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Background and aims: In routine clinical practice, early discontinuation of newly initiated glucose-lowering medications (GLM) is relatively common. We herein evaluated if the clinical characteristics associated with early discontinuation of dapagliflozin were different from those associated with early discontinuation of other GLM. Methods: The DARWIN-T2D was a multicenter retrospective study conducted at diabetes specialist outpatient clinics in Italy. We included 2484 patients who were initiated on dapagliflozin in 2015–2016 and 14,801 patients who were initiated on other GLM (DPP-4 inhibitors, GLP-1 receptor agonists, or gliclazide) in the same period. After excluding patients who had not (yet) returned to follow-up, we compared the characteristics of patients who persisted on drug versus those who were no longer on drug at the first available follow-up after at least 3months. Results: As compared to those who persisted on drug, patients who discontinued dapagliflozin (51.7%) were more often female, had higher baseline fasting plasma glucose (FPG), HbA1c, and eGFR, and less common use of metformin. Upon multiple regression, higher HbA1c, higher eGFR, and lower metformin use remained independently associated with early discontinuation. Among patients who had been initiated on other GLM, 41.7% discontinued. Variables independently associated with discontinuation were older age, longer diabetes duration, higher HbA1c, eGFR, and albumin excretion, more common use of insulin and less metformin. Conclusion: In routine clinical practice, all variables associated with dapagliflozin discontinuation were also associated with discontinuation of other GLM. Thus, despite a distinctive mechanism of action and a peculiar tolerability profile, no specific predictor of dapagliflozin discontinuation was detected.

Importance: Evidence of effective smoking cessation interventions in patients with diabetes is limited. The unique behavioral and metabolic characteristics of smokers with type 2 diabetes warrants a randomized clinical trial of the smoking cessation drug varenicline. Objective: To evaluate the efficacy and safety of varenicline in patients with type 2 diabetes with an intention to quit smoking. Design, setting, and participants: This multicenter, double-blind, placebo-controlled randomized clinical trial recruited patients from 6 outpatient clinics in 5 hospitals in Catania, Italy. Patients with type 2 diabetes, who were smoking at least 10 cigarettes a day, and who intended to quit smoking were screened for eligibility. Eligible patients were randomized to either varenicline or placebo treatment. The trial consisted of a 12-week treatment phase followed by a 40-week follow-up, nontreatment phase. Intention-to-treat data analysis was performed from December 2020 to April 2021. Interventions: Varenicline, 1 mg, twice daily or matched placebo administered for 12 weeks. Patients in both treatment groups also received smoking cessation counseling. Main outcomes and measures: The primary efficacy end point of the study was the continuous abstinence rate (CAR) at weeks 9 to 24. Secondary efficacy end points were the CAR at weeks 9 to 12 and weeks 9 to 52 as well as 7-day point prevalence of abstinence at weeks 12, 24, and 52. Results: A total of 300 patients (mean [SD] age, 57.4 [0.8] years; 117 men [78.0%] in varenicline group and 119 men [79.3%] in placebo group) were randomized to receive varenicline (n = 150) or placebo (n = 150). The CAR at weeks 9 to 24 was significantly higher for the varenicline than placebo group (24.0% vs 6.0%; odds ratio [OR], 4.95; 95% CI, 2.29-10.70; P < .001). The CARs at weeks 9 to 12 (31.3% vs 7.3%; OR, 5.77; 95% CI, 2.85-11.66; P < .001) and weeks 9 to 52 (18.7% vs 5.3%; OR, 4.07; 95% CI, 1.79-9.27; P < .001) as well as the 7-day point prevalence of abstinence at weeks 12, 24, and 52 were also significantly higher for the varenicline vs placebo group. The most frequent adverse events occurring in the varenicline group compared with the placebo group were nausea (41 [27.3%] vs 17 [11.4%]), insomnia (29 [19.4%] vs 19 [12.7%]), abnormal dreams (19 [12.7%] vs 5 [3.4%]), anxiety (17 [11.4%] vs 11 [7.3%]), and irritability (14 [9.4%] vs 8 [5.4%]). Serious adverse events were infrequent in both groups and not treatment-related. Conclusions and relevance: Results of this trial showed that inclusion of varenicline in a smoking cessation program is efficacious in achieving long-term abstinence without serious adverse events. Varenicline should be routinely used in diabetes education programs to help patients with type 2 diabetes stop smoking. Trial registration: ClinicalTrials.gov Identifier: NCT01387425.

Aims According to cardiovascular outcome trials, some sodium‐glucose contransporter‐2 inhibitors (SGLT2i) and glucagon‐like peptide‐1 receptor agonists (GLP‐1RA) are recommended for secondary cardiovascular prevention in type 2 diabetes (T2D). In this real‐world study, we compared the simultaneous reductions in HbA1c, body weight and systolic blood pressure after initiation of dapagliflozin or GLP‐1RA as second or a more advanced line of therapy. Materials and methods DARWIN‐T2D was a retrospective multi‐centre study conducted at diabetes specialist clinics in Italy that compared T2D patients who initiated dapagliflozin or GLP‐1RA (exenatide once weekly or liraglutide). Data were collected at baseline and at the first follow‐up visit after 3 to 12 months. The primary endpoint was the proportion of patients achieving a simultaneous reduction in HbA1c, body weight and systolic blood pressure. To reduce confounding, we used multivariable adjustment (MVA) or propensity score matching (PSM). Results Totals of 473 patients initiating dapagliflozin and 336 patients initiating GLP‐1RA were included. The two groups differed in age, diabetes duration, HbA1c, weight and concomitant medications. The median follow‐up was 6 months in both groups. Using MVA or PSM, the primary endpoint was observed in 30% to 32% of patients, with no difference between groups. Simultaneous reduction of HbA1c, BP and SBP by specific threshold, as well as achievement of final goals, did not differ between groups. GLP‐1RA reduced HbA1c by 0.3% more than the reduction achieved with dapagliflozin. Conclusion In routine specialist care, initiation of dapagliflozin can be as effective as initiation of a GLP‐1RA for attainment of combined risk factor goals.

Obesity represents a major risk factor for metabolic disorders, but some individuals, “metabolically healthy” (MHO), show less clinical evidence of these complications, in contrast to “metabolically unhealthy” (MUO) individuals. The aim of this cross-sectional study is to assess the prevalence of the MHO phenotype in a cohort of 246 overweight/obese Italian children and adolescents, and to evaluate their characteristics and the role of insulin resistance. Homeostasis model assessment–insulin resistance (HOMA-IR), insulin sensitivity index (ISI), insulinogenic index (IGI) and disposition index (DI) were all calculated from the Oral Glucose Tolerance Test (OGTT). MHO was defined by either: (1) HOMA-IR < 2.5 (MHO-IRes), or (2) absence of the criteria for metabolic syndrome (MHO-MetS). The MHO prevalence, according to MHO-MetS or MHO-IRes criteria, was 37.4% and 15.8%, respectively. ISI was the strongest predictor of the MHO phenotype, independently associated with both MHO-IRes and MHO-MetS. The MHO-MetS group was further subdivided into insulin sensitive or insulin resistant on the basis of HOMA-IR (either < or ≥ 2.5). Insulin sensitive MHO-MetS patients had a better metabolic profile compared to both insulin resistant MHO-MetS and MUO-MetS individuals. These data underscore the relevance of insulin sensitivity to identifying, among young individuals with overweight/obesity, the ones who have a more favorable metabolic phenotype.

Introduction DPP-4 inhibitors (DPP4i) and sulfonylureas are popular second-line therapies for type 2 diabetes (T2D), but there is a paucity of real-world studies comparing their effectiveness in routine clinical practice. Methods This was a multicenter retrospective study on diabetes outpatient clinics comparing the effectiveness of DPP4i versus gliclazide extended release. The primary endpoint was change from baseline in HbA1c. Secondary endpoints were changes in fasting plasma glucose, body weight, and systolic blood pressure. Automated software extracted data from the same clinical electronic chart system at all centers. Propensity score matching (PSM) was used to generate comparable cohorts to perform outcome analysis. Results We included data on 2410 patients starting DPP4i and 1590 patients starting gliclazide (mainly 30–60 mg/day). At baseline, the two groups differed in disease duration, body weight, blood pressure, HbA1c, fasting glucose, HDL cholesterol, triglycerides, liver enzymes, eGFR, prevalence of microangiopathy, and use of metformin. Among DPP4i molecules, no difference in glycemic effectiveness was detected. In matched cohorts (n = 1316/group), patients starting DPP4i, as compared with patients starting gliclazide, experienced greater reductions in HbA1c (− 0.6% versus − 0.4%; p

AimsType 2 diabetes (T2D) accelerates the decline in glomerular function; however, some individuals do not develop chronic kidney disease despite advanced age and long-lasting T2D. We aimed to phenotype patients with T2D aged 80years or older who presented with a fully preserved kidney function.MethodsFrom an Italian population of 281,217 T2D outpatients, we collected data on demographics, anthropometrics, diabetes duration, HbA1c, fasting plasma glucose, lipids, liver enzymes, estimated glomerular filtration rate (eGFR), albumin excretion rate (AER), chronic complications, and medication use. We primarily compared patients with a fully preserved kidney function (eGFR>90ml/min/1.73m(2) and AER

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.

Razionale EXPO 2015 affronta un bisogno primario per l’essere umano: “nutrire il pianeta; energia per la vita”. Per le ripercussioni globali a breve-medio termine è una importante occasione di confronto nazionale e internazionale. La problematica dovrebbe essere affrontata in modo razionale, chiaro e, soprattutto, ampiamente compartecipato dall’opinione pubblica. Dato per scontato che il primo nutrimento è l’ossigeno, l’assunto è che la composizione e non solo la qualità del cibo ingerito siano indispensabili per stabilire la porzione e la frequenza di consumo. Il primo aspetto da fare emergere dovrebbe pertanto riguardare le caratteristiche della corretta nutrizione e le modalità per ottenerla, considerando che il comportamento alimentare è la risultante di una complessa interazione tra fattori biologici, psicologici e l’ambiente in cui si vive. Cibo in quantità suf#ciente, sicuro e in grado di fornire il giusto apporto nutrizionale sono le condizioni per mantenere la salute e avere una vita attiva (World Food Summit del 1996). Mentre la Commissione Europea propone un aggiornamento dei Regolamenti a garanzia della sicurezza alimentare con una rinnovata attenzione alla prevenzione e alle ricadute ecologiche dell’alimentazione, le Agenzie Internazionali (OMS, FAO, UE) sottolineano la necessità di porre la giusta attenzione agli aspetti nutrizionali dell’alimentazione e alle sue conseguenze in termini di salute. Sulla scelta al consumo le tre priorità emergenti sono: 1. ricerca del benessere e salute. L’equazione “mangiare bene-stare bene”, sempre più percepita dalla popolazione, necessita di chiarimenti sui rapporti tra sano e naturale, sano e industriale, sano e biologico (più di 700 milioni di euro in Italia nel 2014 per prodotti bio), sano ed eco-friendly; 2. attenzione all’ambiente e alla sostenibilità; 3. criteri etici nella scelta dei prodotti. La visione globale della problematica risulta estremamente complessa, richiedendo una pianificazione a 360° che va oltre il mero ambito sanitario. Imprescindibile alla sua realizzazione, specie a livello nazionale, l’esistenza di un “Sistema Paese” di fatto coeso. Se nutrire l’individuo è lo scopo principale del cibo, dovrebbero risultare de#nite le priorità/emergenze nutrizionali da affrontare su scala nazionale e internazionale per poter rendere efficaci i modelli d’intervento sia di tipo preventivo sia terapeutico e di piani#cazione agro-alimentare per le popolazioni. Purtroppo, le politiche d’intervento attivate nei vari Paesi dimostrano ancora impostazioni fortemente settoriali e in parte condizionate da interessi economico-finanziari. Una constatazione risulta evidente: l’incomprensibile inadeguato investimento strategico in nutrizione clinica e preventiva nell’ambito della politica sanitaria nazionale. E a maggior ragione, alla luce dei grandi cambiamenti demografici avvenuti in tutti i Paesi del mondo: invecchiamento della popolazione, aumento degli adolescenti, specie nei Paesi in via di sviluppo, migrazioni. Ciò ha modificato prevalenza e incidenza delle patologie cronico degenerative, che richiedono un numero crescente d’interventi riabilitativi, specie in relazione alla malnutrizione per eccesso e difetto (calorico-proteica e/o in micronutrienti). Una evidenziazione delle criticità condivisa dai tecnici del settore, nel rispetto della necessaria multidisciplinarietà, risulta pertanto quanto mai necessaria per un serio raffronto, anche a livello internazionale, su problematiche comuni. La “pesatura” delle stesse, sulla base di criteri quantitativi assoluti, rende oggettiva e trasparente all’opinione pubblica e ai policy maker la possibile e ottimale allocazione delle risorse necessarie per contrastarle. Il manifesto delle criticità in nutrizione clinica e preventiva: • faciliterà la riflessione dei cittadini italiani, sottoposti a una eccessiva e costante pressione mediatica – prevalentemente a fini commerciali – su tali argomenti, fonte di crescente confusione e insicurezza circa i comportamenti da seguire. Non bisognerebbe lasciarsi sfuggire l’opportunità di un’ampia ri*essione di carattere scientifico, che possa portare all’attenzione di un pubblico globale temi che sono centrali per l’intera Comunità Internazionale non solo per la durata di Expo 2015; • potrà fungere da strumento operativo d’indirizzo istituzionale per un intervallo temporale di almeno quattro anni, necessario per una ef#cace pianificazione degli interventi. Il documento non è una linea-guida o un decalogo di nobili propositi, ma una analisi oggettiva corredata di azioni strategiche fattibili e auspichiamo vincolanti. Deve aumentare il convincimento che le problematiche nutrizionali (per lo più connesse alla patologia cronica), non sono risolvibili con soli interventi sanitari, ma richiede un cambio di orientamento culturale a livello produttivo, distributivo e di consumo. In questa operazione risulta evidente la centralità del Ministero della Salute e in particolare della Direzione Generale della Igiene e Sicurezza degli Alimenti e della Nutrizione, per un’eventuale revisione delle politiche in materia (tramite strumenti quali linee-guida, LEA, PSN, ecc.) e ricadute in ambito nazionale (politiche regionali in materia sanitaria dedicate alla nutrizione) e internazionale.

Background The long-term effects of sibutramine treatment on the rates of cardiovascular events and cardiovascular death among subjects at high cardiovascular risk have not been established. Methods We enrolled in our study 10,744 overweight or obese subjects, 55 years of age or older, with preexisting cardiovascular disease, type 2 diabetes mellitus, or both to assess the cardiovascular consequences of weight management with and without sibutramine in subjects at high risk for cardiovascular events. All the subjects received sibutramine in addition to participating in a weight-management program during a 6-week, single-blind, lead-in period, after which 9804 subjects underwent random assignment in a double-blind fashion to sibutramine (4906 subjects) or placebo (4898 subjects). The primary end point was the time from randomization to the first occurrence of a primary outcome event (nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death). Results The mean duration of treatment was 3.4 years. The mean weight loss during the lead-in period was 2.6 kg; after randomization, the subjects in the sibutramine group achieved and maintained further weight reduction (mean, 1.7 kg). The mean blood pressure decreased in both groups, with greater reductions in the placebo group than in the sibutramine group (mean difference, 1.2/1.4 mm Hg). The risk of a primary outcome event was 11.4% in the sibutramine group as compared with 10.0% in the placebo group (hazard ratio, 1.16; 95% confidence interval [CI], 1.03 to 1.31; P=0.02). The rates of nonfatal myocardial infarction and nonfatal stroke were 4.1% and 2.6% in the sibutramine group and 3.2% and 1.9% in the placebo group, respectively (hazard ratio for nonfatal myocardial infarction, 1.28; 95% CI, 1.04 to 1.57; P=0.02; hazard ratio for nonfatal stroke, 1.36; 95% CI, 1.04 to 1.77; P=0.03). The rates of cardiovascular death and death from any cause were not increased. Conclusions Subjects with preexisting cardiovascular conditions who were receiving long-term sibutramine treatment had an increased risk of nonfatal myocardial infarction and nonfatal stroke but not of cardiovascular death or death from any cause. (Funded by Abbott; ClinicalTrials.gov number, NCT00234832.)

Backgound and Aims: We evaluated whether hyperinsulinemia and/or insulin resistance are independently associated with plasma lipids, uric acid and blood pressure in nondiabetic subjects. Methods and Results: A database of hyperinsulinemic euglycemic clamp carried out with standard technique (40 mU per min per square meter of body surface area) in nondiabetic Italian subjects has been recently established. In this database we evaluated the relationships existing between fasting plasma insulin (FPI), glucose metabolized during clamp (M) and plasma levels of triglycerides (TG), high density lipoprotein cholesterol (HDL-C), uric acid (UA) as well as blood pressure (BP) in nondiabetic subjects with fasting plasma glucose

Background and aims: We evaluated whether hyperinsulinemia and/or insulin resistance are independently associated with plasma lipids, uric acid and blood pressure in non-diabetic subjects. Methods and results: A database of non-diabetic Italian subjects has recently been set up using data from hyperinsulinemic euglycemic clamp studies carried out using the standard technique (40 mU per min per square meter of body surface area). In this database we evaluated the relationships between fasting plasma insulin (FPI), glucose metabolized during clamp (M) and plasma levels of triglycerides (TG), high density lipoprotein cholesterol (HDL-C), uric acid (UA) as well as blood pressure (BP) in non-diabetic subjects with fasting plasma glucose

The aim of this study was to deeper investigate the mechanisms through which ENPP1, a negative modulator of insulin receptor (IR) activation, plays a role on insulin signaling, insulin secretion and eventually glucose metabolism. ENPP1 cDNA (carrying either K121 or Q121 variant) was transfected in HepG2 liver-, L6 skeletal muscle- and INS1E beta-cells. Insulin-induced IR-autophosphorylation (HepG2, L6, INS1E), Akt-Ser(473), ERK1/2-Thr(202)/Tyr(204) and GSK3-beta Ser(9) phosphorylation (HepG2, L6), PEPCK mRNA levels (HepG2) and 2-deoxy-D-glucose uptake (L6) was studied. GLUT 4 mRNA (L6), insulin secretion and caspase-3 activation (INS1E) were also investigated. Insulin-induced IR-autophosphorylation was decreased in HepG2-K, L6-K, INS1E-K (20%, 52% and 11% reduction vs. untransfected cells) and twice as much in HepG2-Q, L6-Q, INS1E-Q (44%, 92% and 30%). Similar data were obtained with Akt-Ser(473), ERK1/2-Thr(202)/Tyr(204) and GSK3-beta Ser(9) in HepG2 and L6. Insulin-induced reduction of PEPCK mRNA was progressively lower in untransfected, HepG2-K and HepG2-Q cells (65%, 54%, 23%). Insulin-induced glucose uptake in untransfected L6 (60% increase over basal), was totally abolished in L6-K and L6-Q cells. GLUT 4 mRNA was slightly reduced in L6-K and twice as much in L6-Q (13% and 25% reduction vs. untransfected cells). Glucose-induced insulin secretion was 60% reduced in INS1E-K and almost abolished in INS1E-Q. Serum deficiency activated caspase-3 by two, three and four folds in untransfected INS1E, INS1E-K and INS1E-Q. Glyburide-induced insulin secretion was reduced by 50% in isolated human islets from homozygous QQ donors as compared to those from KK and KQ individuals. Our data clearly indicate that ENPP1, especially when the Q121 variant is operating, affects insulin signaling and glucose metabolism in skeletal muscle- and liver-cells and both function and survival of insulin secreting beta-cells, thus representing a strong pathogenic factor predisposing to insulin resistance, defective insulin secretion and glucose metabolism abnormalities.