Table 3.

Reported time in hypoglycemia, hypoglycemia awareness and autonomic response outcomes in clinical trials evaluating continuous glucose monitoring use in type 1 diabetes patients with impaired awareness of hypoglycemia

Author	Time in hypoglycemia at study end † (%)	Hypoglycemia awareness outcomes	Endogenous Glucoregulatory Response Outcomes
Ly et al. (2011) 130	NA	NA	Changes in epinephrine levels during hypoglycemic clamps compared with euglycemic clamps (%) Baseline: CGM: 214 ± 72% Standard: 288 ± 151% (P = 0.688) Study end (4 weeks): CGM: 604 ± 234% Standard: 114 ± 83% (P = 0.048) ‡ Changes in epinephrine levels during hypoglycemic clamps at baseline vs study end: CGM: P = 0.031 Standard: P = 0.375
Little et al. (HypoCOMPaSS; 2014) 131 ; Leelarathna, et al. (HypoCOMPaSS clamp subcohort study; 2013) 132	Glucose <72 mg/dL CGM: 6.3 ± 9.1% SMBG: 5.2 ± 4.2% (P = 0.47) Glucose ≤54 mg/dL CGM: 2.1 ± 5.1% SMBG: 1.3 ± 2.1% (P = 0.36) Clamp Study Subcohort – AUC of the % of time spent with glucose <54 mg/dL (mean ± standard error): CGM: 658 ± 223 SMBG: 797 ± 193 (P = 0.64)	Gold scores Baseline: 5.1 ± 1.1 Study end: 4.1 ± 1.4 (P < 0.001) ‡ Clarke scores Baseline: 4.1 ± 1.6 Study end: 3.2 ± 1.7 (P < 0.001) HypoA‐Q scores Baseline: 13.4 ± 3.4 Study end: 9.1 ± 4.2 (P < 0.001) No differences in hypoglycemia awareness scores between the CGM vs SMBG and CSII vs MDI models. Clamp Study Subcohort Plasma glucose level of first felt hypoglycemia Baseline: 47 ± 2 mg/dL Study end: 56 ± 4 mg/dL (P = 0.02) ‡ Symptom score AUC Baseline: 500 (364–685) Study end: 650 (365–1,285) (P = 0.02) No differences in the above measures between CGM vs SMBG and CSII vs MDI models.	Clamp Study Subcohort –AUC of incremental metanephrine levels Baseline: 2,412 (−3,026 to 7,279) Study end: 5,180 (−771 to 11,513) (P = 0.02) Glucose thresholds for metanephrine response Baseline: 43 (41–45) mg/dL Study end: 49 (41–58) mg/dL (P = 0.03) No differences in the above measures between the CGM vs SMBG and CSII vs MDI models.
van Beers et al. (IN CONTROL; 2016) 133	Glucose ≤70 mg/dL CGM: 6.8% [5.2–8.3] SMBG: 11.4% [9.9–13.0] (P < 0.0001)	Gold scores End of CGM phase: 4.6 [4.3–5.0] End of SMBG phase: 5.0 [4.6–5.4] (P = 0.035) Change in Gold scores from baseline End of CGM phase: −0.5 [−0.8 to −0.1] End of SMBG phase: −0.1 [−0.4–0.2] (P = 0.076) Clarke scores End of CGM phase: 4.4 [3.9–4.8] End of SMBG phase: 4.4 [3.9–4.8] (P = 0.953) Change in Clarke scores from baseline End of CGM phase: −0.1 [−0.5–0.3] End of SMBG phase: −0.4 [−0.8–0.0] (P = 0.216)	NA
Rickels et al. (2018) 134	Glucose <60 mg/dL Run‐in: 6.5 ± 1.6% Study end (18‐months): 4.0 ± 0.7% (P = NS)	Clark scores Baseline: 6 (6–7) 6 months: 4 (4–5) 12 months: 3 (2–5) 18 months: 3 (2–5) (P < 0.01) Clamp Study Autonomic symptoms during hypoglycemic vs euglycemic clamps: Baseline: 3.7 ± 0.9 vs 2.5 ± 0.3 (P = NS) 6 months: 5.1 ± 1.0 vs 1.5 ± 0.7) (P < 0.05) 18 months: 5.6 ± 1.2 vs 2.2 ± 0.6 (P < 0.05) No statistical significance when comparing the symptom scores at 6 and 18 months to baseline.	Epinephrine levels during hypoglycemia Baseline: 152 ± 37 pg/mL 6 months: 204 ± 37 pg/mL (P = NS) 18 months: 152 ± 36 pg/mL (P = NS) Norepinephrine levels during hypoglycemia Baseline: 378 ± 44 pg/mL 6 months: 317 ± 38 pg/mL (P = NS) 18 months: 362 ± 60 pg/mL (P = NS) Endogenous glucose production (compared to baseline): ‡ Baseline: 0.42 ± 0.08 mg/kg/min 6 months: 0.54 ± 0.07 mg/kg/min (P = NS) 18 months: 0.84 ± 0.15 mg/kg/min (P < 0.05)
Heinemann et al. (HypoDE; 2018) 135	Glucose ≤70 mg/dL CGM: 1.6% (0.9–3.7) Control: 6.4% (3.7–12.0) Adjusted between‐group differences: P < 0.0001 Glucose ≤54 mg/dL CGM: 0.3% (0.1–0.9) Control: 2.5% (1.0–6.1) Adjusted between‐group differences: P < 0.0001	Clark scores Baseline CGM: 5.0 (4.0–6.0) Control: 5.0 (4.0–6.0) Follow up CGM: 3.0 (1.0–4.0) Control: 3.0 (1.0–5.0) Adjusted between‐group differences: P = 0.7662	NA
Reddy et al. (I‐HART; 2018) 141	Glucose <70 mg/dL CGM: 6.2% (3.1–10.2) FGM: 11.0% (8.2–17.0) Median change from baseline: P < 0.01 Glucose <50 mg/dL CGM: 0.9% (0.2–1.8) FGM: 3.8% (3.0–6.4) Median change from baseline: P < 0.003	Gold scores Baseline: CGM: 5 (5–6) FGM: 5 (4–5) Study end (8 weeks): CGM: 4.5 (3.0–5.0) FGM: 5.0 (3.5–6.0) Median change from baseline: CGM: 0.0 [−1.0 to 0.0] (P = NS) FGM: 0.0 [−0.8 to 0.0] (P = NS) Differences in median changes from baseline to study end: P = 0.23	NA

Data presented in mean ± standard deviation or median (interquartile range) or mean/median [95% confidence interval], unless noted otherwise.

AUC, area under the curve; CSII, continuous subcutaneous insulin infusion; FGM, flash glucose monitoring; HypoCOMPaSS, comparison of optimised MDI versus pumps with or without sensors in severe hypoglycaemia; HypoDE, hypoglycemia in Deutschland; IAH, impaired awareness of hypoglycemia; I‐HART, impact on hypoglycaemia awareness of real time CGM and intermittent continuous glucose data; IN CONTROL, effects of RT‐CGM on glycemia and QoL in patients with T1DM and IHA; MDI, multiple daily injections; NA, not available; NS, not significant; T1D, type 1 diabetes.

^†Variable definitions for hypoglycemia were used. These trials were performed prior to the current continuous glucose monitoring (CGM)/hypoglycemia guidelines. For self‐monitoring of blood glucose level (SMBG) groups or run‐in phase, time in hypoglycemia were assessed with blinded CGMs.

^‡Primary outcomes of the trials.