GLP-1 receptor agonists and reduction of cardiometabolic risk: Potential underlying mechanisms

Type 2 diabetes mellitus (T2DM) is a metabolic condition with an elevated impact on cardiovascular (CV) risk. The innovative therapeutic approaches for T2DM - incretin-based therapies (IBTs), including glucagon-like peptide 1 (GLP-1) receptor agonists, have become popular and more widely used in recent years. The available scientific data from clinical studies and clinical practice highlights their beyond glucose-lowering effects, which is achieved without any increase in hypoglycaemia. The former effects include reduction in body weight, lipids, blood pressure, inflammatory markers, oxidative stress, endothelial dysfunction, and subclinical atherosclerosis, thus reducing and potentially pr…

Endocrinology in the time of covid-19: A rapid evolution of knowledge and care

American singer-writer and visual artist Bob Dylan produced the song “The Times They Are a-Changin” in the 1960s, which became a rallying cry for the civil rights and anti-war movements in that decade [...]

Combined Dyslipidemia: Should the Focus be LDL Cholesterol or Atherogenic Dyslipidemia?

As the population becomes more obese and the prevalence of diabetes and the metabolic syndrome increases, low-density lipoprotein-cholesterol (LDL-C) may lose its value as a sole predictor for cardiovascular risk among lipids. Combined dyslipidemia is typically characterized by elevations in LDL-C and triglyceride levels, often accompanied by decreased high-density lipoproteincholesterol (HDL-C) concentrations and increased levels of small, dense LDL. This common disorder results from overproduction of hepatically synthesized apolipoprotein B in very low-density lipoproteins. In the last few years most of the international scientific guidelines as well as several expert panels have confirme…

Metabolic Syndrome: From Molecular Mechanisms to Novel Therapies

The metabolic syndrome (MetS) consists of a cluster of metabolic abnormalities including central obesity, insulin resistance, glucose intolerance, hypertension, and atherogenic dyslipidemia [...]

The Relationship between COVID-19 and Hypothalamic-Pituitary-Adrenal Axis: A Large Spectrum from Glucocorticoid Insufficiency to Excess-The CAPISCO International Expert Panel.

Coronavirus disease 2019 (COVID-19) is a highly heterogeneous disease regarding severity, vulnerability to infection due to comorbidities, and treatment approaches. The hypothalamic–pituitary–adrenal (HPA) axis has been identified as one of the most critical endocrine targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that might significantly impact outcomes after infection. Herein we review the rationale for glucocorticoid use in the setting of COVID-19 and emphasize the need to have a low index of suspicion for glucocorticoid-induced adrenal insufficiency, adjusting for the glucocorticoid formulation used, dose, treatment duration, and underlying health problems. We a…

Diabetes and COVID-19: What 2 Years of the Pandemic Has Taught Us

As the world enters its third year of the COVID-19 pandemic, individuals with diabetes have faced particular challenges from the virus. A deleterious bidirectional relationship exists between the two disorders, with heightened inflammatory, immunologic, and cellular mechanisms leading to a more severe illness and increased morbidity and mortality. Tight glucose control, though necessary, is hampered by physical restrictions and difficulty accessing health care. Novel glucose-lowering medications may provide unique benefits in this regard. It is imperative that multi-pronged efforts be prioritized in order to reduce adverse outcomes in patients with diabetes at risk for COVID-19.

Liraglutide Improved Cardiometabolic Parameters More in Obese than in Non-obese Patients with Type 2 Diabetes: A Real-World 18-Month Prospective Study.

Introduction The glucagon-like peptide-1 agonist (GLP1-RA) liraglutide is currently approved for the treatment of both obesity and type 2 diabetes (T2DM). We investigated whether the effect of this agent on cardiometabolic parameters in subjects with T2DM varied in relation to the concomitant presence of obesity. Methods One hundred thirty-five subjects (78 men and 57 women; age: 62 +/- 10 years) naive to incretin-based therapies were treated with low-dose liraglutide (1.2 mg/day) as an add-on to metformin for 18 months. Patients were divided into two subgroups based on their body-mass index (BMI): (a) obese (BMI >= 30) and (b) non-obese (BMI < 30). Clinical and laboratory analyses we…

Gestational diabetes and the metabolic syndrome: Can obesity and small, dense low density lipoproteins be key mediators of this association?

Gestational diabetes mellitus (GDM) represents a condition of glucose intolerance with first appearance or recognition at the time of a pregnancy, associated with an inadequate pancreatic response to the advanced insulin resistance of the later stages of pregnancy, and accompanied by enhancing β-cell mass and secretion of insulin. Women who had GDM exhibit a higher risk for later advent of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). Additionally, previous GDM has been proposed as independently correlated with higher risk for development of atherosclerosis in a healthy population, similar to the metabolic syndrome (MetS) and independently of the presence of established…

Inclisiran: a small interfering RNA strategy targeting PCSK9 to treat hypercholesterolemia

Introduction: Inclisiran is a novel posttranscriptional gene silencing therapy that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis by RNA interference and has a potent, dose-dependent, durable effect in lowering LDL-C, and therefore is an effective drug to treat dyslipidemia, reducing the risk for acute cardiovascular (CV) events. It is safe and well-tolerated. Areas covered: This paper aims to review the mechanism of action of inclisiran while evaluating its efficacy and safety in the treatment of dyslipidemia from data of the clinical trials in the ORION program. Expert opinion: Data from the clinical trials in the ORION program demonstrated efficacy and safety o…

The therapeutic modulation of atherogenic dyslipidemia and inflammatory markers in the metabolic syndrome: what is the clinical relevance?

The metabolic syndrome consists of a constellation of clinical and biochemical risk factors that cluster together and heighten the risk for atherogenesis, cardiovascular diseases, and diabetes. Established risk cardiovascular factors like hypertension, atherogenic dyslipidaemia, and glucose intolerance occur in the setting of insulin resistance and central adiposity, with genetic and environmental influences modulating the ultimate risk. Chronic insults to the endothelium take its toll in the form of silent as well as clinically evident cardiovascular events. The cellular and vascular accompaniments have shed some light into the underlying pathophysiology. Heightened, low-grade inflammatory…

Diabetes and the COVID-19 Pandemic: How Insights from Recent Experience Might Guide Future Management

Future perspectives of the pharmacological management of diabetic dyslipidemia

Introduction: Diabetic dyslipidemia is frequent among patients with type 2 diabetes mellitus (T2DM) and is characterized by an increase in triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and small-dense (atherogenic) particles, and by a decrease in low high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (Apo) A1 that are strongly related to insulin resistance. The increased flux of free fatty acids from adipose tissue to the liver aggravates hepatic insulin resistance and promotes all of aspects of the dyslipidemic state. Areas covered: Statins are the first-line agents for treatment while other lipid-lowering drugs (ezetimibe, fibrate and proprotein convertase…

Non-glycemic effects of pioglitazone and incretin-based therapies.

Atherosclerosis and cardiovascular events are highly prevalent and represent the major cause of mortality in patients with type 2 diabetes. Therefore, there is significant interest in the non-glycemic properties of anti-diabetic agents, particularly on those that are effective on cardiovascular risk factors. Thiazolidinediones and incretin-based therapies (IBTs) represent some of the most recent treatment options approved for the management of type 2 diabetes; these agents have shown important glycemic effects, as well as a number of non-glycemic effects. The latter include those on body weight, inflammation, hypertension and dyslipidemia, thus impacting the different components of the meta…

Genetic and Epigenetic Biomarkers for Diagnosis, Prognosis and Treatment of Metabolic Syndrome.

Background: Metabolic syndrome is a clinical condition that deserves special attention because it puts the individual at high cardiovascular risk, especially heart attack and stroke. Considering precision medicine, it would be advisable to evaluate the individual cardio-metabolic risk by estimating the coexistence of risk factors (abdominal obesity, low level of High-Density Lipoprotein Cholesterol, High Triglycerides, and small dense Low-Density Lipoproteins sub-classes, hypertension, and elevated fasting glycemia), which could engrave on metabolism increasing cardiovascular mortality. Objective: To identify genetic and epigenetic biomarkers may assist in the possibility of helping follow…

Impact of Glucose-Lowering Medications on Cardiometabolic Risk in Type 2 Diabetes

Type 2 Diabetes Mellitus (T2DM) is associated with a high risk of atherosclerotic cardiovascular (CV) disease. Contributing pathophysiologic factors include endothelial dysfunction caused by excessive production of reactive oxygen species (ROS), increased activity of nuclear factor kB (NFkB), altered macrophage polarization, and reduced synthesis of endothelial progenitor cells (EPC). Consequently, there can be a potentially rapid progression of the atherosclerotic disease with a higher propensity to unstable plaque, leading to increased cardiovascular mortality. Management is aimed at prevention, early diagnosis, and treatment of hyperglycemia and vascular complications. Innovative therape…

Glycemic Variability, Glycated Hemoglobin, and Cardiovascular Complications: Still a Dilemma in Clinical Practice

Liraglutide decreases carotid intima-media thickness in patients with type 2 diabetes: 8-month prospective pilot study.

Background Liraglutide, a long-acting glucagon-like peptide-1 (GLP-1) analog, has several non- glycemic properties, but its effect on carotid intima-media thickness (IMT), a recognized marker of subclinical atherosclerosis, is still unknown. Methods A prospective study of 8 months duration in 64 patients with type-2 diabetes and no prior history of coronary artery disease evaluated whether adding liraglutide to metformin affects carotid IMT, measured by color doppler ultrasound. Results After 8 months, fasting glucose decreased by 2.1 mmol/l and HbA1c by 1.9% (p < 0.01 for all). Liraglutide reduced total-cholesterol and triglycerides by 10%, and LDL-cholesterol by 19%, whereas HDL-cholester…

The efficacy and safety of dipeptidyl peptidase-4 inhibitors compared to other oral glucose-lowering medications in the treatment of type 2 diabetes

ABSTRACT Introduction The dipeptidyl peptidase-4 inhibitors (DPP-4is), which belong to the class of incretin-based medications, are recommended as second or third-line therapies in guidelines for the management of type 2 diabetes mellitus. They have a favorable drug tolerability and safety profile compared to other glucose-lowering agents. Objective This review discusses data concerning the use of DPP-4is and their cardiovascular profile, and gives an updated comparison with the other oral glucose-lowering medications with regards to safety and efficacy. Currently available original studies, abstracts, reviews articles, systematic reviews and meta-analyses were included in the review. Discu…

Reconnoitering the Role of Long-Noncoding RNAs in Hypertrophic Cardiomyopathy: A Descriptive Review

Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy. It is characterized by an unexplained non-dilated hypertrophy of the left ventricle with a conserved or elevated ejection fraction. It is a genetically heterogeneous disease largely caused by variants of genes encoding for cardiac sarcomere proteins, including MYH7, MYBPC3, ACTC1, TPM1, MYL2, MYL3, TNNI3, and TNNT23. Preclinical evidence indicates that the enhanced calcium sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric variations but may also result from secondary mutation-driven alterations. Long non-coding R…

Lipoproteins and Cardiovascular Disease: An Update on the Clinical Significance of Atherogenic Small, Dense LDL and New Therapeutical Options

Dyslipidemia is a potent risk factor for the genesis and progression of cardiovascular disease (CVD), and both the concentration and type of low-density lipoproteins (LDL) augment this association. The small, dense LDL (sdLDL) subfraction is the subtype which is most strongly predictive of atherosclerosis and cardiovascular events. In addition to the traditionally available lipid-lowering treatment options, certain novel therapies have been shown to favorably impact sdLDL, among them the antidiabetic class of agents known as glucagon-like peptide 1 receptor agonists (GLP1-RAs). These drugs seem to alter the pathophysiologic mechanisms responsible for the formation and accumulation of athero…

Cardiometabolic Alterations in the Interplay of COVID-19 and Diabetes: Current Knowledge and Future Avenues

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019 [COVID-19]) pandemic has raged for almost two years, with few signs of a sustained abatement or remission [...]

Promoting a Syndemic Approach for Cardiometabolic Disease Management During COVID-19: The CAPISCO International Expert Panel

Efforts in the fight against COVID-19 are achieving success in many parts of the world, although progress remains slow in other regions. We believe that a syndemic approach needs to be adopted to address this pandemic given the strong apparent interplay between COVID-19, its related complications, and the socio-structural environment. We have assembled an international, multidisciplinary group of researchers and clinical practitioners to promote a novel syndemic approach to COVID-19: the CArdiometabolic Panel of International experts on Syndemic COvid-19 (CAPISCO). This geographically diverse group aims to facilitate collaborative-networking and scientific exchanges between researchers and …

Novel therapeutical approaches to managing atherosclerotic risk

Atherosclerosis is a multifactorial vascular disease that leads to inflammation and stiffening of the arteries and decreases their elasticity due to the accumulation of calcium, small dense Low Density Lipoproteins (sdLDL), inflammatory cells, and fibrotic material. A review of studies pertaining to cardiometabolic risk factors, lipids alterations, hypolipidemic agents, nutraceuticals, hypoglycaemic drugs, atherosclerosis, endothelial dysfunction, and inflammation was performed. There are several therapeutic strategies including Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) inhibitors, inclisiran, bempedoic acid, Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RAs), and nutraceuticals t…

Novel molecular markers of cardiovascular disease risk in type 2 diabetes mellitus

Diabetes represents the leading risk factor for the development of cardiovascular disease (CVD). Chronic hyperglycemia and/or acute post-prandial changes in blood glucose determine an increase in reactive oxygen species (ROS), which play a fundamental role in endothelial dysfunction and in the nuclear transport of pro-atherogenic transcription factors that activate the "inflammasome". In addition, the glycemic alteration favors the formation and stabilization of atherosclerotic plaque through the mechanism of non-enzymatic glycation of different molecules, with the establishment of the so-called "advanced glycosylation end products" (AGE). Laboratory information provided by the level of bio…

Impact of Glucose-Lowering Medications on Cardiovascular and Metabolic Risk in Type 2 Diabetes

Type 2 Diabetes Mellitus (T2DM) is associated with a high risk of atherosclerotic cardiovascular (CV) disease. Among the well-known pathophysiologic factors, crucial roles are played by endothelial dysfunction (caused by oxidative stress and inflammation hyperglycemia-linked), increased activity of nuclear factor kB, altered macrophage polarization, and reduced synthesis of resident endothelial progenitor cells. As consequence, a potentially rapid progression of the atherosclerotic disease with a higher propensity to unstable plaque is arguable, finally leading to significantly increased cardiovascular mortality. Main managements are focused on both prevention and early diagnosis, by target…

Current and emerging drugs for the treatment of atherosclerosis: the evidence to date

Introduction: Atherosclerosis can be considered a chronic inflammatory process that stands out as a dominant cause of cardiovascular disease (CVD). Since blood lipids are the leading risk factor for atherosclerosis development, lowering low-density lipoprotein cholesterol (LDL-C) and other apolipoprotein B-containing lipoproteins reduces the risk of future cardiovascular events. However, there has been significant progress in developing lipid-lowering drugs for aggressive management of dyslipidemia, the rates of CVD events remain unacceptably high, so there is great need to identify novel therapeutic pathways targeting the atherosclerosis process.Areas covered: We discussed the current guid…

Significance of Neutrophil to Lymphocyte Ratio (NLR) and Platelet Lymphocyte Ratio (PLR) in Diabetic Foot Ulcer and Potential New Therapeutic Targets

Diabetic foot ulcer (DFU) is a well-known complication of diabetes and a significant burden on the national health systems. The neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio are inexpensive and easily accessible biomarkers that have proved to be useful in several inflammatory, infectious and cardiovascular diseases. We carried out a comprehensive review examining the association of NLR and PLR with the onset and progression of DFU. PLR and NLR were significantly increased in patients with DFU, compared with a control group of T2DM patients without DFU, and correlate well with DFU severity, evaluated by Wagner and IWGDF grading scales. In patients with diabetic foot infect…

Liraglutide Reduces Oxidative Stress And Restores Heme Oxygenase-1 and Ghrelin Levels in Patients with Type 2 Diabetes: A Prospective Pilot Study

Abstract Context: Liraglutide is a glucagon-like peptide-1 analog and glucose-lowering agent whose effects on cardiovascular risk markers have not been fully elucidated. Objective: We evaluated the effect of liraglutide on markers of oxidative stress, heme oxygenase-1 (HO-1), and plasma ghrelin levels in patients with type-2 diabetes mellitus (T2DM). Design and Setting: A prospective pilot study of 2 months' duration has been performed at the Unit of Diabetes and Cardiovascular Prevention at University of Palermo, Italy. Patients and Intervention(s): Twenty subjects with T2DM (10 men and 10 women; mean age: 57 ± 13 y) were treated with liraglutide sc (0.6 mg/d for 2 wk, followed by 1.2 mg/d…

Glucose lowering and anti-atherogenic effects of incretin-based therapies: GLP-1 analogues and DPP-4-inhibitors

Type 2 diabetes is a chronic, progressive disease with a multi-faceted pathophysiology. Beyond the known defects of insulin resistance and beta-cell insufficiency, derangement of incretin hormones normally produced from the gut wall in response to food intake play an important role. In recent years, the 'incretin-based' therapies (IBTs) have been developed to address hyperglycemia through either mimicking the action of the endogenous incretin glucagon-like polypeptide (GLP-1) (GLP-1 receptor agonists) or by inhibiting the activity of the enzyme that degrades GLP-1 (the dipeptyl peptidase-4 inhibitors).We reviewed available evidence on the glucose lowering and anti-atherogenic effects of IBT…

Adipokines and Lipoproteins: Modulation by Antihyperglycemic and Hypolipidemic Agents

Abstract Adipose tissue is an endocrine organ that secretes a number of hormones and metabolically active substances that impact energy metabolism and insulin sensitivity. These inflammatory markers are collectively referred to as adipocytokines, or adipokines. Adipose tissue's functional capacity and metabolic activity vary among individuals, thus partly explaining the incomplete overlap between obesity and the metabolic syndrome. The functional failure of adipose tissues results in changed energy delivery and impaired glucose consumption, triggering self-regulatory mechanisms to maintain homeostasis. Antihyperglycemic, hypolipidemic, antiobesity, and angiotensin II receptor blocker drugs …

Liraglutide Increases Serum Levels of MicroRNA-27b, -130a and -210 in Patients with Type 2 Diabetes Mellitus: A Novel Epigenetic Effect

Liraglutide has shown favourable effects on several cardiometabolic risk factors, beyond glucose control. MicroRNAs (miRNAs) regulate gene expression, resulting in post-transcriptional modifications of cell response and function. Specific miRNAs, including miRNA-27b, miRNA-130a, and miRNA-210, play a role in cardiometabolic disease. We aimed to determine the effect of liraglutide on the serum levels of miRNA-27b, miRNA-130a and miRNA-210. Twenty-five subjects with type-2 diabetes mellitus (T2DM), na&iuml

The Evolving Role of Fetuin-A in Nonalcoholic Fatty Liver Disease: An Overview from Liver to the Heart

Nonalcoholic fatty liver disease (NAFLD) is strongly associated to the features of metabolic syndrome which can progress to cirrhosis, liver failure and hepatocellular carcinoma. However, the most common cause of mortality in people with NAFLD is not liver-related but stems from atherosclerotic cardiovascular disease (CVD). The prevalence of NAFLD is on the rise, mainly as a consequence of its close association with two major worldwide epidemics, obesity and type 2 diabetes (T2D). The exact pathogenesis of NAFLD and especially the mechanisms leading to disease progression and CVD have not been completely elucidated. Human fetuin-A (alpha-2-Heremans Schmid glycoprotein), a glycoprotein produ…

A Review of the Cardiovascular and Anti-Atherogenic Effects of Ghrelin

Ghrelin is a peptide hormone produced mainly in the stomach that has widespread tissue distribution and diverse hormonal, metabolic and cardiovascular activities. The circulating ghrelin concentration increases during fasting and decreases after food intake. Ghrelin secretion may thus be initiated by food intake and is possibly controlled by nutritional factors. Lean subjects have increased levels of circulating ghrelin compared with obese subjects. Recent reports show that low plasma ghrelin is associated with elevated fasting insulin levels, insulin resistance and type 2 diabetes mellitus. Factors involved in the regulation of ghrelin secretion have not yet been defined; however, it is as…

Post-COVID syndrome, inflammation, and diabetes

The raging COVID-19 pandemic is in its third year of global impact. The SARS CoV 2 virus has a high rate of spread, protean manifestations, and a high morbidity and mortality in individuals with predisposing risk factors. The pathophysiologic mechanisms involve a heightened systemic inflammatory state, cardiometabolic derangements, and varying degrees of glucose intolerance. The latter can be evident as significant hyperglycemia leading to new -onset diabetes or worsening of preexisting disease. Unfortunately, the clinical course beyond the acute phase of the illness may persist in the form of a variety of symptoms that together form the so-called "Long COVID" or "Post-COVID Syndrome". It i…

Uric Acid Metabolism in Pre-hypertension and the Metabolic Syndrome

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). W…

Incretins, Pregnancy, and Gestational Diabetes

The number of pregnant women affected by gestational diabetes mellitus (GDM) is increasing among Caucasians, and East Asians. GDM also increases the risk for later advent of type 2 diabetes mellitus (T2DM), obesity, and cardiovascular disease in both women and their offspring. The underlying mechanism of GDM is not fully elucidated. Incretins such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), have been suggested to have a role in maternal metabolism and weight as well as fetal growth. These hormones might be implicated in mechanisms that compensate for the increment in glycemia and insulin resistance seen during pregnancy, while other factors, such a…

The effects of liraglutide on glucose, inflammatory markers and lipoprotein metabolism: current knowledge and future perspectives.

Glucagon-like peptide-1 is an incretin secreted in response to nutrient ingestion. Derangements in the incretin system may contribute to the onset and progression of hyperglycemia in Type 2 diabetes. Liraglutide is a long-acting human glucagon-like peptide-1-receptor agonist suitable for once-daily administration. Blood glucose- and weightreducing effects, improvements in pancreatic b-cell function and a low risk of hypoglycemic events have been demonstrated with this agent. There is a trend towards improvement in the proinflammatory milieu. Liraglutide also appears to have beneficial effects on plasma lipids and lipoproteins in the form of a reduction in total cholesterol, triglycerides an…

Safety and benefit of incretin-based therapies in patients with type 2 diabetes: learnings and reflections

Liraglutide Reduces Carotid Intima-Media Thickness by Reducing Small Dense Low-Density Lipoproteins in a Real-World Setting of Patients with Type 2 Diabetes: A Novel Anti-Atherogenic Effect

Introduction: Liraglutide has several non-glycemic effects, including those on plasma lipids and lipoproteins, contributing to its cardiovascular benefit; however, the exact underlying mechanisms remain unclear. We investigated a novel anti-atherogenic effect of liraglutide in a real-world prospective study on patients with type 2 diabetes (T2DM). Methods: Sixty-two patients with T2DM (31 men, 31 women; mean age ± standard deviation 61 ± 9 years) naïve to incretin-based therapies were treated with liraglutide (1.2 mg/day) as add-on therapy to metformin (1500–3000 mg/day) for 4 months. Laboratory analyses included the assessment of lipoprotein subclass profile by gel electrophoresis (Lipopri…

Incretin-Based Therapies Role in COVID-19 Era: Evolving Insights

The current coronavirus disease 2019 (COVID-19) pandemic has led the scientific community to breach new frontiers in the understanding of human physiology and disease pathogenesis. It has been hypothesized that the human dipeptidyl peptidase 4 (DPP4) enzyme receptor may be a functional target for the spike proteins of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Since DPP4-inhibitors are currently used for the treatment of patients with type-2 diabetes (T2DM), there is currently high interest in the possibility that these agents, or incretin-based therapies (IBTs) in general, may be of benefit against the new coronavirus infection. Diabetes is associated with increased COV…

Cardiovascular outcomes trials with incretin-based medications: a critical review of data available on GLP-1 receptor agonists and DPP-4 inhibitors

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors are so called “incretin-based therapies” (IBTs) that represent innovative therapeutic approaches and are commonly used in clinical practice for the treatment of type 2 diabetes mellitus (T2DM). The cardiovascular outcome trials (CVOTs) have provided useful information that has helped to shape changes in clinical practice guidelines for the management of T2DM. At the same time, the mechanisms that may explain the nonglycemic and cardiovascular (CV) benefits of these medications are still being explored. A summary of the main findings from CVOTs performed to-date with particular emphasis on vari…

Oxidative stress and small, dense low-density lipoproteins: current and future perspectives

Small, dense low-density lipoproteins (LDLs) are more susceptible to oxidation than their larger, more buoyant counterparts and therefore the biological modification of these LDL particles may, in part, be responsible for their atherogenic properties. Kotani et al. found that at multiple regression analysis there was an independent and significant inverse correlation between the mean LDL particle size and the oxidative stress status; notably, the authors adjusted not only for the traditional cardiovascular risk factors, but also for drug treatments. Higher levels of small, dense LDL concentrations significantly contribute to atherosclerosis, and lipoprotein size and subfractions may refine …

Experimental and Emerging Free Fatty Acid Receptor Agonists for the Treatment of Type 2 Diabetes

The current management of Type 2 Diabetes Mellitus (T2DM) includes incretin-based treatments able to enhance insulin secretion and peripheral insulin sensitivity as well as improve body mass, inflammation, plasma lipids, blood pressure, and cardiovascular outcomes. Dietary Free Fatty Acids (FFA) regulate metabolic and anti-inflammatory processes through their action on incretins. Selective synthetic ligands for FFA1-4 receptors have been developed as potential treatments for T2DM. To comprehensively review the available evidence for the potential role of FFA receptor agonists in the treatment of T2DM, we performed an electronic database search assessing the association between FFAs, T2DM, i…

Use of Novel Antidiabetic Agents in Patients with Type 2 Diabetes and COVID-19: A Critical Review

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). The latter is a pandemic that has the potential of developing into a severe illness manifesting as systemic inflammatory response syndrome, acute respiratory distress syndrome, multi-organ involvement and shock. In addition, advanced age and male sex and certain underlying health conditions, like type 2 diabetes mellitus (T2DM), predispose to a higher risk of greater COVID-19 severity and mortality. This calls for an urgent identification of antidiabetic agents associated with more favourable COVID-19 outcomes among patients with T2DM, as well as recognition of their potential underlying…

Liraglutide improves carotid intima-media thickness in patients with type 2 diabetes and non-alcoholic fatty liver disease: An 8-month prospective pilot study

Objective: To explore the effects of the glucagon-like peptide-1 receptor analogue liraglutide on subclinical atherosclerosis in diabetic subjects with non-alcoholic fatty liver disease (NAFLD).Research design and methods: In this 8-month prospective study, 29 subjects with type 2 diabetes (T2DM) and NAFLD (16 men and 13 women, mean age: 61 ± 10 years) were matched for age and gender with 29 subjects with T2DM without NAFLD (16 men and 13 women, mean age: 61 ± 8 years). Liraglutide 0.6 mg/day for 2 weeks, followed by 1.2 mg/day, was given in addition to metformin.Main outcome measures: Anthropometric variables, glucometabolic parameters and carotid intima-media thickness (IMT) using B-mode …

Liraglutide improves metabolic parameters and carotid intima-media thickness in diabetic patients with the metabolic syndrome: an 18-month prospective study

Abstract Background Liraglutide, a GLP-1 analogue, exerts several beneficial non-glycemic effects in patients with type-2 diabetes (T2DM), such as those on body weight, blood pressure, plasma lipids and inflammation markers. However, the effects of liraglutide on cardiovascular (CV) risk markers in subjects with the metabolic syndrome (MetS) are still largely unknown. We herein explored its effects on various cardio-metabolic risk markers of the MetS in subjects with T2DM. Methods We performed an 18-month prospective, real-world study. All subjects had T2DM and the MetS based on the AHA/NHLBI criteria. Subjects with a history of a major CV event were excluded. One hundred-twenty-one subject…

Incretin-Based Therapies, Glucometabolic Health and Endovascular Inflammation

Incretin peptides are a group of gastrointestinal hormones that play a prominent role in the regulation of glucose metabolism. Incretin-based therapies (IBTs) have recently emerged as an important treatment option for patients with type 2 diabetes mellitus (T2DM). These pharmaceutical agents may be specially well suited for patients who are overweight or obese with primarily post-meal glucose peaks, and in whom traditional first-line oral agents have failed to maintain adequate glycemic control. There are 2 classes of IBTs: the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon-like peptide 1 (GLP-1) receptor agonists. The ultimate effect of both types of agents is to augment GLP-1 …

Pasta Supplemented with Opuntia ficus-indica Extract Improves Metabolic Parameters and Reduces Atherogenic Small Dense Low-Density Lipoproteins in Patients with Risk Factors for the Metabolic Syndrome: A Four-Week Intervention Study

Food supplementation with Opuntia ficus-indica (OFI) has been associated with a significant reduction in total cholesterol, body fat, hyperglycemia and blood pressure. Since OFI may also have antioxidant and anti-atherogenic properties, we hypothesized that its supplementation might reduce atherogenic lipoproteins, including small, dense low-density lipoproteins (sdLDL). Forty-nine patients (13 men and 36 women, mean age: 56 &plusmn

Exenatide once-weekly improves metabolic parameters, endothelial dysfunction and carotid intima-media thickness in patients with type-2 diabetes: An 8-month prospective study.

AIM: To evaluate the effect of exenatide long acting release (LAR) on carotid intima-media thickness (IMT) and endothelial function in patients with type 2 diabetes mellitus. METHODS: Sixty subjects with type 2 diabetes mellitus were treated with exenatide LAR as add-on to stable doses of metformin for 8 months in an open label study. Anthropometric variables, lipid profile and glycemic parameters were assessed by routine analysis. Carotid IMT by Doppler ultrasound and endothelial function by flow-mediated dilation of the brachial artery were also assessed. RESULTS: Exenatide significantly improved fasting glycaemia (from 8.8 ± 2.8 to 7.3 ± 2.2 mmol/L, p &lt; 0.0001), HbA1c (from 8.0 ± 0.4 …

Molecular and pro-inflammatory aspects of COVID-19: The impact on cardiometabolic health

Obesity, type 2 diabetes (T2DM), hypertension (HTN), and Cardiovascular Disease (CVD) often cluster together as "Cardiometabolic Disease" (CMD). Just under 50% of patients with CMD increased the risk of morbidity and mortality right from the beginning of the COVID-19 pandemic as it has been reported in most countries affected by the SARS-CoV2 virus. One of the pathophysiological hallmarks of COVID-19 is the overactivation of the immune system with a prominent IL-6 response, resulting in severe and systemic damage involving also cytokines such as IL2, IL4, IL8, IL10, and interferon-gamma were considered strong predictors of COVID-19 severity. Thus, in this mini-review, we try to describe the…

The role of GLP-1 receptor agonists during COVID-19 pandemia: a hypothetical molecular mechanism

ABSTRACT Introduction A number of anti-diabetic treatments have been favored during the continuing spread of the current SARS-CoV-2 pandemic. Glucagon like peptide-1 receptor agonists (GLP1-RAs) are a group of antidiabetic drugs, the glucose reducing effect of which is founded on augmenting glucose-dependent insulin secretion with concomitant reduction of glucagon secretion and delayed gastric emptying. Apart from their glucose lowering effects, GLP1-RAs also exert a plethora of pleiotropic activities in the form of anti-inflammatory, anti-thrombotic and anti-obesogenic properties, with beneficial cardiovascular and renal impact. All these make this class of drugs a preferred option for man…

The role of elevated growth hormone on the increased atherosclerosis in patients with acromegaly.

Daily Use of Extra Virgin Olive Oil with High Oleocanthal Concentration Reduced Body Weight, Waist Circumference, Alanine Transaminase, Inflammatory Cytokines and Hepatic Steatosis in Subjects with the Metabolic Syndrome: A 2-Month Intervention Study

Extra virgin olive oil (EVOO) intake is associated with reduced cardiovascular risk, and its phenolic compound oleocanthal (OC) has anti-oxidant and anti-inflammatory properties. The cardiometabolic effects of EVOO with a high OC concentration have not been fully elucidated. We administered EVOO with a high OC concentration daily to 23 subjects with the metabolic syndrome (MetS) and hepatic steatosis (15 men and 8 women, age: 60 &plusmn

Cardiovascular effects of glucagon-like peptide-1 receptor agonist therapies in patients with type 1 diabetes

Diabetes and COVID-19: A Tale of 2 Pandemics.

Abstract: Epidemiological studies indicate that diabetes is the second most common comorbidity in COVID-19 (coronavirus disease 2019). Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, exerts direct cardioprotective and nephroprotective effects. DARE-19 (Dapagliflozin in Respiratory Failure in Patients With COVID-19), an ongoing clinical trial, is designed to investigate the impact of dapagliflozin on COVID-19 progression. This article discusses the potential favorable impact of dapagliflozin on COVID-19 and its complications.

Liraglutide Reduces Carotid Intima-Media Thickness by Reducing Small Dense Low-Density Lipoproteins in a Real-World Setting of Patients With Type 2 Diabetes: A Novel Anti-Atherogenic Effect

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