Effect of Saxagliptin and Dapagliflozin on Endothelial Progenitor Cell in Patients With Type 2 Diabetes Mellitus

Diabetes Mellitus, Type 2 Clinical Trial

Official title: Cardio-Protective of Effect of Saxagliptin and Dapagliflozin Combination on Endothelial Progenitor Cells in Patients With Type 2 Diabetes

Status Terminated

Clinical Trial Summary

The Investigator hypothesize that Dapagliflozin will improve EPC number and function AND Saxagliptin in addition to Dapagliflozin (additive effect) may improve EPC number and function even more than Dapa alone, compared to placebo.

The Investigator propose a 3-arm randomized, parallel group, longitudinal study of 16-week intervention duration. Participants will be randomized to 3 groups:

Group A: Dapa (10 mg) + Saxa Placebo, Enroll n=15, retain n=12 Group B: Dapa (10 mg) + Saxa (5 mg), Enroll n=15, retain n=12 Group C: Dapa Placebo + Saxa Placebo, Enroll n=15, retain n=12

Clinical Trial Description

The Investigator hypothesize that Dapagliflozin will improve EPC number and function AND Saxagliptin in addition to Dapagliflozin may have an additive effect to improve EPC number and function even more than Dapa alone, compared to placebo.

In this proposal the investigator plan to conduct a placebo matched study with type 2 diabetes subjects on any doses of metformin or Insulin or a combination of both and has no history of DPP4 ( Dipeptidyl Peptidase-4) DPP4 inhibitor, incretin mimetic or SGLT2 inhibitor intake history. Participants will have known macrovascular complications (such as Cardiovascular Disease (CVD), Cerebrovascular Accident (CVA), and Peripheral Vascular Disease (PVD).

3 STUDY OBJECTIVES

PRIMARY OBJECTIVE:

CELLULAR BIOMARKER OF ENDOTHELIUM

The primary objective is to ascertain if 16 weeks of Dapa or Dapa+Saxa Combo therapy will improve :

CD34+ cell number, CD34+ migratory function and CD34+ gene expression in type 2 diabetes with CVD.

SECONDARY OBJECTIVE:

ARTERIAL STIFFNESS AND RENAL FUNCTION, NON-CELLULAR MARKERS OF ENDOTHELIUM To determine whether use of Dapa or Dapa+Saxa Combo alters markers of endothelial function such as: arterial stiffness measures (via tonometry), biochemical measures derived from plasma, pertaining to endothelial function (hs-CRP, IL-6, TNF-alpha), renal function such as proteinuria (microalbumin/creatinine ratio) and urine exosome study to determine podocyte health. The secondary measures are indirect measures of endothelial inflammation in early type 2 diabetes patients.

Effect on Arterial Stiffness:

I. Pulse Wave Analysis and Vascular Flow will be assessed using SphygmoCor CP system from ATCOR as a measure of central arterial pressure and arterial stiffness.

II. Vessel health will be assessed by degree of arterial stiffness, using arterial tonometry.

III. The central and the aortic pressure is assessed by pulse wave analysis (PWA) and pulse wave velocity (PWV).

Effect on Blood Biochemistry:

The Investigator believes cell based biomarkers are superior to traditional serum and plasma biomarkers and the outcome report will be stronger if one can show positive correlation between the two outcome measures. The Investigator therefore will be looking at:

I. Inflammation, apoptosis and anti-oxidant protein levels: Highly selective C-reactive protein (hs-CRP), IL-6, TNF-alpha.

II. Plasma SDF1 alpha (ELISA) and GLP-1 and Ghrelin (ELISA) will be estimated to assess endothelial health and factors that may influence CD34+ cell chemotaxis III. Podocyte health via urine exosome analysis. IV. The glomerular filtration rate (GFR) will be estimated by MDRD equation.

a. GFR = 141 X min (Scr/κ,1)α X max(Scr/κ,1)-1.209 X 0.993Age X 1.018 [if female] X 1.159 [if African American]; where Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1.32

TERTIARY OBJECTIVE:

METABOLISM MARKERS The tertiary objective is to determine whether use of Dapa or Dapa+Saxa Combo alters body composition, fasting lipid profile, and levels of insulin, glucose, and appetite controlling hormones.

Effect on Blood Biochemistry:

The Investigator believes cell based biomarkers are superior to traditional serum and plasma biomarkers and the outcome report will be stronger if one can show positive co-relation between the two outcome measures.

I. Fasting glucose, and insulin. a. Glycemic control will be evaluated by measuring fasting blood glucose, insulin levels and HbA1c. Fasting blood glucose, insulin and lipid profile will be used to assess insulin resistance.28,31 II. Lipid profile III. Appetite controlling hormones via LabCorp: Leptin, Adiponectin IV. Appetite controlling hormones, via ELISA: GLP1, Ghrelin

Effect of Dapa and Dapa+Saxa Combo on Body Habitus (Determination of body composition and visceral fat) The Investigator plans to study cardio-metabolic effect of Dapa and Dapa+Saxa Combo.

I. Using body composition scale:

1. Height and weight will be measured and the body mass index (BMI=kgm2) used as an indicator of relative weight.

2. The body composition scale calculates body fat%, total body water%, fat free mass, etc., in addition to BMI.

The secondary outcome markers (arterial stiffness and renal outcome measures) and tertiary outcome markers (serum biochemistry) are crucial in order to corroborate the cellular findings with currently accepted clinical efficacy outcome measures such as arterial stiffness and serum biochemistry. This design is similar to our recently published manuscript on Saxagliptin and cellular outcome measures.

4 INVESTIGATIONAL PLAN

STUDY DESIGN AND DURATION

+/- 6 day window for visits

*Assessed at week 0, 8 and 16: Primary, Secondary & Tertiary Outcomes.

Week 20: A telephone call to subjects will be made 4 weeks after last dose of study medication to determine if there have been any adverse events. ;

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Diabetes Mellitus
• Diabetes Mellitus, Type 2

• NCT number: NCT03660683
• Study type: Interventional
• Source: George Washington University
• Status: Terminated
• Phase: Phase 4
• Start date: October 22, 2018
• Completion date: December 10, 2021