Pramlintide (Symlin) for the Treatment of Hypoglycemia Following Gastric Bypass Surgery

This study is an open-label short-term proof of concept study. The investigators will
administer pramlintide to patients with severe post-prandial hypoglycemia following gastric
bypass, in order to determine whether pramlintide is effective in reducing the frequency or
severity of hypoglycemia. Pramlintide will be prescribed for 8 weeks. In order to assess the
efficacy of pramlintide to prevent post-prandial hypoglycemia and hypoglycemic symptoms, the
investigators will compare (a) blood glucose measurements and frequency of hypoglycemic
symptoms, before and at the end of the drug intervention, using both capillary glucose
monitoring and continuous glucose monitoring, and (b) glycemic, hormonal, and energetic
responses to a three-hour mixed meal tolerance test.

The study will utilize an open label design to evaluate the efficacy of pramlintide in
patients who have had gastric bypass and have severe postprandial hypoglycemia. The study
will not be randomized or blinded. The investigators will recruit 26 participants from
Joslin Diabetes Center.

Briefly, participants in this study will be asked to complete 4 study visits. The first
visit will be for screening. They will then be asked to keep a 3-day log in which they
record food intake (including estimated portion sizes), blood glucoses eight times daily, as
well as any hypoglycemic symptoms, before they initiate treatment. At a second study visit,
they will undergo a mixed meal tolerance test, which will serve as a baseline evaluation.
Patterns of (a) glucose excursions (initial postprandial peak, subsequent postprandial fall
and potential hypoglycemia), and (b) hormonal responses (insulin, C-peptide, glucagon,
incretins) will be assessed. At the end of the mixed meal, satiety will be assessed using a
visual analog scale. Baseline hypoglycemia frequency and severity will be assessed by
reviewing patient glucose and hypoglycemia symptom log recorded prior to the visit.

At the completion of visit 2, pramlintide will be prescribed, with instructions for
titration of the drug from minimal to maximal dose (see titration schedule below) to help
reduce the incidence of side effects. During the treatment period, the participants will
keep a record of all hypoglycemic symptoms and blood glucose measurements at those times.

There will be one follow-up visit (visit 3) in the middle of the treatment period for
evaluation of symptoms and tolerance of medication. During the last (eighth) week of
treatment, for comparison with pre-treatment glycemia, participants will again complete a
food diary, and measure and record blood glucoses eight times daily for 3 days. During that
final week of the study, participants will also come to a fourth study visit, during which
they will undergo a repeat mixed meal tolerance test for comparison with the pre-treatment
results.

Inclusion Criteria:

- severe hypoglycemic episodes post-gastric bypass surgery

- normal fasting glucose

- age 21 to 65

- hypoglycemia must not have responded to dietary intervention (low glycemic index,
controlled carbohydrate portions) and a trial of acarbose therapy at the maximally
tolerated dose

Exclusion Criteria:

- Hypoglycemia in the fasting state (greater than 12 hours fast)

- History of preoperative diabetes mellitus

- Use of medications that affect gastrointestinal motility (e.g., cisapride,
metoclopramide)

- Impaired renal function (creatinine clearance < 20 ml/min or on dialysis

- Hepatic disease (defined as liver enzymes > 2 times upper normal limit for ALT and
AST)

- Blood donation for 2 months prior to the study.

- Severe hypoglycemic unawareness, as defined by inability to recognize adrenergic or
neuroglycopenic symptoms of hypoglycemia despite detailed education