Current Vascular Pharmacology - Volume 12, Issue 4, 2014

Although the brain has long been considered an insulin-independent organ, recent research has shown that insulin has significant effects on the brain, where it plays a role in maintaining glucose and energy homeostasis. To avoid peripheral insulin resistance, the brain may act via hypoinsulinemic responses, maintaining glucose metabolism and insulin sensitivity within its own confines; however, brain insulin resistance may develop due to environmental factors. Insulin has two important functions in the brain: controlling food intake and regulating cognitive functions, particularly memory. Notably, defects in insulin signaling in the brain may contribute to neurodegenerative disorders. Insulin resistance may damage the cognitive system and lead to dementia states. Furthermore, inflammatory processes in the hypothalamus, where insulin receptors are expressed at high density, impair local signaling systems and cause glucose and energy metabolism disorders. Excessive caloric intake and high-fat diets initiate insulin and leptin resistance by inducing mitochondrial dysfunction and endoplasmic reticulum stress in the hypothalamus. This may lead to obesity and diabetes mellitus (DM). Exercise can enhance brain and hypothalamic insulin sensitivity, but it is the option least preferred and/or continuously practiced by the general population. Pharmacological treatments that increase brain and hypothalamic insulin sensitivity may provide new insights into the prevention of dementia disorders, obesity, and type 2 DM in the future.

Metabolic syndrome (MetS) is a world-wide epidemic disease associated with increased morbidity and mortality. Treatment strategies include pharmacologic and non-pharmacologic methods, with varying degrees of success rate all over the world. Pharmaceutical interest in this field is growing, together with patients’ requests for supplementary (or “alternative”) treatments. The knowledge of nutraceuticals beneficial effects in subjects with the MetS could help us to better define the appropriate treatment for these subjects, in particular those with contraindications for commonly used drugs, or to achieve guidelines suggested targets. On the other side, it could be not convenient to use a nutraceutical to treat each metabolic syndrome component (i.e. from 3 to 5) in each affected subjects. Thus, this review tries to focus on widely marketed nutraceuticals with clinically demonstrated effects on more than one component of the MetS, namely omega-3 fatty acids, berberine, psyllium and other soluble fibers, cinnamon, chromium picolinate, banaba, and bitter gourd.

In humans uric acid (UA) is the end product of degradation of purines. The handling of UA by the renal system is a complex process which is not fully understood. To date, several urate transporters in the renal proximal tubule have been identified. Among them, urate transporter 1 (URAT1) and a glucose transporter 9 (GLUT9) are considered of greater importance, as potential targets for treatment of hyperuricemia and the potential associated cardio-metabolic risk. Therefore, the recognition of the metabolic pathway of UA and elucidation of occurrence of hyperuricemia may provide important insights about the relationship between UA, pre-hypertension (preHT) and the metabolic syndrome (MetS). We also review the available clinical studies in this field, including experimental studies dealing with the mechanisms of UA transport via different transporters, as well as current treatment options for hyperuricemia in patients with MetS, preHT or cardiovascular risk factors.

In 2003, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure established a definition of a new category of BP levels called ‘prehypertension’ (preHT) that included individuals with a systolic BP of 120–139 mm Hg or a diastolic BP of 80–89 mm Hg. Patients with preHT were considered to be at increased risk for progression to hypertension and in individuals with BP in the range 130/80 to 139/89 mmHg the risk of developing hypertension was twice as high as in subjects with lower values. Still then there has been a large debate whether the introduction of preHT was based on evidence and as a consequence, it was fully justified. It has been suggested that the term prehypertension may in many subjects create anxiety and a need for unnecessary medical visits and examinations. This group of patients is also very heterogeneous and it has been pointed out that subdividing preHT group into individuals with normal BP and high normal BP would much better correspond to the continuum of BP risk for CV disease. Finally, despite some data suggesting the potential benefits of antihypertensive therapy in patients with preHT (high normal BP), there are still no hard evidences on the outcome reduction by giving antihypertensive drugs in these individuals.

This review considers drug combinations and newer treatment strategies for patients with severe hypertriglyceridemia. Hypertriglyceridemia is associated with an atherogenic metabolic profile and in most studies with increased cardiovascular disease risk. Patients with severe hypertriglyceridemia also have increased incidence of pancreatitis. All types of severe hypertriglyceridemia are associated with a reduction in lipoprotein lipase activity. Patients with severe hypertriglyceridemia and abdominal pain or pancreatitis should be hospitalized and treated with hypolipidemic drugs and, if needed, with insulin/dextrose infusion or therapeutic apheresis. Fibrates are the first-line treatment in patients with severe hypertriglyceridemia. Omega-3 fatty acids and niacin are very useful drugs for patients with hypertriglyceridemia. Statins in high doses exhibit a significant hypotriglyceridemic activity. Drugs that interfere with chylomicron production such as orlistat are also useful for hypertriglyceridemic patients. In most patients with severe hypertriglyceridemia drug combinations are needed to maintain an acceptable triglyceride concentration. Gene therapy is under development for patients with known genetic abnormalities of triglyceride metabolism. Clinicians should be vigilant for the recognition and prompt treatment of patients with severe hypertriglyceridemia aimed to avoid the serious complication of pancreatitis and to reduce their cardiovascular risk.

Type 2 diabetes is characterized by insulin resistance together with progressive loss of beta-cell function. After recognition of gluco- and lipo-toxicity, attention was focused on the preservation and/or restoration of beta cell function, especially at the early stages of the diabetes, with better beta-cell reserve and in the absence of complications. Early treatment of glucotoxicity with insulin was searched by early insulin treatment studies, and these studies have some promising results, pointing the possibility of “remission” of diabetes in some patients. According to the results of these studies, patients with early diagnosis of diabetes, the ones with better beta cell reserve, patients with low tendency for “insulin-abuse” could make “U”-turn from insulin to pills or even drug-free life. Criteria to turn back to pills could be listed as disappearance of diabetic symptoms, daily insulin need < 0.25 unit/kg, euglycemia in both fasting and postprandial state, and better beta cell function. The main problems in early insulin treatment are the ‘’insulin resistance’’ of both patients and doctors, hypoglycemia, weight gain and increased appetite. Meanwhile, hyperinsulinemia desensitizes receptors and causes worsening of situation in a vicious cycle of insulin resistance and hyperglycemia. Therefore, patients should be selected properly and U-turn could be performed in relevant conditions explained in the text. It could be possible to see early insulin treatment and U-turn strategies in future guidelines for type 2 diabetes.

Metabolic syndrome (MetS), a cluster of dyslipidaemia, central obesity, hypertension and/or insulin resistance, is associated with increased cardiovascular disease (CVD) type 2 diabetes risk. Different diagnostic criteria for MetS have been proposed but in 2009 a joint statement by several scientific societies was released. Apart from the diagnostic criteria, MetS has also been associated with other risk factors including waist to hip ratio, high density lipoprotein dysfunction, small dense low density lipoprotein, postprandial hypertriglyceridaemia, lipoprotein (a), uric acid, liver function tests, prothrombotic factors, cytokines, adipokines, vitamin D, arterial stiffness, renal dysfunction, nephrolithiasis, polycystic ovary syndrome, obstructive sleep apnea. We discuss the extensive list of MetS-associated factors that may influence vascular risk. Furthermore, we discuss the impact of frequently prescribed drugs (e.g. hypolipidaemic agents) on these variables. These effects may need to be taken into consideration when treating MetS patients.

Screening is the systematic use of a test for a health problem or risk factor when no recognized signs or symptoms would indicate the presence of that problem or risk factor. Abnormal glucose metabolism can be documented years before the onset of overt diabetes. Nowadays, prediabetes can be subdivided into impaired fasting glucose or impaired glucose tolerance. Substantial number of subjects with either will progress to overt diabetes within years. Prediabetes bears also the increased risk of cardiovascular complications. Prehypertension is much newer term introduced by the seventh report of the Joint National Committee (JNC 7) published in 2003 as systolic blood pressure from 120 to 139 mmHg or diastolic blood pressure from 80 to 89 mmHg in adults (not receiving blood pressure-lowering treatment). Similarly prehypertension also increased the risk of cardiovascular complications and progression to hypertension. Chronic kidney disease is also highly prevalent mainly in the elderly. It is associated with important adverse outcomes such as cardiovascular mortality and morbidity. Factors associated with higher risk of chronic kidney disease include mainly hypertension, diabetes, obesity and older age. Early detection and diagnosis of chronic kidney disease may prevent the full blown disease and its end-stage requiring renal replacement therapy. The review focus on the problem of high risk population for development of diabetes, hypertension and whether time has come to focus also on the conditions predisposing to the development of chronic kidney disease.

Low-density lipoprotein (LDL) cholesterol lowering with statins have had a profound impact on cardiovascular (CV) event rates and accordingly have become an integral component of strategies designed to reduce CV risk. The finding of a residual clinical risk, despite LDL cholesterol lowering, supports the need to develop additional therapeutic strategies for CV prevention. Numerous lines of evidence suggest that targeting the protective properties of high-density lipoproteins (HDL) may be beneficial. Disappointing results from recent reports of HDL genetics and raising agents and clinical events has fueled considerable debate as to whether attempts to target HDL will be of clinical benefit or futility. This review will reflect on challenges faced in developing new effective HDL targeted therapies.

There is a global epidemic of obesity, metabolic syndrome, and diabetes mellitus. Insulin resistance (IR) is etiologic for both metabolic syndrome and diabetes mellitus. IR induces a broad range of toxic systemic effects, including dyslipidemia, hypertension, hyperglycemia, increased production of advanced glycosylation end products, increased inflammatory tone, as well as a prothrombotic and pro-oxidative state. Patients with IR are highly vulnerable to the development of accelerated atherosclerosis as well its clinical sequelae, including coronary artery disease and myocardial infarction, carotid artery disease and ischemic stroke, peripheral arterial disease and claudication/lower extremity amputation, and coronary mortality. Among the most important risk factors patients afflicted with IR develop is the so-called atherogenic lipid triad: large numbers of small, dense low-density lipoprotein (sdLDL) particles, hypertriglyceridemia, and low serum concentrations of high-density lipoprotein cholesterol. Though controversial, much recent evidence suggests that the formation of sdLDL particles in the setting of IR is an important metabolic transition. Some studies suggest that these smaller particles are more atherogenic than their larger, more buoyant counterparts. At least part of the explanation for the apparent augmented atherogenicity of small LDL particles is their reduced systemic clearance by the LDL receptor, increased vulnerability to oxidation rendering them more apt for scavenging by macrophages, and possible increased flux into the subendothelial space of arterial walls. Numerous small studies suggest that sdLDL is highly correlated with cardiovascular events. Cardiovascular medicine is in need of a large prospective, randomized study that would more definitively investigate the impact of small, dense LDL (sdLDL) on risk for cardiovascular disease and whether therapeutic interventions designed to specifically reduce the burden of sdLDL are associated with reductions in cardiovascular events over and above that seen with LDL-C reduction per se.