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Randomized Controlled Trial
. 2017 Jul 4;318(1):45-56.
doi: 10.1001/jama.2017.7117.

Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial

Carol Wysham  1 , Anuj Bhargava  2 , Louis Chaykin  3 , Raymond de la Rosa  4 , Yehuda Handelsman  5 , Lone N Troelsen  6 , Kajsa Kvist  7 , Paul Norwood  8
Affiliations
Randomized Controlled Trial

Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial

Carol Wysham et al. JAMA. .

Abstract

Importance: Hypoglycemia, a serious risk for insulin-treated patients with type 2 diabetes, negatively affects glycemic control.

Objective: To test whether treatment with basal insulin degludec is associated with a lower rate of hypoglycemia compared with insulin glargine U100 in patients with type 2 diabetes.

Design, setting, and participants: Randomized, double-blind, treat-to-target crossover trial including two 32-week treatment periods, each with a 16-week titration period and a 16-week maintenance period. The trial was conducted at 152 US centers between January 2014 and December 2015 in 721 adults with type 2 diabetes and at least 1 hypoglycemia risk factor who were previously treated with basal insulin with or without oral antidiabetic drugs.

Interventions: Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 361) or to receive insulin glargine U100 followed by insulin degludec (n = 360) 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 symptomatic hypoglycemic episodes (severe or blood glucose confirmed [<56 mg/dL]) during the maintenance period. Secondary end points were the rate of nocturnal symptomatic hypoglycemic episodes (severe or blood glucose confirmed, occurring between 12:01 am and 5:59 am) and the proportion of patients with severe hypoglycemia during the maintenance period.

Results: Of the 721 patients randomized (mean [SD] age, 61.4 [10.5] years; 53.1% male), 580 (80.4%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were 185.6 vs 265.4 episodes per 100 patient-years of exposure (PYE) (rate ratio = 0.70 [95% CI, 0.61-0.80]; P < .001; difference, -23.66 episodes/100 PYE [95% CI, -33.98 to -13.33]), and the proportions of patients with hypoglycemic episodes were 22.5% vs 31.6% (difference, -9.1% [95% CI, -13.1% to -5.0%]). The rates of nocturnal symptomatic hypoglycemia with insulin degludec vs insulin glargine U100 were 55.2 vs 93.6 episodes/100 PYE (rate ratio = 0.58 [95% CI, 0.46-0.74]; P < .001; difference, -7.41 episodes/100 PYE [95% CI, -11.98 to -2.85]), and the proportions of patients with hypoglycemic episodes were 9.7% vs 14.7% (difference, -5.1% [95% CI, -8.1% to -2.0%]). The proportions of patients experiencing severe hypoglycemia during the maintenance period were 1.6% (95% CI, 0.6%-2.7%) for insulin degludec vs 2.4% (95% CI, 1.1%-3.7%) for insulin glargine U100 (McNemar P = .35; risk difference, -0.8% [95% CI, -2.2% to 0.5%]). Statistically significant reductions in overall and nocturnal symptomatic hypoglycemia for insulin degludec vs insulin glargine U100 were also seen for the full treatment period.

Conclusions and relevance: Among patients with type 2 diabetes treated with insulin and with at least 1 hypoglycemia risk factor, 32 weeks' treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemia.

Trial registration: clinicaltrials.gov Identifier: NCT02030600.

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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 Wysham reported receiving research support from and serving on advisory panels or speaker’s bureaus for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi; receiving personal fees and nonfinancial support from Insulet; and serving as a consultant for Eli Lilly. Dr Bhargava reported serving on advisory panels for Abbott, Janssen, and Sanofi; serving on speaker’s bureaus for Abbott, Sanofi, and AstraZeneca; and receiving research support from Janssen, Sanofi, Boehringer Ingelheim, Bristol-Myers Squibb, Novo Nordisk, Eli Lilly, Dexcom, Medtronic, Mylan, Duke Clinical Research Institute, Jaeb Center for Health Research, GlaxoSmithKline, Orexigen Therapeutics, Hygieia Research, University of Oxford, and AbbVie. Dr Chaykin reported serving on a speaker’s bureau for Novo Nordisk. Dr de la Rosa reported receiving research support from Novo Nordisk, Sanofi, Boehringer Ingelheim, GlaxoSmithKline, Elcelyx, and Merck; serving on speaker’s bureaus for Novo Nordisk, Sanofi, Boehringer Ingelheim, and Abbvie; and being a shareholder with Quest Diagnostics. Dr Handelsman reported receiving research support from Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Grifols, GlaxoSmithKline, Hanmi, Intarcia, Lexicon, Merck, Novo Nordisk, Sanofi, and Takeda; serving as a consultant for Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, diaDeux, DSI, Eisai, Gilead, GlaxoSmithKline, Halozyme, Janssen, LipoScience, Merck, Novo Nordisk, Sanofi, Santarus (Salix), and Vivus; serving on speaker’s bureaus for Amarin, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, DSI, GlaxoSmithKline, Janssen, Novo Nordisk, Santarus (Salix), and Vivus; receiving nonfinancial support from Eisai; serving on advisory boards for Janssen, Eli Lilly, and Regeneron; and receiving speaking honoraria from Janssen and Regeneron. Drs Troelsen and Kvist are employees of Novo Nordisk. Dr Norwood reported receiving research support from Novo Nordisk, Eli Lilly, and Sanofi.

Figures

Figure 1.
Figure 1.. Patient Flow Through the SWITCH 2 Randomized Clinical Trial
aSome patients fulfilled more than 1 inclusion or exclusion criterion.
Figure 2.
Figure 2.. Cumulative Rates of Hypoglycemia per Patient
Overall symptomatic hypoglycemia in the maintenance (A) and full treatment (B) periods, nocturnal symptomatic hypoglycemia in the maintenance (C) and full treatment (D) periods, and severe hypoglycemia in the maintenance (E) and full treatment (F) periods. Data are observed mean number of hypoglycemic episodes per patient for the safety analysis set. Tinted region in blue indicates range from y = 0.06 to 0.6 mean cumulative number of episodes per person; tinted region in purple, y = 0 to 0.06 mean cumulative number of episodes per person.
Figure 3.
Figure 3.. Hemoglobin A1c Level Over Time
Data are observed mean level of hemoglobin A1c for the full analysis set. Error bars indicate 95% confidence intervals. See eFigure 1 in Supplement 1 for the design of the treatment periods.
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