Evidence-informed Clinical Practice Recommendations for Treatment of Type 1 Diabetes Complicated by Problematic Hypoglycemia

Pratik Choudhary; Michael R. Rickels; Peter A. Senior; Marie-Christine Vantyghem; Paola Maffi; Thomas W. Kay; Bart Keymeulen; Nobuya Inagaki; Frantisek Saudek; Roger Lehmann; Bernhard J. Hering


Diabetes Care. 2015;38(6):1016-1029. 

In This Article

Transplant Interventions

Pancreas and, now, islet transplants can effectively prevent hypoglycemia and restore normoglycemia and may stabilize the complications of T1D.[70–75] Patients with T1D who undergo an islet or a pancreas transplant exhibit recovery of physiologic islet cell hormonal responses to insulin-induced hypoglycemia whereby endogenous insulin secretion is suppressed and glucagon secretion restored,[76,77] although in islet transplant recipients, the glucagon response remains partial likely due to lower islet mass being transplanted as evidenced from β-cell secretory capacity testing.[78,79] Both islet and pancreas transplant recipients also have improved epinephrine and normalized autonomic symptom responses to hypoglycemia, providing evidence of amelioration of hypoglycemia-associated autonomic failure (HAAF).[76,77] These improved counterregulatory defense mechanisms may be sustained for more than a decade of pancreas graft function.[80] Most importantly, islet and pancreas transplantation have been shown to normalize the endogenous (predominantly hepatic) glucose production response to insulin-induced hypoglycemia,[77,81] thereby affording recipients protection and recovery from low blood glucose.

Pancreata procured from leaner and younger donors often are preferred for whole-organ pancreas transplants, whereas islets can be isolated from obese and older donors[82] unsuitable for whole-organ transplants, thereby increasing the proportion of donated organs that can contribute to the treatment of T1D. Thus, islet and pancreas transplants are evolving as complementary approaches to β-cell replacement for the elimination of problematic hypoglycemia in T1D.

Most pancreas transplants are performed simultaneously with a kidney transplant. Simultaneous pancreas-kidney (SPK) transplants confer superior long-term graft function compared with pancreas transplant alone or pancreas transplant after a kidney transplant. The 5-year pancreas graft survival rate for recipients of pancreas transplant alone and pancreas transplant after a kidney transplant is between 55 and 70%; for SPK recipients, it is >85%.[83] With SPK transplants, most recipients can expect amelioration of problematic hypoglycemia for more than a decade.[83–85]

Pancreas transplants are usually undertaken in patients who are relatively young (<50 years) and nonobese (<30 kg/m2) and who do not have coronary artery disease. These patient selection criteria minimize operative mortality (<1%) and reduce early technical pancreas graft loss (~10%).[86,87] Removal of technically failed grafts and routine complications of abdominal surgery have led to a reoperation rate as high as 40%.[85]

Islet transplantation, a minimally invasive procedure, allows for inclusion of older patients and patients with coronary artery disease who would be ineligible for a whole-pancreas transplant. In nonobese recipients, the target islet dose of ≥5,000 islet equivalents/kg can be isolated from a deceased donor pancreas.[71] Most islet transplants are performed in nonuremic patients with T1D and problematic hypoglycemia and related excessive glycemic lability.[12,71,88] Careful selection of patients and protocol optimization have led to substantial clinical improvements.[71] Importantly, refined recipient treatment has improved long-term outcomes of islet transplants; insulin independence can now be maintained for 5 years in 50% of recipients.[89,90]

Although restoring insulin independence remains an important objective, several multicenter clinical trials of islet transplants in patients with T1D and problematic hypoglycemia, including the phase 3 licensure trial of human islets conducted by the Clinical Islet Transplantation Consortium, have adopted a combination of near-normal glycemic control (HbA1c <7.0% [53 mmol/mol]) together with the elimination of SH as the primary end point and the clinically relevant dual goal of intervention.[91–93] After having reported successful achievement of that goal in 82% of patients at 1 year[92] and in 70% at 2 years posttransplant,[93] islet transplants are now approved and reimbursed in several countries for the treatment of problematic hypoglycemia in T1D. In the U.S., although a phase 3 trial of islet transplants in this patient population has been completed, a formal license application awaits submission, review, and approval.

Even with partial islet graft function, the endogenous glucose production response to insulin-induced hypoglycemia improves,[94] so islet grafts protect against problematic hypoglycemia even when insulin may be required to maintain near-normoglycemia. This protection from hypoglycemia has been confirmed in CGM studies showing a near absence of time at glucose <70 mg/dL/<3.9 mmol/L.[77] The reductions in mean glucose, glucose variability, and time spent hypoglycemic (<54 mg/dL/<3.0 mmol/L) relative to T1D were similar for both insulin-independent and insulin-requiring islet recipients,[95] and those reductions were sustained for 18 months in one study.[96] Importantly, Vantyghem et al.[23] showed that minimal islet graft function is sufficient to abrogate hypoglycemia (<54 mg/dL/<3.0 mmol/L), confirming that even suboptimal function (requiring insulin) significantly improves mean glucose and glucose variability. That the islet graft imparts these glycemic control benefits has been further supported by the demonstration of significant continuous associations with stimulated C-peptide levels in islet transplant recipients.[97] This avoidance of hypoglycemia with islet or pancreas transplants as documented by CGM best explains the documented reversal of HAAF as well as the recovery of glucose counterregulation and hypoglycemia symptom recognition, thereby reversing the vicious hypoglycemia-begets-hypoglycemia cycle in T1D.[98] Data from the Collaborative Islet Transplant Registry indicate that problematic hypoglycemia ameliorated for the duration of islet graft function is currently retained in 90% of recipients at 4 years posttransplant.[71]

In addition to procedural risks and limited organ availability, the current need for lifelong immunosuppressive therapy represents a major limitation to widespread implementation of β-cell replacement therapies for patients with problematic hypoglycemia refractory to educational and technological interventions. Because kidney transplant recipients are already committed to immunosuppressive therapy, the addition of an islet or pancreas transplant may be considered to normalize glycemia, stabilize diabetes complications, and prevent recurrent diabetic nephropathy. In such T1D kidney transplant recipients, islet transplantation can be considered simultaneously with or after a kidney transplant for patients who are not surgical candidates for or willing to accept the risks of a pancreas transplant.[85] At 5 years[99] and 13 years[85] posttransplant, the insulin independence rate was higher for pancreas than for islet recipients; however, the islet recipients experienced significantly fewer operative complications, and both the pancreas and islet recipients experienced significantly improved glycemic control and a reduction of >90% in the incidence of SH.[85]

Thus, regardless of β-cell replacement approach (pancreas or islets), the majority of recipients can anticipate amelioration from problematic hypoglycemia for at least 5 years together with near-normal glycemic control. In fact, islet and pancreas transplants are the only approaches to date that confer both sustained recovery from HAAF and restoration of glucose counterregulation (by endogenous glucose production) and, thereby, reliable protection from SH in patients with long-standing (>15 years) T1D.