Optimising the glucose sampling performance of an intravascular microdialysisbased continuous glucose monitoring device for use in hospital settings

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Long-term efficacy and safety of oral semaglutide and the effect of switching from sitagliptin to oral semaglutide in patients with type 2 diabetes: A 52-week, randomized, open-label extension of the PIONEER 7 trial

Introduction: The PIONEER 7 trial demonstrated superior glycemic control and weight loss with once-daily oral semaglutide with flexible dose adjustment versus sitagliptin 100 mg in type 2 diabetes. This 52-week extension evaluated long-term oral semaglutide treatment and switching from sitagliptin to oral semaglutide. Research design and methods: A 52-week, open-label extension commenced after the 52-week main phase. Patients on oral semaglutide in the main phase continued treatment (n=184; durability part); those on sitagliptin were rerandomized to continued sitagliptin (n=98) or oral semaglutide (n=100; initiated at 3 mg) (switch part). Oral semaglutide was dose-adjusted (3, 7, or 14 mg) every 8 weeks based on glycated hemoglobin (HbA1c) (target <7.0% (<53 mmol/mol)) and tolerability. Secondary endpoints (no primary) included changes in HbA1c and body weight. Results: In the durability part, mean (SD) changes in HbA1c and body weight from week 0 were -1.5% (0.8) and -1.3% (1.0) and -2.8 kg (3.8) and -3.7 kg (5.2) at weeks 52 and 104, respectively. In the switch part, mean changes in HbA1c from week 52 to week 104 were -0.2% for oral semaglutide and 0.1% for sitagliptin (difference -0.3% (95% CI -0.6 to 0.0); p=0.0791 (superiority not confirmed)). More patients achieved HbA1c <7.0% with oral semaglutide (52.6%) than sitagliptin (28.6%; p=0.0011) and fewer received rescue medication (9% vs 23.5%). Respective mean changes in body weight were -2.4 kg and -0.9 kg (difference -1.5 kg (95% CI -2.8 to -0.1); p=0.0321). Gastrointestinal adverse events were the most commonly reported with oral semaglutide. Conclusions: Long-term oral semaglutide with flexible dose adjustment maintained HbA1c reductions, with additional body weight reductions, and was well tolerated. Switching from sitagliptin to flexibly dosed oral semaglutide maintained HbA1c reductions, helped more patients achieve HbA1c targets with less use of additional glucose-lowering medication, and offers the potential for additional reductions in body weight

Hemoglobin glycation index, calculated from a single fasting glucose value, as a prediction tool for severe hypoglycemia and major adverse cardiovascular events in DEVOTE

Introduction Hemoglobin glycation index (HGI) is the difference between observed and predicted glycated hemoglobin A1c (HbA 1c), derived from mean or fasting plasma glucose (FPG). In this secondary, exploratory analysis of data from DEVOTE, we examined: whether insulin initiation/titration affected the HGI; the relationship between baseline HGI tertile and cardiovascular and hypoglycemia risk; and the relative strengths of HGI and HbA 1c in predicting these risks. Research design and methods In DEVOTE, a randomized, double-blind, cardiovascular outcomes trial, people with type 2 diabetes received once per day insulin degludec or insulin glargine 100 units/mL. The primary outcome was time to first occurrence of a major adverse cardiovascular event (MACE), comprising cardiovascular death, myocardial infarction or stroke; severe hypoglycemia was a secondary outcome. In these analyses, predicted HbA 1c was calculated using a linear regression equation based on DEVOTE data (HbA 1c =0.01313 FPG (mg/dL) (single value)+6.17514), and the population data were grouped into HGI tertiles based on the calculated HGI values. The distributions of time to first event were compared using Kaplan-Meier curves; HRs and 95% CIs were determined by Cox regression models comparing risk of MACE and severe hypoglycemia between tertiles. Results Changes in HGI were observed at 12 months after insulin initiation and stabilized by 24 months for the whole cohort and insulin-naive patients. There were significant differences in MACE risk between baseline HGI tertiles; participants with high HGI were at highest risk (low vs high, HR: 0.73 (0.61 to 0.87) 95% CI; moderate vs high, HR: 0.67 (0.56 to 0.81) 95% CI; p<0.0001). No significant differences between HGI tertiles were observed in the risk of severe hypoglycemia (p=0.0911). With HbA 1c included within the model, HGI no longer significantly predicted MACE. Conclusions High HGI was associated with a higher risk of MACE; this finding is of uncertain significance given the association of HGI with insulin initiation and HbA 1c. Trial registration number NCT01959529

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

Risk factors for kidney disorders in patients with type 2 diabetes at high cardiovascular risk: An exploratory analysis (DEVOTE 12)

Aim: To investigate risk factors associated with kidney disorders in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk. Methods: In DEVOTE, a cardiovascular outcomes trial, 7637 patients were randomised to insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100), with standard of care. In these exploratory post hoc analyses, serious adverse event reports were searched using Standardised MedDRA® Queries related to chronic kidney disease (CKD) or acute kidney injury (AKI). Baseline predictors of CKD, AKI and change in estimated glomerular filtration rate (eGFR) were identified using stepwise selection and Cox or linear regression. Results: Over 2 years, eGFR (mL/min/1.73 m2) decline was small and similar between treatments (degludec: 2.70; glargine U100: 2.92). Overall, 97 and 208 patients experienced CKD and AKI events, respectively. A history of heart failure was a risk factor for CKD (hazard ratio [HR] 1.97 [95% confidence interval [CI] 1.41; 2.75]) and AKI (HR 2.28 [95% CI 1.64; 3.17]). A history of hepatic impairment was a significant predictor of CKD (HR 3.28 [95% CI 2.12; 5.07]) and change in eGFR (estimate: −8.59 [95% CI −10.20; −7.00]). Conclusion: Our findings indicate that traditional, non-modifiable risk factors for kidney disorders apply to insulin-treated patients with T2D at high CV risk. Trial registration: NCT01959529 (ClinicalTrials.gov)

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

Development of a hypoglycaemia risk score to identify high-risk individuals with advanced type 2 diabetes in DEVOTE

Aims: The ability to differentiate patient populations with type 2 diabetes at high risk of severe hypoglycaemia could impact clinical decision making. The aim of this study was to develop a risk score, using patient characteristics, that could differentiate between populations with higher and lower 2-year risk of severe hypoglycaemia among individuals at increased risk of cardiovascular disease. Materials and methods: Two models were developed for the risk score based on data from the DEVOTE cardiovascular outcomes trials. The first, a data-driven machine-learning model, used stepwise regression with bidirectional elimination to identify risk factors for severe hypoglycaemia. The second, a risk score based on known clinical risk factors accessible in clinical practice identified from the data-driven model, included: insulin treatment regimen; diabetes duration; sex; age; and glycated haemoglobin, all at baseline. Both the data-driven model and simple risk score were evaluated for discrimination, calibration and generalizability using data from DEVOTE, and were validated against the external LEADER cardiovascular outcomes trial dataset. Results: Both the data-driven model and the simple risk score discriminated between patients at higher and lower hypoglycaemia risk, and performed similarly well based on the time-dependent area under the curve index (0.63 and 0.66, respectively) over a 2-year time horizon. Conclusions: Both the data-driven model and the simple hypoglycaemia risk score were able to discriminate between patients at higher and lower risk of severe hypoglycaemia, the latter doing so using easily accessible clinical data. The implementation of such a tool (http://www.hyporiskscore.com/) may facilitate improved recognition of, and education about, severe hypoglycaemia risk, potentially improving patient care