Combined therapy with ramipril and simvastatin has beneficial additive effects on tissue factor activity and prothrombin fragment 1+2 in patients with type 2 diabetes
ABSTRACT Tissue factor (TF) plays a pivotal role in thrombus formation. Statins and angiotensin converting enzyme inhibitors attenuate expression of TF by distinct mechanism. Therefore, we hypothesized that combined therapy with simvastatin and ramipril may have additive beneficial anti-atherogenic effects to lower TF activity when compared with either drug alone. This was a randomized, double-blind, placebo-controlled cross-over trial with three treatment arms (each 2 months) and two washout periods (each 2 months). Fifty patients with type 2 diabetes were given simvastatin 20 mg and placebo, simvastatin 20 mg and ramipril 10 mg, or ramipril 10 mg and placebo daily during each treatment period. Simvastatin and ramipril monotherapy tended to reduce TF activity (0.53 to 0.46 nM, P=0.056; 0.54 to 0.50 nM, P=0.167, respectively) while combined therapy had a significant effect (0.64 to 0.43 nM, P<0.001). All three therapies significantly reduced prothrombin fragment 1+2 (F1+2) levels from their respective baselines (P=0.037, P<0.001, and P=0.057, respectively). Combined therapy significantly reduced TF activity and F1+2 levels to a greater extent than either simvastatin or ramipril alone (P=0.029 and P=0.040 by ANOVA, respectively). Percent changes in TF activity and percent changes in F1+2 levels were significantly correlated. All three therapies reduced CD40 ligand levels from their respective baselines (P=0.098, P<0.001, and P=0.002, respectively) with no significant differences among these three therapies (P=0.204 by ANOVA). Ramipril combined with simvastatin significantly reduces plasma TF activity and F1+2 levels to a greater extent than monotherapy with either drug in patients with type 2 diabetes.
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ABSTRACT: Type 2 diabetes is a chronic metabolic disorder that results from defects in both insulin action and secretion, which is now increasing at pace throughout the world, and its intensity of occurrence can be inferred by the International Diabetes Federation (IDF) 2006 report stating that around 246 million people worldwide are suffering from this disease and the prevalence is expected to cross the figure of 380 million within 20 years.Traditional treatment strategies include various oral hypoglycemic agents but practically none of these agents maintain glucose levels indefinitely and thus many type 2 diabetics require exogenous insulin therapy. Although combination therapies are available, however, these drug combinations have limitations in their application to late stage type 2 diabetics. To overcome these issues new treatment strategies are being developed. This review is an attempt to focus on detailed aspects of several recent approaches based on receptors targeting, acetyl-CoA carboxylase 2, I kappa kinase (IKK) beta (IKKB), islet cell transplantation, gene expression profiling, glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase IV inhibitors, CSII (insulin pump therapy), nuclear receptors as drug targets, modulators of peroxisome proliferator-activated receptors (PPAR), glucagon receptor antagonists, insulin receptor activators and protein tyrosine phosphatase inhibitors, combination therapies together with latest findings aimed at identifying new antidiabetic agents with novel mechanisms. Further exploration of these targets will hopefully lead to safe and efficacious drugs that will become the mainstays of next generation therapeutics for diabetes.Diabetes and Metabolic Syndrome Clinical Research and Reviews 01/2010; DOI:10.1016/j.dsx.2008.04.011
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ABSTRACT: Endothelial dysfunction is universal in diabetes, being intimately involved with the development of cardiovascular disease. The pathogenesis of endothelial dysfunction in diabetes is complex. It is initially related to the effects of fatty acids and insulin resistance on 'uncoupling' of both endothelial nitric oxide synthase activity and mitochondrial function. Oxidative stress activates protein kinase C (PKC), polyol, hexosamine and nuclear factor kappa B pathways, thereby aggravating endothelial dysfunction. Improvements in endothelial function in the peripheral circulation in diabetes have been demonstrated with monotherapies, including statins, fibrates, angiotensin-converting enzyme (ACE) inhibitors, metformin and fish oils. These observations are supported by large clinical end point trials. Other studies show benefits with certain antioxidants, L-arginine, folate, PKC-inhibitors, peroxisome proliferator activated receptor (PPAR)-alpha and -gamma agonists and phosphodiesterase (PDE-5) inhibitors. However, the benefits of these agents remain to be shown in clinical end point trials. Combination treatments, for example, statins plus ACE inhibitors and statins plus fibrates, have also been demonstrated to have additive benefits on endothelial function in diabetes, but there are no clinical outcome data to date. Measurement of endothelial dysfunction in cardiovascular research can provide fresh opportunities for exploring the mechanism of benefit of new therapeutic regimens and for planning and designing large clinical trials.Diabetes & Vascular Disease Research 07/2007; 4(2):89-102. DOI:10.3132/dvdr.2007.026 · 3.04 Impact Factor
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ABSTRACT: Hypercholesterolemia and Type 2 diabetes are well-recognized risk factors for cardiovascular disease, promoted by a condition of subclinical inflammation and a hypercoagulable state. Soluble CD40 ligand (sCD40L), a marker of vascular inflammation, seems to predict vascular damage in patients with Type 2 diabetes. Beside the lipid-lowering effect, statins seem to slow the progression of atherosclerosis through a series of anti-inflammatory effects, including a reduction of sCD40L levels. This study compared the effect of a short-term (12 weeks) treatment with rosuvastatin or simvastatin on some markers of inflammation in 36 patients with Type 2 diabetes and moderate hypercholesterolemia. As expected, both drugs significantly modified lipid profile; moreover, rosuvastatin and simvastatin were both able to significantly reduce albumin excretion rate in these patients, without affecting urinary N-acetyl-beta-D-glucosaminidase. Serum homocysteine was not influenced by the treatment, as interleukin-6 levels, while C reactive protein diminished; moreover, rosuvastatin, but not simvastatin, was able to significantly reduce sCD40L. The only clinical parameter related with the variations in sCD40L was systolic blood pressure. In hypercholesterolemic Type 2 diabetic patients, sCD40L, a factor playing a pivotal role in the pathogenesis of atherosclerosis and associated with more rupture-prone lesions, is reduced by short-term treatment with rosuvastatin.Journal of endocrinological investigation 08/2008; 31(7):660-5. DOI:10.1007/BF03345621 · 1.55 Impact Factor