Assessing the risk of ketoacidosis due to sodium-glucose cotransporter (SGLT)-2 inhibitors in patients with type 1 diabetes: A meta-analysis and meta-regression.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) showed benefits in type 1 diabetes mellitus (T1DM), but the risk of diabetic ketoacidosis (DKA) limits their use. Ability to predict DKA risk and therapeutic responses would enable appropriate patient selection for SGLT2i. We conducted a meta-analysis and meta-regression of randomized controlled trials (RCTs) evaluating SGLT2i in T1DM to assess moderators of the relative risk (RR) of DKA, of glycemic (HbA1c, fasting plasma glucose, continuous glucose monitoring parameters, insulin dose, and insulin sensitivity indices) and non-glycemic (body mass index (BMI), systolic BP, renal function, albuminuria, and diabetic eye disorders) efficacy, and of other safety outcomes (including hypoglycemia, infections, major adverse cardiovascular events, and death). METHODS AND FINDINGS: We searched MEDLINE, Cochrane Library, EMBASE, ClinicalTrials.gov, Cochrane CENTRAL Register of Controlled Trials, and other electronic sources through August 30, 2020, for RCTs comparing SGLT2i with active comparators or placebo in adult patients with T1DM. Reviewers extracted data for relevant outcomes, performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. The strength of evidence was summarized with the GRADE approach. Among 9,914 records identified, 18 placebo-controlled RCTs (7,396 participants, 50% males, mean age 42 y (range 23 to 55 y), 5 different SGLT2i evaluated), were included. Main outcome measures were effect sizes and moderators of glycemic and non-glycemic efficacy and of safety outcomes. In a multivariable meta-regression model, baseline BMI (ß = 0.439 [95% CI: 0.211, 0.666], p < 0.001) and estimated glucose disposal rate (eGDR) (ß = -0.766 [-1.276, -0.256], p = 0.001) were associated with the RR of DKA (RR: 2.81; 95% CI:1.97, 4.01; p < 0.001, R2 = 61%). A model including also treatment-related parameters (insulin dose change-to-baseline insulin sensitivity ratio and volume depletion) explained 86% of variance across studies in the risk of DKA (R2 = 86%). The association of DKA with a BMI >27 kg/m2 and with an eGDR <8.3 mg/kg/min was confirmed also in subgroup analyses. Among efficacy outcomes, the novel findings were a reduction in albuminuria (WMD: -9.91, 95% CI: -16.26, -3.55 mg/g, p = 0.002), and in RR of diabetic eye disorders (RR: 0.27[0.11, 0.67], p = 0.005) associated with SGLT2i. A SGLT2i dose-response gradient was consistently observed for main efficacy outcomes, but not for adverse events (AEs). Overall, predictors of DKA and of other AEs differed substantially from those of glycemic and non-glycemic efficacy. A limitation of our analysis was the relatively short (≤52 weeks) duration of included RCTs. The potential relevance for clinical practice needs also to be confirmed by real-world prospective studies. CONCLUSIONS: In T1DM, the risk of DKA and main therapeutic responses to SGLT2i are modified by baseline BMI and insulin resistance, by total insulin dose reduction-to-baseline insulin sensitivity ratio, and by volume depletion, which may enable the targeted use of these drugs in patients with the greatest benefit and the lowest risk of DKA.

MERTK rs4374383 variant predicts incident nonalcoholic fatty liver disease and diabetes: role of mononuclear cell activation and adipokine response to dietary fat.

The loss-of-function rs4374383 G > A variant in Myeloid-epithelial-reproductive Tyrosine Kinase (MERTK) gene has been linked to hepatic fibrosis in chronic liver diseases. MERTK is expressed by immune and non-immune cells involved in inflammation, metabolism and vascular homeostasis. We assessed the impact of MERTK rs4374383 G > A variant on nonalcoholic fatty liver disease (NAFLD) incidence and severity and on glucose and lipid metabolism. We followed-up 305 healthy nonobese nondiabetic, metabolic syndrome-free insulin sensitive participants in a population-based study, characterized for MERTK G > A polymorphism, adipokine profile and inflammatory markers.An independent cohort of 69 biopsy-proven nondiabetic NAFLD patients and 69 healthy controls underwent indirect calorimetry, an OGTT with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP-1, and of Nuclear Factor (NF)-κB activation in circulating mononuclear cells (MNCs). In the longitudinal cohort, MERTK G > A polymorphism protected against 9-year incident NAFLD (OR:0.48,95%CI:0.26-0.79) and diabetes (OR: 0.47, 95% CI: 0.19-0.87).In the cross-sectional cohort, MERTK A-allele carriers had higher fat oxidation rates and tissue insulin sensitivity. Despite comparable fastign and postprandial lipid profiles, MERTK A-allele carriers showed lower resistin and MCP-1 responses, milder MNC NF-κB activation, and a higher postprandial adiponectin response to fat, which predicted tissue insulin resistance hepatocyte apoptosis and liver histology. MERTK G > A variant affects liver disease, nutrient oxidation and glucose metabolism in NAFLD. The modulation of adipokine, chemokine and pro-inflammatory MNC activation in response to fat ingestion may contribute to the observed effects on liver and metabolic disease.

Gut microbiota, hypertension and chronic kidney disease: Recent advances.

A large number of different microbial species populates intestine. Extensive research has studied the entire microbial population and their genes (microbiome) by using metagenomics, metatranscriptomics and metabolomic analysis. Studies suggest that the imbalances of the microbial community causes alterations in the intestinal homeostasis, leading to repercussions on other systems: metabolic, nervous, cardiovascular, immune. These studies have also shown that alterations in the structure and function of the gut microbiota play a key role in the pathogenesis and complications of Hypertension (HTN) and Chronic Kidney Disease (CKD). Increased blood pressure (BP) and CKD are two leading risk factors for cardiovascular disease and their treatment represents a challenge for the clinicians. In this Review, we discuss mechanisms whereby gut microbiota (GM) and its metabolites act on downstream cellular targets to contribute to the pathogenesis of HTN and CKD, and potential therapeutic implications.

Recent Insight into the Role of Fibrosis in Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most widespread tumors in the world and its prognosis is poor because of lack of effective treatments. Epidemiological studies show that non-alcoholic steatohepatitis (NASH) and advanced fibrosis represent a relevant risk factors to the HCC development. However little is known of pathophysiological mechanisms linking liver fibrogenesis to HCC in NASH. Recent advances in scientific research allowed to discover some mechanisms that may represent potential therapeutic targets. These include the integrin signaling, hepatic stellate cells (HSCs) activation, Hedgehog signaling and alteration of immune system. In the near future, knowledge of fibrosis-dependent carcinogenic mechanisms, will help optimize antifibrotic therapies as an approach to prevent and treat HCC in patients with NASH and advanced fibrosis.

Altered Gut Microbiota in Type 2 Diabetes: Just a Coincidence?

PURPOSE OF REVIEW: In the last decade many studies have suggested an association between the altered gut microbiota and multiple systemic diseases including diabetes. In this review, we will discuss potential pathophysiological mechanisms, the latest findings regarding the mechanisms linking gut dysbiosis and type 2 diabetes (T2D), and the results obtained with experimental modulation of microbiota. RECENT FINDINGS: In T2D, gut dysbiosis contributes to onset and maintenance of insulin resistance. Different strategies that reduce dysbiosis can improve glycemic control. Evidence in animals and humans reveals differences between the gut microbial composition in healthy individuals and those with T2D. Changes in the intestinal ecosystem could cause inflammation, alter intestinal permeability, and modulate metabolism of bile acids, short-chain fatty acids and metabolites that act synergistically on metabolic regulation systems contributing to insulin resistance. Interventions that restore equilibrium in the gut appear to have beneficial effects and improve glycemic control. Future research should examine in detail and in larger studies other possible pathophysiological mechanisms to identify specific pathways modulated by microbiota modulation and identify new potential therapeutic targets.

TM6SF2 rs58542926 variant affects postprandial lipoprotein metabolism and glucose homeostasis in NAFLD.

Mechanisms underlying the opposite effects of transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C>T polymorphism on liver injury and cardiometabolic risk in nonalcoholic fatty liver disease (NAFLD) are unclear. We assessed the impact of this polymorphism on postprandial lipoprotein metabolism, glucose homeostasis, and nutrient oxidation in NAFLD. Sixty nonobese nondiabetic normolipidemic biopsy-proven NAFLD patients and 60 matched controls genotyped for TM6SF2 C>T polymorphism underwent: indirect calorimetry; an oral fat tolerance test with measurement of plasma lipoprotein subfractions, adipokines, and incretin glucose-dependent insulinotropic polypeptide (GIP); and an oral glucose tolerance test with minimal model analysis of glucose homeostasis. The TM6SF2 T-allele was associated with higher hepatic and adipose insulin resistance, impaired pancreatic ß-cell function and incretin effect, and higher muscle insulin sensitivity and whole-body fat oxidation rate. Compared with the TM6SF2 C-allele, the T-allele entailed lower postprandial lipemia and nefaemia, a less atherogenic lipoprotein profile, and a postprandial cholesterol (Chol) redistribution from smaller atherogenic lipoprotein subfractions to larger intestinal and hepatic VLDL1 subfractions. Postprandial plasma VLDL1-Chol response independently predicted the severity of liver histology. In conclusion, the TM6SF2 C>T polymorphism affects nutrient oxidation, glucose homeostasis, and postprandial lipoprotein, adipokine, and GIP responses to fat ingestion independently of fasting values. These differences may contribute to the dual and opposite effect of this polymorphism on liver injury and cardiometabolic risk in NAFLD.

Specialized Proresolving Mediators: Enhancing Nonalcoholic Steatohepatitis and Fibrosis Resolution.

The resolution of necroinflammation and fibrosis remains a primary clinical target in nonalcoholic steatohepatitis (NASH), the most common chronic liver disease and a major cause of end-stage liver disease. Our understanding of the basic molecular mechanisms driving inflammation and fibrosis and their resolution in obesity-related conditions, including NASH, have led to the proposal of a novel, tractable therapeutic paradigm involving specialized proresolving mediators (SPMs), namely lipoxins (LXs), resolvins (Rvs), protectins (PDs), and maresins (MaRs). Growing evidence from cellular and in vivo animal models, as well as observational human data, suggests that the therapeutic potential of SPMs and their synthetic mimetics expands to the regression of hepatic necroinflammatory and fibrotic changes in NASH. Here, we review preclinical and clinical evidence linking SPMs to the pathogenesis of inflammation and fibrosis in NASH, as well as potential therapeutic use of these new molecules for the resolution of steatohepatitis and of fibrosis in NASH.

Multicentre Italian analysis on cardiovascular diseases: impact of immigrants' referral to emergency department.

During the recent years, immigration in Italy has increased. There are few data on the health status of immigrants and there is a need to improve their healthcare. Cardiovascular disorders account for 7.6% of immigrants' diseases and cause 3.6% of the total deaths. Lack of healthcare services to general medicine support and prescriptions leads immigrants to contact the Emergency Department (ED) to receive medical assistance. Primary endpoints of this study were to assess the use of national healthcare system by immigrants and to determine the incidence of cardiovascular diseases, and the frequency and type of risk factors for cardiovascular diseases in these patients. A no-profit, observational, multicentre study was conducted from April to September 2012. We studied 642 foreign patients referring to the ED for various symptoms/signs. One hundred and fourteen patients referred for suspected cardiovascular disease and 105 had a confirmed final diagnosis of cardiovascular disease. The more represented ethnic origin was Caucasian (59%), whereas the most represented country was Romania (24%). The main symptom recorded at ED arrival was chest pain (37.1%). Final cardiovascular diagnoses were represented by: hypertensive crisis (28.5%), acute coronary syndrome (20%), acute heart failure (12.3%), atrial fibrillation (10.4%) and chest pain (10.4%). Past medical history of cardiovascular disease, hypertension, obesity and male sex showed independent significant predictive value for cardiovascular disease diagnosis.Our study provides support for the development of specific primary prevention of cardiovascular risk factors in immigrants with the important role of culturally competent education of individuals and families. Better outpatient management seems to be needed in order to limit the need for emergency room referral.