Dose Optimization of Sitagliptin and Duloxetine in Diabetic Cirrhosis

Evaluation of Model-Guided Dose Adjustment of Sitagliptin and Duloxetine Across Child-Pugh Classes Compared to Non-Cirrhotic Diabetic Patients

This study was a prospective, interventional, two-part pilot clinical study conducted over 3 months on cirrhotic patients with diabetes mellitus and diabetic neuropathy, evaluating the real-world applicability of selected PBPK-guided dosing regimens. Patients were stratified according to Child-Pugh class (CP-A , CP-B, and CP-C) in case of sitagliptin and CP-A in duloxetine at doses corresponding to the closest commercially available strengths to Simcyp®-optimized doses.

Clinical evaluation included glycemic parameters(HbA1C,fasting blood glucose,2-hr post prandial glucose level) and pain reduction. Routine laboratory investigations were conducted to assess efficacy and safety and included liver function tests (serum albumin, total bilirubin, alanine aminotransferase [ALT],and aspartate aminotransferase [AST]), kidney function tests (serum creatinine and blood urea nitrogen [BUN]),and CBC.

Study Overview

• Status: Completed
• Conditions: Liver Cirrhosis With Diabetes
• Intervention / Treatment: Drug: Sitagliptin (JANUVIA®); Drug: Sitagliptin (JANUVIA®); Drug: Sitagliptin (JANUVIA®); Drug: Sitagliptin (Januvia); Drug: Duloxetine (60 mg) once daily; Drug: Duloxetine 30mg once daily

Detailed Description

This study was a prospective, interventional, two-part pilot clinical study conducted over 3 months on Egyptian cirrhotic patients with diabetes mellitus and diabetic neuropathy. Adult patients aged >18 years with confirmed liver cirrhosis, concomitant diabetes mellitus and diabetic neuropathy were eligible for inclusion. Patients were experienced acute episodes of disease associated with deterioration of hepatic function within 2 months prior to screening, and received concomitant medications known to strongly interact with the study drugs were excluded. In part 1: Sitagliptin dosing was determined based on Simcyp -generated predictions and clinical assessment. 100mg,100 mg, 50 mg, and 50 mg received by control, CP-A, CP-B, and CP-C cirrhosis patients, respectively, orally once daily. In part 2: Duloxetine dosing was determined based on Simcyp-generated predictions and clinical assessment. 60 mg ,30 mg received by control, and CP-A cirrhotic patients orally once daily, respectively. Clinical evaluation included glycemic parameters(HbA1C,fasting blood glucose,2-hr post prandial glucose level) and pain reduction. Routine laboratory investigations were conducted to assess efficacy and safety and included liver function tests (serum albumin, total bilirubin, alanine aminotransferase [ALT],and aspartate aminotransferase [AST]), kidney function tests (serum creatinine and blood urea nitrogen [BUN]),and CBC.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 4

Contacts and Locations

Study Locations

• Egypt
  • Kafrelsheikh
    • Cairo, Kafrelsheikh, Egypt, 33511
      • Kafr El-Sheikh University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Clinical diagnosis of cirrhosis.
• Diagnosed with diabetes mellitus.
• Presence of diabetic neuropathy.
• Age of patients > 18 years.

Exclusion Criteria:

• Patients with kidney disorder or dialysis
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control -Standard Dose Sitagliptin; Sitagliptin (100 mg)	Drug: Sitagliptin (JANUVIA®); Diabetic patients with Child-Pugh class C hepatic cirrhosis receiving 50 mg model -informed adjusted dose of sitagliptin. Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar.; Drug: Sitagliptin (JANUVIA®); Diabetic patients with Child-Pugh class B hepatic cirrhosis receiving 50 mg model -informed adjusted dose of sitagliptin. Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar.; Drug: Sitagliptin (JANUVIA®); Diabetic patients without hepatic cirrhosis receiving the standard recommended dose of 100 mg sitagliptin. Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar.
Experimental: Child-Pugh A Sitagliptin; CP-A: Sitagliptin 100 mg	Drug: Sitagliptin (Januvia); Diabetic patients with Child-Pugh class A hepatic cirrhosis receiving 100 mg model -informed adjusted dose of sitagliptin. Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar.
Experimental: Child-Pugh B Sitagliptin; CP-B: Sitagliptin 50 mg	Drug: Sitagliptin (JANUVIA®); Diabetic patients with Child-Pugh class C hepatic cirrhosis receiving 50 mg model -informed adjusted dose of sitagliptin. Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar.; Drug: Sitagliptin (JANUVIA®); Diabetic patients with Child-Pugh class B hepatic cirrhosis receiving 50 mg model -informed adjusted dose of sitagliptin. Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar.; Drug: Sitagliptin (JANUVIA®); Diabetic patients without hepatic cirrhosis receiving the standard recommended dose of 100 mg sitagliptin. Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar.
Experimental: Child-Pugh C Sitagliptin; CP-C :Sitagliptin 50 mg	Drug: Sitagliptin (JANUVIA®); Diabetic patients with Child-Pugh class C hepatic cirrhosis receiving 50 mg model -informed adjusted dose of sitagliptin. Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar.; Drug: Sitagliptin (JANUVIA®); Diabetic patients with Child-Pugh class B hepatic cirrhosis receiving 50 mg model -informed adjusted dose of sitagliptin. Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar.; Drug: Sitagliptin (JANUVIA®); Diabetic patients without hepatic cirrhosis receiving the standard recommended dose of 100 mg sitagliptin. Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar.
Active Comparator: Control -Standard Dose Duloxetine; Duloxetine (60 mg)	Drug: Duloxetine (60 mg) once daily; Diabetic patients without hepatic cirrhosis receiving the standard recommended dose of 60 mg Duloxetine. Duloxetine is a dual serotonin and norepinephrine reuptake inhibitor, It has since received approval for a variety of indications including the treatment of neuropathic pain.
Experimental: Child-Pugh A; CP-A: 30 mg Duloxetine	Drug: Duloxetine 30mg once daily; Diabetic patients with peripheral diabetic neuropathy and Child-Pugh class A hepatic cirrhosis receiving 30 mg model -informed adjusted dose of duloxetine. Duloxetine is a dual serotonin and norepinephrine reuptake inhibitor, It has since received approval for a variety of indications including the treatment of neuropathic pain.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Management of diabetes mellitus and diabetic neuropathy	by measuring glycemic parameters ( fasting blood glucose level,2-hr postprandial glucose level) (mg/dL).	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Effects Monitoring	Adverse effects including headache, dry mouth, nasopharyngitis, dizziness, nausea, and diarrhea will be recorded	3 months

Collaborators and Investigators

• Sponsor: Kafrelsheikh University
• Investigators: Study Director: Noha Mahmoud ELkhodary, PhD, Clinical Pharmacy Department, Faculty of Pharmacy, Kafrelsheikh University; Principal Investigator: Aya Emad Fouda, MSc in Clinical Pharmacy, Clinical Pharmacy Department, Faculty of Pharmacy, Kafrelsheikh University

Publications and helpful links

General Publications

• Asakawa M, Mitsui H, Akihisa M, et al. Efficacy and safety of sitagliptin for the treatment of diabetes mellitus complicated by chronic liver injury. Springerplus. 2015;4(1):346.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2024
• Primary Completion (Actual): July 1, 2025
• Study Completion (Actual): October 1, 2025

Study Registration Dates

• First Submitted: February 17, 2026
• First Submitted That Met QC Criteria: February 23, 2026
• First Posted (Actual): February 27, 2026

Study Record Updates

• Last Update Posted (Actual): February 27, 2026
• Last Update Submitted That Met QC Criteria: February 23, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Diabetes; Liver Cirrhosis; Duloxetine; Sitagliptin
• Additional Relevant MeSH Terms: Endocrine System Diseases; Pathologic Processes; Metabolic Diseases; Digestive System Diseases; Glucose Metabolism Disorders; Liver Diseases; Fibrosis; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Diabetes Mellitus; Liver Cirrhosis; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Pyrazines; Thiophenes; Triazoles; Duloxetine Hydrochloride; Sitagliptin Phosphate
• Other Study ID Numbers: KFSIRB200-211/1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No