Short-term effectiveness of dapagliflozin versus DPP-4 inhibitors in elderly patients with type 2 diabetes: a multicentre retrospective study.

AIM: To compare effectiveness of dapagliflozin versus DPP-4 inhibitors on individualized HbA1c targets and extra-glycaemic endpoints among elderly patients with type 2 diabetes (T2D). METHODS: This was a multicentre retrospective study on patients aged 70-80 years with HbA1c above individualized target and starting dapagliflozin or DPP-4 inhibitors in 2015-2017. The primary outcome was the proportion reaching individualized HbA1c targets. Confounding by indication was addressed by inverse probability of treatment weighting (IPTW), multivariable adjustment (MVA), or propensity score matching (PSM). RESULTS: Patients initiating dapagliflozin (n = 445) differed from those initiating DPP-4i (n = 977) and balance between groups was achieved with IPTW or PSM. The median follow-up was 7.5 months and baseline HbA1c was 8.3%. A smaller proportion of patients initiating dapagliflozin attained individualized HbA1c target as compared to those initiating DPP-4 inhibitors (RR 0.73, p < 0.0001). IPTW, MVA, and PSM yielded similar results. Between-group difference in the primary outcome was observed among patients with lower eGFR or longer disease duration. Dapagliflozin allowed greater reductions in body weight and blood pressure than DPP-4 inhibitors. CONCLUSIONS: Elderly patients with T2D initiating dapagliflozin had a lower probability of achieving individualized HbA1c targets than those initiating DPP-4 inhibitors but displayed better improvements in extra-glycaemic endpoints.

Time series of diabetes attributable mortality from 2008 to 2017.

PURPOSE: Diabetes is a growing health problem. The aim of this study was to capture time trends in mortality associated with diabetes. METHODS: The mortality database of the Veneto region (Italy) includes both the underlying causes of death, and all the diseases mentioned in the death certificate. The annual percent change (APC) in age-standardized rates from 2008 to 2017 was computed by the Joinpoint Regression Program. RESULTS: Overall 453,972 deaths (56,074 with mention of diabetes) were observed among subjects aged ≥ 40 years. Mortality rates declined for diabetes as the underlying cause of death and from diabetes-related circulatory diseases. The latter declined especially in females - 4.4 (CI 95% - 5.3/- 3.4), while in males the APC was - 2.8 (CI 95% - 4.0/- 1.6). CONCLUSION: We observed a significant reduction in mortality during the period 2008-2017 in diabetes either as underlying cause of death or when all mentions of diabetes in the death certificate were considered.

Haplotypes of the genes (GCK and G6PC2) underlying the glucose/glucose-6-phosphate cycle are associated with pancreatic beta cell glucose sensitivity in patients with newly diagnosed type 2 diabetes from the VNDS study (VNDS 11).

BACKGROUND: Elevated fasting plasma glucose has been associated with increased risk for development of type 2 diabetes (T2D). The balance between glucokinase (GCK) and glucose-6-phosphate catalytic subunit 2 (G6PC2) activity are involved in glucose homeostasis through glycolytic flux, and subsequent insulin secretion. AIM: In this study, we evaluated the association between the genetic variability of G6PC2 and GCK genes and T2D-related quantitative traits. METHODS: In 794 drug-naïve, GADA-negative, newly diagnosed T2D patients (VNDS; NTC01526720) we performed: genotyping of 6 independent tag-SNPs within GCK gene and 5 tag-SNPs within G6PC2 gene; euglycaemic insulin clamp to assess insulin sensitivity; OGTT to estimate beta-cell function (derivative and proportional control; DC, PC) by mathematical modeling. Genetic association analysis has been conducted using Plink software. RESULTS: Two SNPs within GCK gene (rs882019 and rs1303722) were associated to DC in opposite way (both p < 0.004). Two G6PC2 variants (rs13387347 and rs560887) were associated to both parameters of insulin secretion (DC and PC) and to fasting C-peptide levels (all p < 0.038). Moreover, subjects carrying the A allele of rs560887 showed higher values of 2h-plasma glucose (2hPG) (p = 0.033). Haplotype analysis revealed that GCK (AACAAA) haplotype was associated to decreased fasting C-peptide levels, whereas, the most frequent haplotype of G6PC2 (GGAAG) was associated with higher fasting C-peptide levels (p = 0.001), higher PC (ß = 6.87, p = 0.022) and the lower 2hPG (p = 0.012). CONCLUSION: Our findings confirmed the role of GCK and G6PC2 in regulating the pulsatility in insulin secretion thereby influencing insulin-signaling and leading to a gradual modulation in glucose levels in Italian patients with newly diagnosed T2D.

Assessment of simple strategies for identifying undiagnosed diabetes and prediabetes in the general population.

BACKGROUND AND AIMS: The rising tide of diabetes mellitus (DM) and prediabetes (PDM) is urgently calling for strategies easily applicable to anticipate diagnosis. We assessed the effectiveness of random capillary blood glucose (RCBG), administration of a validated DM risk questionnaire, or the combination of both. MATERIALS AND METHODS: RCBG measurement and/or questionnaire administration were offered to all individuals presenting at gazebos organized during the World Diabetes Day or similar public initiatives on diabetes awareness. Subjects with suspicious DM or PDM were invited to the Diabetes Center (DC) for laboratory confirmation (fasting plasma glucose and HbA1c). RESULTS: Among 8563 individuals without known diabetes undergoing RCBG measurement, 341 (4%) had suspicious values. Diagnosis of DM was confirmed in 36 (41.9%) of the 86 subjects who came to the DC and PDM was found in 40 (46.5%). Among 3351 subjects to whom the questionnaire was administered, 480 (14.3%) had suspicious scores. Diagnosis of DM was confirmed in 40 (10.1%) of the 397 who came to the DC and PDM was found in 214 (53.9%). These 3351 subjects also had RCBG measurement and 30 out of them had both tests positive. Among them, 27 subjects came to DC and DM was diagnosed in 17 (63.0%) and PDM was found in 9 (33.3%). CONCLUSIONS: These data suggest that RCBG definitely outperforms the questionnaire to identify unknown DM and PDM. RCBG measurement, with questionnaire as an adjunctive tool, appears to be a simple, fast, and feasible opportunistic strategy in detecting undiagnosed DM and PDM.

The use of real time continuous glucose monitoring or flash glucose monitoring in the management of diabetes: A consensus view of Italian diabetes experts using the Delphi method.

Until recently, in Italy, the use of continuous glucose monitoring (CGM) systems has been limited, but is now rapidly increasing, including the so-called real-time CGM (rtCGM) and the intermittently viewed CGM (iCGM), also called Flash Glucose Monitoring (FGM). These technologies overcome many of the limitations of self-monitoring of blood glucose (SMBG) by fingerprick and allow to go beyond HbA1c to check glucose control in diabetes. However, standardized protocols for applying and interpreting rtCGM and FGM data are lacking. In this paper, we delineate a consensus amongst Italian diabetes physicians on the attributes of rtCGM and FGM technologies, and introduce a consistent approach for their use by Italian healthcare professionals. Most experts consider rtCGM and FGM as two separate categories of interstitial subcutaneous fluid (ISF) sensing technologies, and see them as superior to SMBG. Furthermore, there is strong consensus that rtCGM and FGM reduce hypoglycemia risk, increase the amount of time in the target glucose range and augment treatment satisfaction. However, there is still no agreement on the indication of the FGM for subjects who suffer asymptomatic hypoglycemia. Consensus on the role of education in initiating and optimizing use of rtCGM/FGM and about the interpretation of glucose trends was near unanimous, whereas no consensus was reached on the statement that there are no disadvantages/risks of rtCGM/FGM. Some issues remain in rtCGM/FGM management: a) risk of excessive correction of high or low glucose; b) risk of alert fatigue leading to alert silencing or rtCGM termination; c) allergic reaction to the adhesive keeping rtCGM or FGM sensors in place. The panel almost unanimously agreed that sensor accuracy depends on multiple variables, that alarm setting should be individualized, and that global glycemic profile represent an useful tool in interpreting glucose data. More clinical studies and a wider use of these devices will increase the efficacy and effectiveness of continuous glucose monitoring in Italy.

Increased aortic stiffness index in patients with type 1 diabetes without cardiovascular disease compared to controls.

PURPOSE: Increased arterial stiffness is an early sign of endothelial dysfunction. Nevertheless, measures of the elastic properties of the aortic root in patients with type 1 diabetes are still lacking. The aim of this study was to compare aortic root stiffness index in type 1 diabetes and healthy controls. METHODS: Ninety-three patients with type 1 diabetes without cardiovascular diseases were recruited and compared to 33 healthy controls. Aortic root elastic properties were estimated by measuring the systolic and diastolic diameters on M-mode acquisition. RESULTS: None of the subjects showed alterations of either systolic or diastolic echocardiographic parameters. Patients with type 1 diabetes had a very low prevalence of chronic complications and their metabolic control was good. Significantly increased aortic stiffness index was found in type 1 diabetes compared to controls, and the same different pattern was found in men and women. The presence of type 1 diabetes and increased pulse pressure was significantly associated with aortic stiffness index in a multivariate linear analysis. CONCLUSION: This study strongly suggests that patients with type 1 diabetes develop aortic root stiffness in the absence of cardiovascular diseases. This alteration may be part of a more generalized arterial dysfunction in type 1 diabetes.

Dietary intake and major food sources of polyphenols in people with type 2 diabetes: The TOSCA.IT Study.

PURPOSE: Proper evaluation of polyphenols intake at the population level is a necessary step in order to establish possible associations with health outcomes. Available data are limited, and so far no study has been performed in people with diabetes. The aim of this work was to document the intake of polyphenols and their major food sources in a cohort of people with type 2 diabetes and in socio-demographic subgroups. METHODS: We studied 2573 men and women aged 50-75 years. Among others, anthropometry was measured by standard protocol and dietary habits were investigated by food frequency questionnaire (EPIC). The intake of polyphenols was evaluated using US Department of Agriculture and Phenol-Explorer databases. RESULTS: The mean total polyphenol intake was 683.3 ± 5.8 mg/day. Non-alcoholic beverages represented the main food source of dietary polyphenols and provided 35.5% of total polyphenol intake, followed by fruits (23.0%), alcoholic beverages (14.0%), vegetables (12.4%), cereal products and tubers (4.6%), legumes (3.7%) and oils (2.1%); chocolate, cakes and nuts are negligible sources of polyphenols in this cohort. The two most important polyphenol classes contributing to the total intake were flavonoids (47.5%) and phenolic acids (47.4%). Polyphenol intake increased with age and education level and decreased with BMI; furthermore, in the northern regions of Italy, the polyphenol intake was slightly, but significantly higher than in the central or southern regions. CONCLUSIONS: The study documents for the first time the intake of polyphenols and their main food sources in people with diabetes using validated and complete databases of the polyphenol content of food. Compared with published data, collected in people without diabetes, these results suggest a lower intake and a different pattern of intake in people with diabetes.

Attending Diabetes Clinics is associated with a lower all-cause mortality. A meta-analysis of observational studies performed in Italy.

OBJECTIVE: The epidemiological explosion of diabetes is a challenge for Health Systems and the identification of the most appropriate models of care are warranted. The inclusion of primary care physicians in the models is unquestioned whereas the role played by secondary and tertiary care (Diabetes Clinic) is often debated. However, studies focusing on hard endpoints and comparing Diabetes Clinic attendance vs. no attendance are scant. RESEARCH DESIGN AND METHODS: A meta-analysis was performed including all observational cohort studies performed in Italy, reporting crude and/or adjusted estimates of all-cause mortality in patients with diabetes attending or not attending Diabetes Clinics. Attendance was defined by prescriptions and reimbursement of specialist visits by the National Health System. RESULTS: Three studies enrolling 191,847 subjects with diabetes were included in the analysis, and about half of them had at least one visit in the Diabetes Clinic per year. During the follow-up, ranging 1-11 years, 9653 subjects died. Mortality was remarkably lower in subjects attending Diabetes Clinic (MH-OR 0.70, 95% CI 0.55-0.88, p = 0.002). Results were confirmed after adjusting for confounders (MH-OR 0.81, 95% CI 0.69-0.95, p = 0.009). CONCLUSIONS: The results of the present study suggest that attending Diabetes Clinics is associated with a lower all-cause mortality. This finding might be instrumental to implement the best models of care for persons with diabetes.

Association of free-living physical activity measures with metabolic phenotypes in type 2 diabetes at the time of diagnosis. The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS).

BACKGROUND AND AIM: Lifestyle is considered a major determinant of risk of type 2 diabetes (T2D). We investigated whether daily physical activity (DPA) is associated with beta-cell function (BF) and/or insulin sensitivity (IS) in patients with T2D at the time of diagnosis. METHODS AND RESULTS: In 41 subjects enrolled in the Verona Newly-Diagnosed Type 2 Diabetes Study we assessed: (1) IS, by euglycaemic insulin clamp; (2) BF, estimated by prolonged-OGTT minimal modeling and expressed as derivative and proportional control; (3) DPA and energy expenditure (EE), assessed over 48-h monitoring by a validated wearable armband system. Study participants (median [IQR]; age: 62 [53-67] years, BMI: 30.8 [26.5-34.3] Kg m-2, HbA1c: 6.7 [6.3-7.3]%; 49.7 [45.4-56.3] mmol/mol) were moderately active (footsteps/day: 7773 [5748-10,927]; DPA≥3MET: 70 [38-125] min/day), but none of them exercised above 6 metabolic equivalents (MET). EE, expressed as EETOT (total daily-EE) and EE≥3MET (EE due to DPA≥3MET) were 2398 [2226-2801] and 364 [238-617] Kcal/day, respectively. IS (M-clamp 630 [371-878] µmol/min/m2) was positively associated with DPA and EE, independent of age, sex and BMI (p < 0.05). Among the DPA and EE parameters assessed, DPA≥3MET and EETOT were independent predictors of IS in multivariable regression analyses, adjusted for age, sex, BMI (R2 = 16%, R2 = 19%, respectively; p < 0.01). None of model-derived components of BF was significantly associated with DPA or accompanying EE. CONCLUSIONS: Our study highlighted moderate levels of DPA and total EE as potential determinants of IS, but not BF, in T2D at the time of diagnosis. Intervention studies are needed to conclusively elucidate the effect of DPA on these features. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT01526720.

Mortality from infectious diseases in diabetes.

BACKGROUND AND AIMS: To investigate the risk of mortality from infections by comparing the underlying causes of death versus the multiple causes of death in known diabetic subjects living in the Veneto region of Northern Italy. METHODS AND RESULTS: A total of 185,341 subjects with diabetes aged 30-89 years were identified in the year 2010, and causes of death were assessed from 2010 to 2015. Standardized Mortality Ratios (SMRs) with 95% confidence intervals (CIs) were computed with regional mortality rates as reference. The underlying causes of death and all the diseases reported in the death certificates were scrutinized. At the end of the follow-up, 36,382 subjects had deceased. We observed an increased risk of death from infection-related causes in subjects with diabetes with a SMR of 1.83 (95% CI, 1.71-1.94). The SMR for death from septicemia was 1.91 (95% CI, 1.76-2.06) and from pneumonia was 1.47 (95% CI, 1.36-1.59). The use of the multiple causes of death approach emphasized the association of infectious diseases with mortality. CONCLUSION: The results of the present study demonstrate an excess mortality due to infection-related diseases in patients with diabetes; more interestingly, by routine mortality analyses, the results show a possible underestimation of the effect of these diseases on mortality.

Effects of aerobic or resistance exercise training on cardiovascular autonomic function of subjects with type 2 diabetes: A pilot study.

BACKGROUND AND AIMS: Both aerobic (AER) and resistance (RES) training improve metabolic control in patients with type 2 diabetes (T2DM). However, information on the effects of these training modalities on cardiovascular autonomic control is limited. Our aim was to compare the effects of AER and RES training on cardiovascular autonomic function in these subjects. METHODS AND RESULTS: Cardiovascular autonomic control was assessed by Power Spectral Analysis (PSA) of Heart Rate Variability (HRV) and baroreceptors function indexes in 30 subjects with T2DM, randomly assigned to aerobic or resistance training for 4 months. In particular, PSA of HRV measured the Low Frequency (LF) and High Frequency (HF) bands of RR variations, expression of prevalent sympathetic and parasympathetic drive, respectively. Furthermore, we measured the correlation occurring between systolic blood pressure and heart rate during a standardized Valsalva maneuver using two indexes, b2 and b4, considered an expression of baroreceptor sensitivity and peripheral vasoactive adaptations during predominant sympathetic and parasympathetic drive, respectively. After training, the LF/HF ratio, which summarizes the sympatho-vagal balance in HRV control, was similarly decreased in the AER and RES groups. After AER, b2 and b4 significantly improved. After RES, changes of b2 were of borderline significance, whereas changes of b4 did not reach statistical significance. However, comparison of changes in baroreceptor sensitivity indexes between groups did not show statistically significant differences. CONCLUSION: Both aerobic and resistance training improve several indices of the autonomic control of the cardiovascular system in patients with T2DM. Although these improvements seem to occur to a similar extent in both training modalities, some differences cannot be ruled out. CLINICAL TRIAL REGISTRATION NUMBER: NCT01182948, clinicaltrials.gov.

Management of diabetes in older adults.

Type 2 diabetes prevalence is high in older adults and is expected to rise in the next decades. Diabetes in the population of frail older adults is accompanied by functional disability, several comorbidities, and premature mortality. A comprehensive geriatric assessment, including functional, cognitive, mental and social status, is advisable for identifying the glycemic targets and glucose-lowering therapies, focused on patient preferences, needs, and risks. The therapeutic options for older adults with diabetes are like those for the adult population. However, the pharmacological treatments must be carefully prescribed and monitored, taking into consideration the patient cognitive capacities, the potentially life-threatening drug-drug interactions, the cardiovascular risk, and with the main goal of avoiding hypoglycemia. Also, a careful nutritional evaluation with appropriate tools, as well as a balanced and periodically monitored physical activity, contribute to an effective tailored care plan, as needed by older adults with diabetes. This review evaluates the currently available hypoglycemic drugs and the current indications to the Italian diabetology community, specifically with regard to the treatment of adults aged 75 years or older with diabetes, including the unmet needs by the guidelines.

Hyperuricemia is associated with an increased prevalence of paroxysmal atrial fibrillation in patients with type 2 diabetes referred for clinically indicated 24-h Holter monitoring.

PURPOSE: Several studies have reported an association between hyperuricemia and increased risk of permanent atrial fibrillation (AF) in patients with and without type 2 diabetes mellitus (T2DM). Currently, no published data are available on the relationship between hyperuricemia and risk of paroxysmal AF. METHODS: We retrospectively evaluated 245 T2DM outpatients without pre-existing AF, cancer, cirrhosis and end-stage renal disease, who underwent a 24-h ECG-Holter monitoring for various clinical indications. Hyperuricemia was defined as a serum uric acid level >7 mg/dl for men and >6 mg/dl for women or allopurinol use. The diagnosis of paroxysmal AF was confirmed in affected individuals on the basis of 24-h ECG-Holter monitoring by experienced cardiologists. RESULTS: Hyperuricemia was observed in 59 (24.1%) patients, whereas paroxysmal AF was found in 11 (4.5%) patients. The prevalence of paroxysmal AF was higher in patients with hyperuricemia than in those without hyperuricemia (10.2 vs. 2.7%, p = 0.026). Logistic regression analysis showed that hyperuricemia was associated with an increased risk of prevalent paroxysmal AF. This association remained significant even after adjustment for age, metabolic syndrome and chronic kidney disease (adjusted-odds ratio 4.01, 95% CI 1.08-14.9; p = 0.039). Similar results were found when we used serum uric acid levels as a continuous measure. CONCLUSIONS: This study shows for the first time that hyperuricemia is independently associated with an approximately fourfold increased risk of prevalent paroxysmal AF in patients with T2DM. These findings may partly explain the increased risk of permanent atrial fibrillation and cardiovascular death observed among patients with hyperuricemia.

Evolocumab and lipoprotein apheresis combination therapy may have synergic effects to reduce low-density lipoprotein cholesterol levels in heterozygous familial hypercholesterolemia: A case report.

A 49 years old woman (weight 68 kg, BMI 27.3 kg/m2 ) with heterozygous familial hypercholesterolemia (HeFH) and multiple statin intolerance with muscle aches and creatine kinase elevation, presented at the Outpatient Lipid Clinic of Verona University Hospital in May 2015. Hypercholesterolemia was firstly diagnosed during adolescence, followed in adulthood by a diagnosis of Cogan's syndrome, a rheumatologic disorder characterized by corneal and inner ear inflammation. No xanthomas, corneal arcus, or vascular bruits were detectable at physical examination. Screening for macrovascular complications did not reveal relevant damages. Ongoing medical therapy included salicylic acid, methylprednisolone, methotrexate, and protonic-pump inhibitor. In the absence of specific lipid-lowering therapy, plasma lipid levels at first visit were: total-cholesterol = 522 mg/dL, LDL-cholesterol = 434 mg/dL, HDL-cholesterol = 84 mg/dL, triglycerides = 120 mg/dL, Lp(a) = 13 mg/dL. On December 2015, evolocumab 140 mg sc every 2 weeks was initiated. After a 24-week treatment, the LDL-cholesterol levels decreased by an average of 21.2% to 342 ± 22 mg/dL (mean ± SD). On May 2016, LDL-apheresis (H.E.L.P.system) was started as add-on therapy. Compared to the average levels obtained during the evolocumab monotherapy period, the LDL-cholesterol was reduced by 49.4%, thus reaching an inter-apheresis level (mean ± SD) of 173 ± 37 mg/dL. This report suggests that a combination therapy with evolocumab and lipoprotein-apheresis may have synergic effects on circulating lipid levels. Its relevance as a highly effective treatment option for hyperlipidemia in HeFH patients warrants further investigation in larger datasets.

Influence of health locus of control and fear of hypoglycaemia on glycaemic control and treatment satisfaction in people with Type 1 diabetes on insulin pump therapy.

AIM: To assess the influence of health locus of control and fear of hypoglycaemia on metabolic control and treatment satisfaction in people with Type 1 diabetes mellitus on continuous subcutaneous insulin infusion. METHODS: People with Type 1 diabetes on continuous subcutaneous insulin infusion for at least 1 year, sub-classified as an 'acceptable glucose control' group [HbA1c ≤ 58 mmol/mol (7.5%)] and a 'suboptimum glucose control' group [HbA1c > 58 mmol/mol (7.5%)], were consecutively enrolled in a multicentre cross-sectional study. Questionnaires were administered to assess health locus of control [Multidimensional Health Locus of Control (MHLC) scale, with internal and external subscales], fear of hypoglycaemia [Hypoglycaemia Fear Survey II (HFS-II)] and treatment satisfaction [Diabetes Treatment Satisfaction Questionnaire (DTSQ)]. RESULTS: We enrolled 214 participants (mean ± sd age 43.4 ± 12.1 years). The suboptimum glucose control group (n = 127) had lower mean ± sd internal MHLC and DTSQ scores than the acceptable glucose control group (19.6 ± 5.2 vs 21.0 ± 5.0, P = 0.04 and 28.8 ± 4.8 vs 30.9 ± 4.5, P < 0.001). HFS-II scores did not differ between the two groups. Internal MHLC score was negatively associated with HbA1c (r = -0.15, P < 0.05) and positively associated with the number of mild and severe hypoglycaemic episodes (r = 0.16, P < 0.05 and r = 0.18, P < 0.001, respectively) and with DTSQ score (r = 0.17, P < 0.05). HFS-II score was negatively associated with DTSQ score (r = -0.18, P < 0.05) and positively with number of severe hypoglycaemic episodes (r = 0.16, P < 0.5). CONCLUSIONS: In adults with Type 1 diabetes receiving continuous subcutaneous insulin infusion, high internal locus represents the most important locus of control pattern for achieving good metabolic control.

Rationale and design of the DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes): A multicenter retrospective nationwide Italian study and crowdsourcing opportunity.

BACKGROUND: Randomized controlled trials (RCTs) in the field of diabetes have limitations inherent to the fact that design, setting, and patient characteristics may be poorly transferrable to clinical practice. Thus, evidence from studies using routinely accumulated clinical data are increasingly valued. AIMS: We herein describe rationale and design of the DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes), a multicenter retrospective nationwide study conducted at 50 specialist outpatient clinics in Italy and promoted by the Italian Diabetes Society. DATA SYNTHESIS: The primary objective of the study is to describe the baseline clinical characteristics (particularly HbA1c) of patients initiated on dapagliflozin from marketing authorization approval to the end of 2016. Secondary and exploratory objectives will evaluate the changes in glycaemic and extraglycaemic efficacy parameters after initiation of dapagliflozin or after initiation of comparator glucose lowering medications (DPP-4 inhibitors, gliclazide extended release, and long-acting GLP-1 receptor agonists). An automated software will extract relevant data from the same electronic chart system at all centres, thereby minimizing data treatment and human intervention. CONCLUSION: The study is expected to collect an enormous dataset of information on dapagliflozin- and comparator-using patients. After study completion, the Italian Diabetes Society will launch an open crowdsourcing call on the DARWIN-T2D database, challenging diabetes researchers to apply their ideas and approaches to address new unmet needs and knowledge gaps in diabetes. We believe this will move DARWIN-T2D to the next generation of real world studies.

Psychological distress, self-efficacy and glycemic control in type 2 diabetes.

AIM: To investigate the association of glycemic control with depression, anxiety, self-efficacy and other diabetes-specific psychological measures in a cohort of adult patients with type 2 diabetes (T2D) free of severe chronic diabetes-related complications. METHODS AND RESULTS: In 172 T2D outpatients consecutively recruited at the Diabetes Center of Verona City Hospital, we performed a standard medical assessment and completed the Beck Depression Inventory-II (BDI-II), the Beck Anxiety Inventory (BAI) and the Multidimensional Diabetes Questionnaire (MDQ) Age, body mass index (BMI) and glycosylated hemoglobin (HbA1c) were (median [IQR]): 64.0 [58.0-69.0] years, 31.0 [28.0-34.4] kg/m2, and 7.3 [6.7-8.0] %, respectively. The overall prevalence of anxiety and depression was 14.5% and 18.6%, respectively. Higher levels of HbA1c were significantly (p < 0.001) associated with a number of MDQ dimensions, such as higher perceived interference with daily activities (Spearman's rho coefficient = 0.33), higher perceived diabetes severity (rho = 0.28) and lower self-efficacy (rho = -0.27), but not with depression or anxiety. These three variables were also independent predictors of higher HbA1c levels, when entered in a multivariable stepwise-forward regression model that also included age, BMI, diabetes duration and diabetes-specific social support as covariates. CONCLUSION: Lower self-efficacy and higher diabetes distress were closely associated with poorer glycemic control. No direct association between HbA1c and clinical psychological symptoms was detected. These results highlight that a number of diabetes-specific psychological variables may play a role amidst psychological distress and glycemic control. Further studies are needed to elucidate the relevance of diabetes distress and self-efficacy to the achievement of individual glycemic targets.

Influence of dietary fat and carbohydrates proportions on plasma lipids, glucose control and low-grade inflammation in patients with type 2 diabetes-The TOSCA.IT Study.

PURPOSE: The optimal macronutrient composition of the diet for the management of type 2 diabetes is debated, particularly with regard to the ideal proportion of fat and carbohydrates. The aim of the study was to explore the association of different proportions of fat and carbohydrates of the diet-within the ranges recommended by different guidelines-with metabolic risk factors. METHODS: We studied 1785 people with type 2 diabetes, aged 50-75, enrolled in the TOSCA.IT Study. Dietary habits were assessed using a validated food-frequency questionnaire (EPIC). Anthropometry, fasting lipids, HbA1c and C-reactive protein (CRP) were measured. RESULTS: Increasing fat intake from <25 to ≥35 % is associated with a significant increase in LDL-cholesterol, triglycerides, HbA1c and CRP (p < 0.05). Increasing carbohydrates intake from <45 to ≥60 % is associated with significantly lower triglycerides, HbA1c and CRP (p < 0.05). A fiber intake ≥15 g/1000 kcal is associated with a better plasma lipids profile and lower HbA1c and CRP than lower fiber consumption. A consumption of added sugars of ≥10 % of the energy intake is associated with a more adverse plasma lipids profile and higher CRP than lower intake. CONCLUSIONS: In people with type 2 diabetes, variations in the proportion of fat and carbohydrates of the diet, within the relatively narrow ranges recommended by different nutritional guidelines, significantly impact on the metabolic profile and markers of low-grade inflammation. The data support the potential for reducing the intake of fat and added sugars, preferring complex, slowly absorbable, carbohydrates.

A post hoc analysis of saxagliptin efficacy and safety in patients with type 2 diabetes stratified by UKPDS 10-year cardiovascular risk score.

BACKGROUND AND AIMS: To assess the efficacy and safety of saxagliptin 2.5 and 5 mg/d in patients with type 2 diabetes mellitus (T2DM) and high risk of coronary heart disease (CHD) or stroke as estimated by the United Kingdom Prospective Diabetes Study (UKPDS) risk engine. METHODS AND RESULTS: Post hoc analysis of data pooled from 5 previously reported phase 3, randomized, placebo-controlled, 24-week studies was conducted. Patients were stratified into subgroups by UKPDS 10-year CHD and/or stroke risk ≥20% and CHD and stroke risk <20%. End points were adjusted mean change from baseline in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), 120-min postprandial glucose (PPG), and body weight and the proportion of patients achieving HbA1c <7% and ≤8% at week 24. Pooled safety data were analyzed for adverse events (AEs) and hypoglycemia. Both doses of saxagliptin reduced HbA1c, FPG, and PPG to a greater extent than placebo regardless of UKPDS risk score. The proportions of patients achieving HbA1c <7% and ≤8% were greater with saxagliptin than placebo and consistent across risk score groups. AE profile and hypoglycemia incidence were similar for saxagliptin and placebo across UKPDS risk score groups. CONCLUSION: Saxagliptin was well tolerated and improved glycemic control in patients with T2DM regardless of their CHD and stroke UKPDS risk score. Clinical trial registration numbers: Clinicaltrials.gov NCT00121641, NCT00316082, NCT00121667, NCT00313313, and NCT00295633.

Is common genetic variation at IRS1, ENPP1 and TRIB3 loci associated with cardiometabolic phenotypes in type 2 diabetes? An exploratory analysis of the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 5.

BACKGROUND AND AIMS: Insulin resistance is a hallmark of type 2 diabetes (T2DM), it is often accompanied by defective beta-cell function (BF) and is involved in the pathophysiology of cardiovascular disease (CVD). Commonalities among these traits may recognize a genetic background, possibly involving the genetic variation of insulin signaling pathway genes. We conducted an exploratory analysis by testing whether common genetic variability at IRS1, ENPP1 and TRIB3 loci is associated with cardiovascular risk traits and metabolic phenotypes in T2DM. METHODS AND RESULTS: In 597 drug-naïve, GADA-negative, newly-diagnosed T2DM patients we performed: 1) genotyping of 10 independent single-nucleotide polymorphisms covering ∼ 90% of common variability at IRS1, ENPP1 and TRIB3 loci; 2) carotid artery ultrasound; 3) standard ECG (n = 450); 4) euglycaemic insulin clamp to assess insulin sensitivity; 5) 75 g-OGTT to estimate BF (derivative and proportional control) by mathematical modeling. False discovery rate of multiple comparisons was set at 0.20. After adjustment for age, sex and smoking status, rs4675095-T (IRS1) and rs4897549-A (ENPP1) were significantly associated with carotid atherosclerosis severity, whilst rs7265169-A (TRIB3) was associated with ECG abnormalities. Rs858340-G (ENPP1) was significantly associated with decreased insulin sensitivity, independently of age, sex and body-mass-index. No consistent relationships were found with BF. CONCLUSION: Some associations were found between intermediate phenotypes of CVD and common genetic variation of gatekeepers along the insulin signaling pathway. These results need be replicated to support the concept that in T2DM the CVD genetic risk clock may start ticking long before hyperglycemia appears. ClinicalTrials.gov Identifier: NCT01526720.