Effect of Vildagliptin Versus Dapagliflozin as Add on Therapy to Metformin on Cardiovascular Risk Factors

NCT ID: NCT07077525

Last Updated: 2025-07-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 196 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-06-01
• Study Completion Date: 2024-08-31

Brief Summary

The overarching hypothesis of this study is that vildagliptin (vilda) as add on therapy to metformin (met) in Egyptian type 2 diabetic obese patient will produce an equal, if not better, glycemic control and will reduce cardiovascular risk factors compared to dapagliflozin (dapa). However, there are interindividual differences in response to vildagliptin among Egyptian population which might be due to gender difference and/ or mutation in one or more of the DDP-4 gene, GLP1 receptor gene and KATP channel gene. These potential differences could favor pharmacogenomic selection of candidate patient.

Global aim of this study:

To compare effects of the DPP-4 inhibitor (vildagliptin) versus SGLT4 inhibiter (dapagliflozin) as add on therapy to metformin to control cardiovascular risk factors in Egyptian obese patients with type 2 diabetes and furthermore to investigate the possible interindividual variation to vildagliptins response.

Specific aims:

Evaluation of efficacy and safety of vildagliptin plus metformin versus dapagliflozin plus metformin in Egyptian obese patients with type 2 diabetes mellitus (T2DM).

Examining of interindividual difference in hypoglycemic response to the used treatment arms among participants of the study.

Assessment of response in relation to sex difference in Egyptian population. Investigation of vasculoprotective effects of different treatment with special emphasis on atherogenesis.

Investigating the efficacy of different treatment in controlling individual cardiovascular risk factors in preventing or slowing atherosclerotic cardiovascular diseases in people with diabetes Exploring of whether genetic variation in the DPP4 gene, GLP1 receptor and KATP channel affects incretin levels, insulin secretion, and glucose tolerance in participants of the study.

Examining the associations between genetic variations of DPP-4 gene in men and women involved in this study

Detailed Description

Diabetes mellitus (DM) is a metabolic disorder resulting from a defect in insulin secretion, insulin action, or both. It is characterized by chronic hyperglycemia and is associated with a heavy health burden and macrovascular complications.

Because of the associated microvascular and macrovascular disease, diabetes accounts for almost 14% of United States health care expenditures, at least one-half of which are related to complications such as myocardial infarction, stroke, end-stage renal disease, retinopathy, and foot ulcers .

Common conditions coexisting with T2DM (e.g., hypertension and dyslipidemia) are clear risk factors for atherosclerotic cardiovascular diseases (ASCVD). Numerous studies have shown the efficacy of controlling individual cardiovascular risk factors in preventing or slowing ASCVD in people with diabetes. Furthermore, there is evidence that measures of 10-year coronary heart disease (CHD) risk among U.S. adults with diabetes have improved significantly over the past decade and that ASCVD morbidity and mortality have decreased . Thus, cardiovascular risk factors should be systematically assessed at least annually in all patients with diabetes. These risk factors include duration of diabetes, obesity/overweight, hypertension, dyslipidemia, smoking, a family history of premature coronary disease, chronic kidney disease, and the presence of albuminuria. Modifiable abnormal risk factors should be treated as described in the guidelines .

The general goals of the treatment of DM are to provide glycemic control, avoid acute complications, prevent, or delay the appearance of chronic complications of the disease, and thus to improve the quality of life. The management of type 2 DM also includes managing conditions associated with T2DM, such as obesity, hypertension, dyslipidemia, and cardiovascular disease. Initial treatment of T2DM includes both pharmacologic and non-pharmacologic therapy (lifestyle modification) for all patients. First-line therapy depends on comorbidities, patient-centered treatment factors, and management needs and generally includes metformin and comprehensive lifestyle modification. Other medications such as sulfonylureas, Dipeptidyl-peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 receptor agonists (GLP1), sodiumglucose cotransporter 2 inhibitors (SGLT2), are usually added to metformin based on glycemic needs for individuals with T2DM with or at high risk for ASCVDs, heart failure, and/or chronic kidney disease.

Metformin is effective, safe, inexpensive, and may reduce risk of cardiovascular events and death. In addition, metformin is available in an immediate-release form for twice-daily dosing or as an extended-release form that can be given once daily. The latest challenge to the place of metformin has come from the recent demonstration of substantial cardiovascular outcomes benefits with GLP-1 receptor agonists and SGLT2 inhibitors.

Based in clear evince from large-scale randomized trials documenting important benefits of SGLT2 inhibitors to cardiovascular system and kidney, these agents are now recommended as the preferred second-line therapy in people who do not achieve sufficient glucose control on metformin alone, particularly for those with heart failure or chronic kidney disease . Furthermore, new guidelines from the European Society of Cardiology, developed in collaboration with the European Association for the Study of Diabetes, suggest that SGLT2 inhibitors be used in patients with T2DM who are at high or very high cardiovascular risk, irrespective of whether they are treatment-naïve or already receiving metformin .

Vildagliptin is a representative of Dipeptidyl Peptidase-4 (DPP-4) inhibitors, antihyperglycemic drugs, approved for use as monotherapy and combination therapy in type 2 diabetes mellitus. By inhibiting enzymatic decomposition, DPP-4 inhibitors increase the half-life of incretins such as GLP-1 and GIP and prolong their action. Interestingly, some studies present promising results suggesting the anti-sclerotic and vasculoprotective effects of vildagliptin. Vildagliptin can limit inflammation by suppression of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathway and proinflammatory agents such as TNF-α (tumor necrosis factor α)and IL-8 (Interleukin 8). This DPP-4 inhibitor also reduces macrophage foam cell formation, which plays a key role in atheromatous plaque formation and stability. The reasons for the good response and cardio-protective effects of DDP-4 inhibitor drugs are largely unknown. In addition, there is no detailed study on Egyptian obese patients with type 2 diabetes comparing vildagliptin to dapagliflozin concerning controlling cardiovascular risk factors and still all available guidelines prefer use of SGLT2 inhibitors over DDP-4 inhibitors for type 2 diabetic patients with ASCVD or risk, these might be due to lacking sufficient evidence about cardiovascular protective benefits of DDP-4 inhibitors.

Importantly, one relevant DPP-4 substrate, besides glucagon-like peptide-1 (GLP-1), is stromal cell derived factor 1α (SDF-1α). SDF-1∝ may act as a double edge sword with respect to the CV system . It is a potent chemokine stimulating stem cell mobilization from the bone marrow and, it plays a positive role in the angiogenic process following acute ischemic injury. On the other hand, SDF-1α has recently emerged as a robust biomarker of CV diseases and mortality whereas higher SDF-1α levels were associated with the presence of several CV risk factors and independently with heart failure and with 10-year all-cause mortality. Furthermore, in the chronic renal insufficiency cohort study, higher SDF-1∝ levels predicted increased 6-year mortality. Based on these contradictory data it was pertinent to explore the real effect of DDP-4 inhibitor in comparison to already stablished benefits of SGLT2 inhibitors.

Of particular interest, Inter-individual variance in the responsiveness to DPP-4 inhibitors was reported. A common variant, i.e., SNP rs6741949, in the DPP4 gene interacts with body adiposity and negatively affects glucose-stimulated GLP-1 levels, insulin secretion, and glucose tolerance. Another variants rs6923761 in GLP1 receptor gene and rs2285676 in KATP channel gene might also affect the effect to Vildagliptin. Whether this SNP underlies the potential inter-individual variance in responsiveness to DPP-4 inhibitors, at least in subjects with high body fat content, remains to be another hot topic to be addressed to tailor the therapeutic option with vildagliptin to the right patient.

Conditions

Type 2 Diabetes

Study Design

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

Study Groups

Dapagliflozin plus metformin

70 patients with T2DM: will be given metformin plus vildagliptin combination as per the standard of care in a physician's practice.

Group Type: ACTIVE_COMPARATOR

Dapagliflozin + Metformin

Intervention Type: COMBINATION_PRODUCT

70 patients with T2DM were treated once daily with Dapa plus Met combination (Dapavildactin plus®, Liptis Pharmaceuticals, Egypt) in a dose titrated from 5 mg Dapa and 1000 mg Met up to a maximum of 10 mg Dapa and 2000 mg metformin as per the standard of care in a physician's practice

Vildagliptin plus metformin

150 patients with T2DM: will be treated with metformin plus dapagliflozin combination as per the standard of care in a physician's practice.

Group Type: ACTIVE_COMPARATOR

Vildagliptin + Metformin

Intervention Type: COMBINATION_PRODUCT

126 patients with T2DM were treated with Vilda plus Met combination (Gliptus plus®, EVA pharma, Egypt ) in initial daily dose of 50 mg Vilda and 500 mg Met . The medication is titrated gradually up to Vilda 50 mg and metformin 1000 mg twice daily as per the standard of care in a physician's practice

Interventions

Dapagliflozin + Metformin

70 patients with T2DM were treated once daily with Dapa plus Met combination (Dapavildactin plus®, Liptis Pharmaceuticals, Egypt) in a dose titrated from 5 mg Dapa and 1000 mg Met up to a maximum of 10 mg Dapa and 2000 mg metformin as per the standard of care in a physician's practice

Intervention Type: COMBINATION_PRODUCT

Vildagliptin + Metformin

126 patients with T2DM were treated with Vilda plus Met combination (Gliptus plus®, EVA pharma, Egypt ) in initial daily dose of 50 mg Vilda and 500 mg Met . The medication is titrated gradually up to Vilda 50 mg and metformin 1000 mg twice daily as per the standard of care in a physician's practice

Intervention Type: COMBINATION_PRODUCT

Eligibility Criteria

Inclusion Criteria

• 40-60 years old
• HbA1c level between 6.5% - 10.0% (47.5-107.7 mmol/mol) before study initiation
• obese (BMI ≥30 kg/m2)
• no history of established CV disease
• ability to understand and to sign a written informed consent document
• outpatients
• TSH and liver function within normal limit and no evidence of kidney diseases.

Exclusion Criteria

• Diagnosis of T1DM
• subjects with any serious medical condition requiring hospitalization
• subjects with unstable cardiac disorders such as heart failure, refractory angina, uncontrolled arrhythmias, critical valvular heart disease and severe uncontrolled hypertension
• renal or liver failure
• females of childbearing potential or who are pregnant
• breast-feeding
• subjects using any drug that could interfere with the glucose level (e.g. systemic corticosteroids) and participation in any other clinical trial.

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

General Committee of Teaching Hospitals and Institutes, Egypt

OTHER_GOV

Sponsor Role: collaborator

Al-Azhar University

OTHER

Sponsor Role: lead

Responsible Party

Khalid Saber

Assistant Lecturer, Faculty of Pharmacy, Al-Azhar University

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Khalid S Hassanien, Assistant lecturer

Role: PRINCIPAL_INVESTIGATOR

al-azhar university, faculty of pharmacy, cairo.

Memy M Hegazy, professor

Role: STUDY_DIRECTOR

al-azhar university, faculty of pharmacy, cairo.

Atef A Bassyouni, Profepssor

Role: STUDY_CHAIR

Medical consultant . National Institute of Diabetes and Endocrinology

Raed S Ismail, Professor

Role: STUDY_CHAIR

al-azhar university, faculty of pharmacy, cairo.

Mohammed F Elshafie, Assistant professor

Role: STUDY_CHAIR

al-azhar university, faculty of pharmacy, cairo.

Locations

Al-Azhar university

Cairo, Cairo Governorate, Egypt

Countries

Egypt

Other Identifiers

IDE00302

Identifier Type: -

Identifier Source: org_study_id