Dataset Information

Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial.

ABSTRACT: 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 HbA1c ?80 mmol/mol (9.5%) and BMI ?45 kg/m2. 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).

SUBMITTER: Philis-Tsimikas A

PROVIDER: S-EPMC7054369 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial.

Philis-Tsimikas Athena A Klonoff David C DC Khunti Kamlesh K Bajaj Harpreet S HS Leiter Lawrence A LA Hansen Melissa V MV Troelsen Lone N LN Ladelund Steen S Heller Simon S Pieber Thomas R TR

Diabetologia 20200127 4

<h4>Aims/hypothesis</h4>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.<h4>Methods</h4>This randomised (1:1), open-label, treat-to-target, multinational trial included individuals with type 2 diabetes, aged ≥18 years with HbA<sub>1c</sub> ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m<sup>2</sup>. Participants were previ ...[more]

PMID: 31984443

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Project description:Aims/hypothesisInsulin degludec (Des(B30)LysB29(γ-Glu Nε-hexadecandioyl) human insulin; IDeg) is a new basal insulin with an ultra-long flat action profile. The acute physiological responses to hypoglycaemia with IDeg and insulin glargine (A21Gly,B31Arg,B32Arg human insulin; IGlar) were compared.MethodsTwenty-eight adult type 1 diabetic patients with normal hypoglycaemia awareness (age = 41 ± 12 years, HbA1c = 7.8 ± 0.6% [62.8 ± 7 mmol/mol]) were randomised to once-daily IDeg or IGlar for 5 days in a two-period crossover design. Participants and research staff were blinded to group assignment. Patients were assigned the lowest available randomisation number from a set of blinded randomisation codes provided by the trial sponsor. Hypoglycaemia was induced by administering three times the usual daily insulin dose at midnight on day 5. Plasma glucose (PG) was stabilised by glucose clamp (5.5 mmol/l) for 7-9 h post dosing. Next morning, PG was allowed to decrease stepwise from 5.5 to 3.5 mmol/l (maintained for 30 min) to 2.5 mmol/l (for 15 min). PG was then increased to 3.9 mmol/l (for 120 min), before being returned to baseline. Hypoglycaemic symptom score (HSS), hypoglycaemic awareness, cognitive function, counter-regulatory hormones and vital signs were assessed during each glucose plateau. The primary analysis was to compare IDeg vs IGlar with respect to HSS at nadir PG concentration (2.5 mmol/l).ResultsThe full analysis set for treatment comparisons comprised data from all 28 exposed patients. Rates of PG decline and PG at nadir were similar for IDeg and IGlar. No treatment differences in HSS (estimated difference: 0.17 [95% CI -1.71, 2.05]; p > 0.05), cognitive function or awareness were observed at any time. Growth hormone and cortisol responses during hypoglycaemia were greater with IDeg than IGlar (AUC treatment ratio [IDeg/IGlar]: 2.44 [1.30, 4.60], p < 0.01; and 1.23 [1.01, 1.50]; p < 0.05), and adrenaline (epinephrine) responses trended higher (1.40 [0.96, 2.04], p = 0.07). The rates of recovery from hypoglycaemia were similar.Conclusions/interpretationIDeg and IGlar elicit comparable symptomatic and cognitive responses to induced hypoglycaemia. IDeg may elicit a moderately greater endocrine response, but times to PG recovery were similar for the two insulins.Trial registrationClinicalTrials.gov NCT01002768.FundingNovo Nordisk.

Dataset Information

Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial.

Publications

Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial.

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