Once Weekly GLP-1 in Persons With Spinal Cord Injury

Obesity is an underlying condition that predisposes to the development of several medical
disorders and diseases. It is well appreciated that obesity has reached pandemic proportions
in Western societies. The World Health Organization (WHO) estimates that 1.9 billion adults
worldwide are overweight and 600 million of these individuals are further sub-classified as
obese, with a 44% estimated burden for type 2 diabetes mellitus (T2DM) being attributed to
being overweight/obese, as well as a 23% estimated burden for heart disease ("Obesity and
overweight," 2016). Excess adipose tissue is assumed to play an integral role in the
pathogenesis of vascular dysfunction and the development of T2DM (Lau, Dhillon, Yan, Szmitko,
& Verma, 2005).

During the acute and chronic phases of SCI, marked adverse changes occur in soft tissue body
composition and associated carbohydrate and lipid metabolism. After an initial rapid loss of
lean tissue below the neurological level of injury, a more insidious and progressive lean
tissue loss is observed (Modlesky et al., 2004; Spungen et al., 2003), which is accompanied
by an increased total body adiposity (Spungen et al., 2003), with accumulation of fat in the
abdominal (e.g., visceral) compartment (Gorgey, Mather, Poarch, & Gater, 2011). These adverse
changes to body composition contribute to, and are associated with, a higher prevalence of
insulin resistance and disorders of carbohydrate metabolism (e.g., impaired glucose tolerance
and T2DM) than that reported in the general population (Bauman & Spungen, 1994). The primary
approach to treat T2DM in the general population is diet and exercise (i.e., lifestyle
modification). Of note, the profound inactivity and adverse soft tissue body composition
changes that occur in individuals after SCI result in metabolic morbidity which is extremely
difficult to manage with lifestyle modification alone. Conventional therapeutic strategies
employed in the adjunctive treatment of carbohydrate metabolism disorders in the general
population include several pharmacological approaches to maintain and improve glycemic
control are in standard practice and include reducing the serum glucose concentration (i.e.,
insulin, sulphonylureas, thiazolidinediones or glitazones), suppressing hepatic
gluconeogenesis (i.e., insulin, biguanides), stimulating endogenous insulin secretion (i.e.,
sulphonylureas), and/or by inhibiting glucose renal reabsorption and increasing glycosuria
(i.e., SGLT-2 inhibitors).

In 2005 a new class of drugs was approved for the treatment for T2DM by targeting the GLP-1
receptor. Exenatide is a GLP-1 agonist that acts as an incretin hormone, and it belongs to a
class of gastrointestinal hormones which are released from the L cells of the intestines in
response to food ingestion that, as one of its mechanisms of action, increase insulin
secretion from pancreatic beta cells (Vilsboll et al., 2003). This phenomenon that was coined
"the incretin effect" in the 1960's described the significantly higher plasma insulin levels
following orally versus intravenously administered glucose, which can account for 50 to 70%
of the insulin secretion observed after food intake (Baggio & Drucker, 2007). Treatment with
GLP-1's has increased over the past several years because of their mechanism of action to
increase insulin secretion, inhibit glucagon release in a glucose-dependent manner, thus
minimizing the risk for hypoglycemia (Baggio & Drucker, 2007; Nauck, Stockmann, Ebert, &
Creutzfeldt, 1986; Vilsboll, Krarup, Madsbad, & Holst, 2002). Numerous multi-ethnic and
multi-national trials have been performed with exenatide, but none have been reported in
persons with SCI. Previous investigation with exenatide once-weekly in able-bodied
individuals has resulted in weight loss ranging from 1.6 to 3.9 kg following 24 weeks of
intervention (Bergenstal et al., 2010; Blevins et al., 2011; Buse et al., 2013; Chiquette,
Toth, Ramirez, Cobble, & Chilton, 2012; Davies et al., 2013; Diamant et al., 2010; Drucker et
al., 2008; Inagaki, Atsumi, Oura, Saito, & Imaoka, 2012; Ji et al., 2013; Russell-Jones et
al., 2012). As such, to date there is no evidence of the potential efficacy of exenatide to
result in weight loss, improve glycemic control, and/or reduce insulin resistance in persons
with SCI.

Inclusion Criteria:

1. Male or female, age 18 to 69;

2. Chronic (e.g., duration of injury greater than 3 years) stable SCI (regardless of
level of neurological injury);

3. ASIA A-D (non-ambulatory defined as not able to weight bear for more than 20% of the
day);

4. Obese Percent Body Fat defined as > 25% for men and > 35% for women (as determined by
screening DXA scan);

5. Insulin Resistant as determined at screening: (FPI, ≥15 µU/ml); -OR-

6. Pre-diabetic, as determined by any one of the following:

1. HbA1C ≥ 5.7% and < 6.4%; or

2. Impaired glucose tolerance by FSG ≥100 mg/dl and < 125 mg/dl and/or the 2 hour
serum glucose concentration (after an OGTT) ≥ 140 mg/dl and < 200 mg/dl

Exclusion Criteria:

1. Personal history of or family history of medullary thyroid carcinoma;

2. History of multiple endocrine neoplasia syndrome type 2;

3. History of pancreatitis;

4. Existing diagnosis of diabetes mellitus, or the results from screening OGTT that
identify diabetes mellitus (previously undiagnosed); laboratory thresholds for
exclusion will be as follows: HbA1C ≥6.5%, fasting plasma glucose >126 mg/dl, or 2
hour value >200 mg/dl;

5. Receiving treatment for impaired glucose metabolism (i.e., insulin, secretagogues, or
other agents to modify peripheral insulin sensitivity or serum glucose concentration);

6. Reduced kidney function (by glomerular filtration rate (GFR <60 ml/min) or liver
function tests (any single LFT ≥ 2.5 times above the upper limit of normal) as
determined by test results at screening and any time point of the study;

7. Elevated calcitonin level (as determined at screening to rule out thyroid cancer);

8. Pregnancy or women who may become pregnant during the course of the study, or those
who are nursing;

9. Medically unstable;

10. Acute illness or infection;

11. Diminished mental capacity; and

12. Inability or unwillingness of subject to provide informed consent.