Erythrocyte membrane fluidity: A novel biomarker of residual cardiovascular risk in type 2 diabetes.

AIMS: Improving the composition of circulating fatty acids (FA) leads to a reduction in cardiovascular diseases (CVD) in high-risk individuals. The membrane fluidity of red blood cells (RBC), which reflects circulating FA status, may be a valid biomarker of cardiovascular (CV) risk in type 2 diabetes (T2D). METHODS: Red blood cell membrane fluidity, quantified as general polarization (GP), was assessed in 234 subjects with T2D, 86 with prior major CVD. Based on GP distribution, a cut-off of .445 was used to divide the study cohort into two groups: the first with higher GP, called GEL, and the second, defined as lower GP (LGP). Lipidomic analysis was performed to evaluate FA composition of RBC membranes. RESULTS: Although with comparable CV risk factors, the LGP group had a greater percentage of patients with major CVD than the GEL group (40% vs 24%, respectively, p < .05). Moreover, in a logistic regression analysis, a lower GP value was independently associated with the presence of macrovascular complications. Lipidomic analysis showed a clear shift of LGP membranes towards a pro-inflammatory condition due to higher content of arachidonic acid and increased omega 6/omega 3 index. CONCLUSIONS: Increased membrane fluidity is associated with a higher CV risk in subjects with T2D. If confirmed in prospective studies, membrane fluidity could be a new biomarker for residual CV risk assessment in T2D.

Oral or injectable semaglutide for the management of type 2 diabetes in routine care: A multicentre observational study comparing matched cohorts.

AIM: To investigate the real-world utilization and comparative clinical outcomes of injectable and oral semaglutide in individuals with type 2 diabetes (T2D) with the aim of enhancing understanding of the practical implications associated with choosing between these formulations. METHODS: New users of oral or injectable semaglutide were selected from a cohort of 14 079 initiators of glucagon-like peptide-1 receptor agonists. Propensity-score matching (PSM) was employed to create balanced groups, ensuring comparability. The analysis encompassed dose exposure, drug persistence, and clinical outcomes, including changes in glycated haemoglobin (HbA1c) and body weight, with up to 18 months' follow-up. RESULTS: We analysed two matched groups of 107 participants each, who comprised on average 63.6% men, aged 64 years, with diabetes duration of approximately 10 years, body mass index of 29 kg/m2 and HbA1c level of 7.7-7.8% (61-62 mmol/mol). The proportion of low, intermediate and high doses were similar with the oral and the injectable formulation. The change in HbA1c was similar between groups (-0.9% / -10 mmol/mol at 18 months) as was the proportion of individuals reaching HbA1c <6.5% (48 mmol/mol). The average change in body weight was similar in the two groups (-3.7 kg with injectable and -3.3 kg with oral at 18 months) but more new users of injectable semaglutide lost ≥5% body weight. Persistence on drug was longer with injectable than with oral semaglutide. CONCLUSION: In a real-world setting, improvements in HbA1c and body weight were similar after initiation of oral or injectable semaglutide. These results may be specific to the features of the matched cohorts under investigation, with limited generalizability to populations with different characteristics.

Advancing Diabetes Research: A Novel Islet Isolation Method from Living Donors.

Pancreatic islet isolation is critical for type 2 diabetes research. Although -omics approaches have shed light on islet molecular profiles, inconsistencies persist; on the other hand, functional studies are essential, but they require reliable and standardized isolation methods. Here, we propose a simplified protocol applied to very small-sized samples collected from partially pancreatectomized living donors. Islet isolation was performed by digesting tissue specimens collected during surgery within a collagenase P solution, followed by a Lympholyte density gradient separation; finally, functional assays and staining with dithizone were carried out. Isolated pancreatic islets exhibited functional responses to glucose and arginine stimulation mirroring donors' metabolic profiles, with insulin secretion significantly decreasing in diabetic islets compared to non-diabetic islets; conversely, proinsulin secretion showed an increasing trend from non-diabetic to diabetic islets. This novel islet isolation method from living patients undergoing partial pancreatectomy offers a valuable opportunity for targeted study of islet physiology, with the primary advantage of being time-effective and successfully preserving islet viability and functionality. It enables the generation of islet preparations that closely reflect donors' clinical profiles, simplifying the isolation process and eliminating the need for a Ricordi chamber. Thus, this method holds promises for advancing our understanding of diabetes and for new personalized pharmacological approaches.

Intra-islet insulin synthesis defects are associated with endoplasmic reticulum stress and loss of beta cell identity in human diabetes.

AIMS/HYPOTHESIS: Endoplasmic reticulum (ER) stress and beta cell dedifferentiation both play leading roles in impaired insulin secretion in overt type 2 diabetes. Whether and how these factors are related in the natural history of the disease remains, however, unclear. METHODS: In this study, we analysed pancreas biopsies from a cohort of metabolically characterised living donors to identify defects in in situ insulin synthesis and intra-islet expression of ER stress and beta cell phenotype markers. RESULTS: We provide evidence that in situ altered insulin processing is closely connected to in vivo worsening of beta cell function. Further, activation of ER stress genes reflects the alteration of insulin processing in situ. Using a combination of 17 different markers, we characterised individual pancreatic islets from normal glucose tolerant, impaired glucose tolerant and type 2 diabetic participants and reconstructed disease progression. CONCLUSIONS/INTERPRETATION: Our study suggests that increased beta cell workload is accompanied by a progressive increase in ER stress with defects in insulin synthesis and loss of beta cell identity.

Dapagliflozin treatment is associated with a reduction of epicardial adipose tissue thickness and epicardial glucose uptake in human type 2 diabetes.

OBJECTIVE: We recently demonstrated that treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) leads to an increase in myocardial flow reserve in patients with type 2 diabetes (T2D) with stable coronary artery disease (CAD). The mechanism by which this occurs is, however, unclear. One of the risk factors for cardiovascular disease is inflammation of epicardial adipose tissue (EAT). Since the latter is often increased in type 2 diabetes patients, it could play a role in coronary microvascular dysfunction. It is also well known that SGLT-2i modify adipose tissue metabolism. We aimed to investigate the effects of the SGLT-2i dapagliflozin on metabolism and visceral and subcutaneous adipose tissue thickness in T2D patients with stable coronary artery disease and to verify whether these changes could explain observed changes in myocardial flow. METHODS: We performed a single-center, prospective, randomized, double-blind, controlled clinical trial with 14 T2D patients randomized 1:1 to SGLT-2i dapagliflozin (10 mg daily) or placebo. The thickness of visceral (epicardial, mediastinal, perirenal) and subcutaneous adipose tissue and glucose uptake were assessed at baseline and 4 weeks after treatment initiation by 2-deoxy-2-[18F]fluoro-D-glucose Positron Emission Tomography/Computed Tomography during hyperinsulinemic euglycemic clamp. RESULTS: The two groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, BMI, renal and heart function). Dapagliflozin treatment significantly reduced EAT thickness by 19% (p = 0.03). There was a significant 21.6% reduction in EAT glucose uptake during euglycemic hyperinsulinemic clamp in the dapagliflozin group compared with the placebo group (p = 0.014). There were no significant effects on adipose tissue thickness/metabolism in the other depots explored. CONCLUSIONS: SGLT-2 inhibition selectively reduces EAT thickness and EAT glucose uptake in T2D patients, suggesting a reduction of EAT inflammation. This could explain the observed increase in myocardial flow reserve, providing new insights into SGLT-2i cardiovascular benefits.

Why do some glucose-lowering agents improve non-alcoholic fatty liver disease whereas others do not? A narrative review in search of a unifying hypothesis.

Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are metabolic disorders connected by common pathophysiological mechanisms. Since insulin resistance (IR) and metabolic alterations are common to both conditions, almost all glucose-lowering agents which improve IR have also been studied in patients with NAFLD. Some have shown great efficacy, others none. Thus, the mechanisms behind the efficacy of these drugs in improving hepatic steatosis, steatohepatitis, and eventually fibrosis remain controversial. Glycaemic control improves T2D, but probably has limited effects on NAFLD, as all glucose-lowering agents ameliorate glucose control but only a few improve NAFLD features. In contrast, drugs that either improve adipose tissue function, reduce lipid ingestion, or increase lipid oxidation are particularly effective in NAFLD. We therefore hypothesise that improved free fatty acid metabolism may be the unifying mechanism behind the efficacy of some glucose-lowering agents on NAFLD and may represent the key to NAFLD treatment.

Effects of glucose-lowering agents on cardiovascular and renal outcomes in subjects with type 2 diabetes: An updated meta-analysis of randomized controlled trials with external adjudication of events.

AIMS: To investigate the effects of glucose-lowering agents on all-cause mortality, and cardiovascular and renal outcomes in adults with type 2 diabetes. METHODS: A MEDLINE and EMBASE search was performed to identify randomized controlled trials, published up to 28 February 2022, with a follow-up ≥52 weeks, in which glucose-lowering drugs were compared with either placebo or active comparators. We included only trials reporting formal external adjudication of events. All-cause mortality, 3-point MACE (major cardiovascular events), and hospitalization for heart failure (HHF) were considered as principal outcomes. Doubling of serum creatinine, worsening albuminuria, and renal death were considered as secondary endpoints. RESULTS: We included randomized controlled trials performed on metformin (n = 17), pioglitazone (n = 20), alpha-glucosidase inhibitors (n = 9), insulin secretagogues (n = 42), dipeptidyl-peptidase-4 inhibitors (n = 67), glucagon-like peptide-1 receptor agonists (n = 45) or sodium-glucose co-transporter-2 inhibitors (SGLT-2i; n = 42) and insulin (n = 18). Glucagon-like peptide-1 receptor agonist and SGLT-2i were associated with a significant reduction in all-cause mortality [Mantel-Haenszel odds ratio (MH-OR), 95% confidence interval: 0.88 (0.83; 0.95) and 0.85 (0.79; 0.91), respectively] and MACE [MH-OR, 95% confidence interval: 0.89 (0.84; 0.94) and 0.90 (0.84; 0.96), respectively]. SGLT-2i was associated with a reduced risk of HHF [MH-OR 0.68 (0.62; 0.75)], worsening albuminuria [MH-OR 0.67 (0.55; 0.80)] and doubling of serum creatinine [MH-OR 0.58 (0.44; 0.79)]. Metformin and pioglitazone were associated with a significantly lower risk of MACE [MH-OR 0.60 (0.47; 0.80) and 0.85 (0.74; 0.97), respectively] and pioglitazone with a higher risk of HHF [MH-OR 1.30 (1.04; 1.62)]. Insulin secretagogues were associated with increased risk of all-cause mortality [MH-OR 1.12 (1.01; 1.24)] and MACE [MH-OR 1.19 (1.02; 1.39)]. CONCLUSIONS: The results of this updated meta-analysis need to be considered in the choice of drug treatment for type 2 diabetes mellitus, which cannot be merely based on the effect of glucose-lowering drugs on long-term glycaemic control.

Physicians' misperceived cardiovascular risk and therapeutic inertia as determinants of low LDL-cholesterol targets achievement in diabetes.

BACKGROUND: Greater efforts are needed to overcome the worldwide reported low achievement of LDL-c targets. This survey aimed to dissect whether and how the physician-based evaluation of patients with diabetes is associated with the achievement of LDL-c targets. METHODS: This cross-sectional self-reported survey interviewed physicians working in 67 outpatient services in Italy, collecting records on 2844 patients with diabetes. Each physician reported a median of 47 records (IQR 42-49) and, for each of them, the physician specified its perceived cardiovascular risk, LDL-c targets, and the suggested refinement in lipid-lowering-treatment (LLT). These physician-based evaluations were then compared to recommendations from EAS/EASD guidelines. RESULTS: Collected records were mostly from patients with type 2 diabetes (94%), at very-high (72%) or high-cardiovascular risk (27%). Physician-based assessments of cardiovascular risk and of LDL-c targets, as compared to guidelines recommendation, were misclassified in 34.7% of the records. The misperceived assessment was significantly higher among females and those on primary prevention and was associated with 67% lower odds of achieving guidelines-recommended LDL-c targets (OR 0.33, p < 0.0001). Peripheral artery disease, target organ damage and LLT-initiated by primary-care-physicians were all factors associated with therapeutic-inertia (i.e., lower than expected probability of receiving high-intensity LLT). Physician-suggested LLT refinement was inadequate in 24% of overall records and increased to 38% among subjects on primary prevention and with misclassified cardiovascular risk. CONCLUSIONS: This survey highlights the need to improve the physicians' misperceived cardiovascular risk and therapeutic inertia in patients with diabetes to successfully implement guidelines recommendations into everyday clinical practice.

Dapagliflozin improves myocardial flow reserve in patients with type 2 diabetes: the DAPAHEART Trial: a preliminary report.

OBJECTIVE: Cardiovascular (CV) outcome trials have shown that in patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduces CV mortality and hospital admission rates for heart failure (HF). However, the mechanisms behind these benefits are not fully understood. This study was performed to investigate the effects of the SGLT-2i dapagliflozin on myocardial perfusion and glucose metabolism in patients with T2D and stable coronary artery disease (coronary stenosis ≥ 30% and < 80%), with or without previous percutaneous coronary intervention (> 6 months) but no HF. METHODS: This was a single-center, prospective, randomized, double-blind, controlled clinical trial including 16 patients with T2D randomized to SGLT-2i dapagliflozin (10 mg daily) or placebo. The primary outcome was to detect changes in myocardial glucose uptake (MGU) from baseline to 4 weeks after treatment initiation by [(18)F]2-deoxy-2-fluoro-D-glucose (FDG) PET/CT during hyperinsulinemic euglycemic clamp. The main secondary outcome was to assess whether the hypothetical changes in MGU were associated with changes in myocardial blood flow (MBF) and myocardial flow reserve (MFR) measured by 13N-ammonia PET/CT. The study was registered at eudract.ema.europa.eu (EudraCT No. 2016-003614-27) and ClinicalTrials.gov (NCT03313752). RESULTS: 16 patients were randomized to dapagliflozin (n = 8) or placebo (n = 8). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function). There was no significant change in MGU during euglycemic hyperinsulinemic clamp in the dapagliflozin group (2.22 ± 0.59 vs 1.92 ± 0.42 µmol/100 g/min, p = 0.41) compared with the placebo group (2.00 ± 0.55 vs 1.60 ± 0.45 µmol/100 g/min, p = 0.5). Dapagliflozin significantly improved MFR (2.56 ± 0.26 vs 3.59 ± 0.35 p = 0.006 compared with the placebo group 2.34 ± 0.21 vs 2.38 ± 0.24 p = 0.81; pint = 0.001) associated with a reduction in resting MBF corrected for cardiac workload (p = 0.005; pint = 0.045). A trend toward an increase in stress MBF was also detected (p = 0.054). CONCLUSIONS: SGLT-2 inhibition increases MFR in T2D patients. We provide new insight into SGLT-2i CV benefits, as our data show that patients on SGLT-2i are more resistant to the detrimental effects of obstructive coronary atherosclerosis due to increased MFR, probably caused by an improvement in coronary microvascular dysfunction. Trial registration EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.

A novel low-density lipoprotein receptor variant in a Ukrainian patient: a case report and overview of the disease-causing low-density lipoprotein receptor variants associated to familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein-cholesterol levels and it is primarily caused by pathogenic/likely pathogenic variants (P/LPVs) in LDLR, APOB or PCSK9 genes. Next generation sequencing (NGS) technology allows the evaluation of more genes simultaneously, rising the diagnostic throughput of genomics laboratories. MATERIALS AND METHODS: We report a Ukrainian 37-year-old woman hypercholesterolemic since 2010. Despite a suggestive family history, FH was suspected only when the patient referred to the Endocrine and Metabolic Diseases Center of the Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome. After specialist advice, genetic testing was offered to the patient at our Molecular and Genomic Diagnostics Unit. RESULTS: A targeted NGS-based pipeline highlighted a novel out-of-frame deletion in the LDLR gene. This variant has a clear deleterious effect on the LDLR protein and it can be classified as PV. CONCLUSIONS: The ideal model of care for FH is an evidence-based system aimed to provide the highest-quality health services to all FH patients. In fact, this study reports that the integrated care pathway adopted in our hospital for FH patients led successfully to the discovery of a novel LDLR PV in an Ukrainian patient. The finding of this LDLR variant allowed the clinical FH diagnosis in this patient and in her family, expanding the knowledge of FH-related genetic variants in the Ukrainian population.

Effects of insulin on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A meta-analysis of randomized controlled trials.

AIM: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin with this respect. DATA SYNTHESIS: A MEDLINE database search was performed to identify all RCTs, up to June 1st, 2021, with duration≥52 weeks, in which insulin was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Six RCTs (enrolling 8091 patients and 10,139 in the insulin and control group, respectively) were included in the analysis for MACEs and HF, and 18 in that for all-cause mortality (9760 and 11,694 patients in the insulin and control group, respectively). Treatment with insulin neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 1.09, 95% CI 0.97-1.23; 0.99, 95% CI 0.91, 1.08; and 0.90, 95% CI 0.78, 1.04, respectively). CONCLUSIONS: This meta-analysis showed no significant effects of insulin on incident MACE, all-cause mortality, and HHF.

All-cause mortality and cardiovascular events in patients with type 2 diabetes treated with alpha-glucosidase inhibitors: A meta-analysis of randomized controlled trials.

AIM: Alpha-glucosidase inhibitors are approved drugs for treating type 2 diabetes (T2DM); however, their effects on mortality and cardiovascular safety are unclear. This meta-analysis was aimed at evaluating the effects of alpha-glucosidase inhibitors on all-cause mortality and major cardiovascular events (MACE). DATA SYNTHESIS: A Medline, Embase, Cochrane database searching for alpha-glucosidase inhibitors was performed up to July 1st, 2021. All randomized controlled trials (RCT) with a duration ≥52 weeks and comparing the effects of alpha-glucosidase inhibitors with placebo or active drugs were collected. Further inclusion criteria were: RCT reporting MACE within their primary outcome, or as pre-defined secondary outcome; and RCT enrolling at least 100 patients with T2DM. Mantel-Haenszel odds ratio (MH-OR) with 95% confidence intervals were calculated for the aforementioned outcomes. A total of eight RCTs, enrolling 1124 and 908 patients on alpha-glucosidase inhibitors and comparators, respectively, were identified. No trials reported information on MACE. Treatment with alpha-glucosidase inhibitors was not associated with a significant increase of all-cause mortality compared with other therapies or no therapy/placebo (MH-OR 0.76 [0.28; 2.05]). CONCLUSIONS: The evidence of beneficial or detrimental effects of alpha-glucosidase inhibitors on all-cause mortality and cardiovascular events is not sufficient to draw any conclusions.

Effects of pioglitazone on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A meta-analysis of randomized controlled trials.

AIM: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. After identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, the experts decided to perform a systematic review and meta-analysis on the effect of pioglitazone with this respect. DATA SYNTHESIS: A MEDLINE database search was performed to identify RCTs, up to June 1st, 2021, with duration≥52 weeks, in which pioglitazone was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Eight RCTs were included in the analysis for MACEs and HF (5048 and 5117 patients in the pioglitazone and control group, respectively), and 24 in that for all-cause mortality (10,682 and 9674 patients). Pioglitazone neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 0.90, 95% CI 0.78-1.03, 0.91, 95% CI 0.77, 1.09, and 1.16, 95% CI 0.73, 1.83, respectively). Pioglitazone was associated with a significant reduction of MACE in patients with prior cardiovascular events (MH-OR 0.84, 95% CI 0.72-0.99). CONCLUSIONS: This meta-analysis showed no significant effects of pioglitazone on incident MACE, all-cause mortality, and HHF.

Self-management in patients with type 2 diabetes: Group-based versus individual education. A systematic review with meta-analysis of randomized trails.

AIM: Patient education is an essential component of the treatment of type 2 diabetes mellitus (T2DM). The present meta-analysis was aimed at verifying the efficacy of group-based versus individual education for self-management in patients with T2DM. DATA SYNTHESIS: A Medline and Embase search up to January 1st, 2021, was performed, including Randomized Controlled Trials (RCT) with duration>6 months, enrolling patients with T2DM and comparing individual-based with group-based educational programs. The primary outcome was endpoint HbA1c; secondary endpoints were lipid profile, body weight, blood pressure, patients' adherence/knowledge, and quality of life. The weighed difference in means (WMD) and Mantel-Haenzel Odds Ratio (MH-OR), with 95% Confidence Interval (CI), were calculated. We retrieved 14 RCT. No significant between-group difference in HbA1c (WMD -0.39[-0.89; 0.09] mmol/mol, p = 0.11) was observed. At metaregression analyses, longer trial duration, higher baseline mean age and duration of diabetes, and lower baseline HbA1c were correlated with greater efficacy of group-based programs in reducing HbA1c. When analyzed separately, trials excluding insulin-treated patients showed a significant reduction of HbA1c in favor of group education. CONCLUSIONS: In patients with T2DM, group education has similar efficacy as individual education on glucose control. Group programs are associated with an improved quality of life and patients' knowledge. PROSPERO AND OSF REGISTRATION: ID243149.

Cardiovascular events and all-cause mortality in patients with type 2 diabetes treated with dipeptidyl peptidase-4 inhibitors: An extensive meta-analysis of randomized controlled trials.

AIMS: Meta-analyses of randomized trials on Dipeptidyl Peptidase-4 inhibitors (DPP4i) reported discordant results on major cardiovascular events (MACE), mortality, and heart failure. Aim of this meta-analysis of randomized trials is the assessment of the cardiovascular safety of DPP4i. DATA SYNTHESIS: A Medline, Embase, Cochrane database search for sitagliptin, vildagliptin, omarigliptin, saxagliptin, alogliptin, trelagliptin, anagliptin, linagliptin, gemigliptin, evogliptin, and teneligliptin was performed up to up January 1st, 2020. All trials with a duration ≥24 weeks and comparing the effects of DPP4i with placebo or active drugs were collected. Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all outcomes defined above. A total of 182 eligible trials were identified. DPP-4i were not associated with an increased risk of MACE (MH-OR 0.99 [0.93, 1.04]), all-cause mortality (MH-OR 0.99 [0.93, 1.06]), and heart failure (MH-OR 1.05 [0.96, 1.15]) with no significant differences across individual molecules, except for saxagliptin, which was associated with an increased risk of heart failure. CONCLUSIONS: As a class, DPP4i are not associated with any increase or reduction of MACE, all-cause mortality, and heart failure. Saxagliptin seems to be associated with an increased risk of hospitalization for heart failure.

Comparable efficacy with similarly low risk of hypoglycaemia in patient- vs physician-managed basal insulin initiation and titration in insulin-naïve type 2 diabetic subjects: The Italian Titration Approach Study.

AIMS: People with uncontrolled type 2 diabetes (T2DM) often delay initiating and titrating basal insulin. Patient-managed titration may reduce such deferral. The Italian Titration Approach Study (ITAS) compared the efficacy and safety of insulin glargine 300 U/mL (Gla-300) initiation and titration using patient- (nurse-supported) or physician-management in insulin-naïve patients with uncontrolled T2DM. MATERIALS AND METHODS: ITAS was a multicentre, phase IV, 24-week, open-label, randomized (1:1), parallel-group study. Insulin-naïve adults with T2DM for ≥1 year with poor metabolic control initiated Gla-300 after discontinuation of SU/glinides, and were randomized to self-titrate insulin dose (nurse-assisted) or have it done by the physician. The primary endpoint was change in HbA1c . Secondary outcomes included hypoglycaemia incidence and rate, change in fasting self-monitored plasma glucose, patient-reported outcomes (PROs), and adverse events. RESULTS: Three hundred and fifty five participants were included in the intention-to-treat population. At Week 24, HbA1c reduction from baseline was non-inferior in patient- vs physician-managed arms [least squares mean (LSM) change (SE): -1.60% (0.06) vs -1.49% (0.06), respectively; LSM difference: -0.11% (95% CI: -0.26 to 0.04)]. The incidence and rates of hypoglycaemia were similarly low in both arms: relative risk of confirmed and/or severe nocturnal (00:00-05:59 hours) hypoglycaemia was 0.77 (95% CI: 0.27 to 2.18). No differences were observed for improvement in PROs. No safety concerns were reported. CONCLUSIONS: In the T2DM insulin-naïve, SU/glinides discontinued population, patient-managed (nurse-assisted) titration of Gla-300 may be a suitable option as it provides improved glycaemic control with low risk of hypoglycaemia, similar to physician-managed titration.

Sotagliflozin added to optimized insulin therapy leads to HbA1c reduction without weight gain in adults with type 1 diabetes: A pooled analysis of inTandem1 and inTandem2.

AIM: To evaluate whether the addition of sotagliflozin to optimized insulin significantly increases the proportion of adults with type 1 diabetes who achieve HbA1c goals without weight gain. MATERIALS AND METHODS: In a patient-level pooled analysis (n = 1575) of data from two phase 3, 52-week clinical trials (inTandem1 and inTandem2), the change from baseline in HbA1c and weight as well as the proportion of participants achieving an HbA1c of less than 7% without weight gain were compared between groups treated with placebo, sotagliflozin 200 mg and sotagliflozin 400 mg. RESULTS: From a mean baseline HbA1c of 7.7%, mean HbA1c changes at week 24 were -0.36% (95% CI -0.44% to -0.29%) and -0.38% (-0.45% to -0.31%) with sotagliflozin 200 and 400 mg versus placebo (P = .001 for both), respectively, with sustained effects through week 52. Weight significantly decreased at weeks 24 and 52 in both sotagliflozin groups compared with placebo. At week 52, the proportion of patients who achieved an HbA1c of less than 7% without weight gain was 21.8% with sotagliflozin 200 mg, 26.1% with sotagliflozin 400 mg and 9.1% with placebo (P < .001). Other HbA1c, weight and safety composite variables showed similar significant trends. CONCLUSION: When added to optimized insulin therapy, sotagliflozin improved glycaemic control and body weight and enabled more adults with type 1 diabetes to achieve HbA1c goals without weight gain over 52 weeks, although there was more diabetic ketoacidosis relative to placebo.

Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives.

Sotagliflozin is a dual sodium-glucose co-transporter-2 and 1 (SGLT2/1) inhibitor for the treatment of both type 1 (T1D) and type 2 diabetes (T2D). Sotagliflozin inhibits renal sodium-glucose co-transporter 2 (determining significant excretion of glucose in the urine, in the same way as other, already available SGLT-2 selective inhibitors) and intestinal SGLT-1, delaying glucose absorption and therefore reducing post prandial glucose. Well-designed clinical trials, have shown that sotagliflozin (as monotherapy or add-on therapy to other anti-hyperglycemic agents) improves glycated hemoglobin in adults with T2D, with beneficial effects on bodyweight and blood pressure. Similar results have been obtained in adults with T1D treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections, even after insulin optimization. A still ongoing phase 3 study is currently evaluating the effect of sotagliflozin on cardiovascular outcomes (ClinicalTrials.gov NCT03315143). In this review we illustrate the advantages and disadvantages of dual SGLT 2/1 inhibition, in order to better characterize and investigate its mechanisms of action and potentialities.

Sodium-glucose co-transporter inhibitors: Medications that mimic fasting for cardiovascular prevention.

Recent evidence that some diabetes drugs can prevent cardiovascular disease (CVD) has profoundly modified the treatment approach to type 2 diabetes mellitus. Sodium-glucose co-transporter-2 (SGLT2) inhibitors and almost all glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown, beyond their effect on glucose control, to lead to a significant decrease in the cardiovascular burden of diabetes. Although these results are well known, the mechanisms of action by which they prevent cardiovascular events are still poorly understood. Both GLP-1RAs and SGLT2 inhibitors promote weight loss, although through different mechanisms. SGLT2 inhibitors promote glycosuria, leading to significant caloric deficit and weight loss. Similarly, GLP-1RAs, probably through an anorexic effect on certain brain areas, inhibit calorie intake, with ensuing weight loss. Although it features less prominently in current treatment pathways, pioglitazone has also demonstrated cardiovascular benefits. Pioglitazone profoundly modifies several mechanisms and risk factors responsible for CVD; however, these mechanisms certainly do not include weight loss. Obesity, and consequent insulin resistance, are well known risk factors for CVD, and it would appear logical to attribute the positive cardiovascular effects of these two classes of drugs to weight loss. The direct metabolic effects of these two classes, however, are profoundly different. The present review proposes a unifying hypothesis to explain the reduction in CVD through three different mechanisms of curbing free fatty acid excess, all leading to the common mechanism of cellular caloric restriction. If this hypothesis is correct, the excellent results obtained with SGLT2 inhibitors could be attributed to their close simulation of fasting.

The Interplay between Immune System and Microbiota in Diabetes.

Diabetes is not a single and homogeneous disease, but a cluster of metabolic diseases characterized by the common feature of hyperglycemia. The pathogenesis of type 1 diabetes (T1D) and type 2 diabetes (T2D) (and all other intermediate forms of diabetes) involves the immune system, in terms of inflammation and autoimmunity. The past decades have seen an increase in all types of diabetes, accompanied by changes in eating habits and consequently a structural evolution of gut microbiota. It is likely that all these events could be related and that gut microbiota alterations might be involved in the immunomodulation of diabetes. Thus, gut microbiota seems to have a direct, even causative role in mediating connections between the environment, food intake, and chronic disease. As many conditions that increase the risk of diabetes modulate gut microbiota composition, it is likely that immune-mediated reactions, induced by alterations in the composition of the microbiota, can act as facilitators for the onset of diabetes in predisposed subjects. In this review, we summarize recent evidence in the field of gut microbiota and the role of the latter in modulating the immune reactions involved in the pathogenesis of diabetes.