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 HbA_1c ≤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).

Keywords: Clinical science; Hypoglycaemia; Insulin degludec; Insulin glargine; Insulin therapy.

Fig. 1

Patient disposition. ^aSome participants fulfilled more than one inclusion or exclusion criterion. ^bTwo additional participants discontinued treatment before the protocol amendment and neither withdrew nor re-consented. ^cNew, 36 week maintenance period (52–88 weeks). The number of participants who entered the maintenance period = (participants randomised) – (participants withdrawn from the trial). The number of participants who entered the maintenance period on-treatment = (participants exposed) – (participants who discontinued treatment). The number of participants who completed trial = (participants who entered the maintenance period) – (participants withdrawn from the trial). The number of participants who completed trial on-treatment = (participants who entered the maintenance period on treatment) – (participants who discontinued treatment). Exposed was defined as ‘randomised and received treatment’. The number of participants that discontinued treatment includes the number that withdrew from the trial. FAS, full analysis set; SAS, safety analysis set

Fig. 2

The rate of hypoglycaemia. Overall symptomatic hypoglycaemia was defined as severe hypoglycaemia (an event requiring third-party assistance as per the ADA definition [28]) or blood glucose <3.1 mmol/l confirmed with symptoms. Nocturnal symptomatic hypoglycaemia was defined as severe hypoglycaemia or blood glucose <3.1 mmol/l confirmed with symptoms, occurring between 00:01 and 05:59 h. ^aPrimary endpoint. E, events; rate, events per 100 person-years of observation

Fig. 3

The proportion of participants with hypoglycaemia (post hoc). Overall symptomatic hypoglycaemia was defined as severe hypoglycaemia (an event requiring third-party assistance as per the ADA definition [28]) or blood glucose <3.1 mmol/l confirmed with symptoms. Nocturnal symptomatic hypoglycaemia was defined as severe hypoglycaemia or blood glucose <3.1 mmol/l confirmed with symptoms, occurring between 00:01 and 05:59 h. %, proportion of participants with events; n, number of participants experiencing events

Fig. 4

Hypoglycaemia endpoints during the titration period. Overall symptomatic hypoglycaemia was defined as severe hypoglycaemia (an event requiring third-party assistance as per the ADA definition [28]) or blood glucose <3.1 mmol/l confirmed with symptoms. Nocturnal symptomatic hypoglycaemia was defined as severe hypoglycaemia or blood glucose <3.1 mmol/l confirmed with symptoms, occurring between 00:01 and 05:59 h. %, proportion of participants with events; E, events; n, number of participants with events; rate, events per 100 person-years of observation

Fig. 5

Hypoglycaemia endpoints during the variable maintenance period. Overall symptomatic hypoglycaemia was defined as severe hypoglycaemia (an event requiring third-party assistance as per the ADA definition [28]) or blood glucose <3.1 mmol/l confirmed with symptoms. Nocturnal symptomatic hypoglycaemia was defined as severe hypoglycaemia or blood glucose <3.1 mmol/l confirmed with symptoms, occurring between 00:01 and 05:59 h. %, proportion of participants with events; E, events; n, number of participants with events; rate, events per 100 person-years of observation

Fig. 6

HbA_1c, FPG and fasting SMBG over time. (a) HbA_1c over the study period. Estimated treatment difference from baseline to end of treatment for degludec U200 vs glargine U300 was −1.07 mmol/mol (95% CI −1.94, −0.20) (−0.10% [95% CI −0.18, −0.02]). (b) FPG over the study period. Estimated treatment difference from baseline to end of treatment for degludec U200 vs glargine U300 was −0.62 mmol/l (95% CI −0.82, −0.43). (c) SMBG over the study period. Estimated treatment difference from baseline to end of treatment for degludec U200 vs glargine U300 was −0.18 mmol/l (95% CI −0.37, 0.01). Data are presented as mean±SEM, with the number of participants (n) shown below each graph. Vertical dotted lines illustrate the end of the titration period (week 16) and the beginning of the maintenance period (week 52). According to the protocol, all participants were not required to complete all visits in the variable maintenance period and therefore the number of participants at each week decreased during this period

Fig. 7

Basal insulin dose over time. Data are presented as mean±SEM, with the number of participants (n) shown below the graph. Vertical dotted lines illustrate the end of the titration period (week 16) and the beginning of the maintenance period (week 52). According to the protocol, all participants were not required to complete all visits in the variable maintenance period and therefore the number of participants at each week decreased during this period