Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 1 Diabetes: The SWITCH 1 Randomized Clinical Trial

Abstract

Importance: Hypoglycemia, common in patients with type 1 diabetes, is a major barrier to achieving good glycemic control. Severe hypoglycemia can lead to coma or death.

Objective: To determine whether insulin degludec is noninferior or superior to insulin glargine U100 in reducing the rate of symptomatic hypoglycemic episodes.

Design, setting, and participants: Double-blind, randomized, crossover noninferiority trial involving 501 adults with at least 1 hypoglycemia risk factor treated at 84 US and 6 Polish centers (January 2014-January 12, 2016) for two 32-week treatment periods, each with a 16-week titration and a 16-week maintenance period.

Interventions: Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 249) or to receive insulin glargine U100 followed by insulin degludec (n = 252) and randomized 1:1 to morning or evening dosing within each treatment sequence.

Main outcomes and measures: The primary end point was the rate of overall severe or blood glucose-confirmed (<56 mg/dL) symptomatic hypoglycemic episodes during the maintenance period. Secondary end points included the rate of nocturnal symptomatic hypoglycemic episodes and proportion of patients with severe hypoglycemia during the maintenance period. The noninferiority criterion for the primary end point and for the secondary end point of nocturnal hypoglycemia was defined as an upper limit of the 2-sided 95% CI for a rate ratio of 1.10 or lower; if noninferiority was established, 2-sided statistical testing for superiority was conducted.

Results: Of the 501 patients randomized (mean age, 45.9 years; 53.7% men), 395 (78.8%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia were 2200.9 episodes per 100 person-years' exposure (PYE) in the insulin degludec group vs 2462.7 episodes per 100 PYE in the insulin glargine U100 group for a rate ratio (RR) of 0.89 (95% CI, 0.85-0.94; P < .001 for noninferiority; P < .001 for superiority; rate difference, -130.31 episodes per 100 PYE; 95% CI, -193.5 to -67.16). The rates of nocturnal symptomatic hypoglycemia were 277.1 per 100 PYE in the insulin degludec group vs 428.6 episodes per 100 PYE in the insulin glargine U100 group, for an RR of 0.64 (95% CI, 0.56-0.73; P < .001 for noninferiority; P < .001 for superiority; rate difference, -61.94 episodes per 100 PYE; 95% CI, -83.85 to -40.03). A lower proportion of patients in the insulin degludec than in the insulin glargine U100 group experienced severe hypoglycemia during the maintenance period (10.3%, 95% CI, 7.3%-13.3% vs 17.1%, 95% CI, 13.4%-20.8%, respectively; McNemar P = .002; risk difference, -6.8%; 95% CI, -10.8% to -2.7%).

Conclusions and relevance: Among patients with type 1 diabetes and at least 1 risk factor for hypoglycemia, 32 weeks' treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemic episodes.

Trial registration: clinicaltrials.gov Identifier: NCT02034513.

Figure 1.. Patient Flow Through the SWITCH 1 Randomized Clinical Trial

^aSome patients fulfilled more than one inclusion or exclusion criterion. ^bWithdrawal at the request of the patient or investigator or patient was unavailable at randomization visit following screening. BMI, indicates body mass index, calculated as weight in kilograms divided by height in meters squared.

Figure 2.. Cumulative Rates of Hypoglycemia per Patient

Data are based on safety analysis set. The tinted region in blue indicates the range from y = 0.7 to 2.5, the mean cumulative number of episodes per person; the tinted region in purple, y = 0 to 0.7, the mean cumulative number of episodes per person.

Figure 3.. Mean Hemoglobin A_1c and Fasting Plasma Glucose Levels Over Time

Data are observed means. Error bars indicate 95% CIs for the full analysis set. Statistical analyses were performed using a mixed-model repeated measures with treatment, sex, region, dosing time, pretrial insulin treatment, and visit as factors and with baseline hemoglobin A_1c (HbA_1c) and age as covariates. All fixed factors and covariates are nested within visit. Analysis of treatment period 1 only included patients having observation time in maintenance period 1; for treatment period 2, all patients having any HbA_1c measurements after crossover contributed to the analysis. Severe hypoglycemia was defined according to the ADA definition (see the Methods section). The numbers of patients represent those contributing to the data at that time point.