Insulin Therapy for Post-transplant Glucocorticoid Induced Hyperglycemia (PTHG)

No consensus guidelines exist for management of post-transplant glucocorticoid induced hyperglycemia, but most published reviews recommend insulin as first line therapy. A variety of insulin regimens have been proposed, including mealtime short-acting regular or analog insulin, once daily neutral protamine hagedorn (NPH) insulin, pre-mixed insulin, or basal insulin alone such as glargine or detemir. However, no randomized trial has ever examined different insulin regimens to determine which most effectively controls post-transplant steroid-induced hyperglycemia. Consequently, the proposed study intends to examine three commonly used insulin regimens used for managing post-transplant once-daily glucocorticoid-induced hyperglycemia to determine which is most effective: Group 1: Intermediate-acting (NPH) insulin at breakfast Group 2: Short-acting insulin (regular or aspart) before meals Group 3: Insulin glargine at breakfast Question/Hypothesis: Among three commonly used insulin regimens, which is most effective for managing post-transplant once-daily glucocorticoid-induced hyperglycemia?

Drug: Neutral protamine hagedorn (NPH) insulin Other Names: Humulin N, Novolin N Route: Subcutaneous; Dosage: No fixed dose, varies between subjects; Frequency: daily before breakfast; Duration: 12 hours; for duration subjects are concurrently administered once-daily glucocorticoid.

Drug: Regular human insulin or Insulin Aspart Other Names: Humulin R, Novolin R, Novolog, NovoRapid Route: Subcutaneous; Dosage: No fixed dose, varies between subjects; Frequency: daily before meals; Duration: 2 hours (Aspart) or 6 hours (Regular); for duration subjects are concurrently administered once-daily glucocorticoid.

Drug: Insulin glargine Other Names: Lantus Route: Subcutaneous; Dosage: No fixed dose, varies between subjects; Frequency: daily before breakfast; Duration: 24 hours; for duration subjects are concurrently administered once-daily glucocorticoid.

Mean time from baseline to achieve at least 80% of pre-meal capillary blood glucose values within 5.0 - 7.8 mmol/L over a 48 hour period during hospitalization

Subjects will be followed from enrollment for the remainder of hospital stay (days), an expected average of 21 days

Mean inpatient two-hour post-lunch capillary blood glucose (mmol/L) from enrollment to discharge from hospital

Subjects will be followed from enrollment for the remainder of hospital stay (days), an expected average of 21 days

Subjects will be followed from enrollment for the remainder of hospital stay (days), an expected average of 21 days

Hypoglycemic episodes defined as: (1) Mild - any measured CBG 3.0-4.0 mmol/L; (2) Severe - any episode of hypoglycemia with a measured CBG < 3.0 mmol/L, OR which the subject is not able to recognize and treat without the direct (substantial) intervention of a professional caregiver, nurse or physician (e.g. intravenous dextrose or intramuscular glucagon)

Hypoglycemic treatment failure: subject experiences ≥3 hypoglycemic episodes (≤ 4.0 mmol/L) over any 5 day period or a single severe hypoglycemic event (as previously defined), they will be withdrawn from study and managed at discretion of attending physician, or hospital endocrine consult service. Hyperglycemic treatment failure: Severe hyperglycemia defined as CBG >20 mmol/L. If subject experiences ≥3 severe hyperglycemic measures over the course of 48 hours they will be withdrawn from the study and managed at discretion of attending physician, or hospital endocrine consult service.

New cardiovascular events defined as: myocardial infarction, new or worsened congestive heart failure, stroke, and cardiac arrhythmia.

Transplant graft failure (as specified by subject's medical transplant physician) from enrollment to 3 months.

New acute renal failure is defined according to Acute Kidney Network Guidelines: rapid time course and decreased kidney function according to an absolute Creatinine (Cr) rise greater than 26 μmol/L, greater than 2-fold increase in serum Cr from baseline, or urine output less than 0.5 mL/kg/hr for greater than 6 hours

Inclusion Criteria: Have undergone bone marrow, liver, lung, or renal transplant. Be using once daily oral glucocorticoid therapy (total daily dose of Prednisone ≥10 mg, Hydrocortisone ≥40 mg, Dexamethasone ≥1.5 mg) administered in the morning and expected to continue for at least 2 weeks. Have pre-existing or newly diagnosed diabetes mellitus established by any of the criteria listed below: Fasting plasma glucose ≥7.0 mmol/L (repeated x 1) Any plasma glucose ≥11.0 mmol/L Have at least three pre-meal inpatient capillary blood glucose (CBG) readings ≥ 7.8 mmol/L Be eating meals by mouth Exclusion Criteria: Heart, Pancreas, Islet cell transplant recipients Previous use of Basal-Bolus or Pre-Mixed Insulin regimen Diabetes mellitus type I NPO (not eating meals by mouth) Receiving enteral (tube feeds) or parenteral (TPN) nutrition

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Multilingual dietary instructions to be distributed to ALL subjects during study from the Canadian Diabetes Association