Effect of Combination Glipizide GITS/Metformin on Fibrinolytic and Metabolic Parameters in Poorly Controlled Type 2 Diabetic Subjects

Cefalu, William T.; Schneider, David J.; Carlson, Harold E.; Migdal, Phyllis; Lim, Leonil Gan; Izon, Meriam P.; Kapoor, Anoop; Bell-Farrow, Audrey D.; Terry, James G.; Sobel, Burton E.

doi:10.2337/diacare.25.12.2123

Cited by 53 publications

(28 citation statements)

References 36 publications

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“…63 Treatment of hyperglycaemia with a sulphonylurea (SU) or metformin reduces PAI-1 levels, suggesting that glucose lowering, rather than the type of hypoglycaemic agent, modulates PAI-1 levels. 64 In addition to hyperglycaemia, hyperinsulinaemia also increases PAI-1 levels, 65 which explains elevated levels of this protein in insulin-resistant states. 66 Activity of tPA has been linked to diabetic complications.…”

Section: Coagulation Proteins Involved In Fibrinolysismentioning

confidence: 99%

Review article: Coagulation and fibrinolysis in diabetes

Alzahrani

Ajjan

2010

Diabetes and Vascular Disease Research

207

188

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Atherothrombotic complications are the main cause of mortality in subjects with diabetes. Premature atherosclerosis, increased platelet reactivity and activation of coagulation factors with associated hypofibrinolysis all contribute to increased cardiovascular risk in this population. Blood clot formation represents the last step in the atherothrombotic process, and the structure of the fibrin network has a role in determining predisposition to cardiovascular disease. In this review, we discuss alterations in coagulation factor plasma levels and/or activity in diabetes and clarify their role in predisposition to cardiovascular events. The effect of diabetes on fibrin network structure/fibrinolysis is reviewed and potential mechanisms that modify clot properties are discussed. Finally, modulation of clotting potential by the various therapeutic agents used in diabetes is examined. Understanding the mechanisms by which diabetes influences the coagulation pathway will help to develop more effective treatment strategies to reduce thrombotic events in subjects with this condition. KeywordsAtherothrombosis, clot structure, coagulation factors, coronary artery disease, diabetes, fibrinogen Clot formation and lysisFibrin clot formation, leading to vessel occlusion, represents the final step in the atherothrombotic process and involves multiple interactions between coagulation factors and platelets.6 Rupture or fissuring in atherosclerotic plaques exposes a prothrombotic core that comes into contact with platelets and coagulation factors. Initially, platelets adhere to the site of the break and become partially activated. Factor VII (FVII) binds to exposed tissue factor (TF) and forms a complex, which subsequently activates FIX and FX, resulting in FV activation. Activated FX and FV cleave prothrombin to generate limited amounts of thrombin, enough to maintain platelet activation but insufficient to sustain thrombus formation. Platelet stimulation by thrombin and exposed collagen results in full activation and degranulation, followed by FV release and activation by both FXa and thrombin. Thrombin also activates FVIII and this can form an active complex with FIXa, further enhancing the coagulation process. Subsequently, enough Diabetes and thrombosis riskCardiovascular disease (CVD) remains the main cause of morbidity and mortality in individuals with diabetes. Up to 80% of diabetes subjects die as a result of cardiovascular complications, and the risk of atherothrombotic events in this population is similar to non-diabetic individuals with a history of ischaemic heart disease (IHD).1 Moreover, the prognosis in these individuals following an event remains poor, despite major advances in treatment.2 Increased atherothrombosis risk is even evident in the pre-diabetes stage, as subjects with insulin resistance and normoglycaemia are at risk of cardiovascular events secondary to clustering of risk factors. 3The underlying mechanisms for increased thrombosis risk in diabetes are complex and involve multiple pathways. S...

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Section: Coagulation Proteins Involved In Fibrinolysismentioning

confidence: 99%

Review article: Coagulation and fibrinolysis in diabetes

Alzahrani

Ajjan

2010

Diabetes and Vascular Disease Research

207

188

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“…Other studies also demonstrated that metformin had benefical effects on Plasminogen Activator Inhibitor-1 (PAI-1), von Willebrand Factor (vWF) and fibrinogen. [12][13][14] Metformin was also shown to improve endothelial dysfuntion. 15,16 Rosiglitazone therapy was shown to reduce serum C reactive protein levels in type 2 diabetic patients.…”

Section: Introductionmentioning

confidence: 99%

Serum transforming growth factor-beta 1 levels in normoalbuminuric and normotensive patients with type 2 diabetes. Effect of metformin and rosiglitazone

Yener¹,

Çömlekçi²,

Akıncı³

et al. 2008

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OBJECTIVE: a)To determine serum Transforming Growth Factor-beta 1 (TGF-β1) levels in patients with type 2 diabetes who do not have diabetes related complications and in healthy controls, b) to evaluate the effects of metformin and rosiglitazone on TGF-β1 levels. DESIGN: In the washout period, 61 patients with Fasting Plasma Glucose levels (FPG) higher than 140 mg/dl, Postprandial Glucose (PPG) levels higher than 180 mg/dl and A1c levels exceeding 6.5% were treated with glimperide. After 4 weeks, 39 of these patients were randomised to receive either metformin or rosiglitazone for 12 weeks. Thirty healthy controls were also studied. RE-SULTS: There were no significant differences with regard to age, gender, body weight and BMI between patients and healthy controls. Type 2 diabetics had higher waist circumference, FPG, total cholesterol, LDL-cholesterol and triglyceride levels. Baseline TGF-β1 levels in diabetics were higher than in controls (29.84±7.04 ng/ml vs 11.37±4.06 ng/ml, p<0.001). Metformin or rosiglitazone did not significantly modify the TGF-β1 levels. In a multiple regression analysis FPG was the only variable that was significantly associated with plasma TGF-β1 levels. CON-CLUSION: The elevated levels of TGF-β1 in subjects with type 2 diabetes possibly indicate a tendency for renal and endothelial damage in such patients. The association of TGF-β1 with FPG possibly links poor diabetic control to vascular damage, leading to diabetic complications. Lack of changes in the levels of TGF-β1 after therapy may reflect inadequate therapy duration.

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“…Sulphonylureas are associated with a long-term failure rate of approximately 5 to 7% per year [9][10][11][12] and combination therapy is then needed to maintain treatment efficacy. Metformin, which acts primarily in the liver to reduce endogenous glucose production [13], in combination with sulphonylurea, is often a successful approach in poorly controlled type 2 diabetes [14][15][16][17].…”

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confidence: 99%