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.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lane has served on speaker and advisory panels for Novo Nordisk A/S and Insulet Corp; as an author for Novo Nordisk A/S; and received research funding from Novo Nordisk A/S, Insulet Corp, and Eli Lilly and Co. Dr Bailey has served as a consultant for AstraZeneca, Bayer Healthcare, BD Biosciences, Medtronic Inc, Novo Nordisk A/S, Sanofi US, Calibri, and Lilly; received research support from Abbott, Ambra, Ascensia, Boehringer Ingelheim, BD Biosciences, Calibra, Companion Medical, Dexcom Inc, Elcelyx, Glysens, Janssen, Lexicon, Lilly, Medtronic, Novo Nordisk, sanofi, Senseonics, Versartis, and Xeris; and as a speaker for Abbott, Insulet, Medtronic, Lilly, Novo Nordisk, and sanofi. Dr Gerety has provided consultancy services for Dexcom Inc; received research support from Boehringer Ingelheim Pharmaceuticals Inc, Lexicon Pharmaceuticals Inc, Novo Nordisk A/S, and Locemia Solutions, LP; and participated in speaker panels for AstraZeneca, Boehringer Ingelheim Pharmaceuticals Inc, Dexcom Inc, Eli Lilly and Co, Merck and Co Inc, Novo Nordisk A/S, and Janssen Pharmaceuticals Inc. Dr Gumprecht has provided consultancy services for Bioyon SA, Merck Sharpe & Dohme Corp, Eli Lilly and Co, and Polpharma SA Pharmaceutical Works and participated in speaker bureaus for Novo Nordisk A/S, Eli Lilly and Co, Servier, Merck Sharpe & Dohme Corp, Bioton SA, and Roche Pharmaceuticals. Dr Philis-Tsimikas has served on advisory panels for Eli Lilly and Co, Dexcom Inc, and Voluntis; provided consultancy services for Novo Nordisk A/S and Sanofi US; and received research support from Merck & Co Inc, Novo Nordisk A/S, Sanofi US, Eli Lilly and Co, AstraZeneca, Janssen Pharmaceuticals Inc, and Genentech Inc. Dr Hansen is an employee of Novo Nordisk A/S and holds stock/shares in Novo Nordisk A/S. Mr Nielsen is an employee of Novo Nordisk A/S and holds stock/shares in Novo Nordisk A/S. Mr Nielsen was employed by Novo Nordisk A/S throughout the duration of the trial, but changed affiliation on May 1, 2017. Dr Warren has served on advisory panels for Novo Nordisk A/S, Eli Lilly and Co; has received research support from Janssen Pharmaceuticals Inc, NPS Pharmaceuticals, Merck, Sharpe & Dohme Corp, Forest Research Institute Inc, Pfizer Inc, Mylan, Sanofi US, Takeda Pharmaceutical Co Limited, Valeant Pharmaceuticals, and Boehringer Ingelheim Pharmaceuticals Inc; and served on speaker panels for Novo Nordisk A/S, Janssen Pharmaceuticals Inc, Eli Lilly and Co, AstraZeneca, Sanofi US, Merck Sharpe & Dohme Corp, Shire Pharmaceuticals, and Boehringer Ingelheim Pharmaceuticals Inc.

Figures

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 A1c 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 A1c (HbA1c) 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 HbA1c 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.