Myo-inositol supplementation to prevent gestational diabetes in overweight non-obese women: bioelectrical impedance analysis, metabolic aspects, obstetric and neonatal outcomes - a randomized and open-label, placebo-controlled clinical trial.

This study aims to evaluate the effects of myo-inositol supplementation on gestational diabetes mellitus (GDM) rates and body water distribution in overweight non-obese women. 223 overweight non-obese women pregnant were randomly assigned to the treatment group (2 g of myo-inositol plus 200 µg of folic acid) or to the placebo one (200 µg of folic acid). The treatment lasted until three weeks after delivery. A tetrapolar impedance analyser was used to study body composition. The incidence of GDM was significantly reduced in the myo-inositol group compared with the placebo group. There was a significant increase in TBW, ECW and ICW values in the placebo group compared to the myo-inositol group. We have recorded a significant reduction in the overall incidence of pregnancy-induced hypertension in the myo-inositol group compared with the placebo group. Our results demonstrate the effectiveness of myo-inositol supplementation in preventing GDM in overweight non-obese pregnant women.

Genistein and endothelial function in postmenopausal women with metabolic syndrome.

BACKGROUND: Previous data have suggested that genistein could exert beneficial effects on endothelial function and on predictors of cardiovascular risk in healthy postmenopausal women. In a randomized clinical trial, we studied the effects of genistein on endothelial function in postmenopausal women with metabolic syndrome (MS). METHODS: Twenty postmenopausal women with MS, according to modified NCEP-ATP III criteria were randomly assigned to receive placebo or genistein (54 mg/day) for 6 months, along with a Mediterranean-style diet. Postmenopausal women without MS (n = 15), served as controls. The primary goal was the assessment of endothelial function by flow-mediated vasodilation (FMD) of brachial artery; moreover, time-to-peak dilation in the FMD response has been evaluated. Secondary outcomes were fasting glucose, fasting insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, visfatin, adiponectin and homocysteine blood levels. Data on adverse events were also recorded. RESULTS: After 6 months of treatment, FMD at 50s and peak FMD significantly increased in genistein recipients compared with placebo. Moreover, genistein significantly decreased the blood levels of total cholesterol, triglycerides, homocysteine and visfatin compared with placebo, while blood adiponectin levels were increased. Genistein recipients neither experienced more side-adverse effects than placebo nor discontinued the study. CONCLUSIONS: Six months of treatment with genistein effectively improves brachial artery flow-mediated vasodilation in postmenopausal women with metabolic syndrome.

Diagnosing Gestational Diabetes with a Probably Too Simplified Diagnostic Procedure Compared to International Criteria: The Indian Case Study.

Diagnostic procedures for the diagnosis of gestational diabetes mellitus (GDM) are not uniformly defined worldwide. We retrospectively applied two diagnostic procedures (i.e., the IADPSG and the Indian) to the same pregnant women in order to compare the clinical characteristics and the prevalence of risk factors for GDM. Overall, 1015 pregnant women were evaluated. GDM was diagnosed in 113 cases (11.1%) by the IADPSG criteria and in 105 cases (10.3%) by the Indian criteria. The women diagnosed with GDM according to the IADPSG criteria had higher pre-gestational BMIs, higher previous macrosomia rates, higher first trimester fasting blood glucose levels, higher fasting and 1 h glucose levels after glucose load at OGTT, and lower 2 h glucose levels at OGTT compared with the women with GDM diagnosed according to the Indian criteria. Only 49.6% of the women who were diagnosed by the IADPSG criteria were also diagnosed with GDM by the Indian diagnostic criteria. For 47.8% of the women who were diagnosed by the IADPSG criteria, a diagnosis of GDM was missed by applying the Indian diagnostic criteria. Interestingly, 49 women were diagnosed with GDM by the Indian criteria but were normal according to the IADPSG criteria. Different diagnostic criteria could lead to different GDM detection rates with different practical approaches.

The Analytical Reliability of the Oral Glucose Tolerance Test for the Diagnosis of Gestational Diabetes: An Observational, Retrospective Study in a Caucasian Population.

The Oral Glucose Tolerance Test (OGTT) is currently the gold standard reference test for the diagnosis of gestational diabetes mellitus (GDM). Several critical issues related to analytical variables have challenged its reproducibility and accuracy. This study aimed to assess the analytical reliability of the OGTT for the diagnosis of GDM. A total of 1015 pregnant women underwent a 2 h 75 g OGTT between 24 and 28 weeks of gestation. As recommended by National Academy of Clinical Biochemistry, we considered the total maximum allowable error for glucose plasma measurement as <6.9%. Assuming the possibility of analytical errors within this range for each OGTT glucose plasma value, different scenarios of GDM occurrence were estimated. GDM prevalence with standard criteria was 12.2%, and no hypothetical scenarios have shown a comparable GDM prevalence. Considering all the three OGTT values estimated at the lowest or the highest allowed value according to total maximum allowable error, GDM prevalence significantly varied (4.5% and 25.3%, respectively). Our results indicate that the OGTT is not completely accurate for GDM diagnosis.

Metabolic and clinical effect of alpha-lipoic acid administration in schizophrenic subjects stabilized with atypical antipsychotics: A 12-week, open-label, uncontrolled study.

Background: Many of the atypical antipsychotics induce metabolic side effects, limiting their use in clinical practice. Alpha-lipoic acid (ALA) was proposed as a new approach in schizophrenia to improve metabolic effects of atypical antipsychotics. The aim of the study is to evaluate the effect of ALA on metabolic and clinical parameters among schizophrenic subjects. Methods: 15 schizophrenic subjects, in stable atypical antipsychotic monotherapy were included in the study. ALA was administrated at the oral daily dose of 600 â€‹mg/d in addition to antipsychotic therapy. Metabolic, clinical, and psychopathological parameters were measured at typical antipsychotics. e initial screening, and after 12 weeks. Results: ALA produced a statistically significant reduction in QTc (p â€‹= â€‹0.012), blood glucose (p â€‹= 0.005), AST (p â€‹= â€‹0.021), γGT (p â€‹= â€‹0.035), CPK (p â€‹= â€‹0.005) and prolactinaemia (p â€‹= â€‹0.026). In contrast, there was a significant increase in HbA1c (p â€‹= â€‹0.026). No effects on body weight and blood lipid levels (triglycerides, total cholesterol, HDL, LDL) emerged. Conclusions: ALA treatment appeared to be effective for reducing diabetes risk, liver functionality parameters, hyperprolactinaemia and QTC interval. ALA appears to be safe as adjunctive components in schizophrenia.

Myoinositol plus α-lactalbumin supplementation, insulin resistance and birth outcomes in women with gestational diabetes mellitus: a randomized, controlled study.

To verify whether myo-inositol plus α-lactalbumin may reduce insulin resistance and excessive fetal growth in women with gestational diabetes mellitus. In a 12-month period, 120 women with a diagnosis of gestational diabetes mellitus were consecutively enrolled with an allocation of 1:1 in each group and randomly treated with myo-inositol plus α-lactalbumin plus folic acid (treated group) or folic acid (control group) for 2 months. Primary outcome was the variation of insulin resistance through the study evaluated by HOMA-IR. Secondary outcome was the evaluation, through the study, of fetal growth by ultrasound measurements of abdominal circumference centiles and estimated fat thickness. Some clinical outcomes were also considered. After 2 months, in the treated group, a significant reduction in insulin resistance (HOMA values 3.1 ± 1.4 vs 6.1 ± 3.4, p = 0.0002) and fetal growth was shown (Abdominal circumference centiles 54.9 ± 23.5 vs 67.5 ± 22.6, P = 0.006). Among clinical outcomes, a significant decrease in the rate of women who needed insulin (6.7% vs 20.3%, p = 0.03) and of pre-term birth (0 vs 15.2%, p = 0.007) was evidenced. A combination of myo-inositol and α-lactalbumin may reduce insulin resistance and excessive fetal growth.Clinical trial registration: ClinicalTrials.gov, http://www.clinicaltrials.gov , NCT03763669, first posted date 04/12/2018; last posted date December 06/12/2018.

High prevalence of arcobacter carriage in older subjects with type 2 diabetes.

Arcobacters are potential pathogens related to diarrheic infections and, rarely, septicaemia. This study evaluated the prevalence of arcobacters in stool samples of subjects with (n = 38) and without (n = 61) type 2 diabetes by using cultural and molecular techniques. Three Arcobacter positive cultures were found, all among diabetic subjects, whereas molecular analysis showed a carriage rate of 79% and 26.2% in subjects with and without type 2 diabetes (P < .001), respectively. The multivariate analysis showed that type 2 diabetes (beta = 1.913; 95%CI: 2.378-19.285; P < .0001) and age (beta = 1.744; 95%CI: 2.077-15.766; P = .001) were the only factors independently associated with arcobacters colonization in this population. Our study demonstrated a high prevalence of arcobacters colonization in type 2 diabetic and older subjects. The clinical significance and the potential health risk associated with these emerging species remain to be determined.

Recommendations and management of hyperglycaemia in pregnancy during COVID-19 pandemic in Italy.

Many specialists use the remote management of people with chronic disease as diabetes, but structured management protocols have not been developed yet. The COVID-19 pandemic has given a big boost to the use of telemedicine, as it allows to maintain the physical distance, essential to the containment of contagion having regular health contact. Encouraging results related to the use of telemedicine in women with hyperglycaemia in pregnancy, have been recently published. It is well known that hyperglycaemia alters the immune response to infections, that inflammation, in turn, worsens glycaemic control and that any form of hyperglycaemia in pregnancy (HIP) has effects not only on the mother but also on development of the foetus. Therefore, the Italian Diabetes and Pregnancy Study Group, together with a group of experts, developed these recommendations in order to guide physicians in the management of HIP, providing specific diagnostic, therapeutic and assistance pathways (PDTAs) for the COVID-19 emergency. Three detailed PDTAs were developed, for type 1, type 2 and gestational diabetes.

[Evaluation of customer satisfaction with the hospital catering system in the city of Palermo (Italy)]. / Valutazione della Customer Satisfaction nella "Ristorazione Ospedaliera" della città di Palermo.

The aim of the study was to evaluate patients' customer satisfaction with the hospital catering services of two public hospitals and one private sector hospital in the city of Palermo (Italy). A multiple choice questionnaire was administered by face-to-face interview to 207 of 227 hospitalized patients. Positive responses regarding the perceived quality of food were given especially by patients of the private sector hospital, 80% of which reported being satisfied with the catering service. A higher percentage of patients in the private sector hospital were satisfied with the food distribution modalities with respect to the two public hospitals. Only 3% of patients in the private sector hospital required their families to bring food from home, with respect to 7.9% and 30% respectively in the two public hospitals. Private sector patients also reported appreciating the wide availability of food and the help given by health care workers (79% vs a mean of 55% in the two public hospitals). No differences were found amongst hospitals with regards to the hygienic characteristics of meals. The results of this study indicate the need to make changes in the management of the catering service of one of the involved public hospitals especially.

Myo-Inositol for the Prevention of Gestational Diabetes Mellitus. A Brief Review.

Gestational Diabetes Mellitus (GDM) is one of the most frequent complications of pregnancy and is characterized by a carbohydrate intolerance which is diagnosed with the oral glucose tolerance test. The prevalence of GDM in our population is about 12%, but risk factors like a previous GDM, ethnicity, a parent with diabetes mellitus type 2 and maternal overweight may increase its occurrence. Complications of GDM are a pre-term birth (before 37 wk gestation), macrosomia (birth weight ≥4 kg) and gestational hypertension. Actually, GDM is principally treated with diet and, if it is necessary, with insulin; but the challenge is the prevention of GDM. Among the measures used, changes in life-style (diet+exercise) failed to prevent GDM whereas metformin showed conflicting results. A promising supplement is myo-inositol (MI) which was given from first trimester until delivery to women at risk for GDM reporting a significant decrease in GDM occurrence by more than 60% comparing to the placebo group. Recently, a secondary analysis from 3 randomized controlled trials demonstrated that MI may also significantly reduce some of GDM complications such as pre-term birth and macrosomia with a favorable impact on mother and fetus well being.

Metabolic effects of breastfeeding in women with previous gestational diabetes diagnosed according to the IADPSG criteria.

BACKGROUND: Some studies have already investigated about the short-term favorable metabolic effects of breastfeeding in women with previous gestational diabetes mellitus (GDM). AIM: The aim of our study is to confirm whether the positive effects reported are maintained in the larger cohorts of patients with mild form of gestational diabetes mellitus (GDM) because recently diagnosed according to IADPSG criteria. MATERIALS AND METHODS: This retrospective study includes 97 evaluable consecutive women with prior GDM who have the follow-up oral glucose tolerance test at least 3 months after delivery. Fasting and 2-h plasma glucose values, homeostasis model assessment (HOMA-IR), total cholesterol, and triglycerides were obtained in pregnancy and during the post-partum control. RESULTS: These patients were divided in 81 (83.5%) who lactate until 3 months and 16 (16.5%) who did not lactate. During pregnancy, there are no significant differences between the two groups for age, BMI, fasting and 2-h plasma glucose values, HOMA-IR, total cholesterol and triglycerides. At the postpartum control, we have at univariate analysis significant differences for all these parameters except total cholesterol. After adjustment for confounders we still have, in the breastfeeding group, HOMA-IR reduction (OR 0.370; 95% CI 0.170-0.805; p < .01) as significant independent variable, whose improvement is the most acknowledged important factor for the prevention of abnormal glucose tolerance later in life. CONCLUSION: These encouraging results confirm our determination to warmly advice the women affected by GDM to breastfeeding at least for 3 months.

Erectile dysfunction in compensated liver cirrhosis.

BACKGROUND: Data on erectile dysfunction (ED) in cirrhotic patients are limited as yet. Aim of this study was to investigate the prevalence of ED and the factors potentially involved in its development in compensated cirrhosis. METHODS: We prospectively enrolled 102 male (mean age 63 ±â€¯10 years) affected by cirrhosis in Child-Pugh Class A. The following questionnaires were used: simplified International Index of Erectile Function (IIEF-5) Questionnaire, Centre of Epidemiologic Studies Depression Scale and ANDROTEST. RESULTS: ED was found in 57/102(55.9%) patients, and was mild, moderate and severe in 21(36.8%), 6(10.5%) and 30(52.6%) subjects, respectively. ED patients were significantly older than those without (66 ±â€¯10 vs 60 ±â€¯10,p = 0.006); ED prevalence gradually increased with age. There was no statistically significant difference between patients with and without ED concerning the coexistence of diabetes, hypertension, and cardiovascular disease. Age(p = 0.040) and serum haemoglobin(p = 0.027) were identified as predictors of ED on multivariate analysis. Liver-related factors and pharmacological treatment, including ß-blockers, were not associated with the presence of ED. CONCLUSIONS: In patients with compensated liver cirrhosis, even in concomitance with other chronic comorbidities, the prevalence of ED is not markedly different from the general population. Compensated cirrhosis per se is not a risk factor for ED occurrence. Older age and low haemoglobin values are significantly associated with ED in cirrhotics.

Guidelines for the screening and diagnosis of gestational diabetes in Italy from 2010 to 2019: critical issues and the potential for improvement.

AIMS: In 2010, Italian health professionals rapidly implemented the one-step screening for gestational diabetes mellitus (GDM) based on a 75 g OGTT, to comply with the diagnostic criteria proposed by the International Association of Diabetes and Pregnancy Study Groups (IADPSG). The change was promoted by the two main Italian scientific societies of diabetology, Associazione Medici Diabetologi (AMD) and Società Italiana di Diabetologia (SID), and it took just a few months for the Istituto Superiore di Sanità, together with several scientific societies, to revise the criteria and include them in the National Guidelines System. Over the last 9 years, the implementation of these guidelines has shown some benefits and some drawbacks. METHODS: In order to evaluate the critical issues arisen from the implementation of the current Italian guidelines for the diagnosis of GDM, the studies published on this topic have been reviewed. The search was performed using the following keywords: "gestational diabetes" AND "diagnostic criteria" OR screening AND Ital*. The study is an expert opinion paper, based on the relevant scientific literature published between 2010 and 2019. The databases screened for the literature review included PubMed, MEDLINE, and Scopus. RESULTS: The implementation of the Guidelines for Screening and Diagnosis of GDM in Italy present some strengths and some weaknesses. One of the positive aspects is that high-risk women are required to perform an OGTT early in pregnancy. By contrast, there are several aspects in need of improvement: (1) In spite of the current indications, only a minority of high-risk women perform OGTT early in pregnancy; (2) several low-risk women are screened for GDM; (3) in some low-risk women affected by GDM, the diagnosis might be missed with the application of the current guidelines; (4) there is a lack of homogeneity in the risk assessment data from different regions. CONCLUSIONS: In order to improve the current Italian GDM guidelines, some practical solutions have been suggested.

Peripheral blood CD34+ cells as a novel and noninvasive early marker of first trimester miscarriage: results from a case-control analysis.

PURPOSE: To evaluate the levels of peripheral blood CD34+ cells in women who subsequently had a spontaneous miscarriage (SM). MATERIALS AND METHODS: We enrolled 11 women who had SM, matching them for age, BMI and gestational age with 33 healthy pregnancies (controls). From a blood sample at 9th-11th weeks of pregnancy, we evaluated PAPP-A, free ß-hCG, T (suppressor and helper), NK, B, CD34+ cells. RESULTS: In peripheral blood of women who had SM, PAPP-A and CD34+ cells were significantly lower (p < 0.001) compared to control group. CONCLUSIONS: CD34+ cell low level in peripheral blood is associated with increased risk of SM.

Positive association between a single abnormal glucose tolerance test value in pregnancy and subsequent abnormal glucose tolerance.

OBJECTIVE: To study the prevalence of abnormal glucose tolerance among women with a single abnormal glucose tolerance test value in previous pregnancy and identify factors predictive of the later development of abnormal glucose tolerance in this group. STUDY DESIGN: In all, 58 women with gestational diabetes, 66 with a single abnormal value in a glucose tolerance test, and 56 control women underwent a 75-g oral glucose tolerance test at a mean of 6.9 years from the index pregnancy. RESULTS: Abnormal glucose tolerance was present in 34.5% of women with previous gestational diabetes and in 28.7% of women with 1 previous abnormal value, significantly different from the controls (9.7%). Independent risk factors that distinguished the subjects who later developed an abnormal glucose tolerance were prepregnancy BMI, parity > 1, and first-degree relatives affected by diabetes mellitus in the group with gestational diabetes, and prepregnancy BMI, maternal age, (> or = 30 y) and parity > 1 in the group with a single abnormal value. Prepregnancy BMI (> or = 26.9) proved to be the most predictive factor of abnormal glucose tolerance later in life. CONCLUSION: Sicilian women with a single abnormal value at the glucose tolerance test in pregnancy have an increased likelihood of developing an abnormal glucose tolerance later in life, similar to gestational diabetes. Prepregnancy BMI was confirmed as the strongest predictive factor in both groups.

Midtrimester amniotic fluid leptin and insulin levels and subsequent gestational diabetes.

AIMS: To evaluate midtrimester amniotic fluid leptin levels in pregnancies subsequently complicated by gestational diabetes. METHODS: We studied 32 pregnant women with gestational diabetes and a control group of 43 normal pregnancies with an adequate gestational age fetus. All underwent a midtrimester amniocentesis: leptin and insulin were measured in the amniotic fluid. Data were compared with the Mann-Whitney U-test. RESULTS: Median leptin concentrations in the amniotic fluid of the gestational diabetes mellitus patients were significantly higher than in the control group (15.1 vs. 7.9 ng/ml) (p = 0.001); amniotic insulin concentrations were also higher in the gestational diabetes mellitus than in the control group (0.67 vs. 0.38 microU/ml) (p = 0.02). Furthermore, amniotic fluid leptin levels were directly correlated with amniotic insulin concentrations; instead, there was no correlation with maternal BMI and birth weight. CONCLUSION: Our data suggest that in pregnancies subsequently complicated by gestational diabetes, amniotic fluid leptin and insulin levels are higher in the early fetal period.

[Depression, anxiety and anger in patients with type 1 diabetes mellitus.] / Depressione, ansia e rabbia in soggetti affetti da diabete mellito di tipo 1.

INTRODUCTION: The aim of this study is to evaluate the influence of negative emotions such as depression, anxiety and anger on clinical expression of type 1 diabetes, also assessing possible gender differences. MATERIALS AND METHODS: 75 subjects with type 1 diabetes mellitus afferent to Diabetology Unit of the University Hospital in Messina underwent the following psychodiagnostic tests: Hamilton Rating Scale For Depression (HDRS), State-Trait Anxiety Inventory form Y (STAI-Y), State-Trait Anger Expression Inventory-2 (STAXI-2). Continuous data were expressed as mean ± standard deviation, and the comparison between groups was performed using T Student test; the data not continuous were expressed as a percentage and the differences between groups were evaluated using Chi-square test. We considered the results for values of p<0.05. RESULTS: The mean age of 75 subjects (49.3% males) was 41.0±11.4 years, age of disease onset was 21.1 ± 11.8 years and mean duration of disease was 19.9±11.9 years; 30.7% of subjects were treated with CSII (Subcutaneus Insulin Infusion). Mild levels of depression (HDRS= 10.71±7.9) and anxiety (STAI-Y= 52.37±6.11) were found, whereas STAXI-2 subscales scores were within the normal range. Statistical analysis did not show significant gender differences. DISCUSSION: Our results, according to data from literature, confirm the association between negative emotions, particularly anxiety, and diabetes. No gender differences were found. CONCLUSIONS: Our results suggest the importance of investigating the association between diabetes and negative emotional states and the psychological and psychopathological dimensions which may have a potential role in the therapeutic management of diabetes.

Genistein Supplementation and Cardiac Function in Postmenopausal Women with Metabolic Syndrome: Results from a Pilot Strain-Echo Study.

Genistein, a soy-derived isoflavone, may improve cardiovascular risk profile in postmenopausal women with metabolic syndrome (MetS), but few literature data on its cardiac effects in humans are available. The aim of this sub-study of a randomized double-blind case-control study was to analyze the effect on cardiac function of one-year genistein dietary supplementation in 22 post-menopausal patients with MetS. Participants received 54 mg/day of genistein (n = 11) or placebo (n = 11) in combination with a Mediterranean-style diet and regular exercise. Left ventricular (LV) systolic function was assessed as the primary endpoint, according to conventional and strain-echocardiography measurements. Also, left atrial (LA) morphofunctional indices were investigated at baseline and at the final visit. Results were expressed as median with interquartile range (IQ). A significant improvement of LV ejection fraction (20.3 (IQ 12.5) vs. -1.67 (IQ 24.8); p = 0.040)), and LA area fractional change (11.1 (IQ 22.6) vs. 2.8 (9.5); p = 0.034)) were observed in genistein patients compared to the controls, following 12 months of treatment. In addition, body surface area indexed LA systolic volume and peak LA longitudinal strain significantly changed from basal to the end of the study in genistein-treated patients. One-year supplementation with 54 mg/day of pure genistein improved both LV ejection fraction and LA remodeling and function in postmenopausal women with MetS.

Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial.

BACKGROUND: The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. METHODS: TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50-75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2-3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15-45 mg) or a sulfonylurea (5-15 mg glibenclamide, 2-6 mg glimepiride, or 30-120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. FINDINGS: Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74-1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p<0·0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer, and fractures were not significantly different between treatment groups. INTERPRETATION: In this long-term, pragmatic trial, incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) and pioglitazone as add-on treatments to metformin. Both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events, although pioglitazone was associated with fewer hypoglycaemia events. FUNDING: Italian Medicines Agency, Diabete Ricerca, and Italian Diabetes Society.