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SWITCH 2: Reduced Hypoglycemia with Insulin Degludec versus Insulin Glargine, both U100, in Patients with T2D at High Risk of Hypoglycemia: A Randomized, Double-Blind, Crossover Trial

In the phase 3a development program for insulin degludec (IDeg), a basal insulin with a unique mode of protraction and duration of action greater than 42 hours [1], rates of confirmed and nocturnal confirmed hypoglycemia were significantly lower with IDeg versus standard insulin glargine (IGlar) in type 2 diabetes patients. The five trials of that program also revealed IDeg’s non-inferiority to IGlar U100 with respect to HbA1c, said Carol Wysham, MD, clinical associate professor at the University of Washington, Spokane, WA. Because of potential limitation of those trials (lack of blinding, some inclusion/exclusion criteria, indeterminate timing of IGlar administration) SWITCH 2 was launched to confirm those findings.

SWITCH 2 enrolled 720 type 2 diabetes patients (53.1% male, mean age 61.4 years), with a mean diabetes duration of 14.1 years and mean HbA1c of 7.6%, randomizing them 1:1 to 100 U/mL (U100) of IDeg or IGlar once daily and 1:1 to basal insulin in the morning or evening. A 16 week titration to target period was followed by 16 weeks of maintenance, then followed by crossover to the other drug with an identical titration and maintenance period. All patients had previously received basal insulin with or without oral antidiabetic drugs, excluding sulfonylurea/meglitinides. Also, all patients had at least one of the following hypoglycemia risk factors: 1 or more severe hypoglycemic episode in the last year, moderate chronic renal failure, hypoglycemia unawareness, insulin exposure of at least 5 years, episode of hypoglycemia (ADA definition ≤70 mg/dL [≤3.9 mmol/L]) within the last 12 weeks. Basal insulin was titrated weekly to a fasting target glucose of 71–90 mg/dL (3.9–5.0 mmol/L).

Confirmed symptomatic hypoglycemia was defined by a blood glucose (BG) <56 mg/dL (<3.1 mmol/L), and nocturnal hypoglycemia was predefined as any episode occurring between 00:01 and 05:59, both inclusive.

Analysis showed that the prerequisite of achieving non-inferiority for change of HBA1c was met in both treatment periods. Mean HbA1c at the end of treatment period 1 was 7.06% for IDeg and 6.98% for IGlar. At the end of treatment period 2, mean HbA1c was 7.08% (IDeg) versus 7.11% (IGlar).

Severe or BG-confirmed symptomatic hypoglycemia in the maintenance period, the primary endpoint, was 30% lower with IDeg versus IGlar (0.70 [0.607; 0.801] p<0.0001). The number of severe or BG-confirmed symptomatic nocturnal hypoglycemic episodes, a secondary endpoint, was also achieved with a 42% reduction for IDeg versus IGlar (0.58 [0.455; 0.744],p<0.0001). Also, in the full treatment period, the severe hypoglycemia rate was 51% lower with IDeg as compared with IGlar (0.49 [0.257; 0.935],p=0.0306).

Adverse event and serious adverse event rates were similar between IDeg and IGlar (332.6 versus 360.1 adverse events /100 patient-years for IDeg and IGlar, respectively and 20.6 versus 25.0 events/100 patient years, respectively).

The proportion of patients with severe hypoglycemic episodes in both the maintenance and full treatment periods, while numerically lower in the IDeg group, was statistically similar between groups. Dr. Wysham attributed this lack of statistical significance to the low overall event rate.

Dr. Wysham concluded, “This SWITCH 2 trial confirmed, in a randomized blinded setting, the previous finding of less hypoglycemia with IDeg compared with IGlar.

In an interview, Dr. Wysham commented, “These results are important clinically because we know that hypoglycemia is the primary impediment to achieving good glycemic control in our patients with longstanding type 2 diabetes. If we can achieve a very good glycemic goal with less hypoglycemia, it’s going to give us the confidence to titrate our patients more aggressively to lower target fasting glucose levels. With that we can achieve better HbA1c control and still help our patients stay safe.”


[1] Jonassen et al. Pharm Res 2012;29:2104–14.

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