The EMPA-REG outcome study: critical appraisal and potential clinical implications

Diabetes health care professionals have to face a study with results of incomparable success in secondary and tertiary cardiovascular disease prevention. In the past, no studies in patients with type 2 diabetes resulted to be successful in inducing an improvement of cardiovascular prognosis, no matter whether they were focused on a target, on life-style or on pharmacological intervention. On a clinical perspective, should the diabetologist's way to think about the anti-diabetic therapy of patients on secondary cardiovascular prevention change based on the results of Empa-Reg outcome? Due to the complexity of the clinical picture of patients with type 2 diabetes, a tailored therapy based on targets, complications, co-morbidity, familial and social environment, personal and cultural features must be conceived and applied in starting pharmacological therapy; however, the question whether should we consider empagliflozin as first choice therapy in individuals with type 2 diabetes exposed to high cardiovascular risk, the Empa-Reg outcome-like patient, awaits now for an answer. Waiting for data confirming the results of the Empa-Reg outcome study, this report goes through the good reasons in support of this way of thinking, but at the same time explores the many unanswered questions raising potential concerns about this clinical choice

Prevalence, Metabolic Features, and Prognosis of Metabolically Healthy Obese Italian Individuals: The Cremona Study

OBJECTIVE: Some obese individuals have normal insulin sensitivity. It is controversial whether this phenotype is associated with increased all-cause mortality risk. RESEARCH DESIGN AND METHODS: Fifteen-year all-cause mortality data were obtained through the Regional Health Registry for 2,011 of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes in Italy. Individuals were divided in four categories according to BMI (nonobese: <30 kg/m\ub2; obese: 6530 kg/m\ub2) and estimated insulin resistance (insulin sensitive: homeostasis model assessment of insulin resistance <2.5; insulin resistant 652.5). RESULTS: Obese insulin-sensitive subjects represented 11% (95% CI 8.1-14.5) of the obese population. This phenotype had similar BMI but lower waist circumference, blood pressure, fasting glucose, triglycerides, and fibrinogen and higher HDL cholesterol than obese insulin-resistant subjects. In the 15-year follow-up, 495 deaths (cardiovascular disease [CVD]: n = 221; cancer: n = 180) occurred. All-cause mortality adjusted for age and sex was higher in the obese insulin-resistant subjects (hazard ratio 1.40 [95% CI 1.08-1.81], P = 0.01) but not in the obese insulin-sensitive subjects (0.99 [0.46-2.11], P = 0.97) when compared with nonobese insulin-sensitive subjects. Also, mortality for CVD and cancer was higher in the obese insulin-resistant subjects but not in the obese insulin-sensitive subjects when compared with nonobese insulin-sensitive subjects. CONCLUSIONS: In contrast to obese insulin-resistant subjects, metabolically healthy obese individuals are less common than previously thought and do not show increased all-cause, cancer, and CVD mortality risks in a 15-year follow-up study

Association Between Plasma Monocyte Chemoattractant Protein-1 Concentration and Cardiovascular Disease Mortality in Middle-Aged Diabetic and Nondiabetic Individuals

OBJECTIVE Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a chemokine involved into the pathogenesis of atherosclerosis and has prognostic value in the acute and chronic phases in patients with acute coronary syndromes. RESEARCH DESIGN AND METHODS MCP-1/CCL2 concentration was measured in plasma fractions of 363 middle-aged overweight/obese individuals (aged 61 \ub1 12 years, BMI 30.1 \ub1 6.6 kg/m2, 15% with type 2 diabetes, and 12% with impaired glucose tolerance) of a population survey carried out in 1990\u20131991 in Lombardy, Italy (Cremona Study), and cardiovascular disease (CVD) mortality was assessed in 2006 through Regional Health Registry files. RESULTS At baseline MCP-1/CCL2 was increased in individuals with type 2 diabetes (P < 0.05) and showed significant correlations with biochemical risk markers of atherosclerosis. After 15 years, among the 363 subjects, there were 82 deaths due to CVD. In univariate analysis age, sex, fasting glucose and insulin, fibrinogen, glucose tolerance status, smoking habit, and MCP-1/CCL2 were associated with CVD mortality. Age, sex, fasting serum glucose, MCP-1/CCL2, and smoking habit maintained an independent association with CVD mortality in multiple regression analysis. In a subgroup of 113 subjects in whom data for C-reactive protein (CRP) were available, its level was not predictive of CVD mortality. CONCLUSIONS In middle-aged overweight/obese individuals MCP-1/CCL2 was independently associated with CVD mortality. Further studies will be necessary to establish its role as a surrogate biomarker and as a potential therapeutic target

Clinical update on non-alcoholic fatty liver disease and steatohepatitis

clusion of less common causes of fatty liver such as Hepatitis B or C infection, drugs and autoimmune disorders, fatty liver is classified as non-alcoholic (NAFLD) or alcoholic fatty liver disease (AFLD) on the basis of daily ethanol intake. The agreed threshold of ethanol intake used to separate NAFLD from AFLD is 20 g/day, equivalent to 12 drinks per week. 2 The term NAFLD covers a wide spectrum of liver injury, ranging from simple steatosis, i.e. fatty infiltration of hepatocytes > 5%, to non-alcoholic steatohepatitis (NASH). At liver biopsy NASH is characterized by necro-inflammation and/or fibrosis, and is histologically indistinguishable from alcoholic steatohepatitis. The histological classification of NAFLD and NASH is being continuously improved and a refined scoring system has been recently proposed by the National Institutes of Health. 3 NAFLD is presently regarded as the most common liver disease in Western countries and virtually impacts all fields of clinical medicine, being considered a risk factor for advanced liver disease, type 2 diabetes and cardiovascular disease. Although NAFLD had long been recognized as a frequent clinical entity, only recently its importance as a potential cause of progressive and severe liver disease has been fully acknowledged. NAFLD prevalence in the general population ranges from 16 to 25% in adults 4 and from 10 to 19% in children. 5 It increases with age, shows different gender specificity according to geographic areas (generally more prevalent in women in US and viceversa in men in Europe and Japan) and varies with ethnicity, with the highest prevalence among the Hispanic population and the lowest among the AfroAmerican one. 6 Prevalence rates of NAFLD are strikingly increased in certain subpopulations, such as patients with obesity, type 2 diabetes mellitus and dyslipidemia, and the whole spectrum of NAFLD is commonly associated with the metabolic syndrome. The true prevalence of NASH remains largely unknown. According to data derived from autopsy or liver biopsy studies, about 10-15% of NAFLD patients meet the current diagnostic criteria for NASH, pointing to a prevalence of 2-3% in the general population. The incidence and natural course of NAFLD are also difficult to assess because most of the available studies are retrospective and/or performed on clinical series. The few prospective studies are too short to exclude late complications. While simple steatosis has a benign prognosis, NASH may progress to cirrhosis in 30% of cases and is responsible for liver-related death in 3-8%. In clinical series, up to 70% of patients with cryptogenic cirrhosis have clinical features suggestive of NASH.

Effect of combination therapy of hydroxychloroquine and azithromycin on mortality in patients with COVID-19

Conflicting evidence regarding the use of hydroxychloroquine (HCQ) and azithromycin for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection do exist. We performed a retrospective single-center cohort study including 377 consecutive patients admitted for pneumonia related to coronavirus disease 2019 (COVID-19). Of these, 297 were in combination treatment, 17 were on HCQ alone, and 63 did not receive either of these 2 drugs because of contraindications. The primary end point was in-hospital death. Mean age was 71.8&nbsp;±&nbsp;13.4&nbsp;years and 34.2% were women. We recorded 146 deaths: 35 in no treatment, 7 in HCQ treatment group, and 102 in HCQ&nbsp;+&nbsp;azithromycin treatment group (log rank test for Kaplan–Meier curve P&nbsp;&lt;&nbsp;0.001). At multivariable Cox proportional hazard regression analysis, age (hazard ratio (HR) 1.057, 95% confidence interval (CI) 1.035–1.079, P&nbsp;&lt;&nbsp;0.001), mechanical ventilation/continuous positive airway pressure (HR 2.726, 95% CI 1.823–4.074, P&nbsp;&lt;&nbsp;0.001), and C reactive protein above the median (HR 2.191, 95% CI 1.479–3.246, P&nbsp;&lt;&nbsp;0.001) were directly associated with death, whereas use of HCQ&nbsp;+&nbsp;azithromycin (vs. no treatment; HR 0.265, 95% CI 0.171–0.412, P&nbsp;&lt;&nbsp;0.001) was inversely associated. In this study, we found a reduced in-hospital mortality in patients treated with a combination of HCQ and azithromycin after adjustment for comorbidities. A large randomized trial is necessary to confirm these findings

Incorporation of the fasting plasma FFA concentration into QUICKI improves its association with insulin sensitivity in nonobese individuals

Insulin resistance plays a major role in the pathophysiology of diabetes and is associated with obesity and cardiovascular disease. Excellent methods exist for the assessment of insulin sensitivity in the laboratory setting, such as the glucose clamp. However, these methods are not suitable for large population studies, and, thus, surrogate estimates of insulin sensitivity based on measurements in a single blood sample have been developed. Recently an index based on the logarithm and the reciprocal of the insulin-glucose product (QUICKI) has been proposed. QUICKI correlated with insulin sensitivity across the entire spectrum of glucose tolerance, but its performance was less satisfactory in normal subjects. Aim of this study was to ascertain whether the inclusion of fasting plasma free fatty acids concentration into QUICKI improves its association with insulin sensitivity in nonobese subjects. To test this hypothesis, we performed a euglycemic hyperinsulinemic clamp [40 mU/(m(2).min)] in 57 young, healthy, nonobese individuals with (n = 17) or without (n = 40) first-degree relatives affected by type 2 diabetes (the former group being an in vivo model of mild insulin resistance). We then compared the clamp-based index of insulin sensitivity with both QUICKI and a revised QUICKI, the latter index including the contribution of fasting free fatty acid concentration as well. The revised QUICKI considerably improved the relationship with the clamp-based index of insulin sensitivity (r = 0.51, P < 0.0001) with respect to QUICKI (r = 0.27, P < 0.05). In addition, the revised QUICKI revealed a reduction of insulin sensitivity in the offspring of type 2 diabetes (10%; P < 0.006) that QUICKI was unable to detect (3%; P = 0.28). In conclusion, this study suggests that the incorporation of fasting free fatty acid level into QUICKI is useful to improve its correlation with the clamp-based index of insulin sensitivity and its discriminatory power in case of mild insulin resistance. Further investigation is needed to ascertain its applicability to patients with obesity and type 2 diabetes

Similar glycaemic control and risk of hypoglycaemia with patient- versus physician-managed titration of insulin glargine 300 U/mL across subgroups of patients with T2DM: a post hoc analysis of ITAS

Aims: The Italian Titration Approach Study (ITAS) demonstrated comparable HbA1c reductions and similarly low hypoglycaemia risk at 6&nbsp;months in poorly controlled, insulin-naïve adults with T2DM who initiated self- or physician-titrated insulin glargine 300 U/mL (Gla-300) in the absence of sulphonylurea/glinide. The association of patient characteristics with glycaemic and hypoglycaemic outcomes was assessed. Methods: This post hoc analysis investigated whether baseline patient characteristics and previous antihyperglycaemic drugs were associated with HbA1c change and hypoglycaemia risk in patient- versus physician-managed Gla-300 titration. Results: HbA1c change, incidence of hypoglycaemia (any type) and nocturnal rates were comparable between patient- and physician-managed arms in all subgroups. Hypoglycaemia rates across subgroups (0.03 to 3.52 events per patient-year) were generally as low as observed in the full ITAS population. Small increases in rates of 00:00–pre-breakfast and anytime hypoglycaemia were observed in the ≤ 10-year diabetes duration subgroup in the patient- versus physician-managed arm (heterogeneity of effect; p &lt; 0.05). Conclusions: Comparably fair glycaemic control and similarly low hypoglycaemia risk were achieved in almost all patient subgroups with patient- versus physician-led Gla-300 titration. These results reinforce efficacy and safety of Gla-300 self-titration across a range of phenotypes of insulin-naïve people with T2DM. Clinical trial registration: EudraCT 2015-001167-3

Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks?

In this review, we explore the concept of ‘double diabetes’, a combination of type 1 diabetes with features of insulin resistance and type 2 diabetes. After considering whether double diabetes is a useful concept, we discuss potential mechanisms of increased insulin resistance in type 1 diabetes before examining the extent to which double diabetes might increase the risk of cardiovascular disease (CVD). We then go on to consider the proposal that weight gain from intensive insulin regimens may be associated with increased CV risk factors in some patients with type 1 diabetes, and explore the complex relationships between weight gain, insulin resistance, glycaemic control and CV outcome. Important comparisons and contrasts between type 1 diabetes and type 2 diabetes are highlighted in terms of hepatic fat, fat partitioning and lipid profile, and how these may differ between type 1 diabetic patients with and without double diabetes. In so doing, we hope this work will stimulate much-needed research in this area and an improvement in clinical practice

Immunomonitoring of Transplanted Patients Infused With Mesenchymal Stromal Cells (MSC) for Treating Steroid-Refractory GVHD

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