Table 2.
Key intervention studies in hypoglycemia unaware patients with T1D
| Baseline |
End of study |
|||||||
|---|---|---|---|---|---|---|---|---|
| Reference | Intervention and duration of follow-up | Study design and duration | No. and duration of diabetes (years) | HbA1c (%) | SH rate and awareness score | HbA1c (%) | SH rate and awareness score | Comments |
| Fanelli et al. (42) | Change from twice daily to MDI regimen Daily contact Re-education | Prospective, single center Before and after 1-year follow-up | n = 21 (11.4 ± 1.8) | 5.8 ± 0.1 (normal 3.8–5.5) | 9 of 21 had SH in previous year All had IAH | 6.9 ± 0.1 (normal 3.8–5.5) | No SH in 12-month follow-up 10-fold reduction in mild hypoglycemic events | Restoration of symptom and counterregulatory hormone responses; sustained to 1 year |
| Cranston et al. (40) | Intensive insulin therapy Frequent contact Intensive education | Prospective, single center Before and after 4-month follow-up | n = 12 men (11–32) | Group A: 6.9 ± 0.3 Group B: 8.7 ± 0.3 | N/A At least three CBG <3 with no symptoms in 2 weeks | No significant deterioration (numbers not reported) | SH: N/A Restoration of symptoms and improvement in counterregulatory responses after 3 weeks of no CBG <3.0 mmol/L | Mean 4.1 ± 1.1 months of frequent contact required to achieve 3 weeks of hypoglycemia avoidance |
| Dagogo-Jack et al. (41) | Scrupulous avoidance of iatrogenic hypoglycemia | Prospective, single center Before and after 3-month follow-up | n = 6 (15.5 ± 4.4) Age <35 | 8.3 ± 1.0 | 10.6 ± 3.7 All IAH | 9.8 ± 1.1 | SH not reported 60% reduction in CBG <3.3 mmol/L | Restored symptom but not hormonal responses at 3 months |
| Hermanns et al. (44) | HyPOS vs. control intervention, with most patients also moving to CSII with more than one SH or IAH with >10 years of T1D | RCT 6 months (31-month follow-up reported separately) | n = 164, 85.3% with T1D (HyPOS: 20.2 ± 10.8 Control: 22.1 ± 10.9) | HyPOS: 7.2 ± 0.9 Control: 7.4 ± 1.1 | HyPOS: 3.5 ± 3.6/patient-year Clarke score 4.8 Control: 3.6 ± 36/patient-year Clarke score 5.0 | HyPOS: 7.1 ± 0.9 Control: 7.3 ± 1.1 | HyPOS: 0.9 ± 1.9/patient-year Clarke score 2.3 Control: 0.6 ± 1.2/patient-year Clarke score 3.0 | 30% reduction in mild hypoglycemia with HyPOS; further 31-month follow-up shows sustained benefit in HyPOS over standard education |
| Cox et al. (43) | HAAT vs. control Increased SMBG and monthly visits No previous education or SMBG | RCT 18-month follow-up | n = 60 (13) | HAATT: 8.1 ± 0.7 Control: 8.0 ± 0.7 | HAATT: 2.0 Control: 1.8 | HAATT: 8.0 Control: 8.1 | HAATT: 0.4 Control: 1.7 | Hypoglycemia-specific education program performed better than frequent contact |
| Little et al. (48) | HypoCOMPaSS MDI vs. CSII and SMBG vs. CGM in 2 × 2 design Both arms: education and monthly visits plus telephone support | RCT 24-month follow-up | n = 96 (28–30) | 8.2 ± 1.2 | 8.9 ± 13.4 77% had SH in prior year Gold score 5.1 ± 1.1 | 8.1 ± 1.2 | 0.8 ± 1.9 20% had SH in prior year Gold score 4.1 ± 1.6 | No differences among CSII, CGM, and SAP CGM had slightly greater reduction in mild and SH, but higher baseline than SMBG |
| Pedersen-Bjergaard et al. (56) | HypoAna study [Analog insulin (detemir and aspart) vs. human insulin (NPH and regular)] | Multicenter, open-label, crossover RCT (1:1) 2-year follow-up | n = 159 | 8.0 ± 1.0 | All had 2 or more episodes of SH in prior year | Decrease of 0.13% with analog treatment compared with human insulin (P = 0.02) | Insulin analogs: 105 episodes of SH Human insulin: 136 episodes of SH | Absolute rate reduction of 0.51 episodes of SH per patient-year with insulin analogs |
| Ly et al. (65) | CSII vs. SAP in young patients with IAH | RCT 6-month follow-up | n = 95 (11.0) | 7.4 ± 0.2 | SAP-LGS: 6 SH and 0.22/patient-year Clarke score 5.9 ± 1.5 CSII: 6 SH and 0.25/patient-year Clarke score 6.4 ± 1.5 | 7.4 ± 0.2 in both arms | SAP-LGS: 0 events = 0/patient-year Clarke score 4.7 (4.0–5.1) CSII: 6 events = 0.26/patient-year Clarke score 5.1 (5.5–6.4) | Young patients with short duration SAP-LGS reduced SH compared with CSII alone, although event rates were low Reduced time <70 and <60 mg/dL in LGS arm |
| de Zoysa et al. (47) | DAFNE-HART 6 sessions based on cognitive behavioral therapy and motivational interviewing 1-year follow-up | Small trial; 2 sites Uncontrolled pilot clinical trial | n = 24 (31 ± 12) Previous DAFNE 8 CSII | 7.8 ± 1.1 | Median 3.0 (0–103) Clarke score 5.4 ± 1.2 Ryan score 948 | 7.8 ± 1.2 | Median 0 (0–3) 70% reported no further SH Clarke score 3.8 ± 1.8 Ryan score 372 | 9 of 20 restored awareness Some accepted CSII or CGM, which they were resistant to previously |
| Choudhary et al. (66) | Observational clinical audit of CGM in patients with SH despite previous DAFNE and CSII 1-year follow-up | Retrospective audit | n = 35 (29.6 ± 13.6) | 8.1 ± 1.2 | SH 8.1 ± 13.6/patient-year Gold score 5.1 ± 1.5 | 7.6 ± 1.0 | 0.6 ± 1.2/patient-year Gold score 5.2 ± 1.9 54% reported subjective improvement in awareness | Reduction in SH with CGM 23 of 35 used SAP-LGS 3 with SH on SAP had no further episodes on SAP-LGS |
| Giménez et al. (58) | CSII and education program with 2–3- month follow-up | Small, uncontrolled pilot trial 2-year follow-up | n = 20 (16.2) | 6.7 ± 1.1 | 1.25 ± 0.4/patient-year Clarke score 5.5 ± 1.2 | 6.3 ± 0.9 | SH 0.05/patient-year at 2 years Clarke score 1.6 ± 2.03 | 16 of 19 restored awareness Reduced mild hypoglycemia Time <70 mg/dL reduced from 13.7 to 9.1% |
| Sämann et al. (35) | Structured education 5-day course (DTTP) 9,583 patients at 96 centers 1-year follow-up | Subgroup analysis of patients with 3 or more SH at baseline | n = 341 (18.7 ± 11.1) | 7.4 ± 1.9 | 6.1 ± 9.6/patient-year | 7.2 ± 1.5 | 1.4 ± 5.4/patient-year | 56% had 1, 20% had 2, and only 15% had more than 3 SH events Reduced time in hospital 8.6 ± 15.4 to 3.9 ± 10.7 days/patient-year |
| Hopkins et al. (16) | Structured education program in flexible insulin therapy (U.K. DAFNE) 5-day course 1-year follow-up IAH subgroup reported | Retrospective audit | n = 215 (Duration not reported) | N/A | 3.6 ± 13.6/patient-year | N/A | 1.3 ± 5.9/patient-year | Improved awareness of hypoglycemia at a blood glucose >3 mmol/L |
| O’Connell et al. (92) | Islet treatment (961 ± 445 kIEQ) Antithymocyte globulin followed by tacrolimus + mycophenolate mofetil 2 patients had 1 treatment, 7 had 2 treatments, and 8 had 3 islet grafts | 3-center observational study 1-year follow-up | n = 17 Duration not reported | 8.3 ± 2.0 | Hyposcore 2,976 ± 3,494 | 6.5 ± 1.3 | 2 of 17 patients with graft failure had SH | 82% achieved composite end point of HbA1c <7% and absence of SH at 1 year |
| Brooks et al. (93) | Islet treatment (535 kIEQ) | Observational multicenter trial 2-year follow-up | n = 20 30 (16.5–38.5) | 8.0 (7.0–9.6) | 20 (7–50) | 6.2 (5.7–8.4) | 0.3 (0–1.6) | 70% maintained composite end point of HbA1c <7% and no SH at 2 years |
CBG, capillary blood glucose; DTTP, diabetes teaching and treatment program; kIEQ, kilo islet equivalent; N/A, not available.