A first-of-its-kind investigation into the mechanisms behind diabetes and obesity in people with spinal cord injury and the antidiabetic and anti-obesity effects of semaglutide was recently approved for $3 million in National Institutes of Health funding.
“This is one population in which they are susceptible to be more obese and having worse diabetes risk and are not being treated with optimal drugs, one of them being the GLP1-RA,” said Marzieh Salehi, MD, MS, board-certified endocrinologist, clinician scientist, and professor of medicine with the Joe R. and Teresa Lozano Long School of Medicine, The University of Texas Health Science Center at San Antonio (UT Health San Antonio).
Salehi has 20 years of experience in translational research focusing on glucose metabolism mediated by proglucagon-derived peptides (glucagon-like peptide 1 [GLP-1] and glucagon) in patients with and without obesity and type 2 diabetes. As the primary investigator of this clinical trial, she will examine the underlying mechanisms by which spinal cord injury deteriorates glucose metabolism and energy balance as well as the mitigating effects of semaglutide (a potent GLP-1 receptor agonist) and its safety profile in this cohort.
This trial will be the first to study the glucoregulatory effects of semaglutide and its safety profile in a group of individuals with spinal cord injury and type 2 diabetes. The findings from this trial will immediately impact treatment guidelines for obesity and diabetes in patients with spinal cord injury and provide insight into the underlying mechanisms of diabetes in this population.
Salehi said the impetus for this investigation was the dearth of studies involving people with spinal cord injury and the treatment of underlying causes of their metabolic conditions. She teamed up with Michelle Trbovich, MD, associate professor of rehabilitation and a clinician scientist, to address gaps in knowledge that have led to significant health disparities in the management of diabetes and obesity in this population.
Approximately 2 million Americans are living with spinal cord injuries with about 18,000 new injuries in the U.S. each year. This population is 150% more likely than the general population to develop type 2 diabetes. People with spinal cord injury develop diabetes at a much earlier age and at a much higher rate than able-bodied individuals. Although this increased risk is not fully understood, previous studies indicate that impaired insulin action due to muscle atrophy, along with visceral fat and glucose intolerance play a role. Further, cardiometabolic complications are the leading cause of death for people with spinal cord injury. Yet, the optimal treatment for diabetes and related cardiometabolic complications after spinal cord injury is unknown.
Glucagon-like peptide 1 receptor agonists (GLP1-RAs), like semaglutide, are some of the most potent medical treatments for weight loss and glycemic reduction. These drugs act on several internal systems to aid glycemic control by stimulating beta-cell secretion, lowering glucagon secretion and liver glucose production, delaying the emptying of the stomach, and suppressing appetite leading to weight loss, which in turn improves insulin resistance. Preclinical and clinical trials indicate that GLP1-RAs may also have a beta-cell preserving effect, an important benefit in type 2 diabetes treatment because the disease is believed to worsen over time due to a decline in beta-cell function. While there have been more than 25 clinical trials of semaglutide in able-bodied individuals with type 2 diabetes, it is unclear whether the findings can directly translate to patients with spinal cord injury and type 2 diabetes.
A recent survey of physicians who specialize in spinal cord injury shows that 70% were uncomfortable prescribing new anti-diabetes medications, such as semaglutide, for patients with spinal cord injury due to a lack of research in diabetes treatment in this population.
The study will explore underlying causes for diabetes in this high-risk population and assess the effects of the 24-week administration of semaglutide on glucose tolerance and insulin action as well as fat /lean mass. Participants will include men and women recruited from the South Texas Veterans Health Care System, Audie L. Murphy Memorial Veterans’ Hospital and UT Health San Antonio who have a spinal cord injury and type 2 diabetes and are taking metformin.
Also, researchers will monitor how participants tolerate semaglutide over the 24 weeks of treatment. Salehi said preserving lean mass while losing weight is critical in the long-term beneficial effects of weight-loss intervention, especially in this population who tends to have lower lean mass and can have dysregulated metabolic function.
Another aspect of the study will be investigating the effect of semaglutide on bone density in this population. Preclinical data, Salehi said, indicates GLP1-RAs benefit bone health.
Of the dozens of previous GLP1-RA studies in able-bodied populations, Salehi said, few have looked at the effects of these medications beyond glucose control, body mass reduction or cardiovascular function.
“In these studies, with sometimes over 1,000 able-bodied people, very few studies look at underlying pathways and mechanisms of glucose regulatory effects of these drugs. They have been focused on cardiovascular, and rightfully so, but there is lots to be learned beyond that,” said Salehi.