Comparison of Lantus and 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.