What is the evidence for GLP-1 drugs as adjunct therapy for obesity after spinal cord injury?

Comment by InpharmD Researcher

There is limited evidence evaluating GLP-1 receptor agonists as adjunct therapy for obesity in individuals with spinal cord injury (SCI), consisting primarily of case reports (involving tirzepatide and semaglutide) and preclinical studies. These agents have been associated with clinically meaningful reductions in body weight, improved glycemic control, and favorable changes in lipid profiles and body composition when used alongside dietary and exercise interventions. Additionally, preclinical data suggest that GLP-1 receptor agonists may exert anti-inflammatory, neuroprotective, and analgesic effects. Further studies are needed to establish the long-term efficacy and optimal use of these agents in the SCI population.

Background

A 2025 narrative review examined seven pain modalities and the potential of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in treating the different types of pain. Neuropathic pain and visceral pain, both common in spinal cord injury patients, were discussed in the review. Preclinical evidence has shown that GLP-1RAs may alleviate neuropathic pain through enhancing M2 microglial activity (which releases anti-inflammatory markers), promoting beta endorphin release, and attenuating endoplasmic reticulum stress (which may reduce nerve tissue damage). A mix of preclinical and clinical studies, mainly investigating the treatment of irritable bowel syndrome (IBS), have shown that GLP-1RAs may affect visceral hypersensitivity. In animal studies, exendin-4 (a GLP-1 analog) normalized stress-induced defecation, reduced visceral pain hypersensitivity by upregulating serotonin transporter (SERT) expression and downregulating tryptophan hydroxylase-1 (TPH-1) expression. ROSE-010 (an experimental GLP-1 analog) provided rapid relief of IBS abdominal pain in patients, especially those with IBS with constipation who typically have significantly lower serum GLP-1 levels. While these findings demonstrate a lot of therapeutic potential, further clinical trials are needed to fully elucidate the mechanisms of action, efficacy, and safety of GLP-1RAs in treating neuropathic and visceral pain. [1]

Another 2025 article examines the role of GLP-1RAs and DPP-4 inhibitors (DPP-4is) in managing neuropathic pain through literature review. Notably, the review presents evidence highlighting that GLP-1RAs and DPP-4is reduce the expression of pro-inflammatory cytokines such as TNF-α and IL-1β, which are critical mediators in sustaining neuropathic pain. Moreover, these agents are shown to decrease markers of oxidative stress, thus protecting neuronal cells from oxidative damage prevalent in chronic pain conditions. The article explores the preclinical evidence regarding the effectiveness of GLP-1RAs in animal models of neuropathic pain, demonstrating a reduction in behaviors such as hyperalgesia and allodynia. Mechanistically, GLP-1RAs enhance mitochondrial function and energy production, thus preventing neuronal apoptosis and promoting nerve fiber integrity. The research also suggests potential clinical implications, indicating that GLP-1RAs may provide dual benefits in diabetic neuropathy by improving glycemic control alongside pain modulation. The paper calls for further large-scale clinical trials to validate these findings and optimize therapeutic strategies for incorporating GLP-1-based therapies into neuropathic pain management. [2]

References:

[1] He Y, Xu B, Zhang M, et al. Advances in GLP-1 receptor agonists for pain treatment and their future potential. J Headache Pain. 2025;26(1):46. Published 2025 Feb 27. doi:10.1186/s10194-025-01979-4
[2] Kuthati Y, Davuluri VNG, Wong CS. Therapeutic Effects of GLP-1 Receptor Agonists and DPP-4 Inhibitors in Neuropathic Pain: Mechanisms and Clinical Implications. Biomolecules. 2025;15(5):622. Published 2025 Apr 26. doi:10.3390/biom15050622
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the evidence for GLP-1 drugs as adjunct therapy for obesity after spinal cord injury?

Level of evidence

D - Case reports or unreliable data  Read more→


Please see Tables 1-2 for your response.

Preliminary observations on the administration of a glucagon-like peptide-1 receptor agonist on body weight and select carbohydrate endpoints in persons with spinal cord injury: A controlled case series
Design

Open-label, randomized drug intervention case series

N= 5
Objective To describe the effect of semaglutide, a glucagon-like peptide-1 (GLP-1) agonist, to reduce body weight and improve glycemic control in overweight or obese individuals with spinal cord injury (SCI)
Study Groups

Semaglutide (n= 3)

Control (n= 2)
Inclusion Criteria Five individuals with chronic SCI meeting criteria for obesity and abnormal carbohydrate metabolism
Exclusion Criteria

Personal and/or family history of medullary thyroid carcinoma; personal and/or family history of multiple endocrine neoplasia syndrome type 2; personal and/or family history of pancreatitis; existing diagnosis of diabetes mellitus; reduced kidney function (GFR <60 ml/min) or abnormal liver function tests (AST and ALT ≥2.5 times above the upper limit of normal); elevated calcitonin level > 50 pg/mL; pregnancy or women who may become pregnant; medically unstable due to an acute illness or infection; diminished mental capacity to provide informed consent
Methods

Participants were randomized to receive once-weekly semaglutide (subcutaneously) or no treatment for 26 weeks. Semaglutide was initially administered at 0.25 mg once a week, increased to 0.50 mg and 1.0 mg if required glycemic control was not achieved. Body composition and fasting laboratory determinations were performed at baseline and after 26 weeks.
Duration 26 weeks
Outcome Measures

Primary: Change in total body weight (TBW), fat tissue mass (FTM), total body fat percent (TBF%), and visceral adipose tissue volume (VATvol)

Secondary: Fasting plasma glucose (FPG) concentration and serum glycated hemoglobin (HbA1C) values
Baseline Characteristics Characteristic Semaglutide (n= 3) Control (n= 2)
Age, years (standard deviation [SD]) 47 (11) 53 (4)
Height, cm (SD) 186.3 (12.8) 181.6 (1.8)
Weight, kg (SD) 103.2 (17.7) 106.7 (14.7)
BMI, kg/m2 (SD) 29.5 (1.2) 32.6 (4.1)
Duration of Injury, years (SD) 28 (11) 29 (6)
Results Endpoint Semaglutide (n= 3) Control (n= 2)
Change in TBW, kg (SD) -6.0 (2.1) +3.3 (4.6)
Change in FTM, kg (SD) -4.4 (2.5) +4.5 (2.5)
Change in TBF% (SD) -1.7 (0.6) +2.5 (5.1)
Change in VATvol, cm3 (SD) -674 (200) +991 (1365)
Change in FPG, mg/dl (SD) -17 (4) +11 (3)
Change in HbA1C, % (SD) -0.2 (0.1) +0.3 (0.1)
Adverse Events No major safety concerns were observed. AST, ALT, and GFR values remained within normal limits for all participants
Study Author Conclusions Administration of semaglutide for 26 weeks resulted in favorable changes in body composition and glycemic control, suggesting a reduced risk for the development of cardiometabolic disease in obese individuals with SCI.
Critique

The open-label design may introduce bias, and the lack of a follow-up period to assess long-term effects or weight regain is a limitation. Future studies should include a larger sample size and a double-blind design to control for potential confounders.

 

References:

Cirnigliaro CM, La Fountaine MF, Sauer SJ, Cross GT, Kirshblum SC, Bauman WA. Preliminary observations on the administration of a glucagon-like peptide-1 receptor agonist on body weight and select carbohydrate endpoints in persons with spinal cord injury: A controlled case series. J Spinal Cord Med. 2024;47(4):597-604. doi:10.1080/10790268.2023.2207064

 

Treatment of obesity in spinal cord injury with tirzepatide: a case report

Design

Case Report

Case Presentation

A man in his late 40s with a history of spinal cord injury (SCI) sustained 15 years ago from a mountain biking accident presented to his primary care provider for management of obesity, diagnosed two years prior, with no past medical history of Type 2 diabetes mellitus. His maintenance medication regimen included only oxybutynin for bladder relaxation. He had previously worked with multiple registered dietitians and failed pharmacologic therapy with phentermine. He adhered to a hypocaloric diet of 1600 kcal/day composed of 40% carbohydrates, 30% fat, and 30% protein for three months, but was unable to achieve weight loss.

The patient engaged in consistent physical activity, including weightlifting five times per week (1 hour and 15 minutes/session) and modified hand cycling at least twice weekly (1 hour/session). His baseline weight was 115.7 kg (255 lbs), height 190.5 cm (6'3"), with a body mass index (BMI) of 31.87. Relevant laboratory values included glucose of 82 mg/dL and hemoglobin A1c of 5.3%. 

Tirzepatide was initiated as an adjunct therapy to dietary and exercise interventions. He began at 2.5 mg subcutaneously once weekly, with a planned 20-week dose escalation. After one month, his weight decreased to 112.5 kg (248 lbs). In the second month (7.5 mg dose), his weight was 111 kg (244 lbs). Notably, his lipid profile showed overall improvement at that time compared to values from two years earlier. In the third month, he sustained an injury requiring hospitalization, and the patient elected to temporarily discontinue tirzepatide. During his hospital stay, he was placed on a standardized diet of 2100-2300 kcal/day, 130-150 g protein/day, and 2000-2100 mL fluid/day. Despite treatment interruption, his weight continued to decline, with a discharge weight of 101.6 kg (224 lbs).

Post-discharge, tirzepatide was resumed at 15 mg weekly. After one year of treatment, his weight was 100.7 (222 lbs), reflecting a total weight loss of 14.9 kg (33 lbs). The only reported side effect was mild heartburn. He also noted a reduction in cravings for calorie-dense foods.

Study Author Conclusions

Tirzepatide may be a practical, safe, and effective adjunct therapy to exercise and dietary intervention to help facilitate weight loss and prevent cardiometabolic disease in those with SCI.



References:

Juszczak M, Shem K. Treatment of obesity in spinal cord injury with tirzepatide: a case report. Spinal Cord Ser Cases. 2025;11(1):4. Published 2025 Mar 1. doi:10.1038/s41394-025-00699-w