Reducing the burden of hypoglycaemia in people with diabetes through increased understanding:design of the Hypoglycaemia Redefining Solutions for Better Lives (Hypo-RESOLVE) project

Background Hypoglycaemia is the most frequent complication of treatment with insulin or insulin secretagogues in people with diabetes. Severe hypoglycaemia, i.e. an event requiring external help because of cognitive dysfunction, is associated with a higher risk of adverse cardiovascular outcomes and all‐cause mortality, but underlying mechanism(s) are poorly understood. There is also a gap in the understanding of the clinical, psychological and health economic impact of ‘non‐severe’ hypoglycaemia and the glucose level below which hypoglycaemia causes harm. Aim To increase understanding of hypoglycaemia by addressing the above issues over a 4‐year period. Methods Hypo‐RESOLVE is structured across eight work packages, each with a distinct focus. We will construct a large, sustainable database including hypoglycaemia data from >100 clinical trials to examine predictors of hypoglycaemia and establish glucose threshold(s) below which hypoglycaemia constitutes a risk for adverse biomedical and psychological outcomes, and increases healthcare costs. We will also investigate the mechanism(s) underlying the antecedents and consequences of hypoglycaemia, the significance of glucose sensor‐detected hypoglycaemia, the impact of hypoglycaemia in families, and the costs of hypoglycaemia for healthcare systems. Results The outcomes of Hypo‐RESOLVE will inform evidence‐based definitions regarding the classification of hypoglycaemia in diabetes for use in daily clinical practice, future clinical trials and as a benchmark for comparing glucose‐lowering interventions and strategies across trials. Stakeholders will be engaged to achieve broadly adopted agreement. Conclusion Hypo‐RESOLVE will advance our understanding and refine the classification of hypoglycaemia, with the ultimate aim being to alleviate the burden and consequences of hypoglycaemia in people with diabetes

Comparison of insulin detemir and insulin glargine in subjects with type 1 diabetes using intensive insulin therapy

WSTĘP. Celem niniejszej pracy było porównanie kontroli glikemii oraz ryzyka hipoglikemii podczas stosowania insuliny detemir 2 × dziennie lub glarginy raz dziennie u chorych na cukrzycę typu 1. MATERIAŁ I METODY. Podczas trwającego 26 tygodni wieloośrodkowego, otwartego badania z grupami równoległymi 320 chorym na cukrzycę typu 1 podawano albo insulinę detemir 2 × dziennie albo glarginę raz dziennie, każdorazowo w połączeniu z przedposiłkowymi iniekcjami insuliny aspart. WYNIKI. Po 26 tygodniach wartość HbA1c zmniejszyła się z 8,8% do 8,2% w grupie przyjmującej insulinę detemir i z 8,7% do 8,2% w grupie leczonej glarginą. Wartość stężenia glukozy w osoczu (PG) mierzonego na czczo w domu była niższa podczas stosowania glarginy niż w czasie podawania insuliny detemir (7,0 mmol/l vs. 7,7 mmol/l; p < 0,001). Ogólny 9-punktowy profil mierzonych w domu wartości glikemii był porównywalny między grupami (p = 0,125). Nie stwierdzono istotnej różnicy w zmienności pomiarów PG u 1 pacjenta (p = 0,437). Zróżnicowanie pomiarów przedposiłkowego stężenia PG u 1 badanego było niższe podczas stosowania insuliny detemir niż glarginy (p < 0,05). Ogólne ryzyko hipoglikemii było podobne, nie stwierdzono różnic w występowaniu potwierdzonych epizodów hipoglikemii. Ryzyko silnej, nocnej hipoglikemii wynosiło odpowiednio: 72% i 32% i było niższe w grupie stosującej insulinę detemir (p < 0,05). Zwiększenie masy ciała nie różniło się znacząco między grupami przyjmującymi insulinę detemir i glarginę (0,52 kg vs. 0,96 kg; p = 0,193). WNIOSKI. Leczenie insuliną detemir podawaną 2 × dziennie lub glarginą podawaną raz dziennie, każdorazowo w połączeniu z insuliną aspart, powodowało podobną kontrolę glikemii. Ogólne zagrożenie hipoglikemią było porównywalne, natomiast ryzyko nasilonej i nocnej hipoglikemii było istotnie niższe podczas stosowania insuliny detemir.BACKGROUND. To compare glycaemic control and risk of hypoglycaemia of twice-daily insulin detemir with once-daily insulin glargine in subjects with type 1 diabetes. MATERIAL AND METHODS. In this 26-week, multicentre, open-label, parallel-group trial, 320 subjects with type 1 diabetes received either insulin detemir twice daily or insulin glargine once daily, each in combination with premeal insulin aspart. RESULTS. After 26 weeks, HbA1c had decreased from 8.8 to 8.2% in the insulin detemir group and from 8.7% to 8.2% in the insulin glargine group. Homemeasured fasting plasma glucose (PG) was lower with insulin glargine than with insulin detemir (7.0 mmol/l vs. 7.7 mmol/l; p < 0.001). The overall shape of the home-measured nine-point PG profiles was comparable between treatments (p = 0.125). Overall, there was no significant difference in within-subject variation in PG (p = 0.437). Withinsubject variation in predinner PG was lower with insulin detemir than with insulin glargine (p < 0.05). The overall risk of hypoglycaemia was similar with no differences in confirmed hypoglycaemia. However, the risk of severe and nocturnal hypoglycaemia was 72% and 32%, respectively, lower with insulin detemir than with insulin glargine (p < 0.05). Body weight gain was not significantly different comparing insulin detemir and insulin glargine (0.52 kg vs. 0.96 kg, p = 0.193). CONCLUSIONS. Treatment with twice-daily insulin detemir or once-daily insulin glargine, each in combination with insulin aspart, resulted in similar glycaemic control. The overall risk of hypoglycaemia was comparable, whereas the risks of both severe and nocturnal hypoglycaemia were significantly lower with insulin detemir

Integrated safety and efficacy analysis of dasiglucagon for treatment of severe hypoglycaemia in individuals with type 1 diabetes

Aims To perform an integrated analysis of the safety and efficacy of dasiglucagon, a glucagon analogue available in a ready-to-use aqueous formulation, to treat severe hypoglycaemia (SH) in type 1 diabetes (T1D). Materials and Methods An integrated analysis of dasiglucagon safety was conducted on data from two placebo-controlled trials (placebo-controlled pool) and two placebo-controlled and four non-placebo-controlled trials (broad pool) in adults with T1D. An integrated analysis of dasiglucagon efficacy was conducted of pooled data and within demographic subgroups from the two placebo-controlled and two non-placebo-controlled trials in adults with T1D. Results Dasiglucagon had a similar safety and tolerability profile to that of reconstituted glucagon. In the placebo-controlled datasets, no serious adverse events (AEs), AEs leading to withdrawal from the trial, or deaths were reported. The most common causally related AEs were nausea (56.5%) and vomiting (24.6%). The broad pool safety analysis showed similar results. Dasiglucagon efficacy in time to plasma glucose recovery from insulin-induced SH was similar to that of reconstituted glucagon (median 10.0 and 12.0 minutes, respectively) and superior to placebo (median 40.0 minutes; P < 0.0001). The median recovery time was consistent across all placebo-controlled trial subgroups. Conclusions Dasiglucagon was well tolerated and effective as a rapid rescue agent for insulin-induced SH in people with T1D

Glomerular Filtration Rate and Associated Risks of Cardiovascular Events, Mortality, and Severe Hypoglycemia in Patients with Type 2 Diabetes: Secondary Analysis (DEVOTE 11)

Introduction: The associations of chronic kidney disease (CKD) severity, cardiovascular disease (CVD), and insulin with the risks of major adverse cardiovascular events (MACE), mortality, and severe hypoglycemia in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk are not known. This secondary, pooled analysis of data from the DEVOTE trial examined whether baseline glomerular filtration rate (GFR) categories were associated with a higher risk of these outcomes. Methods: DEVOTE was a treat-to-target, double-blind trial involving 7637 patients with T2D at high CV risk who were randomized to once-daily treatment with either insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100). Patients with estimated GFR data at baseline (n = 7522) were analyzed following stratification into four GFR categories. Results: The risks of MACE, CV death, and all-cause mortality increased with worsening baseline GFR category (P < 0.05), with a trend towards higher rates of severe hypoglycemia. Patients with prior CVD, CKD (estimated GFR < 60 mL/min/m2), or both were at higher risk of MACE, CV death, and all-cause mortality. Only CKD was associated with a higher rate of severe hypoglycemia, and the risk of MACE was higher in patients with CVD than in those with CKD (P = 0.0003). There were no significant interactions between randomized treatment and GFR category. Conclusion: The risks of MACE, CV death, and all-cause mortality were higher with lower baseline GFR and with prior CVD, CKD, or both. The relative effects of degludec versus glargine U100 on outcomes were consistent across baseline GFR categories, suggesting that the lower rate of severe hypoglycemia associated with degludec use versus glargine U100 use was independent of baseline GFR category. Funding: Novo Nordisk

Cardiovascular safety and lower severe hypoglycaemia of insulin degludec versus insulin glargine U100 in patients with type 2 diabetes aged 65 years or older: Results from DEVOTE (DEVOTE 7)

Aims: The aim of this study was to describe the risks of cardiovascular (CV) events and severe hypoglycaemia with insulin degludec (degludec) vs insulin glargine 100 units/mL (glargine U100) in patients with type 2 diabetes (T2D) aged 65 years or older. Materials and methods: A total of 7637 patients in the DEVOTE trial, a treat-to-target, randomized, double-blind trial evaluating the CV safety of degludec vs glargine U100, were divided into three age groups (50-64 years, n = 3682; 65-74 years, n = 3136; ≥75 years, n = 819). Outcomes by overall age group and randomized treatment differences were analysed for major adverse cardiovascular events (MACE), all-cause mortality, severe hypoglycaemia and serious adverse events (SAEs). Results: Patients with increasing age had higher risks of CV death, all-cause mortality and SAEs, and there were non-significant trends towards higher risks of MACE and severe hypoglycaemia. Treatment effects on the risk of MACE, all-cause mortality, severe hypoglycaemia and SAEs were consistent across age groups, based on the non-significant interactions between treatment and age with regard to these outcomes. Conclusions: There were higher risks of CV death, all-cause mortality and SAEs, and trends towards higher risks of MACE and severe hypoglycaemia with increasing age after adjusting for baseline differences. The effects across age groups of degludec vs glargine U100 on MACE, all-cause mortality and severe hypoglycaemia were comparable, suggesting that the risk of MACE, as well as all-cause mortality, is similar and the risk of severe hypoglycaemia is lower with degludec regardless of age. Evidence is conclusive only until 74 years of age

International consensus on risk management of diabetic ketoacidosis in patients with type 1 diabetes treated with sodium-glucose cotransporter (SGLT) inhibitors

Sodium-glucose cotransporter (SGLT) inhibitors are new oral antidiabetes medications shown to effectively reduce glycated hemoglobin (A1C) and glycemic variability, blood pressure, and body weight without intrinsic properties to cause hypoglycemia in people with type 1 diabetes. However, recent studies, particularly in individuals with type 1 diabetes, have demonstrated increases in the absolute risk of diabetic ketoacidosis (DKA). Some cases presented with near-normal blood glucose levels or mild hyperglycemia, complicating the recognition/diagnosis of DKAand potentially delaying treatment. Several SGLT inhibitors are currently under review by the U.S. Food and Drug Administration and European regulatory agencies as adjuncts to insulin therapy in people with type 1 diabetes. Strategies must be developed and disseminated to the medical community to mitigate the associated DKA risk. This Consensus Report reviews current data regarding SGLT inhibitor use and provides recommendations to enhance the safety of SGLT inhibitors in people with type 1 diabetes

Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial

Background: Oral semaglutide is the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes. We aimed to compare the efficacy and safety of flexible dose adjustments of oral semaglutide with sitagliptin 100 mg. Methods: In this 52-week, multicentre, randomised, open-label, phase 3a trial, we recruited patients with type 2 diabetes from 81 sites in ten countries. Patients were eligible if they were aged 18 years or older (19 years or older in South Korea), had type 2 diabetes (diagnosed ≥90 days before screening), HbA1c of 7·5–9·5% (58–80 mmol/mol), and were inadequately controlled on stable daily doses of one or two oral glucose-lowering drugs (for 90 days or more before screening). Participants were randomly assigned (1:1) by use of an interactive web-response system, stratified by background glucose-lowering medication at screening, to oral semaglutide with flexible dose adjustments to 3, 7, or 14 mg once daily or sitagliptin 100 mg once daily. To approximate treatment individualisation in clinical practice, oral semaglutide dose could be adjusted on the basis of prespecified HbA1c and tolerability criteria. Two efficacy-related estimands were prespecified: treatment policy (regardless of treatment discontinuation or use of rescue medication) and trial product (on treatment and without use of rescue medication) for participants randomly assigned to treatment. The primary endpoint was achievement of HbA1c of less than 7% (53 mmol/mol) at week 52 and the confirmatory secondary efficacy endpoint was change in bodyweight from baseline to week 52. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02849080, and European Clinical Trials Database, EudraCT number 2015-005593-38, and an open-label extension is ongoing. Findings: Between Sept 20, 2016, and Feb 7, 2017, of 804 patients assessed for eligibility, 504 were eligible and randomly assigned to oral semaglutide (n=253) or sitagliptin (n=251). Most participants were male (285 [57%] of 504) with a mean age of 57·4 years (SD 9·9). All participants were given at least one dose of their allocated study drug except for one participant in the sitagliptin group. From a mean baseline HbA1c of 8·3% (SD 0·6%; 67 mmol/mol [SD 6·4]), a greater proportion of participants achieved an HbA1c of less than 7% with oral semaglutide than did with sitagliptin (treatment policy estimand: 58% [134 of 230] vs 25% [60 of 238]; and trial product estimand: 63% [123 of 196] vs 28% [52 of 184]). The odds of achieving an HbA1c of less than 7% was significantly better with oral semaglutide than sitagliptin (treatment policy estimand: odds ratio [OR] 4·40, 95% CI 2·89–6·70, p&lt;0·0001; and trial product estimand: 5·54, 3·54–8·68, p&lt;0·0001). The odds of decreasing mean bodyweight from baseline to week 52 were higher with oral semaglutide than with sitagliptin (estimated mean change in bodyweight, treatment policy estimand: −2·6 kg [SE 0·3] vs −0·7 kg [SE 0·2], estimated treatment difference [ETD] −1·9 kg, 95% CI −2·6 to −1·2; p&lt;0·0001; and trial product estimand: −2·9 kg [SE 0·3] vs −0·8 kg [SE 0·3], ETD −2·2 kg, −2·9 to −1·5; p&lt;0·0001). Adverse events occurred in 197 (78%) of 253 participants in the oral semaglutide group versus 172 (69%) of 250 in the sitagliptin group, and nausea was the most common adverse event with oral semaglutide (53 [21%]). Two deaths occurred in the sitagliptin group during the trial. Interpretation: Oral semaglutide, with flexible dose adjustment, based on efficacy and tolerability, provided superior glycaemic control and weight loss compared with sitagliptin, and with a safety profile consistent with subcutaneous GLP-1 receptor agonists. Funding: Novo Nordisk A/S

Efficacy and safety of HOE 901 versus NPH insulin in patients with type 1 diabetes. The European Study Group of HOE 901 in type 1 diabetes

HOE 901 (Hoechst Marion Roussel, Frankfurt, Germany) is a biosynthetic insulin with a prolonged action. The aim of this study was to compare the effect of the long-acting insulin analog HOE 901 with NPH insulin regarding glycemic control in patients with type 1 diabetes.A total of 333 type 1 diabetic patients were enrolled in this multinational parallel group trial. Subjects were randomized either to two different formulations of HOE 901 (the formulations differed only in zinc content) or to NPH insulin. The study was only partially blinded because patients can distinguish HOE 901 (a clear solution) from NPH (a cloudy suspension). In addition to premeal injections of regular insulin, patients received HOE 901 at bedtime or NPH once daily at bedtime or twice daily in the morning and at bedtime.Fasting plasma glucose levels were significantly lower with HOE 901 (-1.88 mmol/l. P = 0.0005) as were fasting self-monitored blood glucose levels (-0.80 mmol/l, P = 0.0020). HbA1c levels also showed a significant reduction with HOE 901 (-0.14%) versus NPH (P = 0.030). The overall frequency of hypoglycemia did not differ, but the frequency of nocturnal hypoglycemia was significantly (P = 0.0037) lower with HOE 901 (36 vs. 55%). However, this effect on nocturnal hypoglycemia was significant only versus NPH once daily not NPH twice daily. The pattern of adverse events and injection site reactions with HOE 901 was similar to that with NPH.This study indicates that HOE 901 achieves better control of fasting glucose and HbA1c levels over 4 weeks, and HOE 901 has a possible safety benefit in terms of nocturnal hypoglycemia