The Effect of GLP1 Receptor Agonists on Physical Function, Body Composition, and Biomarkers of Aging in Older Overweight/Obese Adults With Insulin Resistance
Phase: PHASE4
Conditions: Aging, Diabetes Mellitus, Type 2, PreDiabetes, Overweight and Obesity
Sponsor: The University of Texas Health Science Center at San Antonio

 
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COVER PAGE  
 
 
 
 
 
Official Study Title: The Effect of GLP1 Receptor Agonists on Physical Function, Body 
Composition, and Biomarkers of Aging in Older Overweight/Obese Adults with Insulin 
Resistance 
 
NCT number: NCT05786521 
 
IRB Approval Date: 03.23.2023 
 
 
Unique Protocol ID: 20220256HU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Form CT 
UTHSA Clinical Trial Description 
This form is not mandatory.  Other documents are acceptable if equivalent information is provided. 
UTHSCSA Tracking Number 
(internal use only) 
 
20220256HU 
1. Original Version 
Date 
08-31-22 
 
 
1.1. Revision Date(s)  
add rows as needed 
2.0 
 
 
2. Background 
Briefly discuss the important literature relevant to the trial and that provides background for the trial.  Include the importance of the trial and any relevant 
treatment issues or controversies. 
Approximately 25% of older adults in the U.S. have Type 2 Diabetes (T2D) and nearly 50% have 
prediabetes. The mechanisms that cause age-related glucose intolerance and diabetes are unknown, but 
age-dependent decreases in β-cell function and insulin sensitivity are thought to be important in 
deterioration of glucose homeostasis with age.  There are also changes in body composition with age that 
can contribute to insulin resistance with age, including: (1) redistribution of fat from peripheral and 
subcutaneous to a central location, and (2) loss of lean muscle mass . Thus, most older adults have some 
degree of insulin resistance and mechanisms that contribute to insulin resistance become more pronounced 
with aging.  
The usual comorbidities associated with diabetes are recognized as cardiovascular, renal, and neuropathic 
diseases; however, there are physical function and body composition changes which occur which impact 
aging outcomes. A meta-analysis by Wong et showed that those with diabetes had an increased risk of 
mobility disability, defined by walking speed, chair stand, and balance tests, compared to those without 
diabetes (risk ratio=1.51, 95%CI 1.38-1.64). These physical changes have also been seen in those with 
prediabetes. Over 12 years, those with prediabetes compared to normoglycemia had an increased predicted 
trajectory of chair stand time (p<0.05), decreased walking speed (p<0.01) and an accelerated disability 
progression (p<0.01). In multiple longitudinal studies, older adults with diabetes lost more lean mass 
compared to those without diabetes. Further, the decline of physical function as measured by various 
assessments (balance, walking speed, balance) and sarcopenia, decline of lean body mass, are predictive 
of nursing home admission and death .   
Inflammation is one of the key mechanisms underlying aging and age-related diseases.  Chronic 
inflammation contributes to aging through several complex pathways.  One pathway is cellular senescence, 
which contributes to normal aging, but also to the burden of low-grade chronic inflammation through 
activation of a wide range of growth factors, cytokines and other inflammatory factors. Higher levels of 
inflammation markers, interleukin (IL)-6 and C-reactive protein (CRP), have been demonstrated in 
individuals with insulin resistance as well as T2D, and are also predictors of frailty in older adults.  
GLP1 receptor agonists are generally considered second line treatment for patients with T2D, but this class 
of medications maybe considered first-line in patients who are at high risk for cardiovascular disease or 
already have a history of cardiovascular disease. GLP1 receptor agonists increase insulin and decrease 
glucagon in response to hyperglycemia and suppress appetite likely mediated through actions on receptors 
in the hypothalamus and other areas of the central nervous system. Although weight loss is one of the 
benefits of this class, there is concern that the weight loss observed with GLP1 receptor agonist use is 
accompanied by loss of lean mass in addition to fat mass, which is especially concerning in an older adult 
population who have age-related sarcopenia. A review of the effect of GLP1 receptor agonists on body 
composition showed, as expected, a total body weight loss but the breakdown of weight loss from lean body 
and fat mass varied significantly between the studies. Some showed an increase in lean body mass while 
other showed that a significant portion of the weight loss came from lean body mass, up to 65.2%, in those 
treated with GLP1 receptor agonists T2D. Interestingly in rodent models, GLP1 receptor agonists have 
shown to have beneficial effects on skeletal muscle atrophy. A meta-analysis showed an improvement of the 

 
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pro-inflammatory milieu in patients with T2D treated GLP1 receptor agonists compared to placebo or other 
T2D medications with a significant change of CRP (-0.54mg/L, 95% CI -0.7- -0.34), tumor necrosis factor 
alpha (-0.39, 95% CI -0.62 - -0.15), and adiponectin (0.30, 95% CI 0.12-0.49). Although there are known 
cardiovascular and weight management benefits of GLP1 receptor agonists outside of their ability to treat 
hyperglycemia, information about physical function is understudied especially in older adults. Use of GLP1 
agonists is rapidly increasing, but research in older adults is very limited. This pilot work will be an important 
first step in examining the potential usefulness of GLP1 receptor agonists in older adults to improve glycemic 
control, as well as physical function and lean mass. 
 
 
 
3. Objectives and Endpoints     All data points collected in the study should support an objective or have a regulatory purpose.   
Complete the table – add rows as needed.   
3.1. Objective(s)  
Clearly and concisely define the primary and 
secondary outcomes.  
3.2. Endpoint 
Clearly define the endpoints.  
(endpoints are the basis for concluding that 
the objective has been met). 
3.3. Justification for Endpoint 
Briefly explain why the endpoint(s) were chosen. 
Aim 1: To conduct a pilot study to 
examine the effect of GLP1 
receptor agonists on physical 
function and body composition in 
older overweight/obese adults 
with prediabetes or well controlled 
diabetes. 
Aim 2: To examine the impact of 
GLP1 receptor agonists on 
biomarkers of aging (cellular 
senescence and inflammation) in 
older overweight/obese adults 
with prediabetes or well controlled 
diabetes. 
 
Aim 1: Any change in 
-Short physical performance 
battery (SBBP) 
-Handgrip strength  
-6 minute walking distance  
-BMI 
-Body composition (lean body 
mass to fat mass) 
 
Aim 2:  
-Markers of cellular 
senescence and inflammation 
in muscle, adipose, and blood 
GLP1 receptor agonists are an FDA-
approved class of drugs for the 
treatment of T2D which lead to 
improvement in adiposity but possibly 
at the risk of significant decline on 
lean body mass. Additionally, there is 
a lack of studies to determine if these 
changes are associated with a 
significant change in functional status.  
Therefore, Aim 1 will address the 
specific hypothesis that the GLP1 
receptor agonist semaglutide will 
improve physical function (SPPB, 
handgrip strength, walking speed) and 
body composition (BMI, lean body 
mass to fat mass ratio) compared to 
standard of care. 
Diabetes is known to be pro-
inflammatory state that can promote 
cellular senescence. GLP1 receptor 
agonists have shown positive 
improvement of inflammatory makers 
but this has not been studied 
extensively in older adults.  Therefore, 
Aim 2 will test the hypothesis that the 
GLP1 receptor agonist semaglutide 
(by improving glycemia and adiposity) 
will decrease markers of cellular 
senescence and inflammation in 
muscle, adipose tissue and blood. 
 
 
4. Rationale 
Briefly state the reason for conducting the clinical trial.  

 
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The results of this study will provide useful information which could influence the treatment algorithm for 
older adults with prediabetes or T2D. Currently, pharmacological intervention for older adults with 
prediabetes is not widely recommended although has been done in clinical trials with resultant reduction in 
diabetes onset . Further, older adults with diabetes who are otherwise healthy may not have medical 
management (i.e., drug therapy) added until glycemic goals are unmet (HbA1c >7.0-7.5%), which may have 
detrimental, lasting effects on aging muscle. If positive, our results would support the use of GLP1 receptor 
agonists in older adults with prediabetes or in well controlled diabetes earlier in the disease course to halt 
the progression of physical function decline and improve biomarkers of aging. Therefore, this knowledge will 
contribute to future studies in this area that will allow for geroscience-guided therapy for prediabetes and 
T2D in older adults to extend healthspan.  
To minimize the risk of weight loss, we will enroll participants who meet the indication for GLP1 receptor 
agonist therapy for weight management in the presence of at least one comorbid condition which for this 
study will be prediabetes or diabetes (BMI ≥ 27.0, HgbA1c ≥ 5.7). We will have an upper limit for HgbA1c of 
7.5% because at this time most clinicians would start or intensify medical therapy. We will have a BMI upper 
limit of 40.0 for ability to use DXA.    
 
 
5. Study Design 
5.1. Number of Groups/Arms 
2 
Group name(s) 
(1) Medication and lifestyle  (2) Lifestyle alone 
5.2. Overall Design 
Select all applicable   
☒ 
 Randomization   
☐ 
Cluster Randomized 
☐ 
Group-Sequential 
☐ 
Adaptive Design 
☐ 
Parallel Design 
☐ 
Placebo-Controlled 
☐ 
Superiority 
☐ 
Equivalence 
☐ 
Non-inferiority 
Device 
☐ 
Pilot 
☐ 
Pivotal 
☐ 
Post-Approval 
Drug/Biologic 
☒ 
Phase 1 
☐ 
Phase 1/2 
☐ 
Phase 2 
☐ 
Phase 2/3 
☐ 
Phase 3 
☐ 
Phase 4 
☒ 
Dose escalation  
If yes, details → 
0.25mg weekly for 4 weeks, then 0.5mg weekly for 4 weeks, then 1mg weekly for 12 
weeks. If unable to tolerate a higher dose then will adjust titration schedule.  
☐ 
Dose ranging 
If yes, details → 
 
☐ 
Sub-studies 
If yes, details → 
 
5.3. Other Design Details: This will be a 20 week open label, randomized control trial. The study will start after approval from UT 
Health San Antonio IRB department. Subjects will be consented and then screened for eligibly before randomization into either 
the lifestyle or lifestyle plus study drug arm. All study visits will be performed at Barshop Clinical Research Unit.  
 
 
 
6.  Study Population 
 
6.1.  Study Population(s) 
Label/Name 
 
 
 
 
To add more populations – select a row, copy & 
paste 
6.2.  Identify the criteria for inclusion 
The criteria that every potential participant must 
satisfy, to qualify for study entry.  
 
All individuals in this study population must meet 
all of the inclusion criteria in order to be eligible 
to participate in the study  
6.3.  Identify the criteria for exclusion 
The characteristics that make an individual ineligible 
for study participation.   
 
All individuals in this study population meeting 
any of the exclusion criteria at baseline will be 
excluded from study participation. 
Overweight/obese 
community dwelling older 
1) Men and post-menopausal 
women 
2) Age ≥ 65 years 
1) Impaired renal function (GFR ≤ 
29) 
2) Hematocrit ≤ 33  

 
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adults with prediabetes or 
T2D.  
3) All ethnic groups 
4) BMI ≥ 27.0 kg/m2 
5) HbA1c 5.7-7.5%, fasting glucose 
≥ 100,  
7) Community – dwelling  
8) At PI discretion, participant is 
willing/able to comply with the 
protocol requirements  
3) Thyroid-stimulating hormone≥ 7 
with an abnormal free T4 
4) Immunodeficiency 
5) Use of medications known to 
affect glucose homeostasis besides 
metformin (metformin is allowed) 
6) History of cardiovascular events 
7) Poorly controlled blood pressure 
(systolic blood pressure >170, 
diastolic blood pressure >95) 
8) Active inflammatory, autoimmune, 
infectious, hepatic, gastrointestinal, 
malignant, or uncontrolled 
psychiatric disease  
9) stable body weight (<5% change 
during the 3 months prior to 
screening) 
10) personal or family history of 
medullary thyroid cancer (MTC) 
11) personal or family history of 
Multiple Endocrine Neoplasia 
syndrome type 2 (MEN 2) 
12) previous history of pancreatitis, 
13) ECG with QTc prolongation (QTc 
>470 ms in men or >480 ms in 
women) or evidence of ischemic 
changes  
14) Diabetic Retinopathy 
15) Allergy to semaglutide or any of 
the ingredients in the drug 
formulation 
16) Type 1 Diabetes  
17) BMI ≥ 40 kg/m2 
18) Current tobacco or illicit drug use 
6.4.  
Will screen failures be allowed to 
re-screen at a later date? 
☐ 
No 
☒ 
Yes           If yes, describe criteria below ↓ 
Will be able to be rescreened after 12 weeks  
 
 
7.  Study Intervention(s) being tested or evaluated 
This can include prevention, diagnostic or therapeutic interventions (e.g., drug or device) or educational, health services or basic science interventions (e.g., 
educational program, health care delivery model,  or examining basic physiology)  
 
Semaglutide (Ozempic )  
 
8.  Protocol-Directed procedures, items, services or tests 
List all procedures directed by the study plan - including items or services provided as part of routine or conventional care and those needed to diagnosis or treat 
research related complications.    
Important Note – The protocol directed procedures listed must match those in the Schedule of Activities (attachment) 
8.1. Drugs (trade and generic, dosage, route of administration)     
Control group-lifestyle alone group: Subjects will meet with a dietician throughout the study to discuss 
lifestyle counseling based on recommendation in the diabetes prevention program.  

 
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Intervention group- Semaglutide+ lifestyle : Ozempic , starting at 0.25mg once a week for 4 weeks then 
0.5mg once weekly for 4 weeks followed by 1.0mg once a week, subcutaneously as tolerated. Additionally, 
they will meet with a dietician through the study to discuss lifestyle counseling based on recommendation in 
the diabetes prevention program. 
 
 
 
 
 
8.2. Devices 
 
 
8.3. Biologics 
 
 
8.4. Laboratory Tests  
Clinical labs include CBC, lipid panel, CMP, TSH, PT/INR, PTT, and HbA1c will be done to determine 
eligibility and follow the effect of treatment. 
 
8.5. Imaging Procedures  
 
 
8.6. Other Research Procedures (e.g., other safety and efficacy assessments.)  
-ECG: ECG will be performed to examine for  QTc prolongation or other cardiac issues contraindicated for 
exercise 
-Vitals and anthropometric measurements:  Weight will be measured at all visits to track BMI, heart rate, and 
blood pressure 
-Functional assessments of SPPB, 6 minute walking distance, and grip strength will be done at baseline and 
at end of study to determine the effect of the intervention. 
-Questionnaires of SF-12 (quality of life) and CNAQ (appetite assessment) will be done at baseline and at 
end of study determine the effect of the intervention.  
-DXA: body composition will be determined by DXA at baseline and end of study to determine the effect of 
the intervention  
-Assays of cellular senescence and senescence-associated secretory phenotype (SASP) in muscle, adipose 
and blood will be conducted in the Barshop Institute, including   galactosidase staining, PCR (IL-6, TNFα, 
p16, p21, TLR4, and MCP1), and immunoassays (CRP, ADAMTS13, CCL3, CCL4, CCL5, CCL17, CCL22, 
FAS, GDF15, GDNF, ICAM1, IL15, IL6, IL7, IL8, MMP2, MMP9, OPN, PAI1, SOST, TNFR1, TNFα, and 
VEGFA). These will be done at the beginning and end of study to determine the effect of study intervention.  
8.7  Attach a Schedule of Activities (SOA) Excel File  [Download the Template here: Schedule of Activities] 
Check to indicate that the  
SOA Excel File is attached  → X 
☐ 
 
 
9. 
Preparation/Handling/ Storage/Accountability of Investigational Drug, Biologic, or Device 
N/A  - This study does not include any investigational products (e.g. drugs, devices or biologics) 
 
N/A  - An Investigator Brochure is attached 
 
X N/A  - A Drug/Device Manual is attached- The FDA prescribing insert for both Wegovy and Ozempic which are the trade 
names for semaglutide.  
☐ 
☐ 
☐ 

 
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9.1.  Acquisition and accountability 
State how the study intervention and control product will be provided to the investigator. Describe plans about how and by whom the study intervention will be 
distributed, including participation of a drug repository or pharmacy, and plans for disposal of expired or return of unused product. 
Semaglutide will be provided by the pharmacy to Barshop staff. Barshop staff will then dispense medication 
and log in appropriate visits. Unused medication will be returned to pharmacy for disposal.  
9.2. Formulation, Appearance, Packaging, and Labeling 
Describe the formulation, appearance, packaging, and labeling of the study intervention and control product, as supplied.  Information in this section can usually 
be obtained from the IB or the package insert, or device labeling. This section should include the name of the manufacturer of the study intervention and control 
product. 
 
SEMAGLUTIDE DOSAGE FORMS AND STRENGTHS:  
 Injection: 2 mg/1.5 mL (1.34 mg/mL) of semaglutide as a clear, colorless solution available in: 
- Pre-filled, disposable, single-patient-use pen that delivers 0.25 mg (for treatment initiation) or 0.5 mg (for maintenance 
treatment) per injection.  
-Pre-filled, disposable, single-patient-use pen that delivers 1 mg (for maintenance treatment) per injection. 
 
We will only be using Ozempic in this study. Since Ozempic and Wegovy are the same active ingredient used at different 
doses (Wegovy starts at 0.25mg once a week and increases up to 2.4mg once a week), we have add the indications for 
Wegovy.  
 
INDICATIONS AND USAGE 
OZEMPIC (semaglutide) is a glucagon-like peptide 1 (GLP-1) receptor agonist 
indicated as: 
• an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. 
• to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established 
cardiovascular 
disease . 
 
WEGOVY (semaglutide) is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to a reduced calorie 
diet and increased physical 
activity for chronic weight management in adult patients with an initial body mass index (BMI) of 
• 30 kg/m2 or greater (obesity) or 
• 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 
2 diabetes mellitus, or dyslipidemia).  
 
Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd Denmark 
9.3.  Product Storage and Stability 
Describe storage and stability requirements (e.g., protection from light, temperature, humidity) for the study intervention and control product.  For studies in which 
multi-dose vials are utilized, provide additional information regarding stability and expiration time after initial use (e.g., the seal is broken). 
We will be providing participants Ozempic in the intervention arm.  
 
Prior to first use, OZEMPIC should be stored in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC). Do not store in the 
freezer or directly adjacent to the refrigerator cooling element. Do not freeze OZEMPIC and do not use OZEMPIC if it 
has been frozen. Can be used until expiration on pen.  
  
After first use of the OZEMPIC pen, the pen can be stored for 56 days at controlled room temperature (59°F to 86°F; 
15°C to 30°C) or in a refrigerator (36°F to 46°F; 2°C to 8°C). Do not freeze. Keep the pen cap on when not in use. 
OZEMPIC should be protected from excessive heat and sunlight.   
 
9.4.  Preparation 
Describe the preparation of the study intervention and control product, including any preparation required by study staff and/or study participants.  Include 
thawing, diluting, mixing, and reconstitution/preparation instructions in this section. For devices, include any relevant assembly or use instructions. 
NA –Medication will be obtained from MedPlus pharmacy (may change based on cost of medication). The medication 
will be labeled “for investigational use only” in addition to the usual labeling of medication, dose and instructions.  
9.5. Risks and Benefits 
Risks 
Risk of Thyroid C-cell Tumors  

 
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Semaglutide causes thyroid C-cell tumors in rodents and that the human relevance of this finding has not been 
determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia, 
or dyspnea) to their physician [see Boxed Warning and Warnings and Precautions (5.1)]. 
Pancreatitis  
There is a potential risk for pancreatitis. Instruct will be given to patients to discontinue OZEMPIC promptly and contact 
the study team if pancreatitis is suspected (severe abdominal pain that may radiate to the back, and which may or may 
not be accompanied by vomiting). 
Diabetic Retinopathy Complications  
Inform patients to contact the study team immediately if changes in vision are experienced during treatment with 
OZEMPIC  
Never Share an OZEMPIC Pen Between Patients.  
Advise patients that they must never share an OZEMPIC pen with another person, even if the needle is changed, 
because doing so carries a risk for transmission of blood-borne. 
Dehydration and Renal Failure  
There are potential risk of dehydration due to gastrointestinal adverse reactions and precautions should be taken to 
avoid fluid depletion. There is a potential risk for worsening renal function and participants will be informed about the 
associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if 
renal failure occurs.  
Hypersensitivity Reactions  
Participants will be informed to stop taking OZEMPIC and seek medical advice promptly if symptoms of hypersensitivity 
reactions occur. 
 
Most common side effects of semaglutide administration are nausea, vomiting, diarrhea, abdominal pain and 
constipation which usually decrease over time in the majority of patients. 
 
Possible Benefits 
• 
Improved glycemic control in type 2 diabetic participants 
• 
Beneficial weight loss leading to decreased BMI 
• 
Possible improvement of pro-inflammatory milieu 
• 
If positive, study results would support the use of GLP1 receptor agonists in older adults with prediabetes or in 
well controlled diabetes earlier in the disease course to halt the progression of physical function decline and 
improve biomarkers of aging. Therefore, this knowledge will contribute to future studies in this area that will 
allow for geroscience-guided therapy for prediabetes and T2D in older adults to extend healthspan. 
 
 
10.  Study Intervention Additional Details 
10.1.  Measures to Minimize Bias: Randomization and Blinding 
This section should contain a description of randomization and blinding procedures (if applicable to the 
study design).  It should include a description or a table that describes how study participants will be 
assigned to study groups, without being so specific that blinding or randomization might be compromised.  
Plans for the maintenance of trial randomization codes and appropriate blinding for the study should be 
discussed. The timing and procedures for planned and unplanned breaking of randomization codes should be 
included.  Include a statement regarding when unblinding may occur and who may unblind. Provide the 
criteria for breaking the study blind or participant code.  Discuss the circumstances in which the blind would 
be broken for an individual or for all participants (e.g., for serious adverse evets (SAEs)). Indicate to whom 
the intentional and unintentional breaking of the blind should be reported. 
The study is unblinded. Participants (N=20) will be randomized into two groups using a randomization table 
to receive either  (1) semaglutide plus standard lifestyle recommendation or (2) standard lifestyle 
recommendations alone.  
10.2.  Study Intervention Compliance 
Define how adherence to the protocol (e.g., administration of study intervention, use of device,) will be 
assessed, and verified (if applicable, e.g., plasma assays, electronic monitoring devices, daily diaries). 

 
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Participants will have four visits while on study medication to discuss whether they remain eligible and if 
there are any adverse events to report and to verify adherence to protocol. They will be asked to bring in 
their medication to study visits if randomized to the study drug arm to determine adherence.  
 
10.3.  Permitted Concomitant Therapy 
This section should be consistent with the medication restrictions in the inclusion/exclusion criteria 
previously listed.  Describe how allowed concomitant therapy might affect the outcome (e.g., drug-drug 
interaction, direct effects on the study endpoints). 
Use of medications known to affect glucose homeostasis besides metformin (metformin is allowed) is a part 
of exclusion criteria. Other medications will be allowed.  
10.4.  
 
Rescue Medicine 
List all medications, treatments, and/or procedures that may be provided during the study for 
“rescue therapy” and relevant instructions. 
☒ 
: N/A, no rescue medicine 
 
 
 
 
11.  Study Intervention Discontinuation  
11.1.  Discontinuation of Study Intervention 
Describe the criteria for discontinuing the study intervention (e.g., halting rules), including any monitoring test(s) and associated clinical decision point(s). Include 
reasons for temporary discontinuation of the study intervention (e.g., type and quantity of adverse events), clearly stating the length of time, if applicable, and 
describe the data to be collected at the time of study intervention discontinuation and approaches for restarting administration of or re-challenging with study 
intervention.   
Study medication will be discontinued in the event of a severe allergic reaction or development of an episode of pancreatitis.  
If minor GI (nausea, abdominal pain, vomiting, etc ) side effects occur, then the study medication titration will be modified based 
on symptoms and severity of these anticipated side effects.  
11.2.  Continued Follow-up Discontinuation of Study Intervention 
Describe efforts that will be made to continue follow-up of participants who discontinue the study intervention, but remain in the study for follow-up, especially for 
safety and efficacy study endpoints (if applicable).  Reasonable efforts must be made to undertake protocol-specified safety follow-up procedures to capture 
adverse events (AE), serious adverse events (SAE), and unanticipated problems involving risks to subjects or others (UPIRSOs). 
If participants discontinue study medication, then we will follow up with participants to determine resolution of symptoms and 
relationship with medication. 
 
 
12.  Statistical Considerations 
12.1. Statistical Hypotheses   
State the formal and testable null and alternative hypotheses for primary and key secondary endpoints, specifying the type of comparison (e.g., superiority, 
equivalence or non-inferiority, dose response) and time period for which each endpoint will be analyzed. 
We hypothesize that semaglutide will improve physical function (SPPB, handgrip strength, walking speed) and body 
composition (BMI, lean body mass to fat mass ratio) in those with prediabetes and well controlled diabetes. It is 
expected that the pleiotropic effects of GLP1 receptor agonists will also result in improvement of aging biomarkers 
including cellular senescence and inflammation in muscle and adipose tissue.   
12.2.  Sample Size Determination 
Include number of participants to recruit, screen, and enroll to have adequate power to test the key hypotheses for the study.  Provide all information needed to 
validate your calculations and judge the feasibility of enrolling and following the necessary number of participants. 
The effect of GLP1 receptor agonists on aging-related biomarkers and physical function in is not known.  For this pilot 
study, we will screen up to 100 potentially eligible participants to achieve a target of 20 completers. More candidates 
will be screened if attrition (est. 20%) requires it. The data generated through this study will guide sample size and 
power calculations for future studies. 

 
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12.3.  Populations for Analyses 
Clearly identify and describe the analysis datasets (e.g., which participants will be included in each). 
Population for analyses will be divided in the two arms (1) medication and lifestyle and (2) lifestyle alone 
12.4.  Statistical Analyses    
Include analysis of primary efficacy endpoints, secondary endpoints, safety analyses, and any planned interim analyses 
Experimental results will be expressed as means ± SE.  Comparisons of means between all the groups will 
be done by ANOVA for repeated measures.  Associations, within a group, between aging-related biomarkers 
vs. healthspan outcomes will be determined by Pearson’s correlation. For tests of correlation coefficients 
between groups, we will use the Fisher’s Z transformation.  We will also determine the relationship between 
aging-related biomarkers vs healthspan outcomes, by using multiple regression analysis.