It is not known whether a new diabetes drug, semaglutide, is an effective treatment for type 2 diabetes for persons with spinal cord injury (SCI), a population at higher risk for this condition. Therefore, this study looks at the effect of semaglutide on glucose levels in the body and other information about type 2 diabetes and obesity.

This study consists of 7-9 in-person visits and 9-10 phone visits, and participants will be randomized to either semaglutide or placebo for 24 weeks. The participants first visit, will include review of medical history and performance of standard tests to check the participant's health and eligibility for the study. Before starting any medication, participants will have 2 more visits:

• a mixed meal tolerance test, to examine their body's response to nutrient ingestion and
• a glucose clamp study to examine insulin sensitivity. These tests will be scheduled on two separate days. Following the 3 baseline visits, participants will be randomized to either the intervention (once-weekly injection of semaglutide, also known as Ozempic, for 24 weeks) or placebo. During the 24-week intervention participants will receive 9-10 phone calls to discuss their progress and experiences with the interventions and will also be asked to return for a short research visit including interim medical history with or without blood sample collection twice. At the end of 24 weeks, the treatments will be discontinued, and participants will repeat the meal and glucose studies scheduled over two separate days. During participation, fat/lean mass will be measured using DEXA and liver fat mass may be measured using fibroscan. In addition, participants may be asked for a stool sample.

Inclusion Criteria:

1. Male and female subjects aged 18-70 years (inclusive) at screening
2. More than one year after spinal cord injury
3. Levels if injury C2-L2 with Asia Impairment Scale A, B, C or D.
4. Provision of signed and dated written informed consent prior to any study specific procedures
5. Diagnosed with T2DM with glucose control managed with diet and metformin monotherapy where no significant dose changes (increase or decrease ≥ 50%) have occurred in the three months prior to screening
6. HbA1c 6.0-9.0% at screening
7. BMI > 22 kg/m2 at screening
8. Female subjects of childbearing potential must have a negative pregnancy test at screening and randomization, and must not be lactating
9. Females of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception from screening and must agree to continue using such precautions through to the end of the study. It is strongly recommended for the male partner of a female subject to also use male condom plus spermicide throughout this period. Cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.

Exclusion Criteria:

1. History of, or any existing condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product, put the subject at risk, influence the subject's ability to participate or affect the interpretation of the results of the study and/or any subject unable or unwilling to follow study procedures.

2. Any subject who has received another investigational product as part of a clinical study within the last 30 days or 5 half-lives of the drug (whichever is longer) at the time of screening

3. Taking mirabegron or other glucose altering medications

4. Taking steroids within the past 1 year

5. Significant anemia (hemoglobin<11g/dL)

6. History of gastric outlet obstruction or chronic diarrhea

7. History of a chronic neurological illness other than SCI (i.e.; MS, etc)

8. Any subject who has received any of the following medications within the specified time-frame prior to the start of the study

   • Herbal preparations or drugs licensed for control of body weight or appetite (eg, orlistat, bupropion-naltrexone, phentermine-topiramate, phentermine, lorcaserin) within a year prior to the start of the study
   • Pioglitazone, SGLT2 or DPPIV inhibitors, GLP-1RA within the last 60 days at the time of screening

9. Severe allergy/hypersensitivity to any of the proposed study treatments, excipients, acetaminophen

10. Symptoms of acutely decompensated blood glucose control (eg, thirst, polyuria, weight loss), a history of type 1 diabetes mellitus (T1DM) or diabetic ketoacidosis, or if the subject has been treated with daily SC insulin within 90 days prior to screening.

11. Significant inflammatory bowel disease or other severe disease or surgery affecting the upper GI tract (including weight-reducing surgery and procedures) which could affect the interpretation of safety and tolerability data. Prior history of bariatric surgery is not considered exclusion given the ample evidence of safety of use of GLP-1R therapy in this population.

12. Acute or chronic pancreatitis

13. Significant hepatic disease (except for metabolic dysfunction-associated steatohepatitis [MASH] or metabolic dysfunction-associated steatotic liver disease [MASLD]) without portal hypertension or cirrhosis) and/or subjects with any of the following results at screening:

    Aspartate transaminase (AST) ≥ 3 × upper limit of normal (ULN) Alanine transaminase (ALT) ≥ 3 × ULN Total bilirubin ≥ 2 × ULN

14. Impaired renal function defined as estimated glomerular filtration rate (eGFR) < 45 mL/minute/1.73m2 at screening (GFR estimated according to Modification of Diet in Renal Disease (MDRD) using MDRD Study Equation IDMS-traceable [SI units])

15. Unstable angina pectoris, myocardial infarction, transient ischemic attack (TIA) or stroke within 3 months prior to screening, or subjects who have undergone percutaneous coronary intervention or a coronary artery bypass graft within the past 6 months or who are due to undergo these procedures at the time of screening

16. Severe congestive heart failure (New York Heart Association Class III or IV)

17. Basal calcitonin level > 50 ng/L at screening or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia

18. History of neoplastic disease within 5 years prior to screening, except for adequately treated basal cell, squamous cell skin cancer, or in situ cervical cancer

19. History of HIV infection or other immune compromised disease; and history of organ transplantation

20. Substance dependence or history of alcohol abuse and/or excess alcohol intake

21. Patients on ketogenic diet

The shared data will be de-identified according to HIPAA and shared under a repository standard Data Use Agreement (DUA).(e.g., all data will be thoroughly de-identified and will not be traceable to a specific study participant). Plans for archiving and long-term preservation of the data will be implemented, as appropriate.ccess to shared data will be controlled according to the repository policy which requires a request and merit review and will be available according to repository processes. The shared data will be de-identified according to HIPAA and shared under a repository standard Data Use Agreement (DUA).

Study data will be shared as summary results on ClinicalTrials.gov a year after the primary completion date and full results will be shared at study end after data has been analyzed and published in a peer review journal.

The scientific data generated from this study will be shared in the Texas Digital Library

Patients will be blinded to the treatment assignment. The study team will be unblinded. The investigators will deliver the treatment assignments to the hospital pharmacist as they occur.