AimTo investigate the safety and efficacy of insulin degludec/liraglutide (IDegLira), a novel combination product, as add‐on therapy for people with Type 2 diabetes uncontrolled on sulphonylurea therapy.MethodsIn this 26‐week, double‐blind trial, adults with Type 2 diabetes [HbA1c 53–75 mmol/mol (7.0–9.0%)] were randomized to IDegLira (n = 289) or placebo (n = 146) as add‐on to pre‐trial sulphonylurea ± metformin, titrating to a fasting glycaemic target of 4.0–6.0 mmol/l. Treatment initiation was at 10 dose steps, and maximum dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide).ResultsThe mean HbA1c decreased from 63 mmol/mol (7.9%) to 46 mmol/mol (6.4%) with IDegLira and to 57 mmol/mol (7.4%) with placebo [estimated treatment difference –11 mmol/mol (95% CI –13; –10) or –1.02% (95% CI –1.18; –0.87); P < 0.001]. The HbA1c target of 53 mmol/mol (<7%) was achieved by 79.2% of participants in the IDegLira group vs 28.8% in the placebo group [estimated odds ratio 11.95 (95% CI 7.22; 19.77); P < 0.001]. Mean weight change was +0.5 kg with IDegLira vs –1.0 kg with placebo [estimated treatment difference 1.48 kg (95% CI 0.90; 2.06); P < 0.001]. Confirmed hypoglycaemia occurred in 41.7 and 17.1% of IDegLira‐ and placebo‐treated participants, respectively, with rates of 3.5 vs 1.4 events/patient‐years of exposure [estimated rate ratio 3.74 (95% CI 2.28; 6.13); P < 0.001]. IDegLira was generally well tolerated. The rates of serious adverse events were 20.3 and 8.0 per 100 patient‐years of exposure with IDegLira and placebo, respectively, without obvious patterns in the type of events.Conclusions IDegLira can be used in people uncontrolled with sulphonylurea ± metformin to improve efficacy with a safety profile in line with previous DUAL trials.

Tooth development is under strict genetic control. During the last decade, studies in molecular genetics have led to the identification of gene defects causing the congenital absence of permanent teeth. Analyses of PAX9 and MSX1 in nine families with hypodontia and oligodontia revealed one new PAX9 mutation. A LOD score of Z = 1.8 (theta = 0.0) was obtained for D14S75 close to PAX9 in one three-generation family, and sequencing of the gene identified the nonsense mutation c.433C>T. The mutation results in a truncated PAX9 protein containing the paired domain region as a result of the Q145X stop mutation. The family showed a marked phenotypic variability in the number of missing teeth, ranging from 2 to 15 missing teeth. The highest frequency of missing teeth was found for second molars followed by second premolars.

Background and ObjectivesThe time-course when changes in glycemic control and body weight were first manifest in patients with type 2 diabetes mellitus (T2DM) treated with a combination of insulin degludec and liraglutide (IDegLira) was assessed, comparing IDegLira to its individual components.MethodsData from weeks 0–12 from two studies were analyzed, one comparing IDegLira to each component (DUAL I), and one comparing IDegLira to insulin degludec titrated to a maximum 50 units (DUAL II). Efficacy endpoints included glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) reduction, proportion of patients achieving HbA1c [<7.0 % (<53.0 mmol/mol)] and FPG (≤7.2 mmol/L) targets, and proportion achieving HbA1c target without hypoglycemia and without hypoglycemia and weight gain.ResultsMean HbA1c was lower, and the proportion of patients reaching target HbA1c greater, with IDegLira versus comparators (both studies) at weeks 8 and 12. Proportions of patients reaching target HbA1c without hypoglycemia and without hypoglycemia and weight gain were higher for IDegLira versus insulin degludec, though not versus liraglutide. Mean FPG was lower with IDegLira, and the proportion achieving target FPG higher, versus components (both studies) from weeks 4–12. IDegLira was associated with mean weight reduction from weeks 4–12, although less than with liraglutide alone. Hypoglycemia occurred infrequently in weeks 0–12, with no difference in incidence between IDegLira and insulin degludec in either study.ConclusionsIDegLira reduces plasma glucose to a greater extent than its components, measurable within the first 12 weeks of therapy, and without weight gain or an increased hypoglycemia risk versus insulin degludec.Electronic supplementary materialThe online version of this article (doi:10.1007/s40261-016-0376-0) contains supplementary material, which is available to authorized users.

Purpose IDegAsp, a co-formulation of long-acting basal (insulin degludec) and rapid-acting bolus (insulin aspart) insulin, provides separate prandial and basal glucose-lowering effects with relatively low risk of hypoglycaemia. Its efficacy and safety have been investigated in a large clinical trial programme (BOOST). We present the rationale and design of the ARISE study, which aims to assess glycaemic control and other clinical parameters associated with IDegAsp use in real world. Methods ARISE is a ~26-wk-long, prospective, non-interventional, single-arm study of patients with type 2 diabetes (T2D) initiating IDegAsp treatment. Approximately 1112 patients with T2D aged ≥18 years previously on anti-hyperglycaemic drugs except IDegAsp will be enroled across six countries from 15 Aug 2019 to 12 Nov 2020. IDegAsp treatment will be initiated at the physicians’ discretion and as per the local label. Key exclusion criteria include previous participation, or previous IDegAsp treatment. The primary and secondary endpoints are change in HbA1c from baseline (wk 0) to study end (wk 26–36) and the proportion of patients achieving the target HbA1c level of <7% at the study end, respectively. A mixed model for repeated measurements will analyse the primary endpoint. Conclusion Between-country differences in the prescription patterns of glucose-lowering agents in people with T2D warrant examination of their clinical use in different geographical settings. The ARISE study is designed to assess the clinical use of IDegAsp from real world in six different countries. Findings from the ARISE study will supplement those of previous randomised controlled studies by establishing real-world evidence of IDegAsp use in the participating countries. Trial registration ClinicalTrials.gov, NCT04042441. Registered 02 August 2014, https://clinicaltrials.gov/ct2/show/NCT04042441

AimsTo re‐analyse, using a series of alternative hypoglycaemia definitions, the data from 2 trials, DUAL I and V, in which the once‐daily, fixed ratio combination of insulin degludec/liraglutide (IDegLira) was compared with basal insulin therapy.Material and Methods Post hoc analyses of the DUAL I (patients uncontrolled on oral antidiabetic drugs) and DUAL V (patients uncontrolled on insulin glargine (IGlar) U100) trials were carried out using different definitions of hypoglycaemia and according to whether treatments were administered in the morning or afternoon. Rates of hypoglycaemia for the definitions of confirmed and American Diabetes Association (ADA)‐documented symptomatic hypoglycaemia were compared according to age, gender and body mass index (BMI).ResultsAlthough hypoglycaemia rates differed according to the alternative hypoglycaemia definitions, rates were consistently lower with IDegLira vs insulin degludec (IDeg) and IGlar U100. Despite glycated haemoglobin concentrations being lower with IDegLira at end of treatment, confirmed and nocturnal‐confirmed hypoglycaemia rates were lower for IDegLira vs IDeg and IGlar U100, irrespective of dosing time. The definitions of confirmed and ADA‐documented symptomatic hypoglycaemia did not have a significant effect on the treatment difference between IDegLira and IDeg, liraglutide or IGlar U100 when further assessed by baseline age, gender and BMI.ConclusionsTreatment with IDegLira, vs IDeg and IGlar U100, resulted in lower rates of hypoglycaemia regardless of dosing time and definition of hypoglycaemia used. The choice of hypoglycaemia definition did not influence the results of analyses when stratified by age, sex and BMI.