The Role of CYP8B1 Polymorphisms in Modulating the Biochemical Pathways Affected by SGLT2 Inhibitors in T2DM and Obesity

NCT ID: NCT07120828

Last Updated: 2025-08-13

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 260 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-07-15
• Study Completion Date: 2026-05-01

Brief Summary

This study explores the long-term effects of dapagliflozin and empagliflozin on CYP8B1 gene expression and a range of metabolic, oxidative, and inflammatory biomarkers in obese patients with Type 2 Diabetes Mellitus (T2DM). Over a 6-month period, participants are assigned to three treatment arms: metformin (control), dapagliflozin, and empagliflozin. The study aims to determine how these medications influence bile acid metabolism, oxidative stress, leptin, GLP-1, IL-10, and IFN-γ, providing insight into the broader metabolic benefits of SGLT2 inhibitors

Detailed Description

Detailed Description Type 2 Diabetes Mellitus (T2DM) and obesity are major global health burdens with shared pathophysiological mechanisms, including insulin resistance, chronic inflammation, and altered lipid metabolism. SGLT2 inhibitors, such as empagliflozin and dapagliflozin, have emerged as effective glucose-lowering agents that also offer additional benefits, including weight reduction, cardiovascular protection, and renal function preservation.

Despite these advantages, the therapeutic response to SGLT2 inhibitors is variable, often influenced by individual genetic differences. A key genetic determinant is CYP8B1 (cytochrome P450 family 8 subfamily B member 1), a gene encoding sterol 12-alpha-hydroxylase, which regulates bile acid synthesis and lipid metabolism. Polymorphisms in CYP8B1 may impact drug metabolism and alter bile acid-mediated metabolic regulation, potentially affecting both the efficacy and safety profile of SGLT2 inhibitors.

This clinical trial aims to investigate the role of CYP8B1 genetic variations in modifying the clinical and biochemical responses to empagliflozin and dapagliflozin therapy among obese patients recently diagnosed with T2DM.

Participants will be randomized into three groups:

• Group 1: Empagliflozin 10 mg daily
• Group 2: Dapagliflozin 10 mg daily
• Group 3 (Control): Standard care (lifestyle modification and/or metformin)

The intervention period is 6 months, during which multiple parameters will be monitored:

1. Obesity-Related Metrics: Body weight, BMI, waist circumference, and body fat percentage.

2. Adipokines: adiponectin.

3. Lipid Profile: Total cholesterol, HDL, LDL, and triglycerides.

4. Glycemic Control: Fasting glucose, HbA1c, and C-peptide.

5. Oxidative Stress & Inflammation

6. Ketone Bodies & Free Fatty Acids: To assess shifts in metabolic fuel utilization.

7. Insulin Sensitivity: Using QUICKI and Adipo-IR indices.

8. CYP8B1 Genotyping & Expression: PCR-based genotyping and qPCR-based expression profiling to evaluate genetic and transcriptional regulation.

The study integrates molecular genetics (Sanger sequencing and RT-PCR) with clinical biochemistry and metabolic phenotyping to provide a holistic understanding of pharmacogenomic effects.

Expected outcomes include:

• Determining whether CYP8B1 polymorphisms influence the degree of weight loss, lipid and glucose metabolism, and adipokine modulation.
• Comparing the efficacy of empagliflozin vs dapagliflozin in the presence of different CYP8B1 genotypes.
• Proposing a framework for personalized T2DM and obesity management based on genetic screening.

Study Type Observational Clinical Trial

________________________________________ Study Duration Estimated Study Period: 6 months per participant

________________________________________ Eligibility Criteria

Inclusion Criteria:

• Aged ≥18 years
• Newly diagnosed T2DM (<6 months)
• BMI ≥30 kg/m²
• No prior antidiabetic treatment
• Consent to genetic testing

Exclusion Criteria:

• Type 1 diabetes or secondary diabetes

• Severe renal impairment (eGFR <45 mL/min/1.73 m²)

• Liver dysfunction or active liver disease
• Pregnancy or lactation
• Allergy to SGLT2 inhibitors

Primary Outcome Measures

• Change in body weight and BMI at 6 months
• Genotype-specific differences in weight loss Secondary Outcome Measures
• Changes in adipokine levels
• Lipid profile changes
• HbA1c and fasting blood glucose improvement
• Differences in insulin sensitivity indices
• Expression levels of CYP8B1 mRNA
• Relationship between genotype and biochemical/metabolic outcomes

Statistical Analysis Plan

• Paired t-tests and ANOVA for within-group and between-group comparisons
• Genotype-phenotype association using chi-square and regression models
• ROC curve analysis for predicting treatment response
• Cox regression for time-to-event data

Conditions

Type 2 Diabetes; Obese Diabetics; Obese Patients (BMI ≥ 30 kg/m²)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Empagliflozin Group

Participants in this group will receive empagliflozin 10 mg orally once daily for a duration of 6 months. The intervention aims to evaluate the effect of empagliflozin on weight reduction, metabolic parameters, and biochemical outcomes in newly diagnosed obese T2DM patients, with a focus on the influence of CYP8B1 polymorphisms on treatment response.

Group Type: EXPERIMENTAL

Empagliflozin (oral)

Intervention Type: DRUG

Empagliflozin 10 mg oral tablet administered once daily for 6 months.

Dapagliflozin Group

Participants in this group will receive dapagliflozin 10 mg orally once daily for a duration of 6 months. This arm is designed to assess the clinical and biochemical effects of dapagliflozin, particularly regarding changes in adipokines, lipid profile, insulin sensitivity, and the impact of CYP8B1 genetic variations.

Group Type: EXPERIMENTAL

Dapagliflozin (DAPA)

Intervention Type: DRUG

Dapagliflozin 10 mg oral tablet administered once daily for 6 months

Control Group

Participants in this group will receive standard care, including dietary and lifestyle modifications and metformin therapy if clinically indicated, according to ADA guidelines. This arm will serve as a comparator to evaluate the relative efficacy of SGLT2 inhibitors and the role of CYP8B1 polymorphisms in treatment outcomes.

Group Type: ACTIVE_COMPARATOR

Metfomin

Intervention Type: DRUG

metformin 500-1000 mg/day administered as part of standard care, based on clinical indication.

Interventions

Empagliflozin (oral)

Empagliflozin 10 mg oral tablet administered once daily for 6 months.

Intervention Type: DRUG

Dapagliflozin (DAPA)

Dapagliflozin 10 mg oral tablet administered once daily for 6 months

Intervention Type: DRUG

Metfomin

metformin 500-1000 mg/day administered as part of standard care, based on clinical indication.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Newly diagnosed with Type 2 Diabetes Mellitus (within the past 6 months).
• Body Mass Index (BMI) ≥ 30 kg/m² (classified as obese).
• No prior treatment with SGLT2 inhibitors or other antidiabetic medications.
• Willing and able to provide written informed consent.
• Able to comply with study visits, procedures, and sample collection.

Exclusion Criteria

• History or diagnosis of Type 1 diabetes mellitus or secondary forms of diabetes.
• Estimated Glomerular Filtration Rate (eGFR) < 45 mL/min/1.73 m² (moderate to severe renal impairment).
• Active liver disease or significant hepatic dysfunction.
• Current pregnancy or breastfeeding.
• Known hypersensitivity or contraindication to SGLT2 inhibitors.
• hypertension
• Any other condition that, in the opinion of the investigator, may interfere with the patient's ability to complete the study or pose additional risk.

• Minimum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Kurdistan Higher Council of Medical Specialties

OTHER

Sponsor Role: collaborator

Erbil Polytechnic University

OTHER

Sponsor Role: lead

Responsible Party

Ahmed Abdulrazzaq Bapir

PhD Student (under supervision of Prof. goran othman )

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Epu

Erbil, Kurdistan, Iraq

Site Status: RECRUITING

Countries

Iraq

Central Contacts

ahmed Bapir, pHD

Role: CONTACT

ahmed.mhm20@epu.edu.iq

009647507580043

Goran Othman, PHD

Role: CONTACT

goran.othman@epu.edu.iq

+9647504492631

Facility Contacts

burhan salih, pHD

Role: primary

burhan.salih@epu.edu.iq

009647504511374

Goran Othman, PHD

Role: backup

goran.othman@epu.edu.iq

References

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Reference Type: BACKGROUND

PMID: 32855502 (View on PubMed)

Malone JI, Hansen BC. Does obesity cause type 2 diabetes mellitus (T2DM)? Or is it the opposite? Pediatr Diabetes. 2019 Feb;20(1):5-9. doi: 10.1111/pedi.12787. Epub 2018 Nov 5.

Reference Type: BACKGROUND

PMID: 30311716 (View on PubMed)

Klen J, Dolzan V. Treatment Response to SGLT2 Inhibitors: From Clinical Characteristics to Genetic Variations. Int J Mol Sci. 2021 Sep 10;22(18):9800. doi: 10.3390/ijms22189800.

Reference Type: BACKGROUND

PMID: 34575958 (View on PubMed)

Hegyi P, Maleth J, Walters JR, Hofmann AF, Keely SJ. Guts and Gall: Bile Acids in Regulation of Intestinal Epithelial Function in Health and Disease. Physiol Rev. 2018 Oct 1;98(4):1983-2023. doi: 10.1152/physrev.00054.2017.

Reference Type: BACKGROUND

PMID: 30067158 (View on PubMed)

Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R. SGLT2 Inhibitors and the Diabetic Kidney. Diabetes Care. 2016 Aug;39 Suppl 2:S165-71. doi: 10.2337/dcS15-3006.

Reference Type: BACKGROUND

PMID: 27440829 (View on PubMed)

Chiang JYL, Ferrell JM. Bile Acids as Metabolic Regulators and Nutrient Sensors. Annu Rev Nutr. 2019 Aug 21;39:175-200. doi: 10.1146/annurev-nutr-082018-124344. Epub 2019 Apr 24.

Reference Type: BACKGROUND

PMID: 31018107 (View on PubMed)

Chiang JY. Bile acid metabolism and signaling. Compr Physiol. 2013 Jul;3(3):1191-212. doi: 10.1002/cphy.c120023.

Reference Type: BACKGROUND

PMID: 23897684 (View on PubMed)

Sarafidis PA, Tsapas A. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2016 Mar 17;374(11):1092. doi: 10.1056/NEJMc1600827. No abstract available.

Reference Type: BACKGROUND

PMID: 26981941 (View on PubMed)

Other Identifiers

No: 2348524, February 21, 2025

Identifier Type: OTHER

Identifier Source: secondary_id

EPU-CYP8B1-SGLT2-T2DM-2025-01

Identifier Type: -

Identifier Source: org_study_id