HMB Plus Vitamin D to Preserve Muscle in Older Adults Starting Semaglutide

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.