Mitochondrial Fraction of Circulating Cell-Free DNA as an Indicator of Human Pathology.

Circulating cell-free DNA (ccfDNA) of mitochondrial origin (ccf-mtDNA) consists of a minor fraction of total ccfDNA in blood or in other biological fluids. Aberrant levels of ccf-mtDNA have been observed in many pathologies. Here, we introduce a simple and effective standardized Taqman probe-based dual-qPCR assay for the simultaneous detection and relative quantification of nuclear and mitochondrial fragments of ccfDNA. Three pathologies of major burden, one malignancy (Breast Cancer, BrCa), one inflammatory (Osteoarthritis, OA) and one metabolic (Type 2 Diabetes, T2D), were studied. Higher levels of ccf-mtDNA were detected both in BrCa and T2D in relation to health, but not in OA. In BrCa, hormonal receptor status was associated with ccf-mtDNA levels. Machine learning analysis of ccf-mtDNA datasets was used to build biosignatures of clinical relevance. (A) a three-feature biosignature discriminating between health and BrCa (AUC: 0.887) and a five-feature biosignature for predicting the overall survival of BrCa patients (Concordance Index: 0.756). (B) a five-feature biosignature stratifying among T2D, prediabetes and health (AUC: 0.772); a five-feature biosignature discriminating between T2D and health (AUC: 0.797); and a four-feature biosignature identifying prediabetes from health (AUC: 0.795). (C) a biosignature including total plasma ccfDNA with very high performance in discriminating OA from health (AUC: 0.934). Aberrant ccf-mtDNA levels could have diagnostic/prognostic potential in BrCa and Diabetes, while the developed multiparameter biosignatures can add value to their clinical management.

Neuropathy in prediabetes.

Diabetic neuropathies are the most frequent complications of diabetes, contributing to high morbidity, excess mortality, reduced quality of life, and increased healthcare costs. Prediabetes is characterised by glucose levels within an intermediate range above normoglycaemia yet below the diagnostic threshold for diabetes. In 2021, 10.6% and 6.2% of adults worldwide were estimated to have impaired glucose tolerance and impaired fasting glucose, respectively, the majority of whom are unaware of having prediabetes. Evidence has accumulated suggesting that prediabetes is a predictor of cardiovascular disease (CVD) and increased mortality. The past 2 decades have witnessed an extensive debate, particularly among diabetologists and neurologists, as to whether prediabetes is associated with peripheral neuropathy. In this review, we elaborate on the current evidence, particularly from population-based studies supporting an increased risk of distal sensorimotor polyneuropathy (DSPN) and cardiovascular autonomic neuropathy (CAN) in people with prediabetes. Moreover, we discuss whether lifestyle interventions showing efficacy in preventing or delaying the transition from prediabetes to diabetes in persons with prediabetes may also exert favourable effects on the development and progression of DSPN and CAN. This review should help in raising the awareness of and translating the current knowledge on neuropathies in people with prediabetes into clinical practice and public health. The current recommendation that adults who are overweight or obese should be screened for prediabetes and referred to or offered preventive interventions should ultimately culminate in preventing not only CVD but also prediabetic neuropathy.

Myasthenia gravis genome-wide association study implicates AGRN as a risk locus.

BACKGROUND: Myasthenia gravis (MG) is a rare autoimmune disorder affecting the neuromuscular junction (NMJ). Here, we investigate the genetic architecture of MG via a genome-wide association study (GWAS) of the largest MG data set analysed to date. METHODS: We performed GWAS meta-analysis integrating three different data sets (total of 1401 cases and 3508 controls). We carried out human leucocyte antigen (HLA) fine-mapping, gene-based and tissue enrichment analyses and investigated genetic correlation with 13 other autoimmune disorders as well as pleiotropy across MG and correlated disorders. RESULTS: We confirmed the previously reported MG association with TNFRSF11A (rs4369774; p=1.09×10-13, OR=1.4). Furthermore, gene-based analysis revealed AGRN as a novel MG susceptibility gene. HLA fine-mapping pointed to two independent MG loci: HLA-DRB1 and HLA-B. MG onset-specific analysis reveals differences in the genetic architecture of early-onset MG (EOMG) versus late-onset MG (LOMG). Furthermore, we find MG to be genetically correlated with type 1 diabetes (T1D), rheumatoid arthritis (RA), late-onset vitiligo and autoimmune thyroid disease (ATD). Cross-disorder meta-analysis reveals multiple risk loci that appear pleiotropic across MG and correlated disorders. DISCUSSION: Our gene-based analysis identifies AGRN as a novel MG susceptibility gene, implicating for the first time a locus encoding a protein (agrin) that is directly relevant to NMJ activation. Mutations in AGRN have been found to underlie congenital myasthenic syndrome. Our results are also consistent with previous studies highlighting the role of HLA and TNFRSF11A in MG aetiology and the different risk genes in EOMG versus LOMG. Finally, we uncover the genetic correlation of MG with T1D, RA, ATD and late-onset vitiligo, pointing to shared underlying genetic mechanisms.

New strategies to improve clinical outcomes for diabetic kidney disease.

BACKGROUND: Diabetic kidney disease (DKD), the most common cause of kidney failure and end-stage kidney disease worldwide, will develop in almost half of all people with type 2 diabetes. With the incidence of type 2 diabetes continuing to increase, early detection and management of DKD is of great clinical importance. MAIN BODY: This review provides a comprehensive clinical update for DKD in people with type 2 diabetes, with a special focus on new treatment modalities. The traditional strategies for prevention and treatment of DKD, i.e., glycemic control and blood pressure management, have only modest effects on minimizing glomerular filtration rate decline or progression to end-stage kidney disease. While cardiovascular outcome trials of SGLT-2i show a positive effect of SGLT-2i on several kidney disease-related endpoints, the effect of GLP-1 RA on kidney-disease endpoints other than reduced albuminuria remain to be established. Non-steroidal mineralocorticoid receptor antagonists also evoke cardiovascular and kidney protective effects. CONCLUSION: With these new agents and the promise of additional agents under clinical development, clinicians will be more able to personalize treatment of DKD in patients with type 2 diabetes.

Association of serum levels of osteopontin and osteoprotegerin with adverse outcomes after endovascular revascularisation in peripheral artery disease.

BACKGROUND: Osteoprotegerin (OPG) and osteopontin (OPN) are vascular calcification inhibitors with a known role in the atherosclerotic and inflammatory process. We investigated their relationship with adverse outcomes (restenosis/adverse cardiovascular events) after endovascular revascularisation of patients with peripheral arterial disease (PAD). METHODS: 203 consecutive patients were enrolled in the PAD group (PADG) and 78 age and sex-matched subjects with less than two cardiovascular risk factors served as control group (COG). PADG underwent standard medical assessment at baseline and 12 months after the procedure. During follow up major adverse cardiovascular events (MACEs) including arterial restenosis with need for reintervention were documented and the PADG was divided accordingly into two subgroups. RESULTS: During 12-month follow-up, 82 MACE were recorded (MACE subgroup). The rest of 124 PAD patients remained free of MACE (non-MACE subgroup). At baseline, OPG (9.89 ± 2.85 ng/ml vs 3.47 ± 1.95 ng/ml, p < 0.001) and OPN (79.99 ± 38.29 ng/ml vs 35.21 ± 14.84 ng/ml, p < 0.001) levels were significantly higher in PADG compared to COG, as well as in MACE subgroup compared to non-MACE subgroup (13.29 ± 3.23 ng/ml vs 10.86 ± 3 ng/ml and 96.45 ± 40.12 ng/ml vs 78.1 ± 38.29 ng/ml, respectively). An independent association of PAD with OPG and OPN was found in the whole patient cohort. Although OPG and OPN were significantly related to MACE incidence in the univariate analysis, multiple logistic regression analysis failed to detect any independent predictor of MACE within the PADG. CONCLUSION: Baseline high OPG and OPN levels were independently associated with PAD presence. Even higher levels of those biomarkers were detected among PAD patients with MACE, however, their prognostic role should be further clarified.

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 also address several additional mechanisms that may cause HPA axis dysfunction, including critical illness-related corticosteroid insufficiency, the direct cytopathic impacts of SARS-CoV-2 infection on the adrenals, pituitary, and hypothalamus, immune-mediated inflammations, small vessel vasculitis, microthrombotic events, the resistance of cortisol receptors, and impaired post-receptor signaling, as well as the dissociation of ACTH and cortisol regulation. We also discuss the increased risk of infection and more severe illness in COVID-19 patients with pre-existing disorders of the HPA axis, from insufficiency to excess. These insights into the complex regulation of the HPA axis reveal how well the body performs in its adaptive survival mechanism during a severe infection, such as SARS-CoV-2, and how many parameters might disbalance the outcomes of this adaptation.

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, inflammation, and incretins. Evidence indicates that FFA1-4 agonism increases insulin sensitivity, induces body mass loss, reduces inflammation, and has beneficial metabolic effects. There is a strong inter-relationship between FFAs and incretins. FFA receptor agonism represents a potential target for the treatment of T2DM and may provide an avenue for the management of cardiometabolic risk in susceptible individuals. Further research promises to shed more light on this emerging topic.

An Update on the Current and Emerging Use of Thiazolidinediones for Type 2 Diabetes.

Guidelines have increasingly stressed the concept that adequate glycemic control is required to prevent or decrease the macro- and microvascular complications of type 2 diabetes mellitus (T2DM). PPAR-gamma agonists ("glitazones") are no longer prioritized due to their effects on heart failure. However, the association between these drugs and innovative therapies could be a valuable tool to attenuate the risk factors of the metabolic syndrome. Glitazones are used for the treatment of diabetes and associated comorbidities. There is substantial scientific evidence demonstrating the effect of glitazones at a cardiometabolic level, as well as on hematological and neurological pathologies that point to their usefulness. The use of glitazones has always been controversial both for the type of patients who must take these drugs and for the side effects associated with them. Unfortunately, the recent guidelines do not include them among the preferred drugs for the treatment of hyperglycemia and rosiglitazone is out of the market in many countries due to an adverse cardiovascular risk profile. Even though real-life studies have proven otherwise, and their pleiotropic effects have been highlighted, they have been unable to achieve primacy in the choice of antihyperglycemic drugs. It would be appropriate to demonstrate the usefulness of pioglitazone and its therapeutic benefit with further cardiovascular safety studies.

The prognostic role of RBP-4 and adiponectin in patients with peripheral arterial disease undergoing lower limb endovascular revascularization.

BACKGROUND: RBP4 is an adipokine with an established role in atherosclerosis, while adiponectin has unique anti-inflammatory properties. We investigated the association of RBP4 and adiponectin with the presence of symptomatic peripheral artery disease (PAD) and their possible prognostic role in major adverse cardiovascular events (MACE). METHODS: We enrolled 168 consecutive patients with symptomatic, established PAD, requiring revascularization by endovascular means of any or both of their lower limbs. 88 age- and sex-matched subjects with less than 2 classical cardiovascular risk factors served as controls. Clinical parameters, glycemic and lipid profile, RBP4 and adiponectin levels were assayed. The occurrence of MACE was recorded during the 6-month follow-up and patients were assigned to MACE and non-MACE subgroups. RESULTS: The presence of symptomatic PAD was significantly correlated with age, diabetes, hsCRP, RBP4 and low adiponectin levels (p < 0.05). After adjustment for age, RBP4 (ß = 0.498, p < 0.001), and adiponectin (ß = -0.288, p < 0.001) levels remained as independent predictors of PAD presence in the whole study cohort. At baseline, MACE subgroup appeared with higher RBP-4 and hsCRP serum levels than non-MACE subgroup (p < 0.001), but no differences were detected for adiponectin (p = 0.758). Serum RBP4 levels remained independent predictor of MACE (ß = 0.455, p < 0.001) after adjustment for traditional cardiovascular risk factors. CONCLUSIONS: High RBP4 and low adiponectin serum levels are independently associated with PAD presence. In addition, RBP4 is an independent predictor of MACE incidence in symptomatic PAD patients.

The new dual gastric inhibitory peptide/glucagon-like peptide 1 agonist tirzepatide in type 2 diabetes: Is the future bright?

Tirzepatide is a dual gastric inhibitory peptide/glucagon-like peptide 1 (GIP/GLP-1) receptor agonist formulated as a synthetic linear peptide, based on the native GIP sequence. It has a prolonged half-life of 5 days, which enables once-weekly dosing. Studies have hitherto demonstrated its superiority in achieving optimal glycaemic control and body weight management, as compared with various agents used in the treatment of type 2 diabetes mellitus (T2DM), including GLP-1 receptor agonists. Thus, it is expected to enrich our therapeutic armamentarium in T2DM. However, further experience, notably longer follow-up data and information on cardiovascular effects, is still needed.

Skin AGEs and diabetic neuropathy.

Advanced glycation end-products (AGEs) are heterogeneous molecules produced by the non-enzymatic glycation of proteins, lipids, or nucleic acids during hyperglycaemia. Accumulation of AGEs in the peripheral nerves has recently been proposed as an additional risk factor for the development of diabetic neuropathy (DN). The gold standard for measurement of tissue-bound AGEs is tissue biopsy. However, their assessment with the newer, fast and simple method of skin autofluorescence (sAF) has recently gained special interest by virtue of its non-invasive, highly reproducible nature and its acceptable correlation with the reference method of skin biopsy. Accumulation of tissue AGEs evaluated by sAF has been shown to independently correlate with DN. Importantly, increasing evidence underscores their potential value as early biomarkers of the latter. Further important associations include diabetic nephropathy, diabetic retinopathy and cardiovascular autonomic neuropathy. However, the value of the implementation of screening with skin AGEs for DN remains unclear. The aim of the present review is to critically summarise current evidence on the association between skin AGEs and diabetic microvascular complications, with a particular emphasis on diabetic neuropathy, and to note the most important limitations of existing knowledge. Longer follow-up studies are also highly anticipated to clarify its role and provide data on patient selection and cost-effectiveness.

Patients' and Clinicians' Preferences on Outcomes and Medication Attributes for Type 2 Diabetes: a Mixed-Methods Study.

BACKGROUND: Patients' views on the relative importance of treatment outcomes and medication attributes for type 2 diabetes may differ from clinicians' perceptions. OBJECTIVE: To assess which treatment outcomes and medication attributes are considered important by patients and clinicians for therapeutic decisions in type 2 diabetes. DESIGN: Exploratory, sequential, mixed-methods design comprising a qualitative (focus groups) and a quantitative (survey) phase. PARTICIPANTS: Patients in the focus groups (n = 33) and the survey study (n = 656) were recruited from 4 and 9 diabetes clinics across Greece, respectively. Clinicians in the survey study (n = 363) were identified from Greek registries for healthcare professionals. MEASUREMENTS: We conducted 6 focus groups to obtain patients' views regarding the impact of type 2 diabetes on their lives. Identified themes informed the development of a survey, which aimed to assess which outcomes and medication attributes are considered most important by patients and clinicians. We calculated odds ratios to compare patients' and clinicians' responses. RESULTS: The focus groups identified 6 main themes and 15 subthemes. In the survey study, patients were more likely than clinicians to rate prevention of amputation (odds ratio, 9.32; 95% CI, 6.51 to 13.35), diabetic eye disease (6.16; 4.63 to 8.21), sexual dysfunction, and stroke as important, while clinicians were more likely than patients to choose risk for hypoglycemia, and reduction of all-cause mortality, HbA1c, and body weight. Compared with clinicians, patients were less concerned about drug cost (0.16; 0.11 to 0.23), but more concerned about route of administration and need for less frequent glucose self-monitoring. CONCLUSIONS: Patients and clinicians differ in the perception of the relative importance of treatment outcomes and drug characteristics. Individual patient preferences should be explored and implemented in the therapeutic decision-making for type 2 diabetes.

Positioning sulphonylureas in a modern treatment algorithm for patients with type 2 diabetes: Expert opinion from a European consensus panel.

The large number of pharmacological agents available to treat type 2 diabetes (T2D) makes choosing the optimal drug for any given patient a complex task. Because newer agents offer several advantages, whether and when sulphonylureas (SUs) should still be used to treat T2D is controversial. Published treatment guidelines and recommendations should govern the general approach to diabetes management. However, expert opinions can aid in better understanding local practices and in formulating individual choices. The current consensus paper aims to provide additional guidance on the use of SUs in T2D. We summarize current local treatment guidelines in European countries, showing that SUs are still widely proposed as second-line treatment after metformin and are often ranked at the same level as newer glucose-lowering medications. Strong evidence now shows that sodium-glucose co-transporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with low hypoglycaemia risk, promote weight loss, and exert a positive impact on vascular, cardiac and renal endpoints. Thus, using SUs in place of SGLT-2is and GLP-1RAs may deprive patients of key advantages and potentially important cardiorenal benefits. In subjects with ascertained cardiovascular disease or at very high cardiovascular risk, SGLT-2is and/or GLP-1RAs should be used as part of diabetes management, in the absence of contraindications. Routine utilization of SUs as second-line agents continues to be acceptable in resource-constrained settings.

Current Pharmacological Treatment of Painful Diabetic Neuropathy: A Narrative Review.

Background and Objectives: Distal symmetrical polyneuropathy (DSPN) is one of the most common chronic complications of diabetes mellitus. Although it is usually characterized by progressive sensory loss, some patients may develop chronic pain. Assessment of DSPN is not difficult, but the biggest challenge is making the correct diagnosis and choosing the right treatment. The treatment of DSPN has three primary objectives: glycemic control, pathogenic mechanisms, and pain management. The aim of this brief narrative review is to summarize the current pharmacological treatment of painful DSPN. It also summarizes knowledge on pathogenesis-oriented therapy, which is generally overlooked in many publications and guidelines. Materials and Methods: The present review reports the relevant information available on DSPN treatment. The search was performed on PubMed, Cochrane, Semantic Scholar, Medline, Scopus, and Cochrane Library databases, including among others the terms "distal symmetrical polyneuropathy", "neuropathic pain treatment", "diabetic neuropathy", "diabetes complications", "glycaemic control", "antidepressants", "opioids", and "anticonvulsants". Results: First-line drugs include antidepressants (selective serotonin reuptake inhibitors and tricyclic antidepressants) and pregabalin. Second- and third-line drugs include opioids and topical analgesics. While potentially effective in the treatment of neuropathic pain, opioids are not considered to be the first choice because of adverse reactions and addiction concerns. Conclusions: DSPN is a common complication in patients with diabetes, and severely affects the quality of life of these patients. Although multiple therapies are available, the guidelines and recommendations regarding the treatment of diabetic neuropathy have failed to offer a unitary consensus, which often hinders the therapeutic options in clinical practice.

Mean platelet volume and coronary artery disease.

PURPOSE OF REVIEW: To critically review the literature describing links between mean platelet volume (MPV) and cardiovascular disease (CVD). We will focus on coronary artery disease (CAD). The MPV is measured routinely as part of a routine blood count. RECENT FINDINGS: There is accumulating evidence showing that the MPV may predict CVD, as well as outcomes in patients with CAD. There is also evidence linking MPV and comorbidities (e.g. diabetes mellitus and impaired glycaemic control) that are expected in patients with CAD. The effect on MPV of drugs commonly used to treat CAD has not been clarified, but there is some evidence that they may exert a beneficial effect on the MPV. More specifically, the MPV may predict the effect of antiplatelet drugs (e.g. clopidogrel). There is also evidence relating MPV to stroke, atrial fibrillation, coronary artery ectasia and periprocedural outcomes after percutaneous coronary intervention (PCI). SUMMARY: Measuring the MPV may prove useful in CVD risk assessment in patients with established CAD or at risk of developing CAD. Overall, there is evidence pointing to the role of MPV as a contributor rather than simple marker of CVD.

Reduced Serum Vitamin D Levels Are Associated with Insulin Resistance in Patients with Obstructive Sleep Apnea Syndrome.

Background and objectives: Obstructive sleep apnea syndrome (OSAS) is associated with cardiovascular and metabolic risk factors, such as insulin resistance. Furthermore, OSAS has been associated with decreased levels of vitamin D (Vit D). The aim of the study was to assess the association between Vit D levels (expressed as 25(OH)D serum levels) and insulin resistance in patients with OSAS. Materials and Methods: Serum 25(OH)D levels were measured in consecutive subjects who had undergone polysomnography and pulmonary function testing. OSAS patients were divided into those with (homeostatic model assessment [HOMA-IR] ≥ 2) and without insulin resistance (HOMA-IR < 2). Results: Overall, 92 patients (81 males) were included in the study. OSAS patients with insulin resistance significantly differed from those without insulin resistance in terms of the body-mass index (BMI) (36.3 ± 5.8 compared to 32 ± 5.6 kg/m2, respectively, p = 0.001), apnoea-hypopnoea index (AHI) (57.4 ± 28.9 compared to 40.9 ± 27.9 events/h, respectively, p = 0.009) and indices of hypoxia during sleep. Patients with OSAS and insulin resistance had lower levels of serum 25 (OH) D compared with OSAS but without insulin resistance (19.3 ± 11.5 vs 26.7 ± 12.2 ng/mL, respectively, p = 0.005). Regression analysis demonstrated a negative association of 25(OH)D levels (ß = -0.048, odds ratio [OR]: 0.953, 95% confidence interval [CI]: 0.913-0.995, p = 0.030) and a positive association of BMI (ß = 0.110, OR: 1.116, 95% CI: 1.007-1.237, p = 0.036) with insulin resistance. Conclusions: Vit D insufficiency was significantly more frequent among OSAS patients with insulin resistance. Both low 25(OH)D levels and high BMI were associated with the risk of insulin resistance in this population.

Stroke Incidence and Outcomes in Northeastern Greece: The Evros Stroke Registry.

BACKGROUND AND PURPOSE: Data are scarce on both stroke incidence rates and outcomes in Greece and in rural areas in particular. We performed a prospective population-based study evaluating the incidence of first-ever stroke in the Evros prefecture, a region of a total 147 947 residents located in North Eastern Greece. METHODS: Adult patients with first-ever stroke were registered during a 24-month period (2010-2012) and followed up for 12 months. To compare our stroke incidence with that observed in other studies, we standardized our incidence rate data according to the European Standard Population, World Health Organization, and Segi population. We also applied criteria of data quality proposed by the Monitoring Trends and Determinants in Cardiovascular Disease project. Stroke diagnosis and classification were performed using World Health Organization criteria on the basis of neuroimaging and autopsy data. RESULTS: We prospectively documented 703 stroke cases (mean age: 75±12 years; 52.8% men; ischemic stroke: 80.8%; intracerebral hemorrhage: 11.8%; subarachnoid hemorrhage: 4.4%; undefined: 3.0%) with a total follow-up time of 119 805 person-years. The unadjusted and European Standard Population-adjusted incidences of all strokes were 586.8 (95% confidence interval [CI], 543.4-630.2) and 534.1 (95% CI, 494.6-573.6) per 100 000 person-years, respectively. The unadjusted incidence rates for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage were 474.1 (95% CI, 435-513), 69.3 (95% CI, 54-84), and 25.9 (95% CI, 17-35) per 100 000 person-years, respectively. The corresponding European Standard Population-adjusted incidence rates per 100 000 person-years were 425.9 (95% CI, 390.9-460.9), 63.3 (95% CI, 49.7-76.9), and 25.8 (95% CI, 16.7-34.9) for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage, respectively. The overall 28-day case fatality rate was 21.3% (95% CI, 18.3%-24.4%) for all strokes and was higher in hemorrhagic strokes than ischemic stroke (40.4%, 95% CI, 31.3%-49.4% versus 16.2%, 95% CI, 13.2%-19.2%). CONCLUSIONS: This is the largest to date population-based study in Greece documenting one of the highest stroke incidences ever reported in South Europe, highlighting the need for efficient stroke prevention and treatment strategies in Northeastern Greece.

New antihyperglycaemic agents and cardiovascular disease: let's be optimistic.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) substantially increases mortality in diabetes mellitus. This narrative review highlights recent research on the putative associations between dipeptyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose co-transporter 2 inhibitors (SGLT-2is) and several cardiovascular risk factors. RECENT FINDINGS: New antihyperglycaemic agents favourably modulate several CVD risk factors, including fasting and postprandial plasma glucose levels, body weight, blood pressure, lipids, microalbuminuria, nonalcoholic fatty liver disease, serum uric acid, and arterial stiffness. Liraglutide (in LEADER), semaglutide (in SUSTAIN-6), empagliflozin (in EMPA-REG OUTCOME), and canagliflozin (in CANVAS) were all associated with reduction of the primary composite outcome (i.e. cardiovascular death, nonfatal myocardial infarction or stroke). Of note, patients at higher CVD risk, with optimally controlled CVD risk factors seem to benefit more. SUMMARY: Recent trials with SGLT-2is and GLP-1RAs show superiority in CVD event reduction as opposed to only noninferiority. It is still unclear if the results can be generalised to the lower risk population with diabetes but without CVD. Head-to-head comparison and CVD outcome trials involving combination of these two drug classes are also expected to facilitate decision making in clinical practice.