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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
90
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.
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.
Vanderbilt University Medical Center
Nashville, Tennessee, United States
Change in Appendicular Lean Mass
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.
Time frame: Baseline to month 6
Title Change in Body Weight
Body weight measured using a calibrated scale; change calculated as month 6 minus baseline, in kilograms.
Time frame: Baseline to month 6
Change in Total Fat Mass
Total fat mass measured by whole-body DXA; change calculated as month 6 minus baseline, in kilograms.
Time frame: Baseline to month 6
Title Change in Visceral Adipose Tissue
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.
Time frame: Baseline to month 6
Change in Bone Mineral Density
Bone mineral density measured by DXA and/or quantitative CT at protocol-specified skeletal sites. Enter the final site-specific metric and units.
Time frame: Baseline to month 6
Change in Trabecular Bone Score
Trabecular bone score derived from DXA; change calculated as month 6 minus baseline.
Time frame: Baseline to month 6
Change in Glycated Hemoglobin
HbA1c measured from blood samples; change calculated as month 6 minus baseline, in percent.
Time frame: Time Frame Baseline to month 6
Change in Fasting Plasma Glucose
Fasting plasma glucose measured from blood samples; change calculated as month 6 minus baseline, in mg/dL.
Time frame: Baseline to month 6
Change in Resting Metabolic Rate
Resting metabolic rate measured by indirect calorimetry; change calculated as month 6 minus baseline, in kcal/day.
Time frame: Baseline to month 6
Change in Handgrip Strength
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.
Time frame: Baseline, month 3, and month 6
Title Change in Lower-Extremity Strength or Torque
Lower-extremity strength or torque measured using Biodex or other protocol-approved equipment. Enter the final movement, velocity, summary metric, and units.
Time frame: Baseline to month 6
Title Change in Short Physical Performance Battery Score
Short Physical Performance Battery total score, range 0 to 12, with higher scores indicating better lower-extremity physical performance.
Time frame: Baseline, month 3, and month 6
Change in Six-Minute Walk Distance
Distance walked during the six-minute walk test, in meters.
Time frame: Baseline, month 3, and month 6
Change in Gait Measures
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.
Time frame: Baseline, month 3, and month 6
Change in Physical Activity
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
Time frame: Protocol-defined monitoring periods at baseline or month 3 and month 6
Change in Whole-Body CT-Derived Muscle Volume and Composition
Noncontrast whole-body quantitative CT will measure muscle volume and composition. Enter each prespecified CT metric and units as a separate outcome.
Time frame: Baseline to month 6
Change in Total Body Creatine Pool Size
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.
Time frame: Baseline to month 6
Change in Myofibrillar Protein Synthesis
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.
Time frame: Baseline and month 6 Aim 3 metabolic visits
Change in Muscle Protein Breakdown
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.
Time frame: Baseline and month 6 Aim 3 metabolic visits
Change in Net Muscle Protein Balance
Among optional Aim 3 participants, net protein balance will be derived from protocol-specified synthesis and breakdown measurements. Enter the final calculation and units.
Time frame: Baseline and month 6 Aim 3 metabolic visits
Change in Muscle Fiber Size and Type
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.
Time frame: Baseline to month 6
Study-Product Adherence
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.
Time frame: Through month 6
Incidence of Adverse Events
Number and percentage of participants experiencing adverse events and serious adverse events, summarized by treatment group, severity, seriousness, expectedness, and relationship.
Time frame: From first study-product dose through completion of month-6 follow-up or resolution/stabilization of ongoing events
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.