Once Weekly GLP-1 in Persons With Spinal Cord Injury

Obesity Clinical Trial

Official title: The Efficacy of a Once Weekly Glucagon-Like Peptide-1 Agonist on Body Weight/Composition and Metabolic Parameters in Persons With SCI

Status Completed

Clinical Trial Summary

Chronic spinal cord injury (SCI) results in adverse soft tissue body composition changes and an extremely sedentary lifestyle. These abrupt changes often lead to a high prevalence of cardiometabolic diseases, such as impaired glucose tolerance/diabetes mellitus and dyslipidemia, conditions which predispose those with SCI to an increased risk for cardiovascular disease compared to the general population. Due to paralysis and wheel chair dependence, maintaining an adequate level of physical activity to counteract these deleterious metabolic changes presents a unique obstacle because conventional first line interventions are lifestyle modifications (e.g., diet and exercise), which may be difficult to achieve. Recently, a new medication has been approved by the Food and Drug Administration to improve glycemic control in individuals with diabetes mellitus, and it has also been investigated as an off-label treatment to induce weight loss. Glucagon-like peptide-1 (GLP-1) agonists are a class of drugs designed to mimic the endogenous incretin hormones released from the gut in a glucose dependent manner following a meal. The mechanisms of action for this drug class of medications include stimulation of glucose-dependent insulin secretion, inhibiting glucagon release, slowed gastric emptying, and reduction of postprandial glucose excursions following food intake. In addition to improved glycemic control, this class of medications also shows promise for its non-glycemic action of facilitating weight loss. The method of delivery of the GLP-1's is by self-administered injections once daily or once weekly, depending on the severity of the clinical case and therapeutic targets for a specific patient.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Insulin Resistance
• Obesity
• Pre Diabetes
• Prediabetic State
• Spinal Cord Injuries

• NCT number: NCT03292315
• Study type: Interventional
• Source: James J. Peters Veterans Affairs Medical Center
• Status: Completed
• Phase: Phase 4
• Start date: October 16, 2018
• Completion date: March 1, 2023