Insulin Degludec vs Insulin Glargine U100: Hypoglycemic Outcomes in At-Risk Type 2 Diabetics

Insulin Degludec vs Insulin Glargine U100: Hypoglycemic Outcomes in At-Risk Type 2 Diabetics
Kirstin Gramith, Pharm.D., Essentia Health 

Background: Glycemic control is necessary to reduce complications in type 2 diabetic patients. Despite insulin being the most effective blood glucose lowering therapy, patients are often reluctant to start insulin therapy. Concern of hypoglycemia can negatively influence patient perception of insulin therapy and hypoglycemia itself can limit achieving adequate glycemic control. Previous trials conducted for the approval of insulin degludec (IDeg) showed lower rates of overall and nocturnal hypoglycemia compared with insulin glargine U100 (IGlar). The SWITCH 2 Randomized Clinical Trial was designed to further accept or reject these findings. 

Objective: To determine if IDeg is associated with less hypoglycemia compared with IGlar in adults with type 2 diabetes mellitus (T2DM) and at least one risk factor for hypoglycemia. 

Study Design: This was a randomized, double-blind, multicenter, treat-to-target crossover study. There were two 32 week treatment periods, which consisted of a 16 week titration period and a 16 week maintenance period. Participants were randomly assigned in an 1:1 ratio to receive IDeg followed by crossover to IGlar (IDeg-first arm) or vice versa (IGlar-first arm). Insulin was titrated in multiples of two units once weekly to a fasting blood glucose target of 71 to 90 mg/dL. 

Patients were eligible for this study if the following criteria were met: age ≥ 18 years, diagnosed with T2DM, hemoglobin A1c (HbA1c) ≤ 9.5%, treatment with any basal insulin with or without oral antidiabetic medications and presence of at least one risk factor for developing hypoglycemia. Patients were ineligible for this trial if treated with bolus or premixed insulin or a sulfonylurea prior to trial start. 

Rate of overall symptomatic hypoglycemic episodes (either severe and requiring third party assistance or blood glucose confirmed [< 56 mg/dL], with symptoms of hypoglycemia) during the maintenance period was the primary endpoint. Rates of nocturnal symptomatic hypoglycemic episodes occurring between 12:01 AM and 5:59 AM and percentage of patients who experienced severe hypoglycemic episodes in the maintenance period were secondary endpoints. Change in HbA1c after each treatment period was an efficacy endpoint. 

Endpoints were assessed using an intent-to-treat analysis. Assessment of hypoglycemic endpoints only used data from those who received at least one dose of the trial insulins. Hypoglycemic endpoints were superior if the upper bound of the two-sided 95% confidence interval (CI) of the estimated rate ratio (ERR) was less than one. Hemoglobin A1c was considered noninferior if the upper bound of the one-sided 95% CI was no more than 0.4%. 

Results: A total of 721 patients were randomized to treatment sequence (361 to the IDeg-first arm, 360 to the IGlar-first arm). Mean age was 61.4 ± 10.5 years, mean duration of diabetes was 14.1 ± 8.1 years, mean HbA1c was 7.6 ± 1.1%, 53.1% of participants were men, and 79.1% were receiving at least one or more oral antidiabetic medications. Seventy-eight percent of participants in the IDeg-first arm and 83% in the IGlar-first arm completed both treatment periods. Reason for dropouts were similar between arms. 

There was a statistically significantly lower rate of overall symptomatic hypoglycemia with IDeg compared with IGlar (185.6 vs 265.4 episodes per 100 patient-year of exposure (PYE); ERR 0.70 [95% CI 0.61 - 0.80], p<0.001) during the maintenance phase, which also proved true for the rate of nocturnal symptomatic hypoglycemia with IDeg compared with IGlar (55.2 vs 93.6 episodes per 100 PYE; ERR 0.58 [95% CI 0.46 - 0.74], p<0.001). The proportion of patients who experienced a severe hypoglycemic episode during the maintenance period differed by 0.8% between IDeg and IGlar (1.6% vs 2.5%, ERR 0.54 [95% CI 0.21 - 1.42], P=0.35). 

At the end of treatment period one, mean HbA1c was 7.06 ± 1.07% with IDeg and 6.9 ± 1.03% with IGlar (estimated treatment difference [ETD] 0.9% [95% CI -0.04 - 0.23%], p<0.001). Mean HbA1c was 7.08 ± 1.23% with IDeg vs 7.11 ± 1.15% with IGlar (ETD 0.06% [95% CI -0.04 - 0.23%], p<0.001) at the end of treatment period two. 

Conclusions: Results from SWITCH 2 show a 30% reduction in the rate of overall symptomatic hypoglycemia and a 42% reduction in the rate of nocturnal symptomatic hypoglycemia when comparing basal IDeg with IGlar. Mean HbA1c of IDeg remained noninferior to mean HbA1c of IGlar throughout both treatment periods. There was no significant difference in proportion of patients who experienced at least one severe hypoglycemic episode during the maintenance period. 

Key Point: Basal IDeg was associated with less episodes of overall and nocturnal hypoglycemia and noninferior HbA1c control compared with IGlar.

References:

Wysham C, Bhargava A, Chaykin L, et al. Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 2 diabetes: the SWITCH 2 randomized clinical trial. JAMA. 2017:318(1):45-56. doi:10.1001/jama.2017.7117.