Impact of Supplementation in Improving Metabolic Health Outcomes (ISMOS) Study

Vitamins are essential micronutrients that regulate key metabolic pathways involved in energy metabolism, immune function, and neuronal integrity. Adequate vitamin status is critical during midlife (ages 40-60 years), a period marked by hormonal fluctuations and physiological transitions from pre- to peri- and post-menopause. These transitions profoundly affect women's metabolic, musculoskeletal, and mental health trajectories, often predisposing them to metabolic syndrome, insulin resistance, central adiposity, dyslipidaemia, and hypertension. Concurrently, declines in muscle strength, bone mineral density, and mood are frequently observed, heightening the risk of sarcopenia, osteopenia, and depressive symptoms in later life.

Emerging evidence indicates that suboptimal dietary intake or deficiency of vitamins contributes to these adverse outcomes. Vitamin D insufficiency, highly prevalent in Asia, has been linked to metabolic syndrome, insulin resistance, and mood disturbances in postmenopausal women. Similarly, low levels of B-vitamins, vitamin C, vitamin E, and folate have been associated with impaired glucose regulation, higher inflammatory burden, and poorer muscle function. While several studies in Western populations have reported positive correlations between these micronutrients and musculoskeletal or psychological health, corresponding data in Asian women remain limited despite their higher susceptibility to central obesity and metabolic dysfunction at lower BMI thresholds compared to Western populations.

Findings from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) cohort provide novel insights into the role of vitamin status in Asian women. Plasma concentrations of vitamins B6, B9, B12, and D were associated with favorable metabolic profiles, including lower metabolic syndrome severity, improved insulin sensitivity, reduced HbA1c, and higher HDL-cholesterol. Furthermore, higher thiamine monophosphate (vitamin B1) levels correlated with greater handgrip strength, while elevated folate was inversely related to depressive symptoms and perceived stress. Importantly, these associations were more pronounced among women with a BMI ≥ 23 kg/m², emphasizing the compounded metabolic vulnerability of overweight Asian phenotypes. Collectively, these findings highlight the potential of multivitamin/multimineral (MVM) supplementation as a preventive strategy to mitigate age-related metabolic, musculoskeletal, and psychological decline during midlife.

Building on these observational findings, this randomized, double-blind, placebo-controlled trial aims to determine whether 12 months of daily MVM supplementation can improve metabolic and overall health in relatively healthy middle-aged Asian women. The trial will recruit women aged 40-60 years, a critical window for metabolic and hormonal adaptation, who are at increased risk of vitamin insufficiency, insulin resistance, and low-grade chronic inflammation. Participants will be randomized to receive either a daily MVM supplement or placebo for one year, with comprehensive assessments at baseline, 6 months, and 12 months.

The investigators hypothesize that daily MVM supplementation for 12 months will reduce MetaboAge, a composite biomarker of metabolic aging and enhance metabolic, musculoskeletal, and mental health outcomes in midlife women compared with placebo.

Primary Objective is to examine the effect of 12-month MVM supplementation on MetaboAge among relatively healthy middle-aged Asian women.

Secondary Objectives are to;

1. Evaluate the impact of MVM supplementation versus placebo on metabolic markers (fasting glucose, insulin resistance indices, HbA1c, lipid profile, blood pressure); mental health outcomes (depressive symptoms, perceived stress, quality of life); musculoskeletal health (lean mass, fat mass distribution, bone mineral density, and handgrip strength) and circulating micronutrient and inflammatory marker levels. 2. To explore how menopausal status, baseline vitamin status, and body composition modify the observed intervention effects.

Scientific and Public Health Significance This trial is among the first in Asia to integrate multivitamin supplementation with multidimensional health outcomes; metabolic, musculoskeletal, and psychological, within the context of midlife transition. Asians are metabolically predisposed to visceral adiposity and insulin resistance even at lower BMI, placing midlife women at particularly high risk for metabolic syndrome and its sequelae. By addressing micronutrient insufficiency through a low-cost, scalable nutritional approach, this study aims to establish evidence for early preventive strategies that can extend functional health span and reduce the burden of chronic diseases among Asian women.

If proven effective, findings from this trial will support the incorporation of multivitamin supplementation or vitamin status screening into midlife health programs and community-based preventive frameworks, aligning with regional and national goals for promoting healthy longevity and metabolic resilience across the lifespan.

• Anthropometric Measurements [Time frame: Week 0 (Baseline), Week 26 (Midpoint), Week 52 (Endpoint)]
• Blood Pressure Measurements [Time frame: Week 0 (Baseline), Week 26 (Midpoint), Week 52 (Endpoint)]
• Body Composition Assessment [Time frame: Week 0 (Baseline), Week 26 (Midpoint), Week 52 (Endpoint)]
• 36-Item Short Form Survey (SF-36) [Time frame: Week 0 (Baseline), Week 26 (Midpoint), Week 52 (Endpoint)]
• Menopausal Status [Time frame: Week 0 (Baseline), Week 26 (Midpoint), Week 52 (Endpoint)]
• Anxiety [Time frame: Week 0 (Baseline), Week 26 (Midpoint), Week 52 (Endpoint)]
• Depression [Time frame: Week 0 (Baseline), Week 26 (Midpoint), Week 52 (Endpoint)]
• Stress [Time frame: Week 0 (Baseline), Week 26 (Midpoint), Week 52 (Endpoint)]
• Sleep Quality [Time frame: Week 0 (Baseline), Week 26 (Midpoint), Week 52 (Endpoint)]
• Physical Activity [Time frame: Week 0 (Baseline), Week 26 (Midpoint), Week 52 (Endpoint)]
• Dietary Intake [Time frame: Week 0 (Baseline), Week 52 (Endpoint)]
• Musculoskeletal assessment by peripheral quantitative CT (pQCT) [Time frame: From enrollment to the end of 12 months multi-vitamin supplementation.]