Cardiac Autonomic Neuropathy in Obesity, Metabolic Syndrome and Prediabetes: A Narrative Review The authors of the article would like to amend the article title to ‘Cardiac Autonomic Neuropathy in Obesity, Metabolic Syndrome and Prediabetes: A Narrative Review’.

Is There a Role for Informal Caregivers in the Management of Diabetic Foot Ulcers? A Narrative Review Abstract Successful management of diabetic foot ulceration (DFU) is crucial for preventing long-term morbidity and lowering risk of amputations. This can be achieved with a multifaceted approach involving a multidisciplinary team, with the patient at the centre. However, not all healthcare setups enable this, and the rate of lower limb amputations continues to rise. It is therefore time to consider new approaches to diabetic foot care, capitalising on engagement from patients in self-management while supported by their informal caregivers (ICGs) to help improve outcome. The role of ICGs in DFU care has the potential to make a significant difference in outcome, yet this resource remains, in most cases, underutilised. Limited research has been conducted in this area to reveal the true impact on patient outcomes and the caregivers themselves. This narrative review aims to explore how ICGs can benefit DFU management with applicability to different healthcare setups while benefiting from established experience in the care of other chronic health conditions.

Cost-Effectiveness Analysis of Empagliflozin in Comparison to Sitagliptin and Saxagliptin Based on Cardiovascular Outcome Trials in Patients with Type 2 Diabetes and Established Cardiovascular Disease Abstract Introduction In the cardiovascular outcome trials (CVOT) EMPA-REG OUTCOME, TECOS and SAVOR-TIMI 53, empagliflozin [sodium/glucose cotransporter 2 (SGLT2) inhibitor], sitagliptin and saxagliptin [both dipeptidyl peptidase 4 (DPP4) inhibitors] + standard of care (SoC) were compared to SoC in patients with type 2 diabetes and established cardiovascular disease (CVD). This study assessed the cost-effectiveness (CE) of empagliflozin + SoC in comparison to sitagliptin + SoC and saxagliptin + SoC based on the respective CVOT. Methods The IQVIA Core Diabetes Model (CDM) was calibrated to reproduce the CVOT outcomes. EMPA-REG OUTCOME baseline characteristics and CVOT specific treatment effects on risk factors for cardiovascular disease [glycated haemogloblin A1c (HbA1c), body mass index (BMI), blood pressure, lipids] were applied. Three-year observed cardiovascular events of empagliflozin + SoC versus sitagliptin + SoC and saxagliptin + SoC were derived from EMPA-REG OUTCOME and an indirect treatment comparison. Relative risk (RR) adjustments to calibrate the CDM were estimated after consecutive attempts of running the model until the observed and CDM-predicted outcomes matched closely. The drug-specific treatment effects were considered up until treatment switch (when HbA1c reached 8.5%), after which, the United Kingdom Prospective Diabetes Study (UKPDS) 82 risk equations predicted events based on co-existing risk factors and treatment intensification to basal-bolus insulin were applied. The analysis was conducted from the perspective of the UK National Health Service. Costs and quality of life data were derived from UK national sources and published literature. A 50-year time horizon and discount rate of 3.5% were applied. Results The CDM projected quality-adjusted life years (QALYs) of 6.408, 5.917 and 5.704 and total costs of 50,801 GBP, 47,627 GBP and 48,071 GBP for empagliflozin + SoC, sitagliptin + SoC and saxagliptin + SoC, respectively. The incremental CE ratio (ICER) of empagliflozin + SoC versus sitagliptin + SoC and saxagliptin + SoC was 6464 GBP/QALY and 3878 GBP/QALY, respectively. One-way and probabilistic sensitivity analyses demonstrated the robustness of the results. Conclusion Results suggest that empagliflozin + SoC is cost-effective compared to sitagliptin + SoC and saxagliptin + SoC at a willingness to pay threshold of 20,000 GBP/QALY. Funding Boehringer Ingelheim International GmbH.

Safety of Ipragliflozin in Patients with Type 2 Diabetes Mellitus: Pooled Analysis of Phase II/III/IV Clinical Trials Abstract Introduction Ipragliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). The objective of this pooled analysis was to characterise the safety profile of ipragliflozin based on safety data from published randomised controlled trials. Methods Safety data from 12 randomised, phase II/III/IV placebo-controlled, parallel group, comparative studies of ipragliflozin in patients with T2DM were pooled. Treatment-emergent adverse events (TEAEs) were analysed for patients who had received at least one dose of ipragliflozin 50 mg (n = 1209) or placebo (n = 796) in studies lasting for up to 24 weeks. TEAEs of special interest and serious adverse events (SAEs) were assessed, as well as abnormal laboratory test and vital sign measurements. Results The overall incidences of TEAEs and SAEs between the ipragliflozin and placebo groups were similar, 63.8% vs 59.3% and 2.5% vs 3.3%, respectively. The incidence of TEAEs leading to permanent discontinuation was lower for ipragliflozin (3.6%) than placebo (6.5%). The incidences of TEAEs of special interest including those related to urinary tract infection, cardiovascular events, renal disorder, fracture, malignant tumours and hypoglycaemia were also similar between the groups. Genital infections were more frequent with ipragliflozin (2.4%) than placebo (0.6%), as were pollakiuria/polyuria (6.0% vs 2.0%), volume depletion (4.9% vs 1.8%) and skin/subcutaneous tissue disorders (7.7% vs 4.4%). There were no reported cases of diabetic ketoacidosis, fractures, lower-limb amputation or Fournier’s gangrene in ipragliflozin-treated patients across the 12 studies. Conclusion In randomised, placebo-controlled trials of patients with T2DM, ipragliflozin was well tolerated, with a similar overall incidence of TEAEs to placebo. No new safety signals were observed. Trial Registration Numbers NCT01071850, NCT00621868, NCT01057628, NCT01117584, NCT01135433, NCT01225081, NCT01242215, NCT02175784, NCT01505426, NCT02452632, NCT02794792, NCT01316094. Funding Astellas Pharma Inc.

Orally Administered Semaglutide Versus GLP-1 RAs in Patients with Type 2 Diabetes Previously Receiving 1–2 Oral Antidiabetics: Systematic Review and Network Meta-Analysis Abstract Introduction Orally administered semaglutide is the first glucagon-like peptide 1 receptor agonist (GLP-1 RA) for oral administration. As head-to-head trials assessing orally administered semaglutide as an add-on to 1–2 oral antidiabetic drugs (OADs) vs other GLP-1 RAs are limited, a network meta-analysis (NMA) was performed to assess the relative efficacy and safety of orally administered semaglutide 14 mg once-daily (QD) vs injectable GLP-1 RAs in patients with type 2 diabetes inadequately controlled on 1–2 OADs. Methods A systematic literature review was conducted to identify randomised controlled trials of GLP-1 RAs in patients inadequately controlled on 1–2 OADs. Data at 26 ± 4 weeks were extracted for efficacy and safety outcomes feasible for the NMA: change from baseline in glycated haemoglobin (HbA1c), weight, HbA1c target levels (< 7.0% and ≤ 6.5%), blood pressure, and any gastrointestinal adverse events specified in system organ class. Data were synthesised using NMA and a Bayesian framework. Results In total, 27 studies were included in the analyses. Orally administered semaglutide 14 mg QD was associated with significantly greater reductions in HbA1c vs most comparators, and numerically greater reductions vs semaglutide 0.5 mg once-weekly (QW), dulaglutide 1.5 mg QW and liraglutide 1.8 mg QD. HbA1c reductions with semaglutide 1 mg QW were numerically greater than those with orally administered semaglutide 14 mg QD. Reductions in body weight for orally administered semaglutide 14 mg QD were significantly greater than all comparators except semaglutide QW (both doses). Orally administered semaglutide QD 14 mg was associated with statistically similar odds of experiencing gastrointestinal adverse events vs injectable GLP-1 RAs. Conclusion Orally administered semaglutide 14 mg QD as an add-on to 1–2 OADs is one of the most efficacious GLP-1 RAs for reducing HbA1c and body weight at 26 ± 4 weeks. Orally administered semaglutide 14 mg QD is well tolerated, with a safety profile in line with the GLP-1 RA class. Funding Novo Nordisk.

Effect of Liraglutide on Times in Glycaemic Ranges as Assessed by CGM for Type 2 Diabetes Patients Treated With Multiple Daily Insulin Injections Abstract Introduction The effects of the GLP-1 analogue liraglutide on time in hypoglycaemia, time in hyperglycaemia, and time in range for type 2 diabetes patients initially treated with multiple daily insulin injections (MDI) were investigated. Variables associated with hypoglycaemia in the current population were also identified. Methods Analyses were based on data from a previously performed double-blind, placebo-controlled trial in which 124 MDI-treated patients with type 2 diabetes were randomized to liraglutide or placebo. Masked continuous glucose monitoring (CGM) was performed at baseline and week 24 in 99 participants. Results The mean time in hypoglycaemia was similar for participants receiving liraglutide and those receiving placebo after 24 weeks of treatment. Mean time in target was greater in the liraglutide group than in the placebo group: 430 versus 244 min/24 h (p < 0.001) and 960 versus 695 min/24 h (p < 0.001) for the two glycaemic ranges considered, 4–7 mmol/l and 4–10 mmol/l, respectively. Mean time in hyperglycaemia was lower in the liraglutide group: 457 versus 723 min/24 h (p = 0.001) and 134 versus 264 min/24 h (p = 0.023) for the two cutoffs considered, > 10 mmol/l and > 14 mmol/l, respectively. Lower mean glucose level, lower C-peptide, and higher glucose variability were associated with an increased risk of hypoglycaemia in both treatment groups. Higher proinsulin level was associated with a lower risk of hypoglycaemia in the liraglutide group. Conclusion For type 2 diabetes patients initially treated with MDI, introducing liraglutide had a beneficial effect on glucose profiles estimated by masked CGM. Mean glucose level, glycaemic variability, C-peptide, and proinsulin level influenced the risk of hypoglycaemia in this population. Trial Registration ClinicalTrials.gov, number (EudraCT nr: 2012-001941-42). Funding Novo Nordisk funded this study. The Diabetes Research Unit, NU-Hospital Group funded the journal’s Rapid Service Fee.

Mechanism of Placenta Damage in Gestational Diabetes Mellitus by Investigating TXNIP of Patient Samples and Gene Functional Research in Cell Line Abstract Introduction Gestational diabetes mellitus (GDM) is a gestational complication that affects maternal and child health. The placenta provides the fetus with the necessary nutrition and oxygen and takes away the metabolic waste. Patients with GDM are diagnosed and treated merely on the basis of the blood glucose level; this approach does nothing to help evaluate the status of the placenta, which is worth noting in GDM. The purpose of this research was to clarify the relation between thioredoxin-interacting protein (TXNIP) and reactive oxygen species (ROS) in the placenta of patients with GDM, which has thus far remained unclear. Methods The expression of TXNIP in the placentas of 10 patients with GDM and 10 healthy puerperae (control group) was investigated via immunofluorescence. The relation among TXNIP, ROS, and the function of mitochondria was explored in HTR-8/SVneo cells stimulated by high glucose (HG). Results The results showed the expression of TXNIP in the placentas of patients with GDM was higher than that in the control group, and the expression of TXNIP in HTR-8/SVneo cells treated with HG was higher than that in the control group, causing the accumulation of ROS and changes of mitochondria, promoting apoptosis and inhibition of migration. Conclusions High expression of TXNIP caused by HG mediates the increasing ROS and the mitochondria dysfunction in GDM; this impairs the function of the placenta and is the basis for the prediction of perinatal outcome.

Index of Plantar Pressure Alters with Prolonged Diabetes Duration Abstract Introduction Diabetic foot ulcers develop with deviations in the distribution of plantar pressure. It is difficult to interpret any alteration in plantar pressure under different conditions of type 2 diabetes mellitus (T2DM). The aim of this study was to gain a better insight into the variations in plantar pressure with increased duration of diabetes. Methods Plantar pressure was examined in 1196 participants with or without T2DM. Subjects with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) were assigned to control groups, and those with T2DM were divided into five groups according to diabetes duration (< 2 years, 2–5 years, 5–10 years, 10–15 years, and > 15 years). The clinical characteristics, plantar peak pressure, and pressure–time integral (PTI) were compared among the seven study groups, and factors associated with peak pressure and the PTI were analyzed. Results At the hallux, peak pressure exhibited an upward trend in patients with T2DM within 5 years of diabetes duration, followed by a distinct downward slope with further progression of the disease (trend analysis, p  < 0.05). An uneven distribution of peak pressure was found at other locations, but this unevenness was ultimately lower than that in the two control groups (p  < 0.05). No obvious trend was noted for PTI among patients with different diabetes duration; however, those with diabetes for > 10 years manifested a significantly sharper increase in the PTI at the metatarsus (11.63 Ns/cm2, p  < 0.05) and heel (14.12 Ns/cm2, p  < 0.05) than at the hallux (8.76 Ns/cm2). A fluctuation in the PTI was also detected at the hallux and midfoot of diabetes patients, which was broadly flat when compared with that of the two control groups. The stepwise multiple regression analysis revealed that the variation in plantar pressure was independently associated with age, body mass index, and vibration perception threshold (VPT) (p  < 0.05). Conclusions There would appear to be an association between longer diabetes duration and decreased peak pressure for the hallux, suggesting that individuals with diabetes for > 10 years will have an increased PTI for the metatarsus and heel. The reduced pressure on the hallux is believed to be transferred to the metatarsus. Age, BMI, and VPT are distinct risk factors of abnormal plantar pressure.

Improving Type 2 Diabetes Management in General Practice Using a Second-Generation Basal Insulin Analogue Insulin Glargine 300 U/mL: A  Practical Guide Abstract Type 2 diabetes management can be improved by the use of second-generation basal insulin analogues as the first choice on commencement of insulin, in this instance focussing on insulin glargine 300 U/mL (Gla-300). The clinical application of the use of Gla-300 include advantages such as less intra- and interpatient variability in glucose control resulting in rather less hypoglycaemia, longer duration of action and greater flexibility in the timing of administration thus suiting a wide range of patient presentations. Funding: Sanofi Australia.

Efficacy of Dulaglutide as a First Injectable Option for Patients with Type 2 Diabetes: A Post-Hoc Pooled Analysis Abstract Introduction The ADA-EASD consensus report recommends using glucagon-like peptide-1 receptor agonists (GLP-1RAs) as the first injectable therapy prior to basal insulin in most patients with type 2 diabetes (T2D) not at glycemic goals after oral anti-hyperglycemia medications (OH). The objective of this analysis was to assess the glycemic efficacy of once-weekly dulaglutide 1.5 mg in patients with T2D when added on a background of commonly used OH regimens. Methods Patients from seven phase 3 AWARD [Assessment of Weekly AdministRation of LY2189265 (Dulaglutide) in Diabetes] trials, where once-weekly dulaglutide 1.5 mg was added to OHs, were pooled into the following categories based on OH regimens: metformin (MET), sulfonylurea (SU), MET + SU, MET + pioglitazone, and MET + SGLT2i. Change from baseline in glycated hemoglobin A1c (HbA1c), fasting serum glucose and body weight, proportion of patients reaching target HbA1c < 7%, and safety parameters were assessed. Results A total of 1784 patients treated with once-weekly dulaglutide 1.5 mg were included in this analysis. Baseline characteristics of the overall population were (mean ± standard deviation): age, 55.4 ± 9.8 years, HbA1c: 8.2 ± 1.0%, body mass index: 31.4 ± 5.4 kg/m2, duration of diabetes: 8.0 ± 5.6 years, and 878 (49.2%) were female. At 6 months, the addition of once-weekly dulaglutide 1.5 mg to various OH regimens significantly reduced HbA1c (− 1.3 to − 1.6%) and fasting blood glucose (− 29 to − 45 mg/dl) from baseline in all groups (p < 0.001), with 39–61% and 52–76% of these patients achieving HbA1c targets of ≤ 6.5% and < 7%, respectively. Significant reductions in body weight (− 0.8 to − 2.9 kg) were also observed in all groups (p < 0.001). Nausea, vomiting, and diarrhea were reported by 10–35%, 4–19%, and 6–28% of patients, respectively. Severe hypoglycemia occurred in one patient (MET + SU). Conclusion The addition of a once-weekly GLP-1RA, dulaglutide, demonstrated clinically meaningful HbA1c reduction in patients with T2D on different background OH regimens, making it an effective first injectable option. Funding Eli Lilly and Company.