Current Vascular Pharmacology - Volume 10, Issue 6, 2012

Dysglycemia as a pre-stage of diabetes mellitus and abdominal obesity are closely interrelated at multiple levels and by a whole array of complex mechanisms, many of which seem to have the potential of causing harm to large blood vessels, in particular to coronary and peripheral vascular segments. Both conditions are associated with elevated circulating concentrations of free fatty acids in conjunction with insulin resistance, oxidative stress, mitochondrial dysfunction, disordered nitric oxide release, and endothelial dysfunction. Oscillating glucose levels seem to be associated with the most of the injury burden to endothelial cells of large blood vessels and also generate some kind of metabolic memory. In addition, the multiple effects of insulin also on the regulation of the vasculature are shifted towards vasoconstriction and proliferation in the context of insulin resistance and the excessively high levels.

The present paper examines major evidences on the correlation between pre-diabetes, diabetes and cardiovascular risk, especially focusing on early and multifactorial treatment strategies holding the potential to delay the occurrence of micro- and macro-vascular complications causing impaired quality of life and reduced survival.

Diabetic dyslipidemia is due to a multiple array of metabolic abnormalities determining a typical phenotype characterized by increased plasma triglycerides, reduced HDL and a preponderance of small, dense LDL. This dyslipidemia, defined as atherogenic dyslipidemia, is thought to be highly responsible for the increased cardiovascular risk in diabetes mellitus. Several lines of evidence indicate that the increased liver production of VLDL is the main underlying defect in atherogenic dyslipidemia. This review will recapitulate the pathophysiological aspects of diabetic dyslipidemia with special focus on the molecular mechanism causing increased liver production of VLDL in diabetic patients. The consequences of atherogenic dyslipidemia on mechanisms of atherogenesis will be also reviewed.

In almost every epidemiological analysis so far performed a strong correlation always emerges between degree of hyperglycemia and risk of both micro- and macrovascular complications. However, whereas lowering plasma glucose levels by intensive treatment has proven to reduce the risk of development of retinopathy, nephropathy and neuropathy, the effect on macrovascular complications has remained quite doubtful. Multiple factors may have concurred to this negative findings including long duration of diabetes, poor pre-existing glycaemic control, potentially inadequate anti-diabetes drugs. Another potential explanation is that, given the high cardiovascular risk of the diabetic patients they were already aggressively treated as far as their cardiovascular risk factors are concerned. The annual mortality in these diabetic cohorts was, indeed, incredibly close to that of the non-diabetic population. These considerations along with the results of multiintervention studies, such as the Steno-2, supports the need for multifactorial intensive needs, definitely including glucose and lipid lowering.

Patients with diabetes and prediabetes are at high risk for micro- and macrovascular complications. A multifactorial management strategy improves their prognosis considerably. Of concern is that these patients often fall between two specialties: cardiovascular medicine and diabetology. Practice guidelines for this patient category have been issued in collaboration between the European Society of Cardiology and the European Association for the Study of Diabetes to ascertain management according to the best available evidence. This article discusses why and for whom such guidelines are important.

Atherosclerosis is a chronic inflammatory disease that is based on the interaction between inflammatory cell subsets and specific cells in the arterial wall. SIRT1 deacetylates histone and non-histone proteins and has been implicated in protective effects of caloric restriction on lifespan and metabolic pathways in yeast, nematodes, and mice. In the vasculature of rodents, SIRT1 mediates vasodilatation through the release of endothelial nitric oxide synthase-derived nitric oxide and scavenges reactive oxygen species. Using a genetic loss-of-function approach, SIRT1 has been shown to interfere with crucial steps of endothelial activation and atherogenesis by suppressing NFκB signaling: Partial SIRT1 deletion in ApoE-/- mice prevented expression of endothelial adhesion molecules thereby hampering the extravasation of circulating monocytes. In monocyte-derived macrophages SIRT1 deletion reduced the expression of the scavenger receptor lectin-like oxidized low-density lipoprotein receptor 1 (Lox-1) resulting in reduced foam cell formation and atherosclerosis. Moreover, it was reported that SIRT1 regulates the activity of liver X-receptor, thereby promoting ABCA1-driven reverse cholesterol transport in plaque-resident macrophages slowing foam cell formation. Finally, SIRT1 suppressed the expression of endothelial tissue factor, and thus exerted anti-thrombotic properties during induced carotid thrombosis in mice. These findings indicate protective effects of SIRT1 in atherogenesis and thrombosis at an experimental level and highlight the opportunity to translate this concept from bench to bedside. Indeed, SIRT1 activators are available and have been shown to exert beneficial effects at the preclinical level in obesity and type 2 diabetes mellitus (T2DM). SIRT1 activators are currently being evaluated in phase II clinical trials in patients with T2DM. The concept of SIRT1 activation appears a promising strategy for novel therapeutic approaches in patients with atherothrombosis.

The present work is addressing the latest advances made in understanding the molecular mechanisms of vascular aging. Increased production of reactive oxygen species (ROS) is the common denominator of vascular aging, endothelial dysfunction and atherosclerosis. ROS are generated by different intracellular molecular pathways. In view of its role in determining the redox state of the cells and their responses to free radicals, mitochondrial p66Shc protein has been regarded as part of a putative transduction pathway relevant to endothelial integrity. Future efforts should translate our knowledge of the mechanisms of aging and its interaction with risk factors into the development of new therapeutic strategies to prevent age-associated cardiovascular disease.

Cardiovascular disease is multidimensional and new ideas are needed to develop the conventional risk factor paradigm that has been based on the Framingham Heart Study since more than 30 years. Traditional risk factors such as hypertension, smoking, hyperlipidemia and diabetes can only explain about 50% of the distribution of coronary heart disease whereas the inclusion of new risk markers or protective markers may increase the explained proportion up to 80% of myocardial infarction risk according to the INTERHEART study. Still there are substantial differences in cardiovascular risk between regions and populations that are hard to explain. Findings in the former Soviet Union geographical area in Eastern Europe could contribute to new and better understanding of cardiovascular risk as a reflection of ageing in general, as populations in these areas not only run a very high cardiovascular risk but also have a shorter mean life expectancy in general. New understanding of the interaction between genes and the environment in prediction of cardiovascular ageing could contribute to the development of more effective preventive strategies.

Arterial aging, characterized by arterial stiffening that is clinically evaluable as aortic pulse wave velocity, is risky for CV events, disability, and loss of cognitive function. Today the only adopted strategy to decrease arterial aging/ arterial stiffness is represented by decreasing BP. Selective antihypertensive drug classes (calcium channel blockers, converting enzyme inhibitors, angiotensin type 1 receptor antagonists) showed a beneficial effect on the arterial wall and on both large and small arteries over and above the reduction in BP levels. Still, the lower the better paradigm seems only to expose older subjects to higher rate of side effects, that via hypotension result in even transient organ hypoperfusion. This vicious circle may be particularly detrimental for cerebral district and, thus, for cognitive impairment onset and progression until dementia.

Loss of normal endothelial function and bioactivity of nitric oxide (NO), associated with increased production of reactive oxygen species (ROS), are characteristics of cardiovascular disease states. There is good experimental evidence that these abnormalities are causally related to cardiovascular disease pathogeneses, and are amenable to therapeutic intervention. However, simple attempts to increase NO levels or reduce “oxidative stress”, for example using nonselective anti-oxidant drugs, have shown no benefit as treatments of cardiovascular disease. Increasing evidence highlights the need to better understand NO and ROS mediated signaling mechanisms in endothelial function, in order to identify more rational and selective therapeutic targets. The NO synthase co-factor, tetrahydrobiopterin (BH4) is a redox active molecule which regulates NO and ROS production by NO synthase and provides an exemplar of redox dependent signaling in the endothelium, with relevance to cardiovascular disease. Loss of endothelial cell BH4 is observed in cardiovascular disease states and results in loss of NO, but increased ROS production by endothelial NO synthase. Genetic mouse models of augmented endothelial cell BH4 synthesis have shown proof of concept that endothelial cell BH4 can alter cardiovascular disease pathogenesis, but clinical trials of BH4 therapy in vascular disease have been limited by systemic oxidation and limited endothelial cell uptake of BH4. In contrast, some existing therapies such as statins appear to exert favourable effects on endothelial cell BH4 and endothelial NO synthase function. Identifying specific redox mechanisms and targets in the endothelium will provide new potential targets for future drug treatments.

Although the impressive progression of modern diagnostic opportunities and therapeutic options, cardiovascular diseases still represent the leading causes of morbidity and mortality, worldwide. Beyond the effective pharmacological treatment of major cardiovascular disease or sequelae, however, cardiovascular diseases developing in adult individuals are largely preventable. The substantial failure to prevent cardiovascular disease in the 20th century generation is mostly linked to the ineffective use, as well as to the underuse of available preventive strategies. As a consequence, preventive strategies should be encouraged at both individual and population level, to substantially improve healthy status of the general population and reduce the burden of cardiovascular diseases in Western and Developing Countries.

The need of early, preclinical detection of disease is given by the fact that in 50% of patients dying due to coronary death, mortality is neither heralded by cardiac symptoms nor diagnosis make .The risk during life of suffering of consequences of atherosclerosis can be efficiently assessed through the Framingham risk score (among several other global risk scores). Global risk scores although originally formulated to give a numerical estimate of the risk, give generally a rough categorization of the patient into a low, (0-10%) intermediate (10%-20%) or high (>20%) risk. Furthermore the boarders between intermediate and low or high risk are frequently not uniform. Although global risk score evaluation are considered efficient tools in medical practice, over- or underestimation of risk has been reported in several studies. These are the mean reason why many investigators embarked during the last two decades in an effort to discover newer predictive markers. Among them few have passed the threshold of a rigorous assessment of their predictive power including analysis not only of statistical association but also of calibration, discrimination, and reclassification.

All coronary patients should be advised and have the opportunity to access a comprehensive cardiovascular prevention and rehabilitation programme, addressing all aspects of lifestyle - smoking cessation, healthy eating and being physically active - together with more effective management of blood pressure, lipids and glucose. To achieve the clinical benefits of a multidisciplinary and multifactorial prevention programme we need to integrate professional lifestyle interventions with effective risk factor management, and evidence based drug therapies, appropriately adapted to the medical, cultural, and economic setting of a country. The challenge is to engage and motivate cardiologists, physicians and health professionals to routinely practice high quality preventive cardiology in hospital and community, and a health care system which invests in prevention.

Low high-density lipoprotein (HDL) cholesterol levels are associated with an increased risk of coronary artery disease and myocardial infarction. Experimental studies have identified several potential anti-atherogenic properties of HDL, including promotion of macrophage cholesterol efflux, endothelial nitric oxide stimulation, anti-inflammatory and anti-thrombotic effects. These observations have lead to the important question of whether raising of HDL can reduce cardiovacular risk. Notably, recent studies have suggested that vascular effects of HDL can be highly heterogenous and are altered in patients with coronary disease or diabetes, that has been referred to as “HDL dysfunction”. Moreover, studies using gene-targeted mice have indicated that genetic modifications leading to a similar increase of HDL cholesterol levels can either reduce (i.e. apoA1 transgene overexpression) or accelerate (i.e. SR-B1 deficiency) atherosclerosis, depending on the molecular target. These findings therefore suggest that HDL cholesterol levels alone are likely not sufficient as a readout for the vascular effects of HDL-targeted therapeutic interventions, since both, the vascular effects of on-treatment HDL as well as the underlying molecular mechanism used to elevate HDL cholesterol levels may represent critical determinants of the overall vascular effects of therapeutic interventions raising HDL-cholesterol levels. In summary, low HDL cholesterol plasma levels remain associated with an increased cardiovascular risk. However, the above findings suggest that careful clinical trial programms are needed to determine, which HDL raising therapeutic interventions may indeed exert vasoprotective effects.

The plasma levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Traditional HDL-raising therapies, like fibrates, PPAR-γ agonists, and nicacin, among others, are associated with undesirable side effects, limited efficacy, or have not yet been shown to improve morbidity and mortality on top of statins in clinical outcome trials. A novel pharmacological target for raising circulating HDL-C levels is the cholesterol ester transfer protein (CETP), an enzyme that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. Four pharmacological small-molecule inhibitors of CETP, i.e. torcetrapib (Pfizer), dalcetrapib (JTT-705; Roche), anacetrapib (Merck), and evacetrapib (Eli Lilly) have been developed. Notwithstanding a marked increase in HDL, torcetrapib was associated with an increase in all-cause mortality in the ILLUMINATE trial and raised safety concerns related to the off-target effects of CETP inhibition. Most recently, development of dalcetrapib was abruptly stopped due to a lack of clinically meaningful efficacy. Thus, it will be of utmost importance to demonstrate that the remaining CETP inhibitors in development not only increase HDL-C levels in plasma, but also improve HDL-function in patients with coronary disease or an acute coronary syndrome.

Among patients with atherothrombosis, including coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral arterial disease (PAD), patients with PAD generally have the worse prognosis. The Reduction of Atherothrombosis for Continued Health (REACH) Registry characterized the atherothrombotic risk factor profile, and evaluated treatment intensity and cardiovascular events among different atherothrombotic patient populations worldwide. Two thirds of PAD patients had polyvascular disease, defined as symptomatic involvement of more than one vascular bed. The risk factor profile in patients with CAD, CVD and PAD was very much similar. However, optimal risk factor control by medical treatment and lifestyle interventions was least accomplished in PAD patients. Furthermore, PAD patients and patients with polyvascular disease showed the highest cardiovascular event rates. Of note, therapeutic strategies are similar for all atherothrombotic disease categories, irrespective of the presence of polyvascular disease. Therefore, it is of the utmost importance to achieve optimal risk factor control, particularly for PAD patients and for those with polyvascular disease, in order to prevent future cardiovascular events.

Multisite artery or polyvascular disease is common. In the REACH registry, 15.9% of patients with either established atherosclerotic arterial disease or at least 3 risk factors for atherothrombosis had symptomatic polyvascular disease. History of risk factors and known co-morbidities, as well as a thorough physical examination, are mandatory in the initial screening and diagnostic work-up. Various non-invasive imaging techniques (duplex ultrasound, computed tomography angiography, magnetic resonance angiography) can be used for the identification of the polyvascular patient. Digital subtraction angiography is now used almost exclusively in association with endovascular procedures. Appropriate implementation of each technique is based on international guidelines and a multidisciplinary discussion for each case. The presence of co-existing disease in a different vascular bed is associated with a higher risk of recurrent symptoms and complications in the first site. In this context, accumulating evidence suggests that arterial biomarkers, such as arterial stiffness (pulse wave velocity), central blood pressures, wave reflections indices, ankle-brachial index, carotid intimamedia thickness, as well as vasculogenic erectile dysfunction, can predict cardiovascular morbidity and mortality beyond classical risk factors and prediction models. An important pending question is whether identification of multisite arterial disease may improve clinical outcomes in patients who are already in secondary prevention programs. Such screening of asymptomatic multisite artery disease in patients with known CVD would be of paramount importance if it is ultimately proven with hard evidence that it should lead to a different management from the one proposed for CVD patients without multisite artery disease.

Multisite artery disease (MSAD) affects 15% to 30% of patients with clinically manifest atherosclerosis, and has a relevant negative impact on prognosis. However, studies specifically focused on MSAD are very few, and available evidence is scarce. Importantly, patients with MSAD require an integrated management, possibly by a “Vascular Team” composed of the different specialists involved in the treatment of atherosclerosis. A multi-disciplinary, patient-centered approach is mandatory to deal with the variety of clinical scenarios and comorbidities found in MSAD patients. The risk/benefit ratio for multi-site arterial revascularization should always be carefully assessed in MSAD patients, taking into account the additional risks of interventions in this subset of patients. Many therapeutic options have been proposed for multisite revascularization, but little evidence is currently available to support specific recommendations. Percutaneous revascularization of the different arterial districts, when feasible, appears promising because of the lower operative morbidity and mortality.

Carotid stenosis is frequent in the general population, especially in elderly people and is associated with a high risk of stroke and vascular events. In patients with asymptomatic carotid stenosis the overall annual risk of ipsilateral stroke has dramatically decreased over the past decades, due to improvement in medical management. Asymptomatic carotid stenosis is probably a better indicator of generalized atherosclerotic disease than of stroke risk, with an average risk of nonstroke death (mainly due to ischemic heart disease) generally higher than the risk of ipsilateral stroke. Management of risk factors, antiplatelet therapy, and statins are highly beneficial in these patients. Carotid surgery in patients with asymptomatic carotid stenosis is associated with a small absolute benefit compared to medical treatment. The prognosis of patients with symptomatic carotid stenosis is dramatically different from that of patients with asymptomatic carotid stenosis because the risk of stroke on medical treatment alone is very high and highest during the first few days and weeks. In these patients, endarterectomy is highly beneficial and the absolute benefit of is increased in patients with 70- 99% stenosis, men, patients over 75 years, and in those treated within 2 weeks after the last event. The meta-analysis of the 3 major European trials comparing endarterectomy to stenting in symptomatic stenosis has shown an increased risk of perioperative risk of any stroke or death in the stenting group (74% increase in risk in patients treated with stenting). However, the risk of stroke or death after stenting and surgery were equivalent below the age of 70 whereas there was a two-fold increase in risk of stenting over endarterectomy above this age. Thus, surgery remains the first line method in most cases but stenting is potentially an alternative in young patients.

High blood pressure (BP) along with smoking habit and lipid disorders are the most important and modifiable risk factors for cardiovascular diseases. However, the prevalence of high BP has grown progressively over time with a progressive increase not only in the absolute number of patients but in the proportion of those showing BP values out of control. The increasing world-wide prevalence of hypertension and the related increase in burden of the disease due to diagnosis, treatment and management of the complications mandates both Health Authorities and research institutions to find out new strategies to improve the BP control. So, one of the main questions is which are the possible perspectives for the future of high BP management, and in particular how can we face the problem of hypertension in the near future? Four main points will be shortly discussed: the genetic contribution to hypertension development and control, the availability of effective preventive strategies, the improvement of disease management, and the role of extensive control of concomitant risk factors. It is relatively easy to suppose that the integration of the best available knowledge with the more recent diagnostic and therapeutic achievements will improve the management of hypertension through a more effective detection of subjects at risk who will undergo an earlier diagnosis leading to a more tailored, tolerated and effective treatment of the hypertensive disease. This means that the future direction of the hypertension management is the simpler: the patient instead of the disease.

The lecture covered the role of lipids in the pathogenesis and treatment of non-cardiac vascular disease. The following conditions were considered: abdominal aortic aneurysms (AAAs), peripheral arterial disease (PAD), carotid artery disease and atherosclerotic renal artery stenosis (ARAS).

In this issue of Curr Vasc Pharmacol, Pfeiffer et al. [1] and Glorioso et al. [2] report the efficacy and tolerability of aliskiren/amlodipine single-pill combinations (SPCs) in patients with inadequate blood pressure (BP) response to amlodipine or aliskiren monotherapy, respectively.

Many patients with hypertension will require multiple antihypertensive drugs to achieve blood pressure (BP) control. This double-blind study evaluated the efficacy and safety of aliskiren/amlodipine single-pill combinations (SPCs) in patients with mild-to-moderate hypertension who were non-responsive to aliskiren monotherapy. After a 4-week run-in with aliskiren 300 mg, patients with mean sitting diastolic BP (msDBP) ≥ 90 and <110 mmHg were randomized to oncedaily aliskiren/ amlodipine 300/10 mg or 300/5 mg, or aliskiren 300 mg for 8 weeks. Aliskiren/amlodipine SPCs provided significantly greater mean reductions in mean sitting systolic BP/msDBP (300/10 mg, 18.0/13.1 mmHg; 300/5 mg, 14.4/10.5 mmHg) than aliskiren 300 mg (6.4/5.8 mmHg) at week 8 endpoint. This represents additional mean reductions of 11.6/7.2 mmHg (300/10 mg) and 8.0/4.7 mmHg (300/5 mg) over aliskiren alone (both p<0.0001). Significantly more patients achieved BP control (<140/90 mmHg) with aliskiren/amlodipine 300/10 mg (65.5%) and 300/5 mg (56.6%) than with aliskiren (31.5% both p<0.0001). Aliskiren, alone and in combination with amlodipine, was well tolerated, with a slightly higher incidence of adverse events with SPCs (29.0-30.1%) than with monotherapy (22.7%). In conclusion, aliskiren/amlodipine SPCs offer an effective next step for patients who have an inadequate BP response to aliskiren alone.

Intravascular hemolysis is a major component of anemia in sickle cell disease (SCD). Plasma extracellular hemoglobin (ECHb) liberated by intravascular hemolysis has deleterious effects on the vasculature. ECHb scavenges nitric oxide (NO) and promotes the pathogenesis of several clinical events including pulmonary hypertension, priapism and non-hemorrhagic strokes. ECHb reduces the bioavailability of NO which down-regulates platelet activation, leading to platelet aggregation and vascular clot formation. Recently we have identified an additional mechanism whereby increased hemolysis can lead to a prothrombotic state in SCD by increasing the activity of von Willebrand factor (VWF), a multimeric plasma glycoprotein secreted by the endothelium. Our studies show that ECHb binds to the A2-domain on VWF at the proteolytic site of the metalloprotease, ADAMTS13, and blocks VWF cleavage in vitro. Elevated ECHb is associated with high levels of ultralarge and hyperactive VWF multimers in SCD patients' plasma. A sub-population of VWF multimers, bound to ECHb is hyperactive, and exists in greater quantity in SCD patients' plasma compared to normal controls. These results suggest a possible role for plasma ECHb in the accumulation of hyperactive VWF multimers in vivo that may mediate thrombotic and vasoocclusive complications in SCD patients.

Resting endothelial cells lining the inner surface of blood vessels have anti-thrombotic and anti-inflammatory actions, critical for maintaining normal vascular homeostasis. Upon localized or systemic stimulation, endothelial cells are activated to secrete bioactive molecules; among them is von Willebrand factor (VWF). Freshly secreted VWF is enriched in ultra-large (UL) forms that are anchored to endothelial cells to form long string-like structures, to which platelets tether and aggregate. This prothrombotic event is normally prevented by proteolytic cleavage of ULVWF multimers by ADAMTS-13 at a single peptide bond of Tyr1605-Met1606 in the A2 domain. The cleavage reduces the size and adhesion activity of (UL)VWF multimers. Lacking this cleaving activity due to mutations in the ADAMTS13 gene or autoantibodies against the metalloprotease is associated with systemic microvascular thrombosis found in patients with thrombotic thrombocytopenic purpura (TTP). Recombinant ADAMTS-13 has the potential to be a therapeutic agent to reduce prothrombotic activity of ULVWF multimers. Alternatively, blocking an interaction between ULVWF and its platelet receptor could achieve the same therapeutic goal. This review discusses potentials of using recombinant ADAMTS-13 and VWF-blocking agents as therapeutics for TTP and other acquired ADAMTS-13 deficiencies.

Portal hypertension is a hemodynamic abnormality that involves a high risk of disability as well as a reduced life expectancy in patients with cirrhosis. Progress in the knowledge of pathophysiology of portal hypertension has opened a new perspective for different pharmacological approaches. In this context, the pleiotropic actions of statins on endothelial cell function have emerged as new options to reduce portal pressure levels by targeting multiple molecular pathways involved in hepatic vascular homeostasis. We highlight how statins may target some molecular pathways involved in the pathophysiology of portal hypertension and how these drugs may correct impaired hepatic vascular tone.

Most patients with hypertension will require treatment with at least two antihypertensive agents to achieve blood pressure (BP) control. This double-blind study evaluated the efficacy and safety of aliskiren/amlodipine single-pill combination (SPC) therapy in patients with mild-to-moderate hypertension who are inadequately responsive to amlodipine monotherapy. Patients with mean sitting diastolic BP (msDBP) ≥ 90 and < 110 mmHg after 4 weeks' treatment with amlodipine 10 mg were randomized to once-daily aliskiren/amlodipine 300/10 mg (n = 279) or 150/10 mg (n = 285) or amlodipine 10 mg monotherapy (n = 283) for 8 weeks. Aliskiren/amlodipine 300/10 and 150/10 mg SPCs provided significantly greater reductions in mean sitting systolic BP/msDBP (14.4/11.0 and 11.0/9.0 mmHg, respectively) than amlodipine 10 mg (8.2/7.2 mmHg) at week 8 endpoint. This represents additional mean reductions of 6.2/3.8 mmHg (300/10 mg) and 2.8/1.7 mmHg (150/10 mg) over amlodipine alone (all P < 0.01). Significantly more patients achieved BP control (< 140/90 mmHg) with aliskiren/amlodipine 300/10 mg (58.8%) than amlodipine 10 mg (38.4%; P < 0.0001). Aliskiren/amlodipine SPCs were generally well tolerated. In conclusion, aliskiren/amlodipine SPCs offers an effective option for management of patients who have an inadequate BP response to amlodipine alone.

Energy homeostasis in mammalians is a teleological process regulated by the interplay between caloric intake and energy expenditure. Incretins are a significant component of the complex homeostatic network regulating the metabolic state in humans. This narrative review will focus on the basic concepts regarding incretins physiology and their regulatory feedback mechanisms affecting energy homeostasis. In this context, glucagon-like peptide 1 (GLP-1) promotes satiety and weight loss through centrally and peripherally mediated pathways. On the other hand, gastric inhibitory peptide (GIP) is implicated in energy storage by its actions on adipose tissue. Understanding this biological model requires a holistic approach, since it is dually manifested by promoting weight reduction, in the case of GLP-1, or favoring lipid accumulation, in the case of GIP. The complete spectrum of incretin actions related to energy homeostasis is yet to be fully elucidated. Currently, new drugs based on incretin physiology are available for treatment of type 2 diabetes mellitus, whereas the implication of similar drugs in the treatment of obesity is under investigation. These agents exert several beneficial effects that minimize cardiovascular risk.