Current Vascular Pharmacology - Volume 18, Issue 2, 2020

Background: During the past decades, the prevalence of diabetes (DM) has increased significantly, mainly as a result of continuous rise in the incidence of type 2 DM. According to World Health Organization statistics, >422 million adults globally were suffering from DM in 2014 and a continuous rise in DM prevalence is expected. Objective: The present review considers recent epidemiological data providing worldwide estimates regarding the incidence of DM. Methods: A comprehensive literature search was conducted to identify available data from epidemiological studies evaluating the current burden of DM. Results: Over the past few decades the prevalence of DM has risen significantly in nearly all countries and may be considered as a growing epidemic. Urbanization and income status are major factors which influence current rates in the prevalence studies introducing interesting differences between several population groups. Conclusion: Having recognized the global burden of DM, we now realize the urgent need for effective interventions. In order to monitor the public-health strategies and design effective future interventions we need reliable global estimates regarding the prevalence of DM.

Background: Type 2 diabetes mellitus (T2DM) has emerged as a pandemic. It has different complications, both microvascular and macrovascular. Objective: The purpose of this review is to summarize the different types of macrovascular complications associated with T2DM. Methods: A comprehensive review of the literature was performed to identify clinical studies, which determine the macrovascular complications associated with T2DM. Results: Macrovascular complications of T2DM include coronary heart disease, cardiomyopathy, arrhythmias and sudden death, cerebrovascular disease and peripheral artery disease. Cardiovascular disease is the primary cause of death in diabetic patients. Many clinical studies have shown a connection between T2DM and vascular disease, but almost always other risk factors are present in diabetic patients, such as hypertension, obesity and dyslipidaemia. Conclusion: T2DM causes a variety of macrovascular complications through different pathogenetic pathways that include hyperglycaemia and insulin resistance. The association between T2DM and cardiovascular disease is clear, but we need more clinical studies in order to identify the pure effect of T2DM.

Background: Type 2 diabetes mellitus (T2DM) is a chronic, non communicable, multisystem disease that has reached epidemic proportions. Chronic exposure to hyperglycaemia affects the microvasculature, eventually leading to diabetic nephropathy, retinopathy and neuropathy with high impact on the quality of life and overall life expectancy. Sexual dysfunction is an often-overlooked microvascular complication of T2DM, with a complex pathogenesis originating from endothelial dysfunction. Objective: The purpose of this review is to present current definitions, epidemiological data and risk factors for diabetic retinopathy, nephropathy, neuropathy and sexual dysfunction. We also describe the clinical and laboratory evaluation that is mandatory for the diagnosis of these conditions. Methods: A comprehensive review of the literature was performed to identify data from clinical studies for the prevalence, risk factors and diagnostic methods of microvascular complications of T2DM. Results: Diabetic nephropathy and retinopathy affect approximately 25% of patients with T2DM; diabetic neuropathy is encountered in almost 50% of the diabetic population, while the prevalence of erectile dysfunction ranges from 35-90% in diabetic men. The duration of T2DM along with glycemic, blood pressure and lipid control are common risk factors for the development of these complications. Criteria for the diagnosis of these conditions are well established, but exclusion of other causes is mandatory. Conclusion: Early detection of microvascular complications associated with T2DM is important, as early intervention leads to better outcomes. However, this requires awareness of their definition, prevalence and diagnostic modalities.

Background: Type 2 Diabetes Mellitus (T2DM) has emerged as a growing pandemic. Cardiovascular disease (CVD) constitutes another major health problem, with coronary heart disease being the leading cause of cardiovascular death. Patients with T2DM require a multilevel therapeutic approach, both for primary and secondary prevention of CVD. Objective: To present and summarize the most recent, highest level evidence retrieved from literature, relevant to the pharmaceutical management of CVD in T2DM. Methods: We conducted a comprehensive search of the literature on MEDLINE from its inception till today, primarily for relevant systematic reviews, meta-analyses and randomized controlled trials. Results: There is a trend towards more intensified therapeutic interventions in T2DM, concerning glycemic, lipid and blood pressure control. New drugs, such as sodium-glucose co-transporter 2 (SGLT-2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors might evolve as key players in the management of diabetes and its complications within the next years. Classic drugs, such as those targeting the renin-angiotensinaldosterone system, statins and aspirin remain first-line treatment options, both for primary and secondary prevention of CVD. Lifestyle interventions should always be integrated into a complete therapeutic strategy in diabetic patients. Novel drugs, such as finerenone and LCZ696 have provided significant results in cardiovascular outcome studies; however, their role in T2DM has to be further elucidated. Conclusion: Pharmaceutical approach of CVD in T2DM is multilevel and complex. Drug classes featuring pleiotropic effects may boost our armamentarium in the fight against CVD.

Introduction: Diabetes mellitus (DM) is one of the most common diseases worldwide. Its adverse effects on several body organs, have made treatment of DM a priority. One of the most serious complications of DM is diabetic nephropathy (DN). Objective: The aim of this review is to critically discuss available data on the pharmacological management of DN. Methods: A comprehensive review of the literature was performed to identify studies assessing the impact of several drug classes on DN. Results: Several studies have been conducted in order to find a novel and effective treatment of DN. So far, the cornerstone therapy of DN consists of renin-angiotensin system (RAS) inhibitors, agents that decrease the synthesis of intrarenal angiotensin II or block its receptors. Their antiproteinuric and antihypertensive effects can not only decelerate the progress of DN but prevent its onset as well. Novel antidiabetic drugs, such as sodium-glucose cotransporter 2 inhibitors (SGLT-2i) and glucagon-like peptide- 1 receptor agonists (GLP-1 RA), are promising agents in the therapy of DN, due to their positive effect on renal and cardiovascular adverse events. From lipid-lowering agents, atorvastatin improves DN up to stage 3 and substantially reduces CVD. Conclusion: RAS inhibitors, SGLT-2i and GLP-1 agonists were found to be beneficial for the treatment of DN. Larger renal trials are needed in order to incorporate these drugs into the first line treatment of DN.

The cardiac effects of exogenously administered insulin for the treatment of diabetes (DM) have recently attracted much attention. In particular, it has been questioned whether insulin is the appropriate treatment for patients with type 2 diabetes mellitus and heart failure. While several old and some new studies suggested that insulin treatment has beneficial effects on the heart, recent observational studies indicate associations of insulin treatment with an increased risk of developing or worsening of pre-existing heart failure and higher mortality rates. However, there is actually little evidence that the associations of insulin administration with any adverse outcomes are causal. On the other hand, insulin clearly causes weight gain and may also cause serious episodes of hypoglycemia. Moreover, excess of insulin (hyperinsulinemia), as often seen with the use of injected insulin, seems to predispose to inflammation, hypertension, dyslipidemia, atherosclerosis, heart failure, and arrhythmias. Nevertheless, it should be stressed that most of the data concerning the effects of insulin on cardiac function derive from in vitro studies with isolated animal hearts. Therefore, the relevance of the findings of such studies for humans should be considered with caution. In the present review, we summarize the existing data about the potential positive and negative effects of insulin on the heart and attempt to answer the question whether any adverse effects of insulin or the consequences of hyperglycemia are more important and may provide a better explanation of the close association of DM with heart failure.

Neuropathies of the peripheral and autonomic nervous systems affect up to half of all people with diabetes mellitus, and are major risk factors for foot ulceration, amputation and cardiovascular dysfunction. Peripheral neuropathies manifest with either painful or painless symptoms, but many patients experience both. Once diagnosed appropriately, painful diabetic neuropathy management presents a unique challenge for physicians and should be considered as a syndrome, clinically distinct from diabetic peripheral neuropathy. The aetiology is multifactorial: metabolic changes in diabetes may directly affect neural tissue and neurodegenerative changes are precipitated by compromised nerve vascular supply. Metabolic changes include the elevated polyol pathway activity, the increased oxidative stress, the formation of advanced glycation and lipoxidation end products, and various pro-inflammatory changes. These mechanisms work in combination and interact in a mutually facilitatory fashion. This review focuses on the current therapies for the management of peripheral and cardiovascular autonomic neuropathy and of painful neuropathy as a distinct entity, based on the current knowledge of diabetic neuropathy. Moreover, the role of ACE inhibition has been explored in the treatment of Cardiovascular Autonomic Neuropathy.

Background: Non-alcoholic fatty liver disease (NAFLD), affecting over 25% of the general population worldwide, is characterized by a spectrum of clinical and histological manifestations ranging from simple steatosis (>5% hepatic fat accumulation without inflammation) to non-alcoholic steatohepatitis (NASH) which is characterized by inflammation, and finally fibrosis, often leading to liver cirrhosis, and hepatocellular carcinoma. Up to 70% of patients with type 2 diabetes mellitus (T2DM) have NAFLD, and diabetics have much higher rates of NASH compared with the general non-diabetic population. Objective: The aim of this study is to report recent approaches to NAFLD/NASH treatment in T2DM patients. To-date, there are no approved treatments for NAFLD (apart from lifestyle measures). Results: Current guidelines (2016) from 3 major scientific organizations suggest that pioglitazone and vitamin E may be useful in a subset of patients for adult NAFLD/NASH patients with T2DM. Newer selective PPAR-γ modulators (SPPARMs, CHRS 131) have shown to provide even better results with fewer side effects in both animal and human studies in T2DM. Newer antidiabetic drugs might also be useful, but detailed studies with histological outcomes are largely lacking. Nevertheless, prior animal and human studies on incretin mimetics, glucagon-like peptide-1 receptor agonists (GLP-1 RA) approved for T2DM treatment, have provided indirect evidence that they may also ameliorate NAFLD/NASH, whereas dipeptidyl dipeptidase-4 inhibitors (DDP-4i) were not better than placebo in reducing liver fat in T2DM patients with NAFLD. Sodium-glucoseco-transporter-2 inhibitors (SGLT2i) have been reported to improve NAFLD/NASH. Statins, being necessary for most patients with T2DM, may also ameliorate NAFLD/NASH, and could potentially reinforce the beneficial effects of the newer antidiabetic drugs, if used in combination, but this remains to be identified. Conclusion: Newer antidiabetic drugs (SPPARMs, GLP-1 RA and SGLT2i) alone or in combination and acting alone or with potent statin therapy which is recommended in T2DM, might contribute substantially to NAFLD/NASH amelioration, possibly reducing not only liver-specific but also cardiovascular morbidity. These observations warrant long term placebo-controlled randomized trials with appropriate power and outcomes, focusing on the general population and more specifically on T2DM with NAFLD/NASH. Certain statins may be useful for treating NAFLD/NASH, while they substantially reduce cardiovascular disease risk.

Diabetic foot ulcers (DFUs) are one of the major complications of diabetes, representing a leading cause of hospitalisation and non-traumatic lower limb amputations. Multidisciplinary management, patient education, glucose control, debridement, off-loading, infection control, and adequate perfusion are the mainstays of standard care. Despite all these, at least 30% of DFUs fail to heal within 20 weeks. Therefore, dermoepidermal skin substitutes (DSS) have been used as a new therapeutic adjunct for DFUs. This brief review outlines the recent advances in DSS for the treatment of DFUs. PubMed and Cochrane databases were systematically searched in May to July 2018 for systematic reviews published after 2013 and for randomised controlled trials (RCTs). A retrospective evaluation of 28 RCTs was performed. Rates of complete wound closure and time to healing were examined for 17 commonly available DSS. Healing rates after 12 weeks and time to complete closure in DFUs are heterogeneous among the 28 RCT. The best healing rates at 12 weeks were accomplished with dermal cellular substitutes (Epifix®, 100% and Amnioband®, 85%) and with dermal acellular substitutes (Allopatch®, 80% and Hyalograft®, 78.8%). Based on these studies, DSS used in conjunction with standard care appear to improve the healing rates of DFUs, as compared with standard care alone. Nonetheless, new studies with more homogeneous samples are needed to ascertain the role of ulcer size, duration, depth and/or type in the efficacy of DSS. Moreover, future RCTs should include patients with severe comorbidities, in order to be more representative of clinical reality.

Aim: We investigated the incidence of adverse drug reactions (ADRs) in patients treated with statins for cardiovascular (CV) risk among the United Arab Emirates (UAE) population. Methods: This is a retrospective cohort study conducted among statin users attending 2 tertiary care centres: Al Ain and Tawam hospitals in Al Ain city, UAE. We retrieved the clinical profile of all the patients taking statins from January 2011 to January 2015 using our electronic database (Cerner®). Results: Among 556 patients (418 men; 138 women) taking statins, 237 ADRs were reported (186 men; 51 women). The incidence of ADRs was 40.7%, and was more frequent among patients at “high CV disease (CVD) risk” and “moderate CVD risk” than other risk categories. High CVD risk (odds ratio, 1.67; 95% confidence interval [CI], 1.19-2.34), vitamin D deficiency 1.45 (95% CI, 0.89-2.38), type 2 diabetes 1.22 (95% CI, 0.84-1.77) and hypertension 1.13 (95% CI, 0.70-1.83) are some of the factors that were associated with statin ADRs. Conclusion: The incidence of ADRs among statin users was 42.6%, and frequent ADRs (49%) were noted in patients with high CVD risk. Early identification of these ADRs should improve patient adherence to life-saving statin treatment.