Aim
To describe the phase 3a ONWARDS clinical development programme investigating insulin icodec (icodec), a once‐weekly basal insulin, including the design and rationale for each of the ONWARDS 1–6 ...trials.
Materials and Methods
Six randomized controlled trials have been initiated in adults with type 2 diabetes (T2D) (insulin‐naive: ONWARDS 1, 3 and 5; previously insulin‐treated: ONWARDS 2 and 4) and type 1 diabetes (T1D) (ONWARDS 6). Each trial will investigate icodec use in a unique clinical scenario, with consideration of long‐term safety and varied comparator treatments (insulin glargine U100 or U300 or insulin degludec). ONWARDS 5 will incorporate real‐world elements and a digital dose titration solution to guide icodec dosing. The primary objective for each of the trials is to compare the change in HbA1c from baseline to week 26 or week 52 between icodec and comparator arms. Secondary objectives include investigating other glycaemic control and safety parameters, such as fasting glucose, time in glycaemic range and hypoglycaemia. Patient‐reported outcomes will assess treatment satisfaction.
Conclusions
The ONWARDS 1–6 trials will evaluate the efficacy and safety of once‐weekly icodec compared with currently available daily basal insulin analogues in T2D and T1D. These trials will generate comprehensive evidence of icodec use in diverse populations across the spectrum of diabetes progression and treatment experience.
Aims
To compare the safety and efficacy of fast‐acting insulin aspart (faster aspart) with conventional insulin aspart (IAsp) in adults with type 1 diabetes (T1D).
Materials and methods
onset 1 was a ...randomized, multicentre, treat‐to‐target, phase III, 52‐week (initial 26 weeks + additional 26 weeks) trial conducted at 165 sites across 9 countries. Adults with T1D were randomly allocated to double‐blind mealtime faster aspart or IAsp, each with once‐ or twice‐daily insulin detemir. The primary endpoint, change in glycated haemoglobin (HbA1c) from baseline after the initial 26 weeks, has been reported previously. In the present paper, we report data from the full 52‐week study period.
Results
Between August 2013 and June 2015, 381 participants were assigned to double‐blind faster aspart and 380 participants to IAsp. After 52 weeks, estimated mean changes from baseline in HbA1c levels were −0.08% (faster aspart) and +0.01% (IAsp); estimated treatment difference significantly favoured faster aspart (−0.10% 95% confidence interval {CI} −0.19;−0.00; P = .0424). Changes from baseline in 1‐hour postprandial plasma glucose (PPG) increment (meal test; faster aspart −1.05 mmol/L; IAsp −0.14 mmol/L) also significantly favoured faster aspart (estimated treatment difference −0.91 mmol/L 95% CI −1.40;−0.43; −16.48 mg/dL 95% CI −25.17;−7.80; P = .0002). There was no difference in overall severe or blood glucose‐confirmed hypoglycaemic episodes or treatment‐emergent adverse events between treatments.
Conclusions
At 52 weeks, overall glycaemic control had significantly improved with faster aspart vs IAsp, consistent with the 26‐week study findings. Achieving an insulin profile closer to physiological insulin secretion with faster aspart translates into lower PPG and HbA1c levels compared with those achieved with IAsp in people with T1D.
Aim
To investigate the efficacy and safety of insulin degludec/liraglutide (IDegLira) versus insulin glargine 100 units/mL (IGlar U100) as add‐on to sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor ...therapy.
Materials and methods
In this 26‐week, phase IIIb, open‐label, parallel‐group, treat‐to‐target trial, conducted at 74 sites in 11 countries, insulin‐naïve people aged ≥18 years with glycated haemoglobin (HbA1c) 53–97 mmol/mol (7.0–11.0%), body mass index 20–40 kg/m2 and inadequately controlled type 2 diabetes (T2D) on SGLT2 inhibitor ± oral antidiabetic drugs were randomized 1:1 to once‐daily IDegLira or IGlar U100, both as add‐on to existing therapy. The primary endpoint was change in HbA1c from baseline to week 26.
Results
A total of 210 participants were randomized to each treatment arm. Mean HbA1c reductions were 21 mmol/mol (1.9%‐points) with IDegLira and 18 mmol/mol (1.7%‐points) with IGlar U100; confirming non‐inferiority (P < 0.0001) and superiority of IDegLira (difference in HbA1c change –3.90 mmol/mol; 95% confidence interval CI –5.45; –2.35 (−0.36%‐points; 95% CI –0.50, –0.21)). Superiority for IDegLira over IGlar U100 was also confirmed for: body weight (difference −1.92 kg; 95% CI –2.64, –1.19); severe or blood‐glucose‐confirmed symptomatic hypoglycaemia (rate ratio 0.42; 95% CI 0.23, 0.75); total daily insulin dose (difference −15.37 U; 95% CI –19.60, −11.13). The overall treatment‐emergent adverse event rate was higher with IDegLira as a result of higher increased lipase and nausea rates.
Conclusions
The favourable safety and efficacy profile of IDegLira in people with uncontrolled T2D on SGLT2 inhibitors, and lower weight gain and hypoglycaemia risk versus IGlar U100, suggest that clinicians should consider IDegLira initiation in this population.
Aims
Insulin efsitora alfa (efsitora) is a once‐weekly basal insulin. This review describes the study design and rationale of the efsitora phase 3 Once Weekly (QW) Insulin Therapy (QWINT) clinical ...development programme, including the five trials, QWINT‐1 through QWINT‐5.
Materials and Methods
The five trials included insulin‐naïve adults (QWINT‐1 and ‐2) with type 2 diabetes (T2D), adults with T2D previously treated with basal insulin (QWINT‐3 and ‐4), and QWINT‐5 in adults with type 1 diabetes. All five trials were designed as multicentre, randomized, controlled, open‐label, treat‐to‐target studies to investigate the efficacy and safety of efsitora versus active once‐daily basal insulin comparators (insulin glargine U100 or insulin degludec U100). The primary objective of each trial is to compare the change in HbA1c from baseline to week 26 or 52 between efsitora and the active comparator. The key secondary objectives include change in fasting glucose, insulin dose and continuous glucose monitoring variables, and patient‐reported outcome questionnaires.
Conclusions
The QWINT development programme includes a racially and geographically diverse population to provide important information regarding the efficacy and safety of efsitora and its clinical management of people with diabetes.
Aims/hypothesis
A head-to-head randomised trial was conducted to evaluate hypoglycaemia safety with insulin degludec 200 U/ml (degludec U200) and insulin glargine 300 U/ml (glargine U300) in ...individuals with type 2 diabetes treated with basal insulin.
Methods
This randomised (1:1), open-label, treat-to-target, multinational trial included individuals with type 2 diabetes, aged ≥18 years with HbA
1c
≤80 mmol/mol (9.5%) and BMI ≤45 kg/m
2
. Participants were previously treated with basal insulin with or without oral glucose-lowering drugs (excluding insulin secretagogues) and had to fulfil at least one predefined criterion for hypoglycaemia risk. Both degludec U200 and glargine U300 were similarly titrated to a fasting blood glucose target of 4.0–5.0 mmol/l. Endpoints were assessed during a 36 week maintenance period and a total treatment period up to 88 weeks. There were three hypoglycaemia endpoints: (1) overall symptomatic hypoglycaemia (either severe, an event requiring third-party assistance, or confirmed by blood glucose <3.1 mmol/l with symptoms); (2) nocturnal symptomatic hypoglycaemia (severe or confirmed by blood glucose with symptoms, between 00:01 and 05:59 h); and (3) severe hypoglycaemia. The primary endpoint was the number of overall symptomatic hypoglycaemic events in the maintenance period. Secondary hypoglycaemia endpoints included the number of nocturnal symptomatic events and number of severe hypoglycaemic events during the maintenance period.
Results
Of the 1609 randomised participants, 733 of 805 (91.1%) in the degludec U200 arm and 734 of 804 (91.3%) in the glargine U300 arm completed the trial (87.3% and 87.8% completed on treatment, respectively). Baseline characteristics were comparable between the two treatment arms. For the primary endpoint, the rate of overall symptomatic hypoglycaemia was not significantly lower with degludec U200 vs glargine U300 (rate ratio RR 0.88 95% CI 0.73, 1.06). As there was no significant difference between treatments for the primary endpoint, the confirmatory testing procedure for superiority was stopped. The pre-specified confirmatory secondary hypoglycaemia endpoints were analysed using pre-specified statistical models but were now considered exploratory. These endpoints showed a lower rate of nocturnal symptomatic hypoglycaemia (RR 0.63 95% CI 0.48, 0.84) and severe hypoglycaemia (RR 0.20 95% CI 0.07, 0.57) with degludec U200 vs glargine U300.
Conclusions/interpretation
There was no significant difference in the rate of overall symptomatic hypoglycaemia with degludec U200 vs glargine U300 in the maintenance period. The rates of nocturnal symptomatic and severe hypoglycaemia were nominally significantly lower with degludec U200 during the maintenance period compared with glargine U300.
Trial registration
ClinicalTrials.gov
NCT03078478
Funding
This trial was funded by Novo Nordisk (Bagsvaerd, Denmark)
Abstract Primary care practitioners are increasingly responsible for the management of the escalating numbers of patients with type 2 diabetes. The majority of these patients will require insulin ...replacement therapy as their disease progresses, because glycemic control is often unsustainable using oral antidiabetic drugs. This review explains the practicalities of initiating and optimizing basal insulin in clinical practice, emphasizing the need for regular glycated hemoglobin (A1c) monitoring to allow timely initiation of insulin when the A1c target is not met. The importance of patient education in overcoming barriers to insulin is discussed, as well as the choice of available basal insulins and the necessity to optimize basal insulin dosage by self-titration. The traditional view of insulin therapy as a last resort is challenged with the modern basal insulin analogues (insulin detemir and insulin glargine), which offer simple and effective glycemic control with a reduced risk of hypoglycemia compared with older insulin formulations such as neutral protamine Hagedorn.
Aim
To investigate the efficacy and safety of initiating insulin degludec/liraglutide (IDegLira) in patients with type 2 diabetes (T2D) who had discontinued pretrial sulphonylureas (SUs) or ...dipeptidyl peptidase‐4 inhibitors (DPP4is) versus patients not previously treated with these regimens.
Materials and Methods
In DUAL II, patients with T2D uncontrolled on basal insulin and metformin ± SU/glinides were randomized to insulin degludec or IDegLira (both capped at 50 U). In DUAL IX, patients were randomized to insulin glargine U100 (no maximum dose) or IDegLira, as add‐on to sodium‐glucose co‐transporter‐2 inhibitors ± oral antidiabetic drugs. In this post hoc analysis, patients were grouped according to pretrial use of SU (DUAL II) or DPP4i (DUAL IX).
Results
Regardless of pretrial SU/DPP4i use, IDegLira was favourable versus insulin comparators with respect to change in HbA1c and body weight. Lower hypoglycaemia rates and comparable end‐of‐trial daily insulin dose were achieved with IDegLira, regardless of pretrial regimen. There was no clinically relevant increase in mean self‐measured blood glucose in the early weeks after IDegLira initiation. There was no statistically significant interaction between the randomized treatments and previous SU/DPP4i use.
Conclusions
IDegLira was more favourable compared with degludec or glargine U100 in terms of change in HbA1c and body weight, regardless of antecedent treatment. Clinicians should be aware of a potential transient rise in self‐measured blood glucose when transitioning therapy in patients. This shows that SUs/DPP4is can be safely discontinued, without deterioration in glycaemic control when initiating IDegLira, allowing a simplified treatment regimen.
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.
Aims
To investigate the association between day‐to‐day fasting self‐monitored blood glucose (SMBG) variability and risk of hypoglycaemia in type 1 (T1D) and type 2 diabetes (T2D), and to compare ...day‐to‐day fasting SMBG variability between treatments with insulin degludec (degludec) and insulin glargine 100 units/mL (glargine U100).
Materials and Methods
Data were retrieved from two double‐blind, randomized, treat‐to‐target, two‐period (32 weeks each) crossover trials of degludec vs glargine U100 in T1D (SWITCH 1, n = 501) and T2D (SWITCH 2, n = 720). Available fasting SMBGs were used to determine the standard deviation (SD) of day‐to‐day fasting SMBG variability for each patient and the treatment combination. The association between day‐to‐day fasting SMBG variability and overall symptomatic, nocturnal symptomatic and severe hypoglycaemia was analysed for the pooled population using linear regression, with fasting SMBG variability included as a three‐level factor defined by population tertiles. Finally, day‐to‐day fasting SMBG variability was compared between treatments.
Results
Linear regression showed that day‐to‐day fasting SMBG variability was significantly associated with overall symptomatic, nocturnal symptomatic and severe hypoglycaemia risk in T1D and T2D (P < 0.05). Day‐to‐day fasting SMBG variability was significantly associated (P < 0.01) with all categories of hypoglycaemia risk, with the exception of severe hypoglycaemia in T2D when analysed within tertiles. Degludec was associated with 4% lower day‐to‐day fasting SMBG variability than glargine U100 in T1D (P = 0.0082) and with 10% lower day‐to‐day fasting SMBG variability in T2D (P < 0.0001).
Conclusions
Higher day‐to‐day fasting SMBG variability is associated with an increased risk of overall symptomatic, nocturnal symptomatic and severe hypoglycaemia. Degludec has significantly lower day‐to‐day fasting SMBG variability vs glargine U100.
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