glycemic control with gliclazide therapy produced no change in fibrinogen level. These findings suggest that improvement of insulin resistance by troglitazone caused hepatic fibrinogen synthesis to decline, thereby de542
KKUBO
creasing fibrinogen levels. Metformin has also been reported to reduce fibrinogen levels15 and may act by a mechanism similar to that proposed for troglitazone. CONCLUSION
Patients with type II diabetes have a high likelihood of developing increased PAI- activity and hyperfibrinogenemia in connection with insulin resistance. Increased PAI- activity stimulates thrombus formation by reducing fibrinolytic capacity.’ Hyperfibrinogenemia also promotes thrombogenesis through increased coagulability.16 Therefore, patients with type II diabetes have a high risk of suffering the onset and progression of arteriosclerosis as a result of abnormalities of the coagulation-fibrinolysis system. This study demonstrates that the use of troglitazone in the treatment of patients with type II diabetes produced improvement in increased PAIlevel and hyperfibrinogenemia as well as in glycemic control. This improvement in glycemic control, hyperinsulinemia, and coagulationfibrinolysis abnormalities may result in the prevention of vascular complications in these patients. Acknowledgment
This study was sponsored by Sankyo Co., Ltd., Tokyo, Japan.
1. McGill JB, Schneider DJ, Artken CL, et al. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes. 1994;43:104-109. 2. Vague IJ, Alessi MC, Vague P. Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis. Diabetologia. 1991;34:457-462. 3. Iwamoto Y, Kuzuya T, Matsuda A, et al. Effect of new oral antidiabetic agent CS-045 on glucose tolerance and insulin secretion in patients with NIDDM. Diabetes Cure. 1991;14:1083-1086. 4. Iwamoto Y, Kosaka K, Kuzuya T, et al. Effects of combination therapy of troglitazone and sulphonylureas in patients with type 2 diabetes who were poorly controlled by sulphonylurea therapy alone. Diabetic Med. 1996;13:365-370. 5. Ganda OP, Arkin CF. Hyperfibrinogenemia: An important plications in diabetes. Diabetes Cure. 1992;15:1245-1250. 6. Schneider DJ, Nordt TK, Sobel BE. Attenuated fibrinolysis esis in type II diabetic patients. Diabetes. 1993;42:1-7.
risk factor for vascular and accelerated
com-
atherogen-
7. Vague IJ, Koul C, Alessi MC, et al. Increased plasminogen activator inhibitor activity in non insulin dependent diabetic patients-relationship with plasma insulin. Thromb Huemost. 1989;61:370-373. 543
EFFECTS
OF TROGLITAZONE
IN TYPE II DIABETES
MELLITUS
8. Eliasson M, Evrin PE, Roder ME, et al. Proinsulin, intact insulin, and fibrinolytic variables and fibrinogen in healthy subjects. Diabetes Care. 1997;20:1252-1255. 9. Alessi MC, Vague IJ, Kooistra T, et al. Insulin stimulates the synthesis of plasminogen activator inhibitor 1 by the human hepatocellular cell line Hep G2. Thromb Haemost. 1988;60:491494. 10. Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. Diabetes Care. 1993;16:621-629. 11. Maiello M, Boeri D, Podesta F, et al. Increased expression of tissue plasminogen activator and its inhibitor and reduced fibrinolytic potential of human endothelial cells cultured in elevated glucose. Diabetes. 1992;41:1009-1015. 12. Shimomura I, Funahashi T, Takahashi M, et al. Enhanced expression of PAI- in visceral fat: Possible contributor to vascular disease in obesity. Nat Med. 1996;2:800-803. 13. Eriksson P, Reynisdottir S, Liinnqvist F, et al. Adipose tissue secretion of plasminogen activator inhibitor-l in non-obese and obese individuals. Diabetologia. 1998;41:65-71. 14. Ericsson CG, Hamsten A, Nilsson J, et al. Angiographic assessment of effects of bezaiibrate on progression of coronary artery disease in young male postinfarction patients. Luncet. 1996;347:849-853. 15. Giugliano D, Acampora R, Rosa ND, et al. Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive, obese women. Diabetes Care. 1993;16:13871390. 16. Ceriello A, Taboga C, Giacomello R, et al. Fibrinogen plasma levels as a marker of thrombin activation in diabetes. Diabetes. 1994:43:430432.
544
EFFECTS
1998
OF TROGLITAZONE ON COAGUIATION-FIBRINOLYSIS ABNORMALITIES IN PATIENTS WITH TYPE II DIABETES MELLITUS KEXJI KUF30
Department
of Endocrinology,
Hiroshima
Prefectural
Hospital, Hiroshima,
Japan
AlWlRACT Type II diabetes mellitus is frequently complicated by arteriosclerotic disease and by coagulation-fibrinolysis abnormalities, which may be essentially responsible for the development and progression of arteriosclerosis and are positively correlated with insulin resistance. Troglitazone, a drug that improves insulin resistance, was administered to patients with type II diabetes. The effect of troglitazone on coagulation-fibrinolysis abnormalities was observed and compared with that of gliclazide, a sulfonylurea. Twenty-one patients were included in the It-week study; 12 received troglitazone 400 mg/d, and 9 received gliclazide 40 mg/d. Of the 12 patients given troglitazone, 7 were treated with troglitazone only, and 5 received troglltazone and concomitant sulfonylureas. Fasting blood samples were collected before study initiation and after completion of treatment, and variables were measured. After 12 weeks of troglitazone therapy, fastlug plasma glucose and hemoglobin A,, levels showed a signlflcant decrease, as did levels of immunoreactive insulin, plasminogen activator inhibitor-1 (PA&l), and fibrinogen. After gliclazide therapy, fasting plasma glucose and hemoglobin A,, levels showed reductions similar to those produced by troglitazone with a significant increase of immunoreactive insulin, but levels of PAI- and fibrinogen showed no decrease. Thus the use of troglitazone in the treatment of patients with type II diabetes produced improvement in increased PAL1 level and hyperfibrinogenemia as well as in glycemic control. This improvement in glycemic control, hyperlnsulinemia, and coagulation-fibrinolysis abnormalities may result in the prevention of vascular complications in these patients. It ls also concluded that improvement of glycemic control by gliclazide has little effect on coagulation-fibrinolysis abnormalities. Key words: fibrinogen, insulin resistance, plasminogen activator inhibitor-l, troglitazone. INTRODUCTION
Type II diabetes mellitus is frequently complicated by arteriosclerotic disease and by abnormalities of the coagulation-fibrinolysis system,’ which Address correspondence to: Dr. Keiji K&o, Department of Endocrinology, l-5-54, Ujina-Kanda, Minami-ku, Hiroshima, 734-8530, Japan. Received for publication on March 16, 1998. Printed in the USA. Reproduction in whole or part is not permitted.
537
Hiroshima Prefectural Hospital,
0011.393xm/$19.00
EFFECTS
OF TROGLITAZONE
IN TYF’E II DIABETES
MELLITUS
may be essentially responsible for the development and progression of arteriosclerosis. An association between insulin resistance and abnormalities of the coagulation-fibrinolysis system has been reported.’ Troglitazone is a new thiazolidinedione derivative that appears to lower blood glucose concentrations primarily by enhancing insulin action rather than by altering insulin secretion.3p4 Because of its effect on lowering insulin resistance, troglitazone is proposed to have a beneficial effect on coagulation-fibrinolysis abnormalities. Sulfonylureas have been shown to cause an increase in insulin secretion by enhancing the release of insulin; however, their effect on coagulation-fibrinolysis abnormalities is unclear. In the present study, troglitazone, a drug that improves insulin resistance, was administered to patients with type II diabetes. The effect of troglitazone on coagulation-fibrinolysis abnormalities was observed and compared with that of gliclazide, a sulfonylurea. PATIENTS AND METHODS
The study was composed of 21 patients with type II diabetes and stable glycemic control who were attending the outpatient clinic of Hiroshima Prefectural Hospital, Hiroshima, Japan. Patients were allocated randomly to receive either troglitazone or gliclazide for 12 weeks. Twelve patients (3 men and 9 women) received troglitazone 400 mg/d (200 mg twice daily, morning and after dinner), and 9 patients (5 men and 4 women> received gliclazide 40 mg/d. Of the 12 patients given troglitazone, 7 (2 men and 5 women) were treated with troglitazone only and 5 (1 man and 4 women) received troglitazone and concomitant gliclazide. Diet and exercise therapy remained unchanged throughout the study, as well as sulfonylurea dosage. Patients with diabetic retinopathy, nephropathy, neuropathy, or arteriosclerotic disease were excluded. The study protocol was approved by the ethics committee of Hiroshima Prefectural Hospital. Written informed consent was obtained from all patients. Blood samples were collected from fasting patients both before and after treatment, and levels of plasma glucose, hemoglobin A,, (Hb A,,), insulin, C peptide, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, free fatty acids, fibrinogen, and plasminogen activator inhibitor-l (PAI-1) were measured. Blood pressure and body-mass index (BMI) were also determined before and after treatment. Plasma glucose, total cholesterol, triglyceride, and free fatty acid levels were measured by enzymatic methods; Hb A,, level, by high-performance liquid chromatography; and insulin and C peptide levels, by radioimmunoassay. Selective inhibition, thrombin clotting time, and enzyme-linked immunosorbent assay were used to determine levels of HDL cholesterol, fibrinogen, and PAI-1, respectively. 538
K. Km0
Statistical Analysis Results are given as mean * SD for normally distributed data or as median I interquartile range for non-normally distributed data. The Wilcoxon signed-rank test was used for paired data, and the Mann-Whitney U test was used for unpaired data. P < 0.05 was considered statistically significant. RESULTS
Table I shows the clinical and biochemical characteristics of patients before treatment. Between-group differences in PAI- and fibrinogen levels were not statistically significant before treatment. Likewise, the degrees of glycemic control and BMI were similar, but the levels of insulin and C peptide were significantly higher in the troglitazone group than in the sulfonylurea group (P < 0.01 and P < 0.05, respectively). Table II shows the data obtained before and after treatment with troglitazone. After treatment, fasting plasma glucose, II% A,, and triglyceride levels all decreased significantly (P < 0.01, P < 0.01, and P c 0.05, respectively). Insulin and C peptide levels also showed a significant decrease (P < 0.01 and P < 0.01, respectively), but there was no significant change in BMI. As shown in Figure 1, levels of PAI- and fibrinogen decreased significantly (P < 0.01 and P < 0.01, respectively) after troglitazone therapy.
Table I. Clinical and biochemical characteristics of all patients before treatment Values are given as mean * SD unless otherwise noted.
Troglitazone (n= 12) A e(Y)
B
F G (mg/dL)
PAI- (ng/mL) Fibrinogen (mg/dL)
i f f f
=
P
63.1 zt6.7
62.3 * 9.0
162.6 a.2 7.5 2.5
Gliilaziie
(N = 21).
174.4 a.9 4.6 1.6
25.5 1.3 4.8 0.5
* f * i
20.6 0.6 3.2 0.5
<0.05 to.01
101.3 f*37.9 208.2 23.9 61.9 zt 10.5 529.3 f i 79.8
149.6 i 67.6 229.9 33.6 57.0 f 10.1 577.0 * 207.9
!E
1;f5; I ;;5
134.4 85.8 24.9 al.9 273.5
kE
27.1 : 3:5 113.5241.3 296.1 f 60.6
f* * f *
16.9 9.8 3.4 32.9 26.6
E
K NS
FPG = fasting plasma glucose; Hb A,, = hemoglobin A,,;,IRI = immunoreactive insulin; CP = C peptide; TC = total cholesterol; TG = triglyceride; HDL-C = high-density lipoprotein cholesterol; WA = free fatly acids; SBP = systolic blood pressure; DBP = chastolic blood pressure; BMI = body-mass index; PAI- = plasminogen activator inhibitor-l. * Values are given as median f interquartile range. 539
EFFECTS
OF TROGLITAZONE
IN TYPE II DIABETES
MELLITUS
T a b l e II. Clinical a n d b i o c h e m i c a l c h a r a c t e r i s t i c s of p a t i e n t s before a n d a f t e r t r o g l i t a z o n e t r e a t m e n t (n = 12). V a l u e s a r e g i v e n a s m e a n ± SD u n l e s s o t h e r w i s e noted.
FPG ( IldL Hb A. O,ro) IRI (IJ "nL)* CP (n nL)* TC (n ;IL) TG (n dL) HDL-, mg/dL) FFA t nEq/L) SBP mm Hg) DBP mm Hg) BMI ~(g/mz)
Before Treatmenl
After Treatment
162.6 + 25.5
117.8 + 21.3
8.2
7.1
1.3
7.5 + 4.8 2.5 ± 0.5 208.2 ± 23.9 101.3 ± 37.9 61.9 ± 10.5 529.3 ± 179.8 145.7 ± 15.5 87.3 + 6.6 27.1 + 3.5
P <0.01
<0.Ol
1.2
4.5 ± 4.1 1.8 ± 0.7 207.7 ± 32.2 79.9 + 24.2 62.2 ± 12.7 515.6 ± 200.6 145.7 ± 11.1 87.0 ± 6.9 27.6 ± 3.6
<0.01 <0.01 NS <0.05 NS NS NS NS NS
FPG = fasting plasma glucose; Hb Ale = hemoglobin Alc; IRI = immunoreactive insulin; CP = C peptide; TC = total cholesterol; TG = triglyceride; HDL-C = high-density lipoprotein cholesterol; FFA = free fatty acids; SBP = systolic blood pressure; DBP = diastolic blood pressure; BMI = body-mass index. * Values are given as median ~ interquartile range.
After administration of gliclazide, fasting plasma glucose and Hb Ale levels decreased significantly (P < 0.01 and P < 0.01, respectively); differences were similar to those seen in the troglitazone group (Table III). Insulin levels showed a significant increase (P < 0.05), whereas C peptide and triglyceride levels and BMI did not change significantly. There were no changes in PAI-1 or fibrinogen (Figure 2).
P
200 ~,150-
I
400
T
~lOO~r t
I
P
I
113.5 ± 41.3
]
[
E
~'200
50-
Before Treatment
-
-
¢g
m
o loo"~__.
.-g IL
0
i
i
Before
After Treatment
Treatment
296.1 ± 60.8
67.3 ± 29.9
!I
i
After
Treatment 246.3
± 44.1
F i g u r e 1. C h a n g e s in p l a s m i n o g e n a c t i v a t o r inhibitor-1 (PAI-1) a n d fibrinogen w i t h troglitazone t r e a t m e n t (n = 12). V a l u e s a r e g i v e n a s m e a n ± SD. 540
K.
KUBO
Table III. Clinical and biochemical characteristics of patients before and after gliclazide treatment (n = 9). Values are given as mean * SD unless otherwise noted. Before Treatment
After Treatment
P
174.4 f 20.6 ::: : !I
130.8 i 11.0 ::; i r+:
1.6kO.5 229.9 f 33.6 149.6 i 67.8 57.0 f 10.1 577.0 f 207.9 134.4 * 16.9 85.8 * 9.8 24.9 f 3.5
2.1 213.8 127.1 57.3 525.4 132.9 86.9 25.1
* 0:6 i 21.2 2 49.0 i 8.9 i 158.1 i 16.3 f 7.7 2 3.3
E
FPG = fasting plasma $ lucose. A - hemoglobin A,,; IRI = immunoreactive insulin; CP = C peptide; ,’ Hb .1cTC = total cholesterol; G = tnglycende; HDL-C = high-density lipoprotein cholesterol; FFA = free fatty acids; SBP = systolic blood pressure; DBP = diastolic blood pressure; BMI = body-mass index. Values are given as median + interquartile range. l
DISCUSSION
with type II diabetes frequently have coagulation-fibrinolysis abnormalities’-specifically, hyperfibrinogenemia5 and increased PAI- activity6-which are involved in the development and progression of arteriosclerosis. An association between insulin resistance and increased PAIactivity,7 as well as between insulin resistance and hyperfibrinogenemia,8 has been reported. Patients
NS
NS I
I
I
400 1
g300g 5 200F ; loo-
Before
Treatment 81.9 f 32.9
After Treatment
Before Treatment
76.0 f 22.4
273.5
f 26.6
After Treatment 298.3 f 60.4
Figure 2. Changes in plasminogen activator inhibitor-l (PAL1) and fibrinogen with gliclazide treatment (n = 9). Values are given as mean * SD. 541
EFFECTS
OF TROGLITAZONE
IN TYPE II DL4BETES
MELLITUS
Insulin Resistance and Increased Plasminogen Activator Inhibitor-l Activity Vague et al7 observed a positive correlation between fasting insulin levels and PAI- levels in patients with type II diabetes. Furthermore, insulin has been reported to stimulate the synthesis of PAI- in cultured human hepatocytes.g Persistent hyperinsulinemia in the presence of insulin resistance is presumed to enhance hepatic PAI-1 synthesis, leading to elevated PAI- levels. In the present study, administration of troglitazone alone or in combination with sulfonylurea caused a significant decrease in PAI- levels, as well as in fasting insulin and C peptide levels. These results suggest that troglitazone first improved insulin resistance and then improved hyperinsulinemia. As a result of the improvement in hyperinsulinemia, hepatic PAI- synthesis may have declined, reducing the circulating PAI- level. Metformin has also been reported to reduce PAI- levels.” This decrease in PAI- may occur as a result of a mechanism similar to that proposed for troglitazone. One in vitro study” indicated that hyperglycemia augments expression of PAI- messenger ribonucleic acid by cultured human endothelial cells, suggesting another possible influence of hyperglycemia on PAI-1 levels. In our study, however, the level of PAI- was unchanged when glycemic control was improved by gliclazide, so PAIlevel appears to be more strongly influenced by insulin level and insulin resistance than by plasma glucose. Fat cells have been reported to generate PAI-1.12,13In patients with type II diabetes, PAI- is likely to be synthesized and secreted directly from fat cells, and troglitazone may inhibit PAI- release from fat cells by some mechanism. Insulin Resistance and Hgperfibrinogenemia Some data suggest a negative association between insulin resistance and fibrinogen level,* whereas insulin and proinsulin levels are positively correlated with fibrinogen level in healthy subjects. Furthermore, reduced fibrinogen levels have been shown to be effective in preventing the progression of coronary artery disease. ‘* Although insulin does not directly influence fibrinogen synthesis by the liver,g in the presence of insulin resistance, elevated free fatty acid levels stimulate hepatic fibrinogen synthesis.8 In the present study, administration of troglitazone alone or in combination with sulfonylurea significantly decreased fibrinogen levels as well as fasting insulin and fasting C peptide levels. In contrast, improvement of glycemic control with gliclazide therapy produced no change in fibrinogen level. These findings suggest that improvement of insulin resistance by troglitazone caused hepatic fibrinogen synthesis to decline, thereby de542
KKUBO
creasing fibrinogen levels. Metformin has also been reported to reduce fibrinogen levels15 and may act by a mechanism similar to that proposed for troglitazone. CONCLUSION
Patients with type II diabetes have a high likelihood of developing increased PAI- activity and hyperfibrinogenemia in connection with insulin resistance. Increased PAI- activity stimulates thrombus formation by reducing fibrinolytic capacity.’ Hyperfibrinogenemia also promotes thrombogenesis through increased coagulability.16 Therefore, patients with type II diabetes have a high risk of suffering the onset and progression of arteriosclerosis as a result of abnormalities of the coagulation-fibrinolysis system. This study demonstrates that the use of troglitazone in the treatment of patients with type II diabetes produced improvement in increased PAIlevel and hyperfibrinogenemia as well as in glycemic control. This improvement in glycemic control, hyperinsulinemia, and coagulationfibrinolysis abnormalities may result in the prevention of vascular complications in these patients. Acknowledgment
This study was sponsored by Sankyo Co., Ltd., Tokyo, Japan.
1. McGill JB, Schneider DJ, Artken CL, et al. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes. 1994;43:104-109. 2. Vague IJ, Alessi MC, Vague P. Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis. Diabetologia. 1991;34:457-462. 3. Iwamoto Y, Kuzuya T, Matsuda A, et al. Effect of new oral antidiabetic agent CS-045 on glucose tolerance and insulin secretion in patients with NIDDM. Diabetes Cure. 1991;14:1083-1086. 4. Iwamoto Y, Kosaka K, Kuzuya T, et al. Effects of combination therapy of troglitazone and sulphonylureas in patients with type 2 diabetes who were poorly controlled by sulphonylurea therapy alone. Diabetic Med. 1996;13:365-370. 5. Ganda OP, Arkin CF. Hyperfibrinogenemia: An important plications in diabetes. Diabetes Cure. 1992;15:1245-1250. 6. Schneider DJ, Nordt TK, Sobel BE. Attenuated fibrinolysis esis in type II diabetic patients. Diabetes. 1993;42:1-7.
risk factor for vascular and accelerated
com-
atherogen-
7. Vague IJ, Koul C, Alessi MC, et al. Increased plasminogen activator inhibitor activity in non insulin dependent diabetic patients-relationship with plasma insulin. Thromb Huemost. 1989;61:370-373. 543
EFFECTS
OF TROGLITAZONE
IN TYPE II DIABETES
MELLITUS
8. Eliasson M, Evrin PE, Roder ME, et al. Proinsulin, intact insulin, and fibrinolytic variables and fibrinogen in healthy subjects. Diabetes Care. 1997;20:1252-1255. 9. Alessi MC, Vague IJ, Kooistra T, et al. Insulin stimulates the synthesis of plasminogen activator inhibitor 1 by the human hepatocellular cell line Hep G2. Thromb Haemost. 1988;60:491494. 10. Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. Diabetes Care. 1993;16:621-629. 11. Maiello M, Boeri D, Podesta F, et al. Increased expression of tissue plasminogen activator and its inhibitor and reduced fibrinolytic potential of human endothelial cells cultured in elevated glucose. Diabetes. 1992;41:1009-1015. 12. Shimomura I, Funahashi T, Takahashi M, et al. Enhanced expression of PAI- in visceral fat: Possible contributor to vascular disease in obesity. Nat Med. 1996;2:800-803. 13. Eriksson P, Reynisdottir S, Liinnqvist F, et al. Adipose tissue secretion of plasminogen activator inhibitor-l in non-obese and obese individuals. Diabetologia. 1998;41:65-71. 14. Ericsson CG, Hamsten A, Nilsson J, et al. Angiographic assessment of effects of bezaiibrate on progression of coronary artery disease in young male postinfarction patients. Luncet. 1996;347:849-853. 15. Giugliano D, Acampora R, Rosa ND, et al. Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive, obese women. Diabetes Care. 1993;16:13871390. 16. Ceriello A, Taboga C, Giacomello R, et al. Fibrinogen plasma levels as a marker of thrombin activation in diabetes. Diabetes. 1994:43:430432.
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