Hypoglycemia in randomized clinical trials

Study	Investigational vs comparator	Population	n	Hypoglycemia category	Result	RRa/b (95% CI)	P value
BEGIN Basal-Bolus Type 1 [28]	Insulindegludec + insulinaspart vs insulindegludec + insulinaspart	Adults with T1DM (A1C ≤10%) on basal-bolus therapy	629	- Conﬁrmed hypoglycemia (PG <54 mg/dl or severe) - Nocturnal conﬁrmed hypoglycemia - Severe	42.54 vs 40.18 events/PYE 4.41 vs 5.86 events/PYE 0.21 vs 0.16 events/PYE	RRa 1.07 (0.89–1.28) RRa 0.75 (0.59–0.96) RRa 1.38 (0.72–2.64)	0.48 0.021 0.34
BEGIN Flex T1 [62]	Insulin degludec flexible† + insulin aspartvs insulin degludec fixed + insulin aspartvs insulin glargine+insulinaspart	Adults with T1DM (A1C ≤10%) on basal-bolus therapy	493	- Conﬁrmed hypoglycemia (PG <54 mg/dl or severe) - Nocturnal conﬁrmed hypoglycemia - Severe	82.4 vs 88.3 vs 79.7 events/PYE 6.2 vs 9.6 vs 10.0 events/PYE 0.3 vs 0.4 vs 0.5 events/PYE	RRa 1.03 (0.85–1.26) flexible vsglargine RRa 0.92 (0.76–1.12) flexible vs fixed RRa 0.60 (0.44–0.82) flexible vsglargine RRa 0.63 (0.46–0.86) flexible vs fixed 0.89 (0.40–1.99) flexible vsglargine 1.09 (0.48–2.48) flexible vs fixed	NS NS 0.001 0.003 NS NS
EDITION 4 [63]	Insulinglargine U300 vs insulinglargine U100	Adults with T1DM basal insulin + prandial insulin	549	- Conﬁrmed hypoglycemia (PG ≤70 mg/dl or severe) - Nocturnal conﬁrmed hypoglycemia - Severe	78.4 vs 72.5 events/PYE 8.0 vs 8.9 events/PYE 6.6% vs 9.5%	RRa 1.09 (0.94–1.25) RRa0.90 (0.71–1.14) -	- - -
Edition 4 JP 1 [64]	Insulinglargine U300 vs insulinglargine U100	Adults with T1DM basal insulin + prandial insulin	243	- Conﬁrmed hypoglycemia (PG ≤70 mg/dl or severe) - Nocturnal conﬁrmed hypoglycemia - Severe	96.7% vs 97.5% 68.9% vs 81.0% -	RRb 0.99 (0.95–1.04) RRb 0.85 (0.73–0.99) -	- - -
Rosenstock et al., 2013 [65]	LY2605541 + prandial insulin vs insulin glargine + prandial insulin	Adults with T1DM (A1C ≤10.5%) on basal-bolus insulin	137	- Total hypoglycemia (BG ≤70 mg/dl or symptoms - Nocturnal hypoglycemia - Severe	8.74 vs 7.36 events/PME 0.88 vs 1.13 events/PME 6 events in both arms (in 5 vs 3 patients)	RRa 1.12 (1.03–1.23) RRa 0.75 (0.62–0.90) -	0.037 0.012 -
ELEMENT 1 [66]	LY2963016 + insulin lisprovs insulin glargine + insulin lispro	Adults with T1DM (A1C ≤11%) on basal-bolus insulin	535	- Total hypoglycemia (BG ≤70mg/dl or symptoms)	86.5% vs 89.2%	-	0.717
*Requiring assistance; †dosing schedule creating 8-40hours between injections. A1C, glycated hemoglobin; BG, blood glucose; CI, confidence interval; NS, not significant; PG, plasma glucose; PME, patient month of exposure; PYE, patient year of exposure; OADs, oral antidiabetic drugs; RRa, rate ratio; RRb, relative risk; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

Table 2: Hypoglycemia in randomized clinical trials of novel basal analog insulins in T1DM [28,62-66].