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Introdroduction: Obesity and its associated metabolic conditions have become a significant global health problem in recent years, with many people living with obesity fulfilling criteria for pharmacological treatment. The development of the glucagon‐like peptide‐1 receptor agonists for chronic weight management has triggered new interest in the incretins and other hormones as targets for obesity, and investigations into dual and triple co‐agonists. Methods: The objective of this narrative review was to summarize the available data on approved and emerging incretin‐based agents for the treatment of obesity. Results: In clinical trials of currently available agents in people with overweight or obesity, weight loss of between 6% and 21% of baseline body weight has been observed, with between 23% and 94% of participants achieving 10% or higher weight loss, depending on the study and the agent used. Favourable outcomes have also been seen with regard to cardiovascular risk and outcomes, diabetes prevention, metabolic dysfunction‐associated steatotic liver disease/steatohepatitis and prevention of weight regain after metabolic surgery. Limitations associated with these agents include high costs, the potential for weight regain once treatment is stopped, the potential loss of lean body mass and gastrointestinal adverse events; potential issues with respect to gallbladder and biliary diseases require further investigation. Conclusions: Many dual and triple co‐agonists are still in development, and more data are needed to assess the efficacy, safety and tolerability of these emerging therapies versus the established incretin‐based therapies; however, data are promising, and further results are eagerly awaited. [ABSTRACT FROM AUTHOR]

Aims: To assess the cost–utility of the FreeStyle Libre flash continuous glucose monitoring (CGM) system from an Italian healthcare system perspective, when compared with self‐monitoring of blood glucose (SMBG) in people living with type 2 diabetes mellitus (T2DM) receiving basal insulin. Materials and Methods: A patient‐level microsimulation model was run using Microsoft Excel for 10 000 patients over a lifetime horizon, with 3.0% discounting for costs and utilities. Inputs were based on clinical trials and real‐world evidence, with patient characteristics reflecting Italian population data. The effect of flash CGM was modelled as a persistent 0.8% reduction in glycated haemoglobin versus SMBG. Costs (€ 2023) and disutilities were applied to glucose monitoring, diabetes complications, severe hypoglycaemia, and diabetic ketoacidosis. The health outcome was measured as quality‐adjusted life‐years (QALYs). Results: Direct costs were €5338 higher with flash CGM than with SMBG. Flash CGM was associated with 0.51 more QALYs than SMBG, giving an incremental cost‐effectiveness ratio (ICER) of €10 556/QALY. Scenario analysis ICERs ranged from €3825/QALY to €26 737/QALY. In probabilistic analysis, flash CGM was 100% likely to be cost effective at willingness‐to‐pay thresholds > €20 000/QALY. Conclusions: From an Italian healthcare system perspective, flash CGM is cost effective compared with SMBG for people living with T2DM on basal insulin. [ABSTRACT FROM AUTHOR]

Aim: To analyse the effects of albiglutide, a glucagon‐like peptide 1 receptor agonist, on cardiovascular outcomes in older adults aged ≥65 years with type 2 diabetes and cardiovascular disease who participated in the Harmony Outcomes trial (NCT02465515). Materials and methods: We conducted a post hoc analysis of the primary endpoint of the Harmony Outcomes trial—time to first occurrence of a major adverse cardiovascular event—in subgroups of participants aged <65 and ≥65 years and <75 and ≥75 years at baseline. Hazard ratios and 95% confidence intervals (CIs) were generated using Cox proportional hazards regression. Results: The analysis population included 9462 Harmony Outcomes participants, including 4748 patients ≥65 and 1140 patients ≥75 years at baseline. Hazard ratios for the prevention of major adverse cardiovascular events were 0.66 (95% CI, 0.53‐0.82) in persons <65 and 0.86 (95% CI, 0.71‐1.04) in those ≥65 years (age interaction p =.07), and 0.78 (95% CI, 0.67‐0.91) in <75 and 0.70 (95% CI, 0.48‐1.01) in ≥75 year age groups (interaction p =.6). When analysed as a continuous variable, age did not modify the effect of albiglutide on the primary endpoint. Conclusions: This post hoc analysis adds to the body of literature showing that glucagon‐like peptide 1 receptor agonists added to standard type 2 diabetes therapy safely reduce the incidence of cardiovascular events in older adults with established cardiovascular disease. In this analysis, the risk‐benefit profile was similar between younger and older age groups treated with albiglutide. [ABSTRACT FROM AUTHOR]

Aims: To estimate the incidence of a major adverse cardiovascular event (MACE) and a composite kidney outcome across estimated glomerular filtration rate (eGFR) and urine albumin‐to‐creatinine ratio (UACR) levels, and to determine whether efpeglenatide's effect varies with these indices. Materials and Methods: AMPLITUDE‐O trial data were used to estimate the relationship of eGFR, UACR, and Kidney Disease Improving Global Outcomes (KDIGO) category to the hazard of MACE and the kidney composite. Interactions on these outcomes between eGFR and the UACR, and between each of these variables and efpeglenatide were also assessed. Results: Baseline eGFR and UACR were available for 3983 participants (mean age 64.5 years). During a median follow‐up of 1.8 years, the hazards of MACE and the kidney composite for the lowest versus highest eGFR third were 1.6 (95% confidence interval [CI] 1.2, 2.2) and 2.3 (95% CI 1.9, 2.8), respectively. The hazards for the highest versus the lowest UACR third were 2.3 (95% CI 1.8, 3.1) and 18.0 (95% CI 12.7, 25.5), respectively, and for the high‐ versus low‐risk KDIGO categories the hazards were 2.4 (95% CI 1.8, 3.1) and 16.0 (95% CI 11.6, 22.0), respectively. eGFR and UACR were independent determinants of both outcomes, but negatively interacted with each other for the kidney outcome. Efpeglenatide's effect on both outcomes did not vary with any kidney disease measure (all interaction p values ≥0.26). Conclusions: In high‐risk people with diabetes, eGFR, UACR, and KDIGO category have different relationships to incident cardiovascular and kidney outcomes. The beneficial effect of efpeglenatide on these outcomes is independent of kidney‐related risk category. [ABSTRACT FROM AUTHOR]

In the primary care setting providers have more tools available than ever before to impact positively obesity, diabetes, and their complications, such as renal and cardiac diseases. It is important to recognise what is available for treatment taking into account diabetes heterogeneity. For those who develop type 2 diabetes (T2DM), effective treatments are available that for the first time have shown a benefit in reducing mortality and macrovascular complications, in addition to the well‐established benefits of glucose control in reducing microvascular complications. Some of the newer medications for treating hyperglycaemia have also a positive impact in reducing heart failure (HF). Technological advances have also contributed to improving the quality of care in patients with diabetes. The use of technology, such as continuous glucose monitoring systems (CGM), has improved significantly glucose and glycated haemoglobin A1c (HbA1c) values, while limiting the frequency of hypoglycaemia. Other technological support derives from the use of predictive algorithms that need to be refined to help predict those subjects who are at great risk of developing the disease and/or its complications, or who may require care by other specialists. In this review we also provide recommendations for the optimal use of the new medications; sodium‐glucose co‐transporter‐2 inhibitors (SGLT2i) and Glucagon‐like peptide‐receptor agonists 1 (GLP1RA) in the primary care setting considering the relevance of these drugs for the management of T2DM also in its early stage. [ABSTRACT FROM AUTHOR]

Diagnosing heart failure is often difficult due to the non‐specific nature of symptoms, which can be caused by a range of medical conditions. Natriuretic peptides (NPs) have been recognized as important biomarkers for diagnosing heart failure. This document from the Heart Failure Association examines the practical uses of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) in various clinical scenarios. The concentrations of NT‐proBNP vary according to the patient profile and the clinical scenario, therefore values should be interpreted with caution to ensure appropriate diagnosis. Validated cut‐points are provided to rule in or rule out acute heart failure in the emergency department and to diagnose de novo heart failure in the outpatient setting. We also coin the concept of 'heart stress' when NT‐proBNP levels are elevated in an asymptomatic patient with risk factors for heart failure (i.e. diabetes, hypertension, coronary artery disease), underlying the development of cardiac dysfunction and further increased risk. We propose a simple acronym for healthcare professionals and patients, FIND‐HF, which serves as a prompt to consider heart failure: Fatigue, Increased water accumulation, Natriuretic peptide testing, and Dyspnoea. Use of this acronym would enable the early diagnosis of heart failure. Overall, understanding and utilizing NT‐proBNP levels will lead to earlier and more accurate diagnoses of heart failure ultimately improving patient outcomes and reducing healthcare costs. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the impact of assisted reproductive technology (ART) on the risk of gestational diabetes mellitus (GDM) in single pregnancies. Materials and Methods: We retrospectively collected clinical and anthropometric data of 219ART‐ and 256 age‐ and body mass index (BMI)‐matched women with spontaneous conception screened for GDM. The primary outcome was to evaluate GDM prevalence in ART women. Results: There were no differences in age, BMI, and family history of diabetes in the two groups of women. ART‐women were more frequently primiparous, whereas the prevalence of previous GDM was higher in SC‐women. The prevalence of GDM in the whole cohort was 36.1% and was higher in ART‐women (52.3% vs. 23.4%; p < 0.0001). In the whole cohort, on multivariate analysis, family history of diabetes (OR 1.67; 95% CI: 1.03–2.69), previous GDM (OR 7.05; 95% CI: 2.92–17.04), pre‐pregnancy obesity (OR 2.72; 95% CI 1.21–6.13), and ART (OR 4.14; 95% CI 2.65–6.48) were independent risk factors for GDM. Among ART‐women, age over 40 years was associated with GDM. Preterm delivery was more common in ART‐women; gestational week at delivery, birth weight, ponderal index, and Apgar score were lower in ART‐women than in SC‐women, both in the whole cohort and in GDM women. Conclusions: Among women undergoing ART treatment, at least one in two develops GDM. ART appears to be an independent risk factor for GDM in single pregnancies, particularly above the age of 40. ART treatment seems to be associated with an increased rate of preterm delivery and lower neonatal birth weight and Apgar score, especially in GDM women. Clinical Trial Registration: The study was not registered as it is an observational retrospective evaluation. [ABSTRACT FROM AUTHOR]

Aims: Whether different diabetic kidney disease (DKD) phenotypes recognise differences in morphological and vascular properties of the kidney is still unexplored. We evaluated the potential role of kidney ultrasonography in differentiating DKD phenotypes in subjects with type 2 diabetes. Materials and Methods: This is a cross‐sectional, single‐centre study. Total (TRV) and parenchymal renal volumes (PRV) were calculated by applying the ellipsoid formula for conventional (2D) ultrasonography and with manual segmentation for 3D ultrasonography, and then adjusted for body surface area (aTRV, aPRV). Renal resistive index (RI) was contextually determined. DKD phenotypes have been defined based on increased urinary albumin‐to‐creatinine ratio (ACR >30 mg/g) and/or reduced eGFR (<60 ml/min/1.73 m2). Recruitment was planned to have groups of the same size. Results: Among 256 subjects, 26.2% had No‐DKD, 24.6% increased albuminuria only (Alb+), 24.2% non‐albuminuric DKD (Alb−DKD), and 25.0% albuminuric DKD (Alb+DKD). Compared to No‐DKD, RI was significantly higher in all DKD phenotypes, being the highest in Alb+DKD, and with a significant trend of RI > 0.70 to increase across phenotypes. In comparison with No‐DKD, both 2D and 3D volumes were increased in Alb+ and significantly reduced in Alb−DKD as well as in Alb+DKD, with significantly lower volumes in Alb−DKD as compared to Alb+DKD at the same reduced levels of eGFR. In adjusted regressions, compared to No‐DKD, RI was associated with Alb+; both RI and aPRV3D were associated with Alb+DKD; only aPRV3D with Alb‐DKD. Compared to No‐DKD, Receiver Operating Characteristic curve analyses, designed taking into account conventional risk factors, showed that US parameters did not ameliorate the characterisation of Alb+ and Alb+DKD, while aPRV3D significantly improved the phenotyping of Alb‐DKD. Conclusions: As a novel information, we reported that, in type 2 diabetes, the emerging normoalbuminuric DKD phenotype showed reduced TRVs and PRVs even when compared, at similarly reduced eGFR levels, with Alb+DKD opening. In perspective, these findings suggest a possible role of imaging for better discrimination of DKD phenotypes in clinical practice. [ABSTRACT FROM AUTHOR]

Brain plasticity and function is impaired in conditions of metabolic dysregulation, such as obesity. Less is known on whether brain function is also affected by transient and physiological metabolic changes, such as the alternation between fasting and fed state. Here we asked whether these changes affect the transient shift of ocular dominance that follows short‐term monocular deprivation, a form of homeostatic plasticity. We further asked whether variations in three of the main metabolic and hormonal pathways affected in obesity (glucose metabolism, leptin signalling and fatty acid metabolism) correlate with plasticity changes. We measured the effects of 2 h monocular deprivation in three conditions: post‐absorptive state (fasting), after ingestion of a standardised meal and during infusion of glucagon‐like peptide‐1 (GLP‐1), an incretin physiologically released upon meal ingestion that plays a key role in glucose metabolism. We found that short‐term plasticity was less manifest in fasting than in fed state, whereas GLP‐1 infusion did not elicit reliable changes compared to fasting. Although we confirmed a positive association between plasticity and supraphysiological GLP‐1 levels, achieved by GLP‐1 infusion, we found that none of the parameters linked to glucose metabolism could predict the plasticity reduction in the fasting versus fed state. Instead, this was selectively associated with the increase in plasma beta‐hydroxybutyrate (B‐OH) levels during fasting, which suggests a link between neural function and energy substrates alternative to glucose. These results reveal a previously unexplored link between homeostatic brain plasticity and the physiological changes associated with the daily fast‐fed cycle. [ABSTRACT FROM AUTHOR]

Aims: Since it is unknown whether glucose variability (GV) is increased and whether this is related to worsening of insulin secretion and action in prediabetes, we have assessed insulin secretion and sensitivity, and daily GV in early stages of dysglycemia. Materials and Methods: Twenty subjects with normal glucose tolerance (NGT; age 45.0 ± 9.5 years; BMI 31.1 ± 6.4 kg/m2), 25 with NGT and 1hrOGTT>8.6 mmol/L (1hrOGTT; 45.7 ± 8.5 years; 32.4 ± 7.0 kg/m2), and 59 with isolated impaired glucose tolerance (iIGT; 47.7 ± 11.2 years; 31.3 ± 6.1 kg/m2) underwent OGTT and MMTT. CGM was performed with blinded FreeStyle Libre Pro for 24 h under standard conditions. Parameters of beta‐cell function, insulin sensitivity and GV were calculated. Results: Overall insulin secretion and action as well as GV progressively worsened across glucose tolerance categories. On a matrix analysis, GV parameters were inversely related to ISSI‐2; r = −0.37 to −0.52; p < 0.0001; and IGI; r = −0.28 to −0.48; p < 0.0001 for CV, SD, J‐index, LI, HBGI and MAGE. Insulin secretion (IGI) and b‐cell function (ISSI‐2) emerged as independent contributors to GV in early stage of dysglycemia accounting for about 16%–38% of its variability. Conclusions: Our results show that daily GV worsens already with mild impairment of glucose tolerance. The increase in GV is inversely related to insulin secretion and action. [ABSTRACT FROM AUTHOR]

Aims: SIRT1 exerts effects on ageing and lifespan, as well cardiovascular (CV) disease risk. SIRT1 gene is very polymorph with a few tagging single nucleotide polymorphisms (SNPs) so far identified. Some SNPs, including rs7896005, were associated with type 2 diabetes (T2DM). We aimed to ascertain whether this SNP may be associated with CV disease at baseline as well with these same outcomes and all‐cause mortality over a 13‐year follow‐up. Materials and Methods: Genotypes of SIRT1 gene were determined using TaqMan SNP assay. Results: Out of 905 T2DM, 9.1% had the AA genotype, 43.2% the AG, and 47.7% the GG. Hardy–Weinberg Equilibrium was met (minor allele frequency 0.306; p = 0.8899). At baseline, there was no difference across genotypes for sex, age, diabetes duration, CV risk factors, treatments, and microangiopathy. Major CV outcomes, myocardial infarction (MI), any coronary heart disease (CHD), and peripheral artery disease (PAD) were more frequent in GG than in AA/AG (p from 0.013 to 0.027), with no association with cerebrovascular events. By fully adjusted regression, GG remained independently related to major CV outcomes, MI, CHD, and PAD. Over follow‐up, we recorded 258 major CV events (28.5%; AA/AG 25.2%, GG 32.2%; p = 0.014) with an adjusted hazard ratio (HR) of GG versus AA/AG of 1.296 (95% CI 1.007–1.668, p = 0.044); 169 coronary events (18.7%; AA/AG 15.4%, GG 22.2%; p = 0.006) with HR 1.522 (1.113–2.080, p = 0.008); 79 (8.7%) hospitalisation for heart failure (AA/AG 7.0%, GG 10.6%; p = 0.045) and HR 1.457 (0.919–2.309, p = 0.109); 36 PAD (4.0%; AA/AG 2.3%, GG 5.8%; p = 0.007) with HR 2.225 (1.057–4.684, p = 0.035). No association was found with cerebrovascular events, end stage renal disease, and all‐cause mortality. Conclusions: The rs7896005 SNP of SIRT1 might play a role in cardiovascular disease, mainly CHD risk in T2DM. Results call for larger association studies as well as studies to ascertain mechanisms by which this variant confers increased risk. [ABSTRACT FROM AUTHOR]

Summary: Obesity is a chronic, multifactorial, relapsing disease. Despite multicomponent lifestyle interventions, including pharmacotherapy, maintaining bodyweight loss is challenging for many people. The pathophysiology of obesity is complex, and currently approved pharmacotherapies only target a few of the many pathways involved; thus, single‐targeting agents have limited efficacy. Proglucagon‐derived peptides, glucagon, and the incretin hormones glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP), represent attractive targets for managing obesity and metabolic disorders because they may have direct roles in multiple mechanisms including satiety, energy homeostasis, and lipolytic activity. Unimolecular dual and triple agonists targeting glucagon and incretin hormone receptors have been shown to promote bodyweight loss, lower glucose levels, and reduce food intake in animal models of obesity. Multiple dual receptor agonists are in clinical development for the treatment of obesity, including GLP‐1/GIP and GLP‐1/glucagon receptor agonists. The extent to which glucagon contributes to treatment effects remains to be understood, but it may promote bodyweight loss by reducing food intake, while concomitant GLP‐1 receptor agonism ensures normal glucose control. Further research is required to fully understand the molecular mechanisms of action and metabolic effects of both dual and triple receptor agonists. [ABSTRACT FROM AUTHOR]

With increasing population aging and prevalence of type 2 diabetes (T2D) worldwide, prevention of diabetic complications remains a major unmet need. While cardiovascular outcomes of diabetes are improving over time, diabetic kidney disease (DKD) still leads to an exceedingly high rate of end‐stage kidney disease (ESKD). A game‐changing opportunity is offered by treatment with sodium‐glucose cotransporter‐2 (SGLT2) inhibitors. Randomized controlled trials (RCTs) have indisputably shown that SGLT2 inhibitors reduce the rate of DKD progression, the decline in estimated glomerular filtration rate (eGFR), and the development of ESKD. In parallel, SGLT2 inhibitors improve cardiovascular outcomes, especially the risk of hospitalization for heart failure. Real‐world studies (RWSs) have largely confirmed the findings of RCTs in broader populations of subjects with T2D followed under routine care. In the present paper, we review RWSs exploring the renal effects of SGLT2 inhibitors and highlight the most critical challenges that can be encountered in designing and conducting such studies. Channelling bias (confounding by indication), time‐lag bias, conditioning on the future, database heterogeneity, linearity of eGFR change over time, and duration of observation are critical issues that may undermine the robustness of RWS findings. We then elaborate on the new opportunities to overcome such limitations by describing the design and objectives of the DARWIN (DApagliflozin Real‐World evIdeNce)‐Renal study, a new RWS promoted by the Italian Diabetes Society. Fine‐tuning of methods for comparative observational research will improve evidence derived from RWSs on the renal effects of SGLT2 inhibitors, aiding the evolving discussion regarding the place of SGLT2 inhibitors in T2D treatment algorithms in different stages of DKD. [ABSTRACT FROM AUTHOR]

Aim: In people with type 2 diabetes (T2D) requiring intensification beyond glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and oral antihyperglycaemic drugs (OADs), switching to iGlarLixi was shown to be efficacious and well‐tolerated in the LixiLan‐G trial. This exploratory analysis of LixiLan‐G assessed the efficacy and safety of switching to iGlarLixi versus continuing GLP‐1 RA therapy, stratified by screening HbA1c level (≥7.0 to ≤7.5 %; >7.5 to ≤8.0 %; >8.0 to ≤9.0 % [≥53 to ≤58 mmol/mol; >58 to ≤64 mmol/mol; >64 to ≤75 mmol/mol]) and previous GLP‐1 RA regimen at screening (once/twice daily or once weekly). Materials and Methods: Endpoints for all subgroups included: change in HbA1c, achievement of HbA1c <7 % and hypoglycaemia events. Adverse events and changes in fasting plasma glucose (FPG), 2‐hour postprandial plasma glucose (PPG), 2‐hour PPG excursion and weight were analysed according to previous GLP‐1 RA regimen. Results: Switching to iGlarLixi in all subgroups resulted in significantly greater reductions in HbA1c and proportions of participants reaching HbA1c <7 % (including with no documented hypoglycaemia) at Week 26 compared with continued GLP‐1 RA treatment. Switching to iGlarLixi also led to significantly greater reductions in FPG, 2‐hour PPG, and 2‐hour PPG excursion, irrespective of previous GLP‐1 RA regimen. Rates of hypoglycaemia were low, but slightly higher in those who switched to iGlarLixi for all subgroups. Modest weight gain was seen with iGlarLixi, irrespective of previous GLP‐1 RA regimen. Conclusions: Switching to iGlarLixi improved glycaemic control, regardless of screening HbA1c or previous GLP‐1 RA type, offering a simple, efficacious and well‐tolerated treatment intensification option for people with T2D inadequately controlled by GLP‐1 RAs and OADs. [ABSTRACT FROM AUTHOR]

Tackling obesity during the COVID-19 pandemic Obesity in patients younger than 60 years is a risk factor for COVID-19 hospital admission. Keywords: COVID-19; diabetes; obesity; pre-diabetes EN COVID-19 diabetes obesity pre-diabetes 1 5 5 03/19/21 20210301 NES 210301 INTRODUCTION Most people contracting coronavirus disease 2019 (COVID-19) develop a non-serious disease with some remaining entirely asymptomatic. Obesity predisposes to the risk of higher mortality in young COVID-19 patients. [Extracted from the article]

Aim: The effect of the weekly exendin‐based glucagon‐like peptide‐1 receptor agonist efpeglenatide on cardiovascular (CV) outcomes in high‐risk patients with type 2 diabetes (T2DM) with and without chronic kidney disease (CKD) is unknown. Materials and methods: People with T2DM and glycated haemoglobin >7%, ≥18 years old with previous CV disease, or ≥50 years old with CKD [defined as an estimated glomerular filtration rate (eGFR) of 25–59.9 mL/min/1.73 m2], and one or more additional CV risk factors were recruited. Participants were randomized in a 1:1:1 ratio, stratified by current, intended or neither current nor intended use of a sodium‐glucose cotransporter‐2 (SGLT2) inhibitor to receive weekly injections of efpeglenatide (4 mg or 6 mg) or masked placebo. The primary outcome is a major adverse CV event defined as non‐fatal myocardial infarction, non‐fatal stroke or CV death. Secondary outcomes include a composite kidney outcome (new onset macroalbuminuria with an increase from baseline of ≥30%, sustained 40% decrease in eGFR, renal replacement therapy, or sustained eGFR <15 mL/min/1.73 m2). The trial will continue until ≥330 participants have had a major adverse CV event outcome and the sample size was based on accruing enough outcomes to detect non‐inferiority of efpeglenatide versus placebo. Results: Recruitment of 4076 participants (33% women, mean age 64.5 years) occurred between 11 May 2018 and 25 April 2019 at 344 sites in 28 countries. Mean baseline glycated haemoglobin was 8.9% (1.5), 31.6% had an eGFR <60 mL/min/1.73 m2, 89.5% had previous CV disease and 15.0% were on an SGLT2 inhibitor. Conclusions: The results of the AMPLITUDE O trial will inform the use of exendin‐based glucagon‐like peptide‐1 receptor agonist to people with T2DM and high CV risk, with and without CKD, in the presence and absence of an SGLT2 inhibitor. [ABSTRACT FROM AUTHOR]

We analysed glycaemic durability (sustained glycaemic control) with early combination therapy (metformin plus vildagliptin) versus metformin monotherapy, among patients with type 2 diabetes diagnosed before (young‐onset [YOD]) and after (late‐onset [LOD]) the age of 40 years, enrolled in the VERIFY trial. The primary endpoint was time to initial treatment failure (TF), defined as HbA1c of 7.0% or higher at two consecutive scheduled visits after randomization. The time to secondary TF was assessed when both groups were receiving and failing on the combination. A total of 186 (9.3%) patients had YOD and 1815 (90.7%) had LOD with a mean age difference of 20.4 years. Compared with metformin monotherapy, early combination reduced the risk of time to initial TF for both YOD (48%, P <.0006) and LOD (46%, P <.0001). With early combination, risk for time to secondary TF was reduced by 48% (P <.0035) in YOD and 24% (P <.0009) in LOD. Both treatment approaches were well tolerated with no unexpected safety concerns. In treatment‐naïve patients with YOD (HbA1c 6.5%‐7.5%), an early combination strategy improved attainment of the glycaemic target with durability and delayed treatment escalation compared with initial metformin monotherapy. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy of iGlarLixi by C‐peptide levels and duration of diabetes in an exploratory analysis of the LixiLan‐G study. Methods: LixiLan‐G was a 26‐week, randomized, open‐label study in adults with type diabetes (T2D) inadequately controlled while on a glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA), with metformin, with or without pioglitazone and/or a sodium‐glucose co‐transporter‐2 inhibitor. This analysis investigated the efficacy of switching to iGlarLixi by fasting baseline quartile C‐peptide levels and baseline quartile of duration of T2D compared with continued GLP‐1 RA use. Results: Change in glycated hemoglobin (HbA1c) from baseline to week 26 was significantly greater with iGlarLixi compared with continued GLP‐1 RAs across all fasting C‐peptide quartiles (−1.00% to −1.06% vs. –0.23% to −0.54% range, respectively) and irrespective of all T2D duration quartiles (−0.94% to −1.07% vs. –0.25% to −0.50% range). A significantly greater proportion of participants in the iGlarLixi arm achieved an HbA1c of <7% across all C‐peptide quartiles (51%‐73% range) than in the GLP‐1 RA arm (19%‐32% range). The greatest reductions in HbA1c in participants receiving iGlarLixi were observed in those with the shortest duration of disease, although consistently greater than reductions observed with continued GLP‐1 RAs. Reductions in HbA1c were comparable across C‐peptide quartiles within the iGlarLixi arm. Conclusions: The results of this study suggest that iGlarLixi is an effective treatment option, irrespective of C‐peptide levels or duration of diabetes, in adults with insufficiently controlled T2D receiving GLP‐1 RAs. [ABSTRACT FROM AUTHOR]

Aims: To determine the optimal dose(s) of once‐monthly administration of efpeglenatide, a long‐acting glucagon‐like peptide‐1 receptor agonist (GLP‐1RA), in patients with type 2 diabetes (T2D) inadequately controlled on metformin. Materials and methods: In this phase 2, randomized, placebo‐controlled, double‐blind trial (NCT02081118), patients were randomized 1:1:1:1 to subcutaneous efpeglenatide (8, 12 or 16 mg once monthly; n = 158) or placebo (n = 51). The 16‐week treatment period included a 4‐week titration phase with once‐weekly efpeglenatide 4 mg, followed by one dose of efpeglenatide 8 mg once monthly and two doses of the assigned once‐monthly dose. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to week 17. Results: All efpeglenatide doses significantly reduced HbA1c versus placebo (P < 0.0001 for all). Overall, the least squares mean difference in HbA1c reductions between efpeglenatide and placebo was −7.7 mmol/mol (−0.71%; baseline to week 17). At week 17, a significantly greater proportion of efpeglenatide patients had an HbA1c level <53 mmol/mol (<7%) versus placebo (48.7% vs. 30.6%; P = 0.0320). Significant body weight loss occurred across all efpeglenatide doses (placebo‐corrected reduction −2.0 kg [efpeglenatide overall]; P = 0.0003). The safety profile was consistent with GLP‐1RAs, with gastrointestinal (GI) disorders being the most common treatment‐emergent adverse events. Fluctuations in effects on glucose levels and rates of GI events occurred between peak and trough efpeglenatide concentrations. Conclusions: Efpeglenatide once monthly (following once‐weekly titration) has significant benefits with regard to HbA1c and weight reduction versus placebo in patients with T2D. Further studies are needed to evaluate the long‐term efficacy and safety of efpeglenatide once monthly. [ABSTRACT FROM AUTHOR]

Aim: To investigate the effect of sitagliptin (SITA) and metformin (MET) monotherapy as well as in combination (MET+SITA) on beta‐cell function and insulin sensitivity in women with recent gestational diabetes (GDM) and impaired glucose regulation (IGR: impaired fasting glucose and/or impaired glucose tolerance). Material and Methods: Forty women were randomly assigned to receive SITA (100 mg qd), MET (850 mg bid) or MET+SITA (50 + 850 mg bid) for 16 weeks. A 75 g oral glucose tolerance test (OGTT) and +125 mg/dL hyperglycaemic clamp followed by 5 g i.v. L‐arginine were performed at baseline and end of study. The primary outcome of the study was the mean change in arginine‐stimulated insulin secretion rate during the hyperglycaemic clamp test from baseline to 16‐week therapy. Results: At week 16, body mass index declined in all groups (−1.2 ± 0.2 kg/m2; P < 0.05). MET+SITA gave a greater increase of first phase(2–10 min) insulin secretion and arginine‐stimulated response (720.3 ± 299.0 to 995.5 ± 370.3 pmol/L and 3.2 ± 0.6 to 4.8 ± 1.0 pmoL/min, respectively, both P < 0.05) compared with MET and SITA. Similarly, MET+SITA was more effective in increasing OGTT‐based glucose sensitivity (55.7 ± 11.3 to 108 ± 56.2 pmol x min−1 m−2 x mM−1; P = 0.04) and insulin‐stimulated glucose disposal (M/I: 2.2 ± 0.5 to 4.6 ± 1.3 mg/kg/min÷μIU/min/ml; P = 0.04; Matsuda index [SI]: 3.1 ± 0.4 to 5.7 ± 1.1; P = 0.03) compared with either MET or SITA. Disposition index (ISSI‐2) increased with MET+SITA and SITA (both P < 0.05), while no significant change was observed in MET. Among MET+SITA women, 33% reverted to normal glucose tolerance (NGT) compared with 14% with MET and 7% with SITA (P < 0.05). Conclusion: This study shows that MET+SITA is superior to SITA and MET monotherapy regarding beta‐cell function and insulin sensitivity improvement in IGR women with previous GDM, and may offer a potential pharmacologic intervention to reduce the risk of type 2 diabetes in this high‐risk population. [ABSTRACT FROM AUTHOR]

Dapagliflozin is associated with greater reductions in HbA1c and weight than saxagliptin in management of type 2 diabetes mellitus (T2DM). The present post hoc analyses compared the durability of these effects over short‐ and long‐term follow‐up in patients with T2DM who were inadequately controlled with metformin (≥1500 mg/day) and who were receiving either dapagliflozin (10 mg/day) or saxagliptin (5 mg/day). Failure of glycaemiccontrol was assessed using the slope of the change in HbA1c from baseline‐over‐time regression line (coefficient of failure [CoF]). CoF was compared directly (dapagliflozin vs saxagliptin) over the short term (NCT01606007, 24 weeks) and indirectly (placebo‐adjusted) over the long term (NCT00528879 and NCT00121667, 102 weeks). A low CoF value indicated greater durability. CoF was lower for dapagliflozin versus saxagliptin over 18–24 weeks (−1.38%/year; 95% CI, −2.41 to −0.35; P = .009) and 20–102 weeks (−0.37%/year; 95% CI, −0.73 to −0.02; P = .04). Fewer dapagliflozin‐treated patients versus saxagliptin‐treated patients required rescue medication or discontinued the study because of failure to achieve glycaemic control at 24 weeks (3.4% vs 9.4%; P = .0191). In patients with T2DM who were inadequately controlled with metformin, dapagliflozin was associated with greater durability of glycaemic control than saxagliptin over 18–24 and 20–102 weeks. [ABSTRACT FROM AUTHOR]

Aims: To ensure the integrity of the planned analyses and maximize the clinical utility of the VERIFY study results by describing the detailed concepts behind its statistical analysis plan (SAP) before completion of data collection and study database lock. The SAP will be adhered to for the final primary data analysis of the VERIFY trial. Materials and Methods: Vildagliptin efficacy in combination with metformin for early treatment of T2DM (VERIFY) is an ongoing, multicentre, randomized controlled trial aiming to demonstrate the clinical benefits of glycaemic durability and glucose control achieved with an early combination therapy in newly‐diagnosed type 2 diabetes (T2DM) patients. Results: The SAP was initially designed at the study protocol conception phase and later modified, as reported here, in collaboration between the steering committee members, statisticians, and the VERIFY study leadership team. All authors were blinded to treatment allocation. An independent statistician has additionally retrieved and presented unblinded data to the independent data safety monitoring committee. An overview of the trial design with a focus on describing the fine‐tuning of the analysis plan for the primary efficacy endpoint, risk of initial treatment failure, and secondary, exploratory and pre‐specified subgroup analyses is provided here. Conclusion: According to optimal trial practice, the details of the statistical analysis and data‐handling plan prior to locking the database are reported here. The SAP accords with high‐quality standards of internal validity to minimize analysis bias and will enhance the utility of the reported results for improved outcomes in the management of T2DM. [ABSTRACT FROM AUTHOR]

Aims: To compare the efficacy and safety of an intensification strategy of early triple combination therapy with dapagliflozin (DAPA) plus saxagliptin (SAXA) to a dual therapy strategy with sitagliptin (SITA) in patients with type 2 diabetes who are inadequately controlled with metformin (MET) monotherapy. Materials and methods: This multinational, active‐controlled, parallel‐group phase 3b trial randomized 461 patients, at least 18 years of age, with glycated haemoglobin (HbA1c) of 8%–10.5% (64–91 mmol/mol), to either DAPA plus SAXA or SITA, added to MET, for a 26‐week double‐blind treatment period and an extension of a 26‐week blinded treatment period. Results: Mean (± SD) baseline HbA1c was 8.8% ± 0.9% (73.0 ± 9.3 mmol/mol). DAPA plus SAXA (n = 232) provided a greater reduction from baseline in HbA1c at Weeks 26 and 52 compared with SITA (n = 229) (adjusted mean ± SE change, Week 26: −1.41 ± 0.07% vs −1.07 ± 0.07% [−15.4 ± 0.8 mmol/mol vs 11.7 ± 0.8 mmol/mol]; P = 0.0008; Week 52: −1.29 ± 0.08% vs −0.81 ± 0.09% [14.1 ± 0.9 mmol/mol vs 8.9 ± 1.0 mmol/mol]). The between‐group difference in adjusted mean (95% CI) change from baseline in HbA1c increased from −0.34 (−0.54, −0.14) at Week 26 to −0.48 (−0.71, −0.25) at Week 52. DAPA plus SAXA was generally well tolerated and the incidence of adverse events was similar in both treatment arms. Conclusions: Early intensification to triple therapy with DAPA plus SAXA results in better, more durable glycaemic control than addition of SITA only (dual therapy) in patients with high HbA1c levels who are uncontrolled with MET monotherapy. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the changes in renal endpoints in type 2 diabetes patients treated with dapagliflozin versus other glucose‐lowering medications in routine clinical practice. Materials and Methods: DARWIN‐T2D was a retrospective study conducted at 46 outpatient diabetes clinics in Italy. An automated software collected data on 17 285 patients who received dapagliflozin, glucagon‐like peptide‐1 receptor agonists, dipeptidyl peptidase‐4 inhibitors, or gliclazide, 6751 of whom had a follow‐up visit. We analysed changes in albumin excretion rate (AER) and estimated glomerular filtration rate (eGFR). Results: Patients who received dapagliflozin (n = 473) were younger, more obese, and had a poorer glucose control than those who received a comparator (n = 2973). After ~6 months, median (interquartile range) AER declined by 37%, from 19.5 (7.5–78.2) to 13.2 (6.5–45.0) mg/g (P < 0.0001) in the dapagliflozin group and did not change in the comparator group. After adjusting for confounders, therapy with dapagliflozin versus comparators was associated with an AER reduction of 26.4 ± 13.1 mg/g (P = 0.045), and eGFR (mL/min/1.73 m2) diminished by 1.1 ± 0.5 (P = 0.049) in the dapagliflozin group and by 0.6 ± 9.1 (P = 0.002) in the comparator group (P = 0.35 between groups). No patient treated with dapagliflozin versus four patients treated with comparators experienced a doubling of serum creatinine. Conclusions: The antiproteinuric effect of dapagliflozin is confirmed here for the first time by real‐world data. Despite a mild decline in eGFR, there was no evidence of clinically relevant worsening in renal function. [ABSTRACT FROM AUTHOR]

Aims: Dapagliflozin is a selective inhibitor of sodium glucose co‐transporter 2 (SGLT2). This study assessed the efficacy and safety of dapagliflozin 10 mg vs placebo in patients with type 2 diabetes (T2D) and moderate renal impairment (estimated glomerular filtration rate [eGFR], 45–59 mL/min/1.73 m2; chronic kidney disease [CKD] stage 3A). Materials and methods: In this double‐blind, parallel group, Phase 3 study (NCT02413398, clinicaltrials.gov) patients with inadequately controlled T2D (HbA1c 7.0%‐11.0%) were randomized (1:1) to dapagliflozin 10 mg once daily (N = 160) or matching placebo (N = 161) for 24 weeks. Randomization was stratified by pre‐enrolment glucose‐lowering therapy. The primary endpoint was change from baseline in HbA1c at Week 24. Results: At Week 24, compared with placebo, dapagliflozin significantly decreased HbA1c (difference [95% CI], −0.34% [−0.53, −0.15]; P < 0.001), body weight (difference [95% CI], −1.25 kg [−1.90, −0.59]; P < 0.001), fasting plasma glucose (difference [95% CI], −0.9 mmol/L [−1.5, −0.4]; P = 0.001) and systolic blood pressure (difference [95% CI], −3.1 mm Hg [−6.3, 0.0]; P < 0.05). Decreases from baseline in eGFR were greater with dapagliflozin than placebo at Week 24 (−2.49 mL/min/1.73 m2 [−4.96, −0.02]), however, eGFR returned to baseline levels at Week 27 (3 weeks post‐treatment) (0.61 mL/min/1.73 m2 [−1.59, 2.81]). No increase in adverse events (AEs; 41.9% vs 47.8%) or serious AEs (5.6% vs 8.7%) were reported with dapagliflozin versus placebo. No AEs of bone fractures, amputations or DKA were reported. Conclusions: The findings of this study (NCT02413398, clinicaltrials.gov) support the positive benefit/risk profile of dapagliflozin for the treatment of patients with T2D and CKD 3A. [ABSTRACT FROM AUTHOR]

Glucagon‐like peptide‐1 receptor agonists lower blood glucose in type 2 diabetes (T2D) partially through glucose‐dependent stimulation of insulin secretion. The aim of this study was to investigate whether beta‐cell function (as measured by HOMA2‐%B) at baseline affects the glycaemic response to dulaglutide. Dulaglutide‐treated patients from AWARD‐1, AWARD‐3 and AWARD‐6 clinical studies were categorised based on their homeostatic model assessment of beta‐cell function (HOMA2‐%B) tertiles. Changes in glycaemic measures in response to treatment with once‐weekly dulaglutide were evaluated in each HOMA2‐%B tertile. Patients with low HOMA2‐%B had higher baseline glycated haemoglobin (HbA1c), fasting and postprandial blood glucose, and longer duration of diabetes (P < .001, all) (mean low, middle and high tertiles with dulaglutide 1.5 mg: HOMAB‐2%B, 31%, 58%, 109%; HbA1c, 8.7%, 7.7%, 7.3%, respectively). At 26 weeks, the low tertile experienced larger reductions in HbA1c compared to the high tertile with dulaglutide 1.5 mg (mean; −1.55% vs. −0.98% [−16.94 vs. −10.71 mmol/mol]). Differences between low and high tertiles disappeared when adjusted for baseline HbA1c (LSM; −1.00 vs. −1.18% [−10.93 vs. −12.90 mmol/mol]). Greater decreases in fasting blood glucose and greater increases in fasting C‐peptide were observed in the low tertile. Similar increases in HOMA2‐%B were observed in all tertiles. Dulaglutide demonstrated clinically relevant HbA1c reduction irrespective of estimated baseline beta‐cell function. [ABSTRACT FROM AUTHOR]

The safety of triple oral therapy with dapagliflozin plus saxagliptin plus metformin versus dual therapy with dapagliflozin or saxagliptin plus metformin was compared in a post‐hoc analysis of 3 randomized trials of sequential or concomitant add‐on of dapagliflozin and saxagliptin to metformin. In the concomitant add‐on trial, patients with type 2 diabetes on stable metformin received dapagliflozin 10 mg/d plus saxagliptin 5 mg/d. In sequential add‐on trials, patients on metformin plus either saxagliptin 5 mg/d or dapagliflozin 10 mg/d received dapagliflozin 10 mg/d or saxagliptin 5 mg/d, respectively, as add‐on therapy. After 24 weeks, incidences of adverse events and serious adverse events were similar between triple and dual therapy and between concomitant and sequential add‐on regimens. Urinary tract infections were more common with sequential than with concomitant add‐on therapy; genital infections were reported only with sequential add‐on of dapagliflozin to saxagliptin plus metformin. Hypoglycaemia incidence was <2.0% across all analysis groups. In conclusion, the safety and tolerability of triple therapy with dapagliflozin, saxagliptin and metformin, as either concomitant or sequential add‐on, were similar to dual therapy with either agent added to metformin. [ABSTRACT FROM AUTHOR]

Aim: To compare alirocumab, a proprotein convertase subtilisin‐kexin type 9 inhibitor, with usual care (UC) in individuals with type 2 diabetes (T2DM) and mixed dyslipidaemia not optimally managed by maximally tolerated statins in the ODYSSEY DM‐DYSLIPIDEMIA trial (NCT02642159). Materials and Methods: The UC options (no additional lipid‐lowering therapy; fenofibrate; ezetimibe; omega‐3 fatty acid; nicotinic acid) were selected prior to stratified randomization to open‐label alirocumab 75 mg every 2 weeks (with increase to 150 mg every 2 weeks at week 12 if week 8 non‐HDL cholesterol concentration was ≥2.59 mmol/L [100 mg/dL]) or UC for 24 weeks. The primary efficacy endpoint was percentage change in non‐HDL cholesterol from baseline to week 24. Results: The randomized population comprised 413 individuals (intention‐to‐treat population, n = 409; safety population, n = 412). At week 24, the mean non‐HDL cholesterol reductions were superior with alirocumab (−32.5% difference vs UC, 97.5% confidence interval −38.1 to −27.0; P < .0001). Overall, 63.6% of alirocumab‐treated individuals were maintained on 75 mg every 2 weeks. Alirocumab also reduced LDL cholesterol (−43.0%), apolipoprotein B (−32.3%), total cholesterol (−24.6%) and LDL particle number (−37.8%) at week 24 vs UC (all P < .0001). Consistent with the overall trial comparison, alirocumab reduced non‐HDL cholesterol to a greater degree within each UC stratum at week 24. The incidence of treatment‐emergent adverse events was 68.4% (alirocumab) and 66.4% (UC). No clinically meaningful effect on glycated haemoglobin, or change in number of glucose‐lowering agents, was seen. Conclusions: In individuals with T2DM and mixed dyslipidaemia on maximally tolerated statin, alirocumab showed superiority to UC in non‐HDL cholesterol reduction and was generally well tolerated. [ABSTRACT FROM AUTHOR]

Abstract: Aims/Introduction: Type 2 diabetes mellitus is an epidemic in Asia, yet clinical trials of glucose‐lowering therapies often enroll predominantly Western populations. We explored the initial combination of metformin and linagliptin, a dipeptidyl peptidase‐4 inhibitor, in newly diagnosed type 2 diabetes mellitus patients in Asia with marked hyperglycemia. Materials and Methods: This was a post‐hoc subgroup analysis of a multinational, parallel‐group clinical trial in which 316 newly diagnosed type 2 diabetes mellitus patients with glycated hemoglobin A1c (HbA1c) 8.5–12.0% were randomized to double‐blind oral treatment with linagliptin/metformin or linagliptin monotherapy. The primary end‐point was the change from baseline in HbA1c at week 24. We evaluated data for the 125 participants from Asian countries. Results: After 24 weeks, the mean ± standard error reduction from baseline in HbA1c (mean 10.0%) was −2.99 ± 0.18% with linagliptin/metformin and −1.84 ± 0.18% with linagliptin; a treatment difference of −1.15% (95% confidence interval −1.65 to −0.66, P < 0.0001). HbA1c <7.0% was achieved by 60% of participants receiving linagliptin/metformin. The mean bodyweight change after 24 weeks was −0.45 ± 0.41 kg and 1.33 ± 0.45 kg in the linagliptin/metformin and linagliptin groups, respectively (treatment difference −1.78 kg [95% confidence interval −2.99 to −0.57, P = 0.0043]). Drug‐related adverse events occurred in 9.7% of participants receiving linagliptin/metformin and 4.8% of those receiving linagliptin. Hypoglycemia occurred in 6.5% and 4.8% of the linagliptin/metformin and linagliptin groups, respectively, with no severe episodes. Gastrointestinal disorders occurred in 12.9% and 12.7% of the linagliptin/metformin and linagliptin groups, respectively, with no associated treatment discontinuations. Conclusions: In people from Asia with newly diagnosed type 2 diabetes mellitus and marked hyperglycemia, the initial combination of linagliptin and metformin substantially improved glycemic control without weight gain and with infrequent hypoglycemia. Initial oral combination therapy might be a viable treatment for such individuals. [ABSTRACT FROM AUTHOR]

T2DM is a complex disease underlined by multiple pathogenic defects responsible for the development and progression of hyperglycaemia. Each of these factors can now be tackled in a more targeted manner thanks to glucose‐lowering drugs that have been made available in the past 2 to 3 decades. Recognition of the multiplicity of the mechanisms underlying hyperglycaemia calls for treatments that address more than 1 of these mechanisms, with more emphasis placed on the earlier use of combination therapies. Although chronic hyperglycaemia contributes to and amplifies cardiovascular risk, several trials have failed to show a marked effect from intensive glycaemic control. During the past 10 years, the effect of specific glucose‐lowering agents on cardiovascular risk has been explored with dedicated trials. Overall, the cardiovascular safety of the new glucose‐lowering agents has been proven with some of the trials summarized in this review, showing significant reduction of cardiovascular risk. Against this background, pioglitazone, in addition to exerting a sustained glucose‐lowering effect, also has ancillary metabolic actions of potential interest in addressing the cardiovascular risk of T2DM, such as preservation of beta‐cell mass and function. As such, it seems a logical agent to combine with other oral anti‐hyperglycaemic agents, including dipeptidyl peptidase‐4 inhibitors (DPP4i). DPP4i, which may also have a potential to preserve beta‐cell function, is available as a fixed‐dose combination with pioglitazone, and could, potentially, attenuate some of the side effects of pioglitazone, particularly if a lower dose of the thiazolidinedione is used. This review critically discusses the potential for early combination of pioglitazone and DPP4i. [ABSTRACT FROM AUTHOR]

Aims To investigate the efficacy and safety of alirocumab in participants with type 2 (T2D) or type 1 diabetes (T1D) treated with insulin who have elevated LDL cholesterol levels despite maximally tolerated statin therapy. Methods Participants at high cardiovascular risk with T2D (n = 441) or T1D (n = 76) and LDL cholesterol levels ≥1.8 mmol/L (≥70 mg/dL) were randomized 2:1 to alirocumab:placebo administered subcutaneously every 2 weeks, for 24 weeks' double-blind treatment. Alirocumab-treated participants received 75 mg every 2 weeks, with blinded dose increase to 150 mg every 2 weeks at week 12 if week 8 LDL cholesterol levels were ≥1.8 mmol/L. Primary endpoints were percentage change in calculated LDL cholesterol from baseline to week 24, and safety assessments. Results Alirocumab reduced LDL cholesterol from baseline to week 24 by a mean ± standard error of 49.0% ± 2.7% and 47.8% ± 6.5% vs placebo (both P < .0001) in participants with T2D and T1D, respectively. Significant reductions were observed in non-HDL cholesterol ( P < .0001), apolipoprotein B ( P < .0001) and lipoprotein (a) ( P ≤ .0039). At week 24, 76.4% and 70.2% of the alirocumab group achieved LDL cholesterol <1.8 mmol/L in the T2D and T1D populations ( P < .0001), respectively. Glycated haemoglobin and fasting plasma glucose levels remained stable for the study duration. Treatment-emergent adverse events were observed in 64.5% of alirocumab- vs 64.1% of placebo-treated individuals (overall population). Conclusions Alirocumab produced significant LDL cholesterol reductions in participants with insulin-treated diabetes regardless of diabetes type, and was generally well tolerated. Concomitant administration of alirocumab and insulin did not raise any safety concerns (NCT02585778). [ABSTRACT FROM AUTHOR]

Background: Hypoglycaemia is a major burden of the pharmacological therapy of diabetes and is associated with increased morbidity, mortality and treatment costs.Methods: We screened all admissions to the emergency room of the Pisa University Hospital from 1 January 2009 to 31 December 2013, selecting individuals with a discharge diagnosis of hypoglycaemia. We retrieved 500 admissions involving adult diabetic patients: age 71 ± 16 years; M/F 50.2/49.8%; 70.2% type 2 diabetes (T2DM).Results: Among T2DM, 42.2% were on insulin, 10.8% on insulin plus oral anti-diabetes drugs and 38.2% on oral anti-diabetes drugs alone (92% sulphonylureas/glinides ± insulin-sensitizers). Glibenclamide was the most frequently used sulphonylurea (69%). Individuals treated with oral anti-diabetes drugs were older than those on insulin (79 ± 11 versus 74 ± 12 years; p < 0.0001). Among patients taking sulphonylurea, 47% had estimated glomerular filtration rate <60 mL/min/1.73 m(2) and 13.5% had <30 mL/min/1.73 m(2) . In-hospital admission occurred in 20% of cases. Hospitalized patients with T2DM were older than those discharged (80 ± 10 versus 76 ± 12 years, p < 0.01) and were on oral antidiabetic drugs in 54.8% of the cases, whereas 35.7% were on insulin (χ(2) , p < 0.0001) and 8.3% on combined therapy. Notably, 93.5% of those on oral anti-diabetic drugs were taking a secretagogue. Insulin-treated subjects were younger than those treated with oral anti-diabetic drugs alone (77 ± 12 versus 82 ± 7 years; p < 0.02). The mean in-hospital annual mortality rate was 85 deaths per 1000 patients-year.Conclusions: Our results support the recommendation that the risk associated with insulin and insulin-secretagogues should be carefully assessed, particularly when prescribed in vulnerable patients with T2DM. [ABSTRACT FROM AUTHOR]

Background Incidence of ischemic stroke and associated in-hospital mortality is decreasing in Western populations, while the prevalence of diabetes, a well-known risk factor for ischemic stroke, is progressively rising. This study was aimed at evaluating the effect of diabetes on ischemic stroke hospitalization and in-hospital mortality after ischemic stroke. Methods Discharges with diagnosis of ischemic stroke were identified in a database containing all hospitalizations of resident population of Tuscany, Italy, over years 2004-2011. Cases with diabetes were identified through specific drug prescriptions, official certifications or previous hospital diagnosis. Rates of annual ischemic stroke incidence and related in-hospital mortality were separately calculated for gender and age class, in subjects with and without diabetes. Results Sixty-five thousand one hundred sixty-five hospital discharges with ischemic stroke diagnosis were identified. Diabetes was associated with increased risk of stroke odds ratio(95% confidence interval):1.31(1.28-1.34) in men and 1.24(1.21-1.37) in women. Diabetic women, compared with men, had a higher in-hospital mortality risk after ischemic stroke (odds ratio:1.32; 1.06-1.64), whereas in non-diabetic subjects, there was no difference between genders. Incidence of ischemic stroke has declined in non-diabetic subjects, except for women aged ≤70 years; a similar reduction was observed for in-hospital mortality. Among diabetic patients, conversely, annual incidence of ischemic stroke rose by 3% in the elderly people (>70 years), and annual mortality trend remained unchanged. Conclusions In the last decade, the incidence of ischemic stroke and of related in-hospital mortality declined in persons without diabetes, while increasing among diabetic patients of advanced age. Women with diabetes, compared with men, had a higher in-hospital mortality risk. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Recent intervention trials (Veterans Affairs Diabetes Trial, Action to Control Cardiovascular Risk in Diabetes, Action in Diabetes and Vascular Disease) have underscored problems surrounding the risk-benefit balance of most therapeutic strategies in type 2 diabetes given, especially the limited cardiovascular advantage of tight glycaemic control when set against the co-incident risk of severe hypoglycaemia and weight gain. Consequently, therapy should to tailored to the individual. While attractive, such an approach remains highly empiric and to some extent difficult to implement without practical guidance, in particular for the inexperienced physician. To provide a user-friendly guide for a personalized therapeutic approach to type 2 diabetes, we performed a systematic review of the literature and elaborated a simple rule that was debated at a large independent University Symposium on the occasion of the European Association for the Study of Diabetes held in Vienna 2009. As a result of that process, we now propose an A1C and ABCD of glycaemia management in type 2 diabetes to determine appropriate glycaemic targets based on Age, Body weight, Complications and Disease Duration. 'A1C and ABCD' aims to guide clinicians in the use of therapeutic agents more effectively, efficiently and safely. While no regulatory-approved drug can be excluded, given its proven efficacy, there is a need to better phenotype patients, paying particular attention to ABCD. Based on these parameters, physicians can select the therapeutic strategy with minimum risk and maximum benefit for each individual. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background To test the association between gamma-glutamyltransferase level and glucose regulation. Methods We performed a cross-sectional analysis of 500 subjects [199 men/301 women, age 47 ± 11 years, body mass index (BMI) 28.6 ± 5.5 kg/m2] referred to Diabetes Clinics because of potential risk of type 2 diabetes mellitus (T2DM). Results The prevalence of all glucose intolerance categories was higher in the top quartile of gamma-glutamyltransferase than in the first. Subjects with normal glucose tolerance showed lower gamma-glutamyltransferase levels compared with those with impaired glucose tolerance (IGT), impaired fasting glucose (IFG)+ IGT and T2DM (ANOVA, p < 0.0001), but not those with IFG. Homeostasis model assessment-insulin resistance (HOMA-IR) increased with increasing levels of gamma-glutamyltransferase, while the insulinogenic index/HOMA-IR ratio decreased. In an age- and sex-adjusted analysis, the top gamma-glutamyltransferase quartile was independently associated with IFG + IGT [odds ratio (OR) 2.41; 95% confidence interval (CI): 1.13-5.15] and T2DM (OR 2.77; 95% CI: 1.47-5.22). After further adjustment for BMI, alcohol intake, family history of diabetes, cigarette smoking and physical activity, the top quartile of gamma-glutamyltransferase remained an independent predictor of IFG + IGT (OR 2.62; 95% CI: 1.13-6.07) and T2DM (OR 2.39; 95% CI: 1.20-4.76). Only when transaminases and HOMA-IR have been added to the model, the top quartile of gamma-glutamyltransferase resulted no more independently associated to IFG + IGT or T2DM. Conclusions Gamma-glutamyltransferase is closely related to insulin resistance, reduced beta-cell function and deterioration of glucose tolerance. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Inflammation and reactive oxygen species have been implicated in pathogenesis of vascular diabetic complications. However, treatment with classic free-radical scavengers and antioxidants has not been yet proved to reduce the risk of developing such complications. In search of more effective treatment we have tested the protective role of Ergothioneine (EGT), in vitro, on C2C12 cells model on FFA-induced lipotoxicity. Cells were incubated for 24 h in the presence of palmitic acid (PA) (250, 500, 750, 1000 µM), added as pro-oxidant compound, with or without 24-h pre-treatment with EGT. Cells were assessed for cell viability and MAPKs expression by Western Blot. Pre-treatment with EGT resulted in greater cell viability at each PA concentration (EGT 500 µM: 5, 16, 17, 23% and EGT 1000 µM: 9, 18, 21 and 25%). In response to PA exposure, p38 and JNK activity increased significantly while EGT prevented such activation. Moreover the analysis of the IL-6 production reveal that EGT is also able to exert anti-inflammatory action inhibiting the PA IL-6 modulation (P <0.001). In conclusion, these results indicate that 1. EGT has a protective role on PA-induced cell death, possibly via 2. reduced activity of MAPKs cascade having also 3. an anti-inflammatory action exerted on the IL-6 modulation. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is a chronic disease characterized by progressive worsening of glycaemic control as indicated by the United Kingdom Prospective Diabetes Study (UKPDS). The progressive nature of the disease is mainly due to continuous loss of β-cell mass and function. Though much of this loss is due to intrinsic defects of the β-cell several factors may accelerate such process. These include the metabolic environment where hyperglycaemia and increased circulating free-fatty acid exert a toxic effect on the β-cell. Therefore, tight metabolic control may prevent not only the risk of long-term diabetic complication but also preserve β-cell function. Several therapeutic agents are currently used for treatment of type 2 diabetic patients. However, their effect on maintenance of β-cell function has not been yet systematically reviewed. By literature searching we have then analysed in detail the effect of sulfonylureas and non-sulfonylureic secretagogues, incretin-mimetics, insulin sensitizers, α-glucosidase inhibitors, and insulin on β-cell function. Moreover, promising future approaches aiming at preserving β-cell function and mass are discussed. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background Recent data have demonstrated that pro-insulin-derived C-peptide can affect the function of several different cell types. We hypothesized that C-peptide might have an influence on the function and survival of isolated human islets. Methods Islets were prepared by combining enzymatic digestion and density gradient centrifugation, and the effects of human C-peptide were evaluated acutely and after 24-h incubation. Insulin secretion, apoptosis, quantitative RT-PCR and western-blotting experiments were then performed. Results Glucose-stimulated insulin secretion was not affected by C-peptide and, accordingly, mRNA expression of glucose transporter 2 and glucokinase did not differ between islets pre-cultured or not with the hormone. However, apoptosis was significantly lower in islets exposed to C-peptide than in control islets. This was accompanied by a significant increase of mRNA and protein expression of Bcl2, an anti-apoptotic molecule, with no change in the expression of Bax, a pro-apoptotic molecule. Conclusion These results show that in human islets pro-insulin C-peptide has no direct effects on insulin secretion, but it decreases islet cell apoptosis. A direct role of C-peptide on beta-cell mass regulation is therefore suggested. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The long-term benefits of providing intensive insulin therapy to control blood glucose levels have been demonstrated in people with type 1 or type 2 diabetes mellitus. However, achieving good glycaemic control in clinical practice continues to be a major challenge with only a small proportion of people with diabetes achieving current treatment goals. Some of the reasons for this include ineffectual diet and weight control initiatives, limited efficacy of therapeutic agents or association with excessive adverse events, delayed initiation of insulin therapy and poor patient acceptance and compliance with a regimen of multiple daily insulin injections. New ways of delivering insulin without the need for subcutaneous injections may overcome many of these limitations and thus help in the early adoption of insulin treatment by patients, assist in achieving and maintaining long-term optimal glycaemic control and improve patients' quality of life. [ABSTRACT FROM AUTHOR]

Background Type 1 diabetes results from the destruction of pancreatic beta-cell as a consequence of an autoimmune process. To date, information on the properties of islets isolated from type 1 diabetic patients is very scant. Methods Some immunological and functional properties of islets prepared from the pancreas of type 1 diabetic patients were studied shortly after the isolation and after a period of culture in euglycemic condition. Results Compared to control islets, freshly prepared type 1 diabetic islets released a significantly higher amount of cytokines (pg/mL) into the culture medium (TNF-α: 112.9 ± 5.6 vs 75.6 ± 24.4; INF-γ: 286.9 ± 26.9 vs 58.6 ± 6.2; IL-10: 41.8 ± 4.3 vs 10.1 ± 3.2; TGF-1 β: 294.0 ± 20.6 vs 45.1 ± 3.5); had a significantly higher chemotactic index (1.9 ± 0.2 vs 1.2 ± 0.1); showed reduced insulin release (% of insulin content) in response to glucose (2.8 ± 0.7 vs 5.3 ± 1.9), arginine (3.0 ± 0.6 vs 5.6 ± 1.0), and glibenclamide (2.9 ± 0.7 vs 5.4 ± 0.9); and exhibited decreased glucose oxidation capability and diminished mRNA expression of glucokinase, aldolase, pyruvate kinase, and mitochondrial glycerolphosphate dehydrogenase. Ten days after isolation, a normalization of cytokine release (TNF-α: 55.7 ± 2.3; INF-γ: 53.9 ± 4.3; IL-10: 8.6 ± 0.7; TGF-1 β: 60.7 ± 12.4) and chemotactic index (1.3 ± 0.2) were observed. Moreover, there was an improvement of insulin secretion (3.8 ± 0.3, 4.7 ± 0.6 and 3.5 ± 0.2 respectively in response to glucose, arginine, and glibenclamide) and glucose oxidation, and a partial recovery of the measured mRNA expressions. Conclusions These novel results, obtained with islets prepared from patients with type 1 diabetes, demonstrate that even after months after diabetes diagnosis, a period of culture of the islets in a more favorable environment has beneficial effects on the islet function. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article explores the effects of the GLP-1 RA efpeglenatide on HbA1c levels in individuals with type 2 diabetes mellitus. The study found that efpeglenatide significantly reduced HbA1c levels, but the nonglycaemic effects of the drug, such as weight loss, did not account for a significant portion of this reduction. The document provides additional information on the study and discusses potential mechanisms for efpeglenatide's glucose-lowering effects. It concludes that further research is needed to understand if these mechanisms apply to other similar drugs. [Extracted from the article]

Discusses the findings of a study on the impact of glucose routing through hexosamine biosynthesis pathway on β-cells survival. Effects of high glucose and glucosamine on human pancreatic β-cell survival; Influence of glucosamine on O-glycosylation of insulin receptor on RIN β-cells; Clinical significance of the study.

Background: Increasing evidence suggests that metabolism affects brain physiology. Here, we examine the effect of GLP-1 on simple visual-evoked functional Magnetic Resonance Imaging (fMRI) responses in cortical areas.Methods: Lean (n = 10) and nondiabetic obese (n = 10) subjects received exenatide (a GLP-1 agonist) or saline infusion, and fMRI responses to visual stimuli (food and nonfood images) were recorded. We analysed the effect of exenatide on fMRI signals across the cortical surface with special reference to the visual areas. We evaluated the effects of exenatide on the raw fMRI signal and on the fMRI signal change during visual stimulation (vs rest).Results: In line with previous studies, we find that exenatide eliminates the preference for food (over nonfood) images present under saline infusion in high-level visual cortex (temporal pole). In addition, we find that exenatide (vs saline) also modulates the response of early visual areas, enhancing responses to both food and nonfood images in several extrastriate occipital areas, similarly in obese and lean participants. Unexpectedly, exenatide increased fMRI raw signals (signal intensity during rest periods without stimulation) in a large occipital region, which were negatively correlated to BMI.Conclusions: In both lean and obese individuals, exenatide affects neural processing in visual cortex, both in early visual areas and in higher order areas. This effect may contribute to the known effect of GLP1 analogues on food-related behaviour. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is a chronic disease characterized by progressive worsening of glycaemic control as indicated by the United Kingdom Prospective Diabetes Study (UKPDS). The progressive nature of the disease is mainly due to continuous loss of beta-cell mass and function. Though much of this loss is due to intrinsic defects of the beta-cell several factors may accelerate such process. These include the metabolic environment where hyperglycaemia and increased circulating free-fatty acid exert a toxic effect on the beta-cell. Therefore, tight metabolic control may prevent not only the risk of long-term diabetic complication but also preserve beta-cell function. Several therapeutic agents are currently used for treatment of type 2 diabetic patients. However, their effect on maintenance of beta-cell function has not been yet systematically reviewed. By literature searching we have then analysed in detail the effect of sulfonylureas and non-sulfonylureic secretagogues, incretin-mimetics, insulin sensitizers, alpha-glucosidase inhibitors, and insulin on beta-cell function. Moreover, promising future approaches aiming at preserving beta-cell function and mass are discussed., ((c) 2007 John Wiley & Sons, Ltd.)