Comparison of Lantus and Neutral Protamine Hagedorn (NPH) Insulin in the Dawn Phenomenon

Title: COMPARISON of LANTUS and NPH INSULIN IN THE DAWN PHENOMENON

I. Background and Significance

Diabetes mellitus affects greater than 6% of the population, with type 2 more prevalent than type 1. For individuals with type 1 diabetes, the challenge has been to replicate insulin secretion of the healthy pancreas to maintain blood glucose as close to the non-diabetic range as possible. Insulin regimes using insulins with varied activity profiles (multiple daily injections or MDI) and continuous subcutaneous insulin infusion (CSII) have been somewhat successful in "mimicking" normal pancreatic function (1, 2). For individuals with type 1 diabetes, the benefits of near-normal, long-term glycemic control in delaying the development and slowing the progression of long-term complications was demonstrated in the Diabetes Control and Complications Trial (3). Intensive insulin therapy to achieve near-normal glycemic control has been limited by a three-fold increase in episodes of hypoglycemia (3, 4). Insulin analogs that provide more stable physiologic insulin levels have led to the development of newer MDI regimes (5). Glargine (Lantus) is a long-acting recombinant human insulin analog demonstrated to provide a continuous, smooth supply of insulin with no pronounced peak over a 24-hour period (6).

An increase in blood glucose in type 1 and type 2 diabetics, and an increase in insulin secretion to maintain normoglycemia in non-diabetics, was documented in several studies in the 1980s (15-17). This physiological requirement for more insulin delivery (or secretion) in the early (4:00-6:00 AM) hours was termed the "dawn phenomenon". The mechanism for the dawn phenomenon was thought to be the overnight increase in growth hormone section, rather than diurnal glucocorticoids (16, 18, 19). Most intensive treatment regimens of the 1980-90's, with MDI or CSII, were designed to provide more insulin in the 4:00-7:00 AM period to cope with the dawn phenomenon which cannot be be achieved with glargine (20-21). Continuous monitoring of blood glucose has revealed that individuals treated with CSII had significantly better glycemic control than glargine treated individuals (22). Whether the dawn phenomenon, with increased area under the curve blood glucose levels during the dawn period is limiting the effectiveness of regimens with glargine is of crucial importance.

Inclusion criteria

• Written informed consent obtained prior to performing screening evaluations.
• Male or female, 18 yrs or older.
• Diagnosis of type 1 diabetes made 5 years prior to screening visit.
• A1C > 6.0% and 9.0% at screening visit.
• Body Mass Index (BMI) 35 kg/m2 at screening visit.
• Documented undetectable C-Peptide
• Ability to follow instructions for Continuous Glucose Monitoring System (CGMS).
• Multiple daily injection participants on at least 3 injections per day. May be treated with NPH or glargine.

Exclusion criteria

• Pregnant or lactating females, or females planning to become pregnant during the study or not using an acceptable method of contraception. Females of childbearing potential must have a negative pregnancy test at Visit 3 and Visit 5. Females who become pregnant during the study will be discontinued.
• Type 2 diabetes.
• Two or more severe hypoglycemic episodes (requiring assistance) within six months of Screening.
• Drugs known to affect glycemia (eg. steroids, beta blockers) or conditions that are likely to require steroid therapy or cause metabolic instability in the next 6 months.
• History of allergy or intolerance to NPH or glargine.
• History of hypoglycemia unawareness i.e. no warning symptoms accompanying low (<50 mg/dl) blood glucose levels.
• Unable and/or unlikely to comprehend and/or follow the study protocol (including self blood glucose monitoring, CGMS).
• Currently using an insulin pump.
• Pituitary disorder (Acromegaly, Cushing's, Hypothyroidism etc.) or tumor.
• Two or more severe hypoglycemic episodes (requiring assistance) within six months of Screening.