2022 Canadian Cardiovascular Society Guideline for Use of GLP-1 Receptor Agonists and SGLT2 Inhibitors for Cardiorenal Risk Reduction in Adults.

This guideline synthesizes clinical trial data supporting the role of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors (SGLT2i) for treatment of heart failure (HF), chronic kidney disease, and for optimizing prevention of cardiorenal morbidity and mortality in patients with type 2 diabetes. It is on the basis of a companion systematic review and meta-analysis guided by a focused set of population, intervention, control, and outcomes (PICO) questions that address priority cardiorenal end points. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system and a modified Delphi process were used. We encourage comprehensive assessment of cardiovascular (CV) patients with routine measurement of estimated glomerular filtration rate, urinary albumin-creatinine ratio, glycosylated hemoglobin (A1c), and documentation of left ventricular ejection fraction (LVEF) when evaluating symptoms of HF. For patients with HF, we recommend integration of SGLT2i with other guideline-directed pharmacotherapy for the reduction of hospitalization for HF when LVEF is > 40% and for the reduction of all-cause and CV mortality, hospitalization for HF, and renal protection when LVEF is ≤ 40%. In patients with albuminuric chronic kidney disease, we recommend integration of SGLT2i with other guideline-directed pharmacotherapy to reduce all-cause and CV mortality, nonfatal myocardial infarction, and hospitalization for HF. We provide recommendations and algorithms for the selection of glucagon-like peptide-1 receptor agonists and SGLT2i for patients with type 2 diabetes and either established atherosclerotic CV disease or risk factors for atherosclerotic CV disease to reduce all-cause and CV mortality, nonfatal stroke, and for the prevention of hospitalization for HF and decline in renal function. We offer practical advice for safe use of these diabetes-associated agents with profound cardiorenal benefits.

The Role of Hypoglycemia in Cardiovascular Outcomes in Diabetes.

Intensive glucose management, targeting lower glycated hemoglobin (A1C) levels, has been shown to reduce the microvascular complications of diabetes, but the effect on cardiovascular (CV) outcomes is less clear. Observational follow-up of intensive glucose management studies suggest possible long-term CV benefits, but no clear reduction in CV events has been seen over 3 to 5 years. Intensive glucose management also increases the risk for hypoglycemia, particularly in patients with longstanding diabetes, cognitive impairment and hypoglycemia unawareness. Severe hypoglycemia has been linked to adverse consequences, including cardiac dysrhythmias, CV events and death, but the precise role of hypoglycemia in CV outcomes is uncertain. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was terminated early because of a higher rate of CV events in the intensive arm. Post hoc analyses of ACCORD and other trials suggest that cardiac autonomic neuropathy may be a predisposing factor to CV events. The Analyses of the Action in Diabetes and Vascular Disease (ADVANCE) trial and the Veterans Affairs Diabetes Trial (VADT) showed that subjects with severe hypoglycemia had more frequent adverse outcomes. However, rather than causing adverse events, it appears that severe hypoglycemia may be a marker of vulnerability for such events. This review focuses on the current understanding of the association between hypoglycemia and CV risk.

The First Step First Bite Program: guidance to increase physical activity and daily intake of low-glycemic index foods.

Practical lifestyle interventions are needed to help people with type 2 diabetes increase their physical activity and follow nutrition therapy guidelines. This study examined whether combining instructions to walk more and to eat more low-glycemic index (GI) foods (First Step First Bite Program) improved hemoglobin A1c and anthropometric and cardiovascular health outcomes in people with type 2 diabetes vs the First Step Program (instruction only on walking). Subjects were randomly assigned to the First Step Program or First Step First Bite Program (n=22 in each group) and attended four weekly group meetings with minimal follow-up during weeks 5 to 16. All subjects monitored steps per day throughout the study; First Step First Bite Program subjects also monitored daily intake of low-GI foods. At week 16 (n=19 per group), both groups had increased steps per day by approximately 3,000 compared with baseline (P<0.01). In the First Step Program vs First Step First Bite Program groups, respectively, waist girth decreased by 5.9+/-0.9 cm vs 3.7+/-0.5 cm and hip decreased by 3.7+/-0.6 cm vs 2.2+/-0.5 cm (P<0.01 over time, both groups). There was no significant difference between groups at week 16 for anthropometric or metabolic variables measured, including hemoglobin A1c. Both the First Step First Bite Program and First Step Program resulted in increased physical activity; First Step First Bite Program also increased daily intake of low-GI foods. Both groups experienced similar significant reductions in waist and hip girth. Thus, adding a low-GI component to a walking program in people with type 2 diabetes in good glycemic control did not improve anthropometric or metabolic outcomes. A great number and/or longer duration of low-GI foods may be required to observe improved clinical outcomes.

Assessment of glycemic control after islet transplantation using the continuous glucose monitor in insulin-independent versus insulin-requiring type 1 diabetes subjects.

BACKGROUND: The aim of this study was to assess and compare glycemic control using the continuous glucose monitor (CGMS, Medtronic Minimed, Northridge, CA) in type 1 diabetes mellitus (T1DM) subjects who are insulin-independent versus those who require insulin after islet transplantation alone (ITA). METHODS: Glycemic control was assessed using 72-h CGMS in eight T1DM subjects who were insulin-independent after ITA (ITA-II), eight T1DM subjects who were C-peptide-positive but insulin-requiring after ITA (ITA-IR), and eight non-transplanted (NT) T1DM subjects. RESULTS: Standard deviation of glucose values was not significantly different between ITA-II and ITA-IR subjects (ITA-II, 1.2 +/- 0.1 mM; ITA-IR, 2.0 +/- 0.3 mM; P = 0.072). Both ITA groups were more stable than NT subjects (NT, 3.3 +/- 0.3 mM; P = 0.001 vs. ITA). Mean high glucose values were significantly lower in ITA subjects compared with NT subjects (ITA-II, 10.5 +/- 0.6 mM; ITA-IR, 13.0 +/- 1.0 mM; NT, 16.1 +/- 1.1 mM; P = 0.002). Mean average glucose values were not significantly different among all groups (ITA-I, 6.7 +/- 0.2 mM; ITA-IR, 7.8 +/- 0.3 mM; NT, 7.7 +/- 0.6 mM; P = 0.198). Mean low glucose values were significantly higher in both ITA groups compared with NT subjects (ITA-II, 4.5 +/- 0.2 mM; ITA-IR, 4.3 +/- 0.3 mM; NT, 3.0 +/- 0.2 mM; P = 0.003). Duration of hypoglycemic excursions (<3.0 mM) was markedly reduced in both ITA groups (ITA-II, 0%; ITA-IR, 2.4 +/- 0.2%; NT, 11.8 +/- 4.2%). Glycated hemoglobin was not significantly different between ITA groups (ITA-II, 6.4 +/- 0.2%; ITA-IR, 6.5 +/- 0.3%) and was significantly higher in NT subjects (8.3 +/- 0.2%; P < 0.001 vs. ITA). CONCLUSIONS: CGMS monitoring demonstrates that glycemic lability and hypoglycemia are significantly reduced in C-peptide-positive islet transplant recipients, whether or not supplementary, exogenous insulin is used, compared with non-transplanted T1DM subjects.

Sirolimus-induced ulceration of the small bowel in islet transplant recipients: report of two cases.

Sirolimus (SRL) has been used for most islet recipients over the past 5 years. It provides balanced immunosuppression in combination with low-dose calcineurin inhibitors, while avoiding corticosteroids. This regimen decreases the risk of nephrotoxicity, neurotoxicity and diabetogenicity. SRL has also been used selectively in clinical liver and kidney transplantation. A number of common side effects including anemia, leucopenia, thrombocytopenia, hypercholesterolemia, mouth ulceration, joint pain, extremity edema and impaired wound healing have been associated with the use of SRL. As SRL is used more frequently, evidence has been gathered on its rare but severe side effects. We report 2 patients who underwent islet transplantation and developed symptomatic small bowel ulceration that resolved after complete withdrawal of SRL. Although small bowel ulceration is rare, it can potentially progress to more serious complications if not treated adequately. Our experience highlights an uncommon but potentially serious adverse effect of high-dose SRL in islet recipients.

Proteinuria developing after clinical islet transplantation resolves with sirolimus withdrawal and increased tacrolimus dosing.

Sirolimus is a potent immunosuppressant, which may permit the avoidance of nephrotoxic calcineurin inhibitors (CNI). However, cases of proteinuria associated with sirolimus have been reported following renal transplantation. Here, we report three cases of proteinuria (1, 2 and 7 g/day) developing during therapy with sirolimus plus low-dose tacrolimus following clinical islet transplantation (CIT) in type I diabetic subjects. The proteinuria resolved after discontinuation of sirolimus, substituted by mycophenolate mofetil (MMF) combined with an increased dose of tacrolimus. A renal biopsy in one case indicated only the presence of diabetic glomerulopathy. Five other CIT recipients developed microalbuminuria while on sirolimus which all resolved after switching to tacrolimus and MMF. The resolution of proteinuria from the native kidneys of CIT recipients after the discontinuation sirolimus suggests that, at least in some individuals, sirolimus itself may have adverse renal effects. Sirolimus should be used cautiously with close monitoring for proteinuria or renal dysfunction.

Five-year follow-up after clinical islet transplantation.

Islet transplantation can restore endogenous beta-cell function to subjects with type 1 diabetes. Sixty-five patients received an islet transplant in Edmonton as of 1 November 2004. Their mean age was 42.9 +/- 1.2 years, their mean duration of diabetes was 27.1 +/- 1.3 years, and 57% were women. The main indication was problematic hypoglycemia. Forty-four patients completed the islet transplant as defined by insulin independence, and three further patients received >16,000 islet equivalents (IE)/kg but remained on insulin and are deemed complete. Those who became insulin independent received a total of 799,912 +/- 30,220 IE (11,910 +/- 469 IE/kg). Five subjects became insulin independent after one transplant. Fifty-two patients had two transplants, and 11 subjects had three transplants. In the completed patients, 5-year follow-up reveals that the majority ( approximately 80%) have C-peptide present post-islet transplant, but only a minority ( approximately 10%) maintain insulin independence. The median duration of insulin independence was 15 months (interquartile range 6.2-25.5). The HbA(1c) (A1C) level was well controlled in those off insulin (6.4% [6.1-6.7]) and in those back on insulin but C-peptide positive (6.7% [5.9-7.5]) and higher in those who lost all graft function (9.0% [6.7-9.3]) (P < 0.05). Those who resumed insulin therapy did not appear more insulin resistant compared with those off insulin and required half their pretransplant daily dose of insulin but had a lower increment of C-peptide to a standard meal challenge (0.44 +/- 0.06 vs. 0.76 +/- 0.06 nmol/l, P < 0.001). The Hypoglycemic score and lability index both improved significantly posttransplant. In the 128 procedures performed, bleeding occurred in 15 and branch portal vein thrombosis in 5 subjects. Complications of immunosuppressive therapy included mouth ulcers, diarrhea, anemia, and ovarian cysts. Of the 47 completed patients, 4 required retinal laser photocoagulation or vitrectomy and 5 patients with microalbuminuria developed macroproteinuria. The need for multiple antihypertensive medications increased from 6% pretransplant to 42% posttransplant, while the use of statin therapy increased from 23 to 83% posttransplant. There was no change in the neurothesiometer scores pre- versus posttransplant. In conclusion, islet transplantation can relieve glucose instability and problems with hypoglycemia. C-peptide secretion was maintained in the majority of subjects for up to 5 years, although most reverted to using some insulin. The results, though promising, still point to the need for further progress in the availability of transplantable islets, improving islet engraftment, preserving islet function, and reducing toxic immunosuppression.

Strategic opportunities in clinical islet transplantation.

More than 471 patients with type 1 diabetes have received islet transplants at 43 institutions worldwide in the past 5 years. High rates of insulin independence have been observed at 1 year in the leading islet transplant centers, and an international multicenter trial has demonstrated reproducible success of the approach. Loss of insulin independence by 5 years in the majority of recipients remains of concern, and immunosuppressant drug side effects necessitate stringent inclusion criteria for islet-alone candidates that have the most severe, unstable glycemic control despite optimal insulin therapy. The advent of new immunosuppressive drugs with superior side-effect profiles (e.g., LEA29Y and FTY720) may open up opportunities for more "islet-friendly" approaches. Future opportunities to expand the donor pool using living donor islet transplantation are within reach, and will be enhanced considerably with both donor and recipient adjunctive treatment using islet-specific growth-factors.

Coronary artery disease is common in nonuremic, asymptomatic type 1 diabetic islet transplant candidates.

OBJECTIVE: Coronary artery disease (CAD) is the most common cause of death in patients with type 1 diabetes. Asymptomatic CAD is common in uremic diabetic patients, but its prevalence in nonuremic type 1 diabetic patients is unknown. The prevalence of CAD was determined by coronary angiography and the performance of noninvasive cardiac investigation evaluated in type 1 diabetic islet transplant (ITX) candidates with preserved renal function. RESEARCH DESIGN AND METHODS: A total of 60 consecutive type 1 diabetic ITX candidates (average age 46 years [mean 24-64], 23 men, and 47% ever smokers) underwent coronary angiography, electrocardiographic stress testing (EST), and myocardial perfusion imaging (MPI) in a prospective cohort study. CAD was indicated on angiography by the presence of stenoses >50%. Models to predict CAD were examined by logistic regression. RESULTS: Most subjects (53 of 60) had no history or symptoms of CAD; 23 (43%) of these asymptomatic subjects had stenoses >50%. CAD was associated with age, duration of diabetes, hypertension, and smoking. Although specific, EST and MPI were not sensitive as predictors of CAD on angiography (specificity 0.97 and 0.93, sensitivity 0.17 and 0.04, respectively) but helped identify two of three subjects requiring revascularization. EST and MPI did not enhance logistic regression models. A clinical algorithm to identify low-risk subjects who may not require angiography was highly sensitive but was applicable only to a minority (n = 8, sensitivity 1.0, specificity 0.27, negative predictive value 1.0). CONCLUSIONS: Nonuremic type 1 diabetic patients with hypoglycemic unawareness and/or metabolic lability referred for ITX are at high risk for asymptomatic CAD despite negative noninvasive investigations. Aggressive management of cardiovascular risk factors and further investigation into optimal cardiac risk stratification in type 1 diabetes are warranted.

Beta-score: an assessment of beta-cell function after islet transplantation.

OBJECTIVE: Success after islet transplantation can be defined in terms of insulin independence, C-peptide secretion, or glycemic control. These measures are interdependent and all need to be considered in evaluating beta-cell function after islet transplantation. For the current study, a composite beta-score was developed that provides an integrated measure of beta-cell function success after islet transplantation. RESEARCH DESIGN AND METHODS: The proposed scoring system gave 2 points each for normal fasting glucose, HbA(1c), stimulated C-peptide, and absence of insulin or oral hypoglycemic agent use. No points were awarded if the fasting glucose was in the diabetic range, the HbA(1c) was >6.9%, C-peptide secretion was absent on stimulation, or daily insulin use was in excess of 0.24 units/kg. One point was given for intermediate values. The score ranged from 0 to 8 and was correlated with the glucose value 90 min after a standard mixed meal challenge (n = 218) in 57 subjects before and after islet transplantation. The score was also used to follow subjects for up to 5 years after islet transplantation. RESULTS: The beta-score correlated well with the plasma glucose level 90 min after a mixed meal challenge (r = -0.849, P < 0.001). On follow-up, the beta-score rose after the first transplant and was maintained up to 5 years, demonstrating continuing function of the transplanted beta-cells. CONCLUSIONS: The beta-score provides a simple clinical scoring system that encompasses glycemic control, diabetes therapy, and endogenous insulin secretion that correlates well with physiological measures of beta-cell function. On this basis, it is suitable as an overall measure of beta-cell transplant function. The beta-score gives an integrated measure of beta-cell function as a continuum that may be more useful than simply assessing the presence or absence of insulin independence.

Islet transplantation for type 1 diabetes: An overview.

Islet transplantation is a method of restoring endogenous insulin secretion in individuals with type 1 diabetes by transplanting insulin-secreting islet cells from cadaveric donor pancreases into eligible recipients. Since 2000, the one-year insulin independence rate observed in islet transplant recipients has risen from less than 10% to approximately 80%. However, the continued requirement for at least two donor pancreases for each islet transplant recipient, the occurrence of suboptimal islet engraftment, the need for chronic immunosuppressive therapy and a decline in islet function over time continue to make this procedure unsuitable for the majority of patients with type 1 diabetes. Despite these challenges, the recent progress in islet transplantation has reinforced the potential of beta cell replacement for the treatment of type 1 diabetes.

Cross-sectional and prospective association between proinsulin secretion and graft function after clinical islet transplantation.

Proinsulin levels as a marker of beta-cell dysfunction have not been described after clinical islet transplantation. Proinsulin secretion was studied in 23 type 1 diabetic patients after islet allotransplantation and in 20 age-matched nondiabetic controls. Fasting serum insulin, total proinsulin (TP), intact proinsulin, proinsulin fragments (PFs) and their ratios to insulin were determined 1 and 12 months after patients became insulin independent. TP, PF, and proinsulin/insulin ratios were lower in transplant recipients compared with controls, in patients who retained long-term insulin independence. Insulin, C-peptide, and intact proinsulin values were similar in transplant recipients and controls. Hormone levels remained stable over time in the group of patients who retained long-term insulin independence, but the TP and PF levels were higher at 12 months compared with 1 month in the group of patients who resumed insulin therapy. TP and PF levels were reduced in transplant recipients compared with controls but increased over time if insulin independence was lost.

Magnetic resonance-defined perinephric edema after clinical islet transplantation: a benign finding associated with mild renal impairment.

Immunosuppression with sirolimus and low-dose tacrolimus has facilitated successful clinical islet transplantation (CIT). Because the long-term effects on the kidney are unknown and immunosuppressant drugs can be nephrotoxic, CIT is currently restricted to patients with preserved renal function or a functioning renal transplant. The impact of CIT on the native kidney of islet-alone recipients was assessed with magnetic resonance imaging (MRI). After successful CIT, MRI revealed perinephric edema (PNE) in 10 of 30 recipients. PNE was associated with a mild degree of renal impairment but was not associated with preexisting diabetic nephropathy, albuminuria, microscopic hematuria, graft function, or other clinical and metabolic parameters. The presence of PNE on MRI after CIT seems to be a common but benign finding, most likely an adverse effect of sirolimus. Although this novel observation does not seem to be of concern, further studies are required to examine the long-term impact of CIT and immunosuppression on renal function.

Risks and side effects of islet transplantation.

Islet transplantation can deliver stable glycemic control, relief from recurrent severe hypoglycemia, and insulin independence. Accessing the portal vein via the percutaneous hepatic approach carries the risk of bleeding, and the infusion of islets a risk of portal vein thrombosis. In the long term, common minor problems with immunosuppression are mouth ulcers, diarrhea, and acne. Longer-term risks include malignancy and serious infection, both rare to date in clinical islet transplantation. Sensitization to donor antigens may also occur. The long-term diabetes complications may stabilize, but of this aspect little is known to date. In the short term, there may be some elevation of serum cholesterol and blood pressure, in some patients there has been a decline in renal function, and in a few, acute retinal bleeds. For most, improvement in glucose control with resolution of glycemic lability and hypoglycemia has been a net benefit.

Prevalence of hepatic steatosis after islet transplantation and its relation to graft function.

Islet allotransplantation can provide insulin independence in selected individuals with type 1 diabetes. The long-term effects of these transplants on the liver are unknown. Recently, two cases of periportal steatosis after islet transplantation have been described. In this study, we performed ultrasound and magnetic resonance imaging (MRI) in 30 C-peptide-positive islet transplant recipients to detect steatosis and to explore the association of the radiological findings with clinical and metabolic factors. Steatosis was observed on MRI in six (20%) subjects. Histological findings of hepatic steatosis concurred with the imaging findings. Steatosis completely resolved in one subject whose graft failed. More subjects with steatosis required supplementary exogenous insulin than not (67 vs. 21%; P < 0.05). The clinical features of subjects with and without steatosis were otherwise similar, although C-peptide levels were higher in insulin-independent subjects with steatosis (0.98 +/- 0.12 vs. 0.70 +/- 0.18 nmol/l; P = 0.05), despite similar blood glucose levels. Serum triglycerides and the use of exogenous insulin were associated with increased odds of steatosis in a logistic regression model (chi(2) [degrees freedom] = 13.6 [2]); P = 0.001). MRI-detected steatosis is a common finding; the steatosis appears to be due to a paracrine action of insulin secreted from intrahepatic islets. Hepatic steatosis may be associated with insulin resistance or graft dysfunction.

Toward development of imaging modalities for islets after transplantation: insights from the National Institutes of Health Workshop on Beta Cell Imaging.

BACKGROUND: Pancreatic islet transplantation can provide insulin independence and near normal glucose control in selected patients with type 1 diabetes mellitus. However, in most cases, achieving insulin independence necessitates the use of at least two donor pancreases per recipient and the rate of insulin independence may decline after transplantation. To better understand the fate of transplanted islets and the relationship between transplanted islet mass, graft function, and overall glucose homeostasis, an accurate and reproducible method of imaging islets in vivo is needed. METHODS: Recent advances in noninvasive imaging techniques such as magnetic resonance imaging, positron emission tomography, and other imaging modalities show great promise as potential tools to monitor islet number, mass, and function in the clinical setting. A recent international workshop, "Imaging the Pancreatic Beta Cell," sponsored by the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Juvenile Diabetes Research Foundation International focused on these emerging efforts to develop novel ways of imaging pancreatic beta cells in vivo. RESULTS: Potential clinically applicable techniques include the use of directed magnetic resonance contrast agents such as lanthanides (Ln(3+)) and manganese (Mn(2+)) or magnetic resonance imaging probes such as superparamagnetic iron oxide nanoparticles. Potential techniques for positron emission tomography imaging include the use of beta cell-specific antibodies, or pharmacologic agents such as glyburide analogs, or d-mannoheptulose. Optical imaging techniques are also being used to evaluate various aspects of beta cell metabolism including intracellular Ca(2+) flux, glucokinase activity, and insulin granular exocytosis. CONCLUSIONS: The consensus among investigators at the imaging workshop was that an accurate and reproducible in vivo measure of functional islet mass is critically needed to further the strides that have been made in both islet transplantation and diabetes research as a whole. Such measures would potentially allow the assessment of islet engraftment and the early recognition of graft loss, leading to greater improvements in islet graft survival and function.

Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation.

Currently, the major indications for solitary islet transplantation are recurrent severe hypoglycemia and labile glucose control. Quantifying these problems remains subjective. We have developed a scoring system for both hypoglycemia and glycemic lability, established normative data, and used them in patients who have undergone islet transplantation. A composite hypoglycemic score (HYPO score) was devised based on the frequency, severity, and degree of unawareness of the hypoglycemia. In addition, using 4 weeks of glucose records, a lability index (LI) was calculated based on the change in glucose levels over time and compared with a clinical assessment of glycemic lability. A mean amplitude of glycemic excursions (MAGE) was also calculated based on 2 consecutive days of seven readings each day. These scores were determined in 100 randomly selected subjects with type 1 diabetes from our general clinic to serve as a control group and in patients before and after islet transplantation. The mean age of the control diabetic subjects was 38.4 +/- 1.3 years (+/-SE), with a duration of diabetes of 21.5 +/- 1.1 years. The median HYPO score in the control subjects was 143 (25th to 75th interquartile range: 46-423). The LI in the diabetic control subjects was 223 (25th to 75th interquartile range: 130-329 mmol/l(2)/h.week(-1)). The LI correlated much more closely than the MAGE with the clinical assessment of lability. A HYPO score of > or = 1,047 (90th percentile) or an LI > or = 433 mmol/l(2)/h.week(-1) (90th percentile) indicated serious problems with hypoglycemia or glycemic lability, respectively. The islet transplant patients (n = 51) were 42.1 +/- 1.4 years old, with a duration of diabetes of 25.7 +/- 1.4 years. Islet transplant patients had a mean HYPO score of 1,234 +/- 184 pretransplant, which was significantly higher than that of the control subjects (P < 0.001), which became negligible posttransplantation with the elimination of hypoglycemia. The median LI pretransplant was 497 mmol/l(2)/h.week(-1) (25th to 75th interquartile range: 330-692), significantly higher than that of control subjects (P < 0.001), and fell to 40 (25th to 75th interquartile range: 14-83) within a month after the final transplant. In those who had lost graft function, the LI rose again. The HYPO score and LI provide measures of the extent of problems with hypoglycemia and glycemic lability, respectively, complement the clinical assessment of the problems with glucose control before islet transplantation, and will allow comparison of selection of subjects for transplants between centers.