An observational study in Metabolic Disease, sponsored by Hillel Yaffe Medical Center. Completed at 1 site in Israel. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2025-07-09.
Sponsored by Hillel Yaffe Medical Center · Observational
Objective: Semaglutide, a glucagon-like peptide-1 receptor agonist, is an established therapy for type 2 diabetes (T2D), offering robust glycemic control and weight reduction. Vitamin D has been implicated in metabolic regulation, yet its influence on semaglutide-induced outcomes remains unclear.
Research Design and Methods: the investigators conducted a cross-sectional analysis of 5,300 adults with T2D, enrolled in Leumit Health Services, who initiated semaglutide therapy between February 1, 2019, and December 31, 2022. All patients had documented serum 25-hydroxyvitamin D [25(OH)D] levels prior to treatment initiation. Metabolic outcomes- including glycemic control (HbA1c), body mass index (BMI), and lipid profile- were assessed at 12 months. Associations between baseline 25(OH)D levels and metabolic changes were evaluated using multivariable regression models, adjusted for demographic and clinical covariates.
Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, was initially approved for the treatment of type 2 diabetes mellitus (T2DM) due to its superior glucose-lowering efficacy compared to oral antidiabetic agents, with a favorable safety profile regarding hypoglycemia risk. In June 2021, the U.S. Food and Drug Administration (FDA) approved higher doses of semaglutide for long-term weight management, marking the first pharmacologic advancement in obesity treatment since 2014 (FDA, 2021).
Semaglutide exerts its effects through multiple mechanisms, including delayed gastric emptying, appetite suppression, enhanced glucose-stimulated insulin secretion from pancreatic β-cells, and reduced glucagon secretion. In individuals with overweight and obese, semaglutide induces substantial and sustained weight reduction, with an average decrease of approximately 14.9% of baseline body weight.
The pathophysiology of T2DM varies across racial and ethnic groups. For example, T2DM in Caucasian populations is primarily characterized by obesity and insulin resistance, whereas in East Asians, including the Japanese, early-onset β-cell dysfunction and insulin deficiency predominate. Consequently, the glycemic response to semaglutide is not uniform across populations. Notably, semaglutide predominantly enhances first-phase insulin secretion, an effect that may be particularly beneficial in individuals with insulin deficiency. Several blinded, controlled trials have demonstrated superior glycemic control with semaglutide in Asian populations, reinforcing the significance of insulin resistance versus insulin deficiency in determining its net metabolic effects.
While genetic and ethnic determinants of semaglutide response are largely non-modifiable, certain adjunctive interventions may optimize its therapeutic effects. Among these, vitamin D has emerged as a potential modulator of molecular pathways involved in metabolic regulation. In regard to diabetes control, vitamin D is a key immunomodulatory factor, and preclinical studies have demonstrated its protective effects against β-cell dysfunction in diabetes. In murine models, early vitamin D administration mitigated the inflammatory insults responsible for β-cell destruction, thereby preventing autoimmune diabetes onset. These findings are supported by human studies in prediabetic and newly diagnosed T2DM individuals, in whom long-term vitamin D supplementation (six months) significantly improved peripheral insulin sensitivity and β-cell function, potentially delaying diabetes progression.
Obesity has long been linked to vitamin D deficiency. While the role of vitamin D in weight loss remains debated, a recent meta-analysis highlighted its potential clinical efficacy in optimizing weight reduction. Specifically, three months of vitamin D supplementation in obese women significantly augmented weight loss and improved metabolic parameters.
Given the high prevalence of vitamin D deficiency, particularly among individuals with obesity and T2DM, supplementation may offer metabolic benefits.
To date, the relationship between vitamin D status and the metabolic effects of semaglutide has not been well characterized. In this retrospective cross-sectional study, The investigators aimed to investigate the association between baseline vitamin D levels and semaglutide-induced glycemic control and weight loss in an Israeli T2DM population.
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This study's enrollment of 5,300 is above the median of 176 across 300 observational studies indexed under Metabolic Diseases.
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diabetic patients on semaglutide treatment and with available baseline vitamin D levels
Exclusion Criteria:
we tested the relation between baseline vitamin D levels and metabolic amplification of semaglutide metabolic effects
Drug: semaglutide
testing the effect of baseline vitamin D on metabolic effects of semaglutide
relative weight loss measured by BMI
testing semaglutide induced weight loss as a function of baseline vitamin D levels
Time frame: 12 months from semaglutide initiation
glycemic control using Hgb1C
testing semaglutide induced glycemic control as a function of baseline vitamin D levels
Time frame: 12 months from semaglutide initiation
lipid control using LDL and TG
testing semaglutide induced lipid control as a function of baseline vitamin D levels
Time frame: 12 months from semaglutide initiation
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Hillel Yaffe Medical Center