Efficacy of Semaglutide in Glycemic Control, Weight Loss, and Improving Lipid Profile- the Role of Baseline Vitamin D Levels
Conditions: Metabolic Disease
Sponsor: Hillel Yaffe Medical Center

December 18, 2023 
 
Official Title of the study: 
 
Efficacy of Semaglutide in glycemic control, weight loss, and improving lipid 
profiles- the role of baseline vitamin D 
 
 
Study number: 0034-23-LEU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Introduction 
Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, was initially approved 
for the treatment of type 2 diabetes mellitus (T2DM) (1) due to its superior glucose-
lowering efficacy compared to oral antidiabetic agents, with a favorable safety profile 
regarding hypoglycemia risk (2-5). 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 (6). 
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 (7,8). 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 (9,10). 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 (7,8,11,12,13). 
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 (14). 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 (15). 
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 (16). Specifically, three months of vitamin D 
supplementation in obese women significantly augmented weight loss and improved 
metabolic parameters (17). 
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. 
 
Materials and Methods 
Study Population 
The investigators conducted a population-based study among adult members of Leumit 
Health Services (LHS), a large Israeli nationwide health maintenance organization 
(HMO), which provides health services to nearly 730,000 members. LHS has a 
comprehensive computerized database, continuously updated regarding the 
demographics, medical diagnoses and clinic visits, hospitalizations, and laboratory tests 
of insured members. 
The socio-economic status (SES) was defined according to the home address. The Israeli 
Central Bureau of Statistics categorizes all cities and settlements into 20 SES levels. 
Classification at levels 1–9 is considered low–medium SES, while levels 10–20 represent 
the medium–high SES. Ethnicity was also defined according to the home address of the 
HMO members, and categorized into three groups: general population, ultra-orthodox 
Jews, and Arabs . 
All LHS members have identical health insurance coverage and access to healthcare 
services. Relevant diagnoses are entered or updated according to the International 
Classification of Diseases 9th revision (ICD-9). The validity of chronic diagnoses in the 
registry has been previously established (Hamood et al., 2016; Rennert and Peterburg, 
2001). The study population included all LHS members aged 18 or older, with T2DM 
who were prescribed semaglutide since 2019 and fulfilled the following criteria: 
- 
Consumed semaglutide regularly for at leastsix months. 
- 
Have at least one plasma 25(OH)D level prior to semaglutide initiation. 

Baseline medical conditions including obesity, T2DM, hypertension, asthma, chronic 
obstructive pulmonary disease, ischemic heart disease, the presence of malignancy, and 
chronic kidney disease, were recorded. Obesity was defined as BMI > 30 kg/m2. 
According to LHS guidelines, vitamin D tests were collected after overnight fasting and 
transported on ice to the central laboratory for processing within 4 h of collection using 
the DiaSorin Chemiluminescence assay (18-21). For categorization of vitamin D levels, 
the investigators calculated the median value and divided the patients into three 
categories: 0-15 ng/ml, 15-25 mg/dl, and > 25 ng/ml. The study protocol was approved 
by the LHS Institutional Review Board (0034-23-LEU). 
3 .Statistical Analysis 
Descriptive statistics, including mean, standard deviation, median, and percentiles, 
were reported for all study parameters. Group differences were assessed using the t-
test for continuous variables and Fisher’s exact test for categorical variables. To 
evaluate the impact of vitamin D level categories on changes in HbA1c, BMI, and LDL 
cholesterol following GLP-1 treatment, linear regression models were fitted with 
vitamin D category as the main explanatory variable. Models were adjusted for age, 
gender, and the last recorded values of HbA1c, BMI, and LDL cholesterol before 
treatment initiation. 
Variables included in the multivariate analysis were selected based on their statistical 
significance in univariate analyses. A p-value < 0.05 was considered statistically 
significant. All statistical analyses were conducted using R version 4.4.0 . 
Only inpatients aged ≥18 years with a definite diagnosis of T2DM (recorded in the 
diabetes mellitus registry) were included in the study. T2DM was defined according to 
the American Diabetes Association classification (26). The exclusion criteria were as 
follows: (1) with missing serum 25-hydroxyvitamin D (25[OH]D) data; (2) pregnant or 
lactating females  
Data Collection 
General demographic information, including age, sex, smoking status, duration of 
diabetes, and family history of diabetes were collected. Body mass index (BMI) was 
calculated as weight divided by height squared . 
The laboratory measurements collected in this study included: serum 25(OH)D, 
albumin, triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), 
low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose, glycated 
hemoglobin (HbA1c), and serum creatinine. Notably, serum 25(OH)D concentration was 
determined by chemiluminescence assay (Siemens ADVIA Centaur XP, Germany) and 
the detection limit was <10.5 nmol/L. Estimated glomerular filtration rate (eGFR) was 

calculated using the abbreviated Modification of Diet in Renal Disease (MDRD) 
equation: 186× (serum creatinine) −1.154×(age)−0.203× (0.742 if female). 
In addition, diabetic complications (i.e., DR, DKD, DFU, diabetic peripheral neuropathy 
[DPN]) and related comorbidities (i.e., hypertension, dyslipidemia, coronary heart 
disease, cerebrovascular disease) were also evaluated.  
Participants were divided into three groups by vitamin D level (i.e., 0.1-14.9 ng/ml; 15–
24.9 ng/ml; And 25-100 ng/ml). Participants were also categorized into four groups based 
on the levels of BMI: underweight (<18.5 kg/m2), normal weight (18.5–24.9 kg/m2), 
overweight (25.0–29.9 kg/m2), and obese (≥30.0 kg/m2). Glycemic control was classified 
based on HbA1c levels.