Outcomes for Adults with Type 1 Diabetes Referred with Severe Hypoglycaemia and/or Referred for Islet Transplantation to a Specialist Hypoglycaemia Service

Abstract

Islet transplantation alone (ITA) is indicated for patients with type 1 diabetes (T1D) with disabling severe hypoglycaemia (SH) despite optimised medical therapy. We examined outcomes for patients referred to an islet transplant unit with recurrent SH. Retrospective case note audit of 45 patients with ≥1 SH per year who were referred to our ITA unit between 2009-2012; 36 patients attended follow-up appointments. The cohort was 52.8% male, mean (± SD) age 43.9 (± 11.4) years, and duration of diabetes 26.5 (± 12.9) years. Baseline HbA1c was 8.3% (± 1.7) (67.2 mmol/mol), median (IQR) frequency of SH was 6.0 (2.0-24.0) per/patient/year and 83.3% had impaired awareness of hypoglycaemia (IAH). 80.6% of patients were referred from other secondary diabetes services, 22.2% had completed structured education, and 30.6% were using continuous subcutaneous insulin infusion (CSII). Seventeen patients were optimised with conventional therapy; SH reduced from 2.0 (1.5-9.0) to 0.0 (0.0-0.5) episodes/patient/year; p<0.001, and there was concurrent improvement in HbA1c (8.1-7.7%; 65.0 vs. 60.7 mmol/mol; p=0.072). Ten patients were listed for transplantation as they were not optimised despite structured education, CSII, and continuous glucose monitoring (CGM). The remaining 9 had a reduction in SH [7.0 (4.8-40.5) to 4.0 (2.5-6.3) episodes/patient/year; p=0.058] and either left the service (n=5) or are still being optimised (n=4). In conclusion, 47.2% of patients presenting with problematic hypoglycaemia resolved with optimal medical therapy, with a further 25% achieving clinically relevant improvement, however 27.8% required transplantation despite access to all therapies. Provision of expertise in hypoglycaemia management is essential to focus limited transplant resources on those who need it most.

Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia

“…Severe hypoglycemia is a debilitating, life-threatening complication of T1D (1,2,6,29) that, in some patients, is refractory to medical treatment (7,8,10). CSII, real-time CGMSs, and sensor-augmented insulin pumps with automated low-glucose insulin suspension can reduce the incidence of major hypoglycemic events (30–32) but do not restore hypoglycemia awareness or normal hormonal counterregulation of hypoglycemia or eliminate SHEs (7,8).…”

“…CSII, real-time CGMSs, and sensor-augmented insulin pumps with automated low-glucose insulin suspension can reduce the incidence of major hypoglycemic events (30–32) but do not restore hypoglycemia awareness or normal hormonal counterregulation of hypoglycemia or eliminate SHEs (7,8). Meticulous prevention of hypoglycemia (33–35) and structured education and/or behavioral therapies aimed at hypoglycemia awareness restoration (4,36,37) improve the awareness of hypoglycemia, hormonal counterregulation to hypoglycemia, and protection from SHEs, but 20–30% of patients so treated have persistent SHEs and IAH, as evidenced by elevated Clarke or Gold scores (4,10,36,37). In addition, their HbA 1c levels remain elevated at 7.8% (62 mmol/mol) to 8.4% (68 mmol/mol) (4,10,36,37).…”

“…Meticulous prevention of hypoglycemia (33–35) and structured education and/or behavioral therapies aimed at hypoglycemia awareness restoration (4,36,37) improve the awareness of hypoglycemia, hormonal counterregulation to hypoglycemia, and protection from SHEs, but 20–30% of patients so treated have persistent SHEs and IAH, as evidenced by elevated Clarke or Gold scores (4,10,36,37). In addition, their HbA 1c levels remain elevated at 7.8% (62 mmol/mol) to 8.4% (68 mmol/mol) (4,10,36,37). Thus, this trial is the first phase 3 trial to show effectiveness of any therapy in restoring both sustained normoglycemia and protection from SHEs in patients with long-standing T1D complicated by IAH and recent SHEs.…”

“…Structured diabetes education on flexible insulin therapy and diabetes technologies have improved. Currently, the majority of patients presenting with problematic hypoglycemia are expected to experience resolution of severe hypoglycemia with optimal medical therapy that includes access to these interventions in a stepped-care approach (7,8,10). Accordingly, some of the 48 subjects who were considered treatment failures at the time of enrollment in this trial, including the 11 who had not used CSII and the 27 who had not used a CGMS prior to enrollment, might well have responded to the medical and technological interventions now available.…”

“…However, despite acceptance of an elevated HbA 1c target of <8.0% (64 mmol/mol) (9), these interventions are not successful in all patients (4,10–13). In a recently reported cohort at a specialist hypoglycemia service (10), 50% of patients with T1D and recurrent SHEs experienced resolution of SHEs, and 30% subsequently underwent pancreas or islet transplantation for persistent severe hypoglycemia. Thus, SHEs persist in some patients despite having access to all medical interventions and accepting an elevated HbA 1c level of <8.0% (64 mmol/mol) (as recommended by the American Diabetes Association [ADA] in 2012) (9).…”