Muscle Loss, Obesity, Older Adults, Sarcopenia, Type 2 Diabetes Mellitus (T2DM)
Conditions
Keywords
semaglutide, GLP-1 receptor agonist, beta-hydroxy-beta-methylbutyrate, HMB, calcium-HMB, vitamin D3, appendicular lean mass, metabolic adaptation, resting metabolic rate, skeletal muscle, older adults, D3-creatine, muscle protein synthesis, muscle protein breakdown
Brief summary
This randomized, double-blind, placebo-controlled trial will evaluate whether daily calcium beta-hydroxy-beta-methylbutyrate (calcium-HMB) plus vitamin D3 preserves muscle mass, physical function, and resting metabolism in adults aged 65 to 85 years with type 2 diabetes who are newly starting semaglutide as part of usual clinical care. Participants will receive calcium-HMB plus vitamin D3 or matching placebo for approximately 6 months. The primary outcome is change in appendicular lean mass measured by dual-energy X-ray absorptiometry from baseline to month 6. Secondary assessments include body composition, muscle strength, physical performance, gait, physical activity, resting metabolic rate, metabolic measures, and whole-body quantitative computed tomography. An optional mechanistic substudy of up to 36 participants will include D3-creatine dilution, nonradioactive stable isotope infusions, repeated blood sampling, a standardized meal, breath sampling, and vastus lateralis muscle biopsies at baseline and month 6.
Detailed description
Semaglutide treatment can produce substantial weight loss and improve glycemic control, but some weight loss may be accompanied by loss of lean tissue and skeletal muscle. Older adults with type 2 diabetes may be particularly vulnerable to loss of muscle mass, strength, mobility, and physical independence. Metabolic adaptation, defined as a reduction in resting metabolic rate beyond that expected from changes in body composition, may also occur during rapid weight loss. Calcium-HMB is a leucine metabolite with anabolic and anti-catabolic properties. This study will test whether supplementation with calcium-HMB plus vitamin D3 during the first 6 months of standard-of-care semaglutide therapy preserves appendicular lean mass and improves physical and metabolic outcomes compared with placebo. Semaglutide is prescribed and managed by each participant's treating clinician and is not assigned, supplied, or managed by the research study. Participants will be randomized 1:1, stratified by sex, to active study product or matching placebo. The active intervention provides 3 g calcium-HMB and 800 IU vitamin D3 daily. Main-study assessments occur at baseline, month 3, and month 6. Baseline and month 6 assessments include whole-body DXA, noncontrast whole-body quantitative CT, resting indirect calorimetry, blood and urine collection, strength and physical-function testing, gait assessment, questionnaires, and physical-activity assessment. Month 3 includes interval safety, adherence, medication, anthropometric, questionnaire, urine, and physical-function assessments as specified by the protocol. Up to 36 participants, targeted as 18 per randomized group, may join optional Aim 3. Aim 3 includes D3-creatine dosing with timed urine collection, an overnight Clinical Research Center stay, two peripheral intravenous catheters, nonradioactive L-\[ring-13C6\]phenylalanine and Nτ-\[2H3\]-3-methylhistidine infusions, serial blood and breath sampling, a standardized meal, and three vastus lateralis muscle-biopsy time points during each baseline and month 6 metabolic visit. Aim 3 evaluates contractile muscle mass and muscle protein synthesis and breakdown. Blood collected in the main study also supports peripheral blood mononuclear cell isolation and ancillary immune analyses.
Interventions
DIETARY_SUPPLEMENTCalcium-HMB Plus Vitamin D3
Each active capsule contains 750 mg calcium-HMB and 200 IU vitamin D3. Participants take two capsules twice daily, providing 3 g calcium-HMB and 800 IU vitamin D3 per day, for approximately 6 months.
OTHERMatching placebo
Participants take two matching placebo capsules twice daily for approximately 6 months. Placebo capsules are matched to active product in appearance, packaging, labeling, and dosing schedule. Insert the final placebo ingredients if the PRS administrator requests them.
Sponsors
Vanderbilt University Medical Center
American Diabetes Association
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
TSI/MTI or its designated independent code custodian maintains the treatment code. Active and placebo products are matched in appearance, packaging, labeling, and dosing schedule. Participants, the principal investigator, study coordinators, outcome assessors, and primary analysts remain blinded except for authorized personnel requiring access for product accountability or emergency safety unblinding.
Intervention model description
Participants are assigned 1:1, with stratification by sex, to calcium-HMB plus vitamin D3 or matching placebo for approximately 6 months while receiving semaglutide as standard clinical care.
Eligibility
Sex/Gender
ALL
Age
65 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Age 65 to 85 years, inclusive. * Type 2 diabetes mellitus, defined by HbA1c at or above 6.5% or current use of antihyperglycemic medication. * Body mass index at or above 27 kg/m2. * Newly initiating semaglutide as standard clinical care under the direction of a treating clinician. * Able to walk 400 meters without assistance; use of a cane is permitted. * Able to understand and provide legally effective informed consent. * English speaking for the initial study because the consent documents, questionnaires, study-product instructions, safety instructions, and procedure-specific materials are available only in English.
Exclusion criteria
* Estimated glomerular filtration rate below 45 mL/min/1.73 m2. * Use of HMB, creatine, or high-dose whey protein supplements within the previous 3 months. * Weight change greater than 5% during the previous 3 months. * Recent fracture within the previous 6 months. * Neuromuscular disease, including Parkinson disease, or another condition that would interfere with study outcomes or safe participation. * Chronic corticosteroid use. * Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. * History of pancreatitis. * Smoking more than 7 cigarettes per day. * Previous malabsorptive or restrictive intestinal surgery or a malabsorptive syndrome. * Pregnancy or breastfeeding. * Recent history of neoplasia within the previous 5 years, as defined by the protocol. * Other active inflammatory conditions or neuromuscular disorders that could interfere with study outcomes or safety. * Serum 25-hydroxyvitamin D below 15 ng/mL. * Any medical, functional, laboratory, medication-related, or safety condition that the investigator determines makes study participation unsafe or prevents completion of essential procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Appendicular Lean Mass | Baseline to month 6 | Appendicular lean mass will be measured by whole-body dual-energy X-ray absorptiometry. The outcome is the month-6 value minus the baseline value, reported in kilograms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Physical Activity | Protocol-defined monitoring periods at baseline or month 3 and month 6 | Physical activity measured by accelerometer or wearable activity monitor. Enter each prespecified analytic variable, such as steps/day or minutes/day of moderate-to-vigorous activity, as a separate outcome |
| Change in Whole-Body CT-Derived Muscle Volume and Composition | Baseline to month 6 | Noncontrast whole-body quantitative CT will measure muscle volume and composition. Enter each prespecified CT metric and units as a separate outcome. |
| Change in Total Body Creatine Pool Size | Baseline to month 6 | Among optional Aim 3 participants, D3-creatine dilution will estimate total body creatine pool size and derived contractile muscle mass. Enter the final units used by the analytic laboratory. |
| Change in Myofibrillar Protein Synthesis | Baseline and month 6 Aim 3 metabolic visits | Description Among optional Aim 3 participants, myofibrillar fractional synthesis rate will be derived from L-\[ring-13C6\]phenylalanine tracer enrichment and muscle-biopsy measurements. Enter the final expression, expected to be percent per hour. |
| Change in Muscle Protein Breakdown | Baseline and month 6 Aim 3 metabolic visits | Among optional Aim 3 participants, muscle protein breakdown will be estimated using Nτ-\[2H3\]-3-methylhistidine tracer kinetics. Enter the final kinetic measure and units. |
| Change in Net Muscle Protein Balance | Baseline and month 6 Aim 3 metabolic visits | Among optional Aim 3 participants, net protein balance will be derived from protocol-specified synthesis and breakdown measurements. Enter the final calculation and units. |
| Change in Muscle Fiber Size and Type | Baseline to month 6 | Among optional Aim 3 participants, vastus lateralis biopsy specimens will be analyzed for muscle-fiber cross-sectional area and fiber-type distribution. Enter cross-sectional area and fiber-type outcomes separately with units. |
| Study-Product Adherence | Through month 6 | Adherence assessed by returned-product count, participant report, and protocol-specified HMB measurements. Report the prespecified primary adherence metric, such as percentage of expected doses taken. |
| Incidence of Adverse Events | From first study-product dose through completion of month-6 follow-up or resolution/stabilization of ongoing events | Number and percentage of participants experiencing adverse events and serious adverse events, summarized by treatment group, severity, seriousness, expectedness, and relationship. |
| Title Change in Body Weight | Baseline to month 6 | Body weight measured using a calibrated scale; change calculated as month 6 minus baseline, in kilograms. |
| Change in Total Fat Mass | Baseline to month 6 | Total fat mass measured by whole-body DXA; change calculated as month 6 minus baseline, in kilograms. |
| Title Change in Visceral Adipose Tissue | Baseline to month 6 | Visceral adipose tissue measured using the protocol-specified DXA or CT-derived measure. Enter the final metric and units used by the imaging analysis plan. |
| Change in Bone Mineral Density | Baseline to month 6 | Bone mineral density measured by DXA and/or quantitative CT at protocol-specified skeletal sites. Enter the final site-specific metric and units. |
| Change in Trabecular Bone Score | Baseline to month 6 | Trabecular bone score derived from DXA; change calculated as month 6 minus baseline. |
| Change in Glycated Hemoglobin | Time Frame Baseline to month 6 | HbA1c measured from blood samples; change calculated as month 6 minus baseline, in percent. |
| Change in Fasting Plasma Glucose | Baseline to month 6 | Fasting plasma glucose measured from blood samples; change calculated as month 6 minus baseline, in mg/dL. |
| Change in Resting Metabolic Rate | Baseline to month 6 | Resting metabolic rate measured by indirect calorimetry; change calculated as month 6 minus baseline, in kcal/day. |
| Change in Handgrip Strength | Baseline, month 3, and month 6 | Maximum handgrip strength measured by dynamometry; change from baseline. Enter the final hand and aggregation rule, such as maximum of trials, and units in kilograms or newtons. |
| Title Change in Lower-Extremity Strength or Torque | Baseline to month 6 | Lower-extremity strength or torque measured using Biodex or other protocol-approved equipment. Enter the final movement, velocity, summary metric, and units. |
| Title Change in Short Physical Performance Battery Score | Baseline, month 3, and month 6 | Short Physical Performance Battery total score, range 0 to 12, with higher scores indicating better lower-extremity physical performance. |
| Change in Gait Measures | Baseline, month 3, and month 6 | Gait assessed using wearable inertial sensors. Enter each prespecified gait metric as a separate outcome if inferential testing is planned, including the metric name and units. |
| Change in Six-Minute Walk Distance | Baseline, month 3, and month 6 | Distance walked during the six-minute walk test, in meters. |
Countries
United States
Contacts
CONTACTRobb Flynn, PhD
PRINCIPAL_INVESTIGATORRobb Flynn, PhD
Vanderbilt University Medical Center
Outcome results
None listed