Giovanni Anfossi

Cardiovascular events occurring in type 2 diabetes (T2DM) are a major problem in clinical practice. In particular, the risk of myocardial infarction (MI) presented by patients affected by T2DM without previous cardiac events is similar to that of non-diabetic patients with previous MI. To reduce the elevated cardiovascular risk associated with T2DM, tight glycemic control and aggressive therapy against all known cardiovascular risk factors are strictly required. Despite the role played by hyperglycemia in the pathogenesis of cardiovascular events, studies showing an improvement of cardiovascular outcomes by anti-hyperglycemic or hypoglycemic agents are not conclusive. The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that in obese type 2 diabetic patients metformin reduces the risk of MI more than sulphonylureas or insulin. This observation identified metformin as the first-line treatment for T2DM. The vasoprotective role of metformin is largely independent of its hypoglycemic action and has been ascribed to pleiotropic effects. The present review considers the putative beneficial action exerted by metformin on arterial vessels by evaluating its effects on lipids, inflammation, hemostasis, endothelial and platelet function and vessel wall abnormalities. Furthermore, the molecular mechanisms of the beneficial metabolic and vascular effects of metformin will be considered, with a particular attention for its ability to activate AMP-activated protein kinase.

Platelets from patients affected by diabetes mellitus and metabolic syndrome show an impaired sensitivity to physiological antiaggregating agents and an enhanced activation state, mirrored by an increased expression of membrane activation markers; furthermore, they are more prone to form spontaneous microaggregates with ADP receptor involvement. These abnormalities are responsible for a pro-thrombotic condition, contributing to a high cardiovascular risk. This pattern of platelet abnormalities provides a strong rationale for aggressive antiplatelet therapy strongly recommended by guidelines both in diabetes mellitus and in metabolic syndrome, not only in the setting of acute coronary syndromes, but also for the long-term prevention of the cardiovascular events. Antiplatelet therapy in these pathological conditions, however, is still a matter of intense debate, especially because a high prevalence of “resistance” to these drugs (and to aspirin in particular) has been described in these patients. This may result in non-significant reductions in cardiovascular events. Different factors seem to be involved, including: i) genetic polymorphisms; ii) hyperglycemia and poor metabolic control; iii) reduced sensitivity to nitric oxide; iv) a pro-inflammatory and/or pro-thrombotic status, and, v) increased oxidative stress. This review will take into consideration: i) the results of the most relevant studies addressing the effects of the antiaggregating treatment in patients affected by diabetes mellitus and/or metabolic syndrome, and, ii) the biochemical mechanisms accounting for the impaired sensitivity to aspirin and thienopyridines in the above mentioned clinical conditions.

Ezetimibe is the first lipid-lowering drug which selectively inhibits the intestinal uptake of dietary and biliary cholesterol by binding to the cholesterol transporter protein Niemann-Pick C1 Like 1 (NPC1L1). This drug is an effective new tool for cholesterol lowering and allows to better investigate the mechanisms involved in cholesterol absorption by small intestine. Ezetimibe is rapidly absorbed after oral administration and extensively metabolized ( > 80%) to the pharmacologically active ezetimibe-glucuronide compound; furthermore, it shows a favourable drug-drug interaction profile due to the absence of clinically relevant interactions with a variety of drugs commonly used in patients with hypercholesterolemia (in particular, statins, fibrates and nicotinic acid). In primary hypercholesterolemia, ezetimibe alone reduces low density lipoprotein (LDL) cholesterol by about 18% and induces an additional 25% reduction when added to on-going statins. The combination therapy of ezetimibe with statins or fibrates is effective and safe also in patients affected by the Metabolic Syndrome, which is characterized by complex lipid alterations, including increased triglyceride levels, low high density lipoprotein (HDL) cholesterol concentrations, preponderance of small dense LDL particles and post-prandial hyperlipidemia. In this review, we considered the main studies evaluating the rationale and the efficacy of therapy with ezetimibe alone or in combination with other lipid-lowering drugs, in order to provide clinical indications.

Abstract: Beyond carbohydrate, lipid and protein metabolism, insulin influences hemostasis, vascular tone and angiogenesis. Insulin per se causes a slow-acting vasodilation selectively occurring in skeletal muscle tissue, mainly related to an endothelium-dependent mechanism. Insulin-induced vasodilation is attenuated by the secretion of endothelin-1 and by the stimulation of sympathetic activity. The direct vasodilating effect of insulin is deeply reduced in the insulin-resistant states. The insulin effects on platelet aggregation and inflammatory response are attributable to increased synthesis of nitric oxide, and are deeply reduced in the insulin-resistant states. Furthermore, insulin reduces oxidative stress and promotes angiogenesis and proliferation of vascular smooth muscle cells. The involvement of insulin signalling pathways in these different insulin actions both in insulin sensitive and in insulin resistant states and the concept of “selective insulin resistance” are discussed. The vascular effects of insulin are generally ignored in the clinical practice, despite the evidences that insulin infusion with algorithms aiming to provide an optimal blood glucose control improves the clinical outcomes of patients with severe acute illness and myocardial infarction. Aim of this review is to clarify whether the vascular effects of insulin could represent a new “rationale” for its therapeutical use, independently of the well known metabolic actions.

The Metabolic Syndrome is commonly associated with an atherogenic dyslipidemia which accounts for a high risk of atherothrombosis and cardiovascular events. The fundamental defect of patients with the Metabolic Syndrome is the resistance to insulin action which is involved in the appearance of a combined dyslipidemia -i.e. hypertriglyceridemia, low HDL cholesterol, preponderance of small dense LDL particles and post-prandial lipidemia- owing to a reduced suppression of lipolysis in adipose tissue which leads to higher flux of free fatty acids to liver and increased synthesis and secretion of VLDL particles. Beyond the primary management which involves lifestyle intervention, patients with the Metabolic Syndrome could be treated with different therapeutic strategies to reduce cardiovascular risk. The main therapeutic option is statin therapy which provides effective decrease of LDL cholesterol levels and is shown effective in the prevention of coronary artery events, even though controlled studies are available only for few molecules. In turn, controlled trials -such as BIP, VA-HIT and FIELD- have proposed a possible benefit from fibrate administration in normalizing lipid profile and decrease insulin resistance in patients with the Metabolic Syndrome which exhibit low HDL cholesterol and hypertriglyceridemia. Other lipid modifying strategies based on nicotinic acid or ezetimibe have recently proposed as effective in the Metabolic Syndrome on the basis of preliminary results and could be future options. Finally, the simultaneous use of different drugs could provide benefits, avoiding inappropriate combinations due to the potential hazard of adverse drug interaction. The present review extensively examines the most recent results in the field of treatment of dyslipidemia in patients with the Metabolic Syndrome, starting from the trials with statin therapy. We consider also the role of drugs which regulate serum lipids by different mechanisms, such as fibrates, ezetimibe, nicotinic acid and omega3 fatty acids, on the basis of the evidences of effectiveness and safety. Finally, we take into account the therapeutic efficacy of new drugs, such as glitazones and rimonabant, whose main target is to improve the insulin sensitivity.

Background: Impairment of platelet response to antiaggregatory agents is seen in individuals with central obesity and may play a role in the increased cardiovascular risk associated with obesity. In this study we evaluated whether this impairment involves the antiaggregatory pathways regulated by cAMP and cGMP.Methods: We obtained platelet-rich plasma from 12 obese individuals and 12 controls. We investigated the effects of the cyclic nucleotide analogs 8-pCPT-cAMP (10–500 μmol/L) and 8-pCPT-cGMP (10–500 μmol/L) on ADP-induced platelet aggregation as assessed by decreased light scattering. We assessed the activation of cAMP- and cGMP-dependent protein kinases by measuring phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) at Ser157 and Ser239.Results: The antiaggregatory effect of both cyclic nucleotide analogs was impaired in obese individuals compared to controls, with mean (SE) half-maximal inhibitory concentrations (IC50) (after 20-min incubation) of 123 (33) μmol/L vs 5 (1) μmol/L, respectively, for 8-pCPT-cAMP (P <0.01) and of 172 (43) μmol/L vs 17 (8) μmol/L, respectively, for 8-pCPT-cGMP (P <0.01). The Homeostasis Model Assessment Index of Insulin Resistance was independently correlated with cyclic nucleotide analog IC50. In obese individuals, VASP phosphorylation at Ser157 and Ser239 in response to cyclic nucleotides was significantly lower than in controls.Conclusions: In central obesity the reduced ability of cyclic nucleotides to inhibit platelet aggregation is associated with reduced activation of their specific kinases. Because cyclic nucleotides help regulate platelet antiaggregation, alteration of this ability is consistent with platelet hyperactivity in obesity.

Abstract: The insulin resistance syndrome, which presents among its many facets obesity and type 2 diabetes mellitus, is a major risk factor for cardiovascular events. Thus, therapeutic guidelines recommend multifactorial treatment programs including, especially in the presence of type 2 diabetes, antiplatelet drugs. Few data, however, are available about the protective effect of antiplatelet therapy in both obese and type 2 diabetic patients. Furthermore, some reports showed a decreased sensitivity to the platelet antiaggregating effect of acetylsalicylic acid in diabetic patients. In the first part of this review, we focused our attention to alterations of platelets from insulin resistant subjects with or without type 2 diabetes, underlining that platelet hyperactivation is explained, at least in part, by: i) a reduced sensitivity to agents exerting an inhibitory modulation of platelet responses, ii) an altered intracellular milieu with elevated cytosolic Ca2+, iii) an enhanced thromboxane A2 synthesis, and iv) an increased number and/or function of GPIIb/IIIa complexes on platelet membranes. Furthermore, oxidative stress, which increases isoprostane production from arachidonic acid, may be involved in platelet hyperactivation, since isoprostanes activate platelets by interplaying with thromboxane receptors. These defects explain why antiplatelet therapy for both chronic atherosclerotic vascular disease and acute coronary syndromes should be specifically tailored in obese, insulin resistant subjects, especially in the presence of type 2 diabetes mellitus. Thus, in the second part of this review we carried out a critical overview of the clinical trials in subjects with metabolic syndrome and type 2 diabetes mellitus with or without macroangiopathy.

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Subjects with central obesity exhibit platelet hyperactivity, which is involved in the atherosclerotic process and therefore can account for the increased risk of cardiovascular morbidity and mortality. The aim of the study was to evaluate whether alterations of platelet function in obesity involve synthesis and/or action of the two antiaggregating cyclic nucleotides adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP). In platelets from 16 obese and 15 control subjects we investigated the influence on platelet responses to the Adenosine-5-diphosphate sodium salt (ADP) exerted by (i) prostacyclin analogue Iloprost (0.31-5 nmol L(-1)) and the cAMP analogue 8-bromo-cAMP (10-500 micro mol L(-1)); and by (ii) nitric oxide (NO) donor sodium nitroprusside (SNP) (5-100 micro mol L(-1)) and the cGMP analogue 8-bromo-cGMP (10-500 micro mol L(-1)). IC(50) (minimal concentration of each inhibitor necessary to reduce platelet response to ADP by half) was determined. Iloprost and SNP ability to increase cyclic nucleotides was also measured. Significantly greater IC(50) were observed in obese subjects than in healthy controls (1.59 +/- 0.16 vs. 0.80 +/- 0.08 nmol L(-1), P = 0.0001 for Iloprost, and 27.6 +/- 6.5 vs. 7.0 +/- 1.7 micro mol L(-1), P = 0.006, for SNP); when data from control and obese subjects were pooled together, IC(50) of Iloprost and SNP correlated with the homeostasis model assessment (HOMA IR), which is a parameter used to measure the insulin resistance (r = 0.588, P = 0.029 and r = 0.640, P = 0.006, respectively). Also the antiaggregating effect of 8-Br-cAMP and 8-Br-cGMP was smaller in the obese subjects. Finally, the ability of Iloprost to increase platelet cAMP and the ability of SNP to increase both cGMP and cAMP were reduced in obese subjects. Platelet resistance to the antiaggregating effects of prostacyclin and NO in obesity is attributable to impairment of cyclic nucleotide synthesis and action. As cyclic nucleotides are the main effectors of platelet antiaggregation, the resistance to them can account for platelet hyperactivity in obesity.