Efficacy of Pramlintide on Prevention of Weight Gain Early Onset of Type 1 Diabetes

The autoimmune process along with a strong genetic-mediated destruction and dysfunction of
pancreatic β-cells are the main pathogeneses of type 1 diabetes. These processes cause
absolute and relative insulin and amylin deficiencies. For the last decades, insulin therapy
has been the primary therapy for type 1 diabetes.

Amylin is a 37 amino acid peptide hormone co-secreted with insulin mostly by the pancreatic β
cells in response to meals. Amylin has several known effects including suppression of
postprandial glucagon secretion, regulation of gastric emptying, and reduction of food
intake. Pramlintide is an amylin analog recently approved by the Food and Drug Administration
(FDA) to be given at meal time as an adjunct to insulin therapy in patients with type 1 or
type 2 diabetes who have failed to achieve desired glucose control despite optimal insulin
therapy or insulin therapy with or without a sulfonylurea agent and/or metformin. Several
clinical trials showed that meal time amylin replacement with pramlintide along with insulin
therapy improved post-prandial hyperglucagonemia, and reduced post-prandial glucose
excursion. A recent randomized control trial showed that pramlintaide reduced weight by up to
2kg in both type 1 and type 2 diabetes.

The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive diabetes
therapy delays the onset and progression of microvascular disease such as retinopathy,
nephropathy and neuropathy. The DCCT also showed that the prevalence of obesity, defined as a
body mass index (BMI) ≥ 27.8 kg/m2 for men and ≥ 27.3 kg/m2 for women, was 33.1% in the
intensive treatment group compared with 19.1% in the conventional treatment group.
Intensively treated patients gained an average of 4.75 kg more than conventionally treated
patients (P < 0.0001). Weight gain was most rapid during the first year of therapy. Several
mechanisms have been proposed to explain the weight gain associated with insulin therapy.
These include decreased glycosuria due to improved glycemic control, the direct lipogenic
effects of insulin on adipose tissue, and increased food intake due to recurrent mild
hypoglycemia.

Obesity, especially in type 2 diabetes, is associated with the accumulation of triglyceride
in muscle as well as in the liver. These are thought to cause insulin resistance and diabetic
metabolic complications. Sub-analysis of the DCCT showed that in the intensive treatment
group, higher weight gain correlated with a higher waist to hip ratio as well as higher LDL
and lower HDL levels similar to what is seen in the metabolic syndrome. An association
between weight gain due to intensive insulin therapy in type 1 diabetes and the risk of
coronary artery disease has yet to be determined. However, the DCCT showed some reduction in
cardiovascular risk factors among the intensive treatment group as well as reduction in
cardiovascular events. The DCCT did not evaluate cardiovascular risk based on degree of
obesity within the intensive insulin treatment group.

The DCCT has shown that the intensive insulin therapy group maintained a higher stimulated
C-peptide level than the conventional group. Preserving β cell function, even modest levels
of activity can be advantage in preventing hypoglycemic episodes and also reducing the
incidence of retinopathy and nephropathy. No study to date has been designed to analyze the
effect of pramlintide treatment on the preservation of β cell function in newly diagnosed
type 1 diabetic subjects.

This pilot study will evaluate the effect of pramlintide on the prevention of weight gain and
its effects on beta cell function among early onset type 1 diabetes patients. Early onset is
defined as those who are diagnosed with type 1 diabetes six to twelve months prior to entry
in this study.

Inclusion Criteria:

- 12 to 40 years old

- Type 1 diabetes

- Fasting C-peptide ≤ 1.0 ng/ml

- Early diagnosed type 1 diabetes. (<6 months since diagnosis of type 1 diabetes.)

- HbA1c greater than 7.0 %

- Male, or If female, is nonlactating and has a negative pregnancy test (human chorionic
gonadotropin, beta subunit [βhCG]) at Visit 1 (screening).

Exclusion Criteria:

- Has a clinically significant medical condition that could potentially affect study
participation and/or personal well-being, as judged by the investigator, including but
not limited to the following conditions:

- Hepatic disease

- Gastrointestinal disease

- Haematologic disorder

- Cardiovascular disorder

- Organ transplantation

- Hemochromatosis

- HIV, HBV, or HCV infection

- Abuses drugs or alcohol or has a history of abuse

- Eating disorder

- Has donated blood within 60 days

- Has had major surgery or a blood transfusion within 2 months

- Usage of medications that affect weight changes

- Use of medications that affect gastrointestinal motility

- Usage of medications that affect glucose/insulin metabolism

- Received any study medication or has participated in any type of clinical trial within
30 days prior to screening.

- Has known allergies or hypersensitivity to any component of study treatment.