Date of Award

11-2016

Document type

Thesis

Degree Name

MD (Medical Doctor)

First Supervisor

Dr John H. McDermott

Keywords

Diabetes, Endothelial Progenitor Cells, Saxagliptin, Taurine, Endothelial Dysfunction, Pulse Wave Velocity

Abstract

Abstract Study 1

Cardiovascular safety of DPP-4 inhibition in participants with Type 2 Diabetes Mellitus: Endothelial Progenitor Cells as an early marker of long-term cardiovascular risk

Endothelial Progenitor Cells (EPCs) play a central role in cardiovascular repair and increasing EPC number is a strong determinant of future cardiovascular risk(1). Interventions, which modify cardiovascular risk, have early effects on EPC number and function (2). Establishing cardiovascular safety of any new anti-diabetic agent typically requires long-term post-marketing trials. DPP-4 inhibitors are a new class of glucose-lowering medication(3). We aimed to evaluate the long-term cardiovascular safety of Saxagliptin (SAX, a DPP-4 inhibitor) versus Gliclazide Modified Release (GLC) using EPC number and function as surrogate markers of cardiovascular risk. 18 participants with T2DM on Metformin monotherapy were randomized to SAX (n=7) or GLC (n=11). EPC number and adhesion capacity were measured, using methods as previously described (4), at baseline and at 6 months after treatment. There was no difference in the median EPC number of 33 (19 – 44) vs. 25 (22 – 46) cells per high power field (HPF), p=0.9) or adhesion capacity of 0.22 (0.17 – 0.86) vs. 0.27 (0.1 – 0.67 fluorescence units, p=0.75) at baseline between SAX and GLC groups respectively. Compared to baseline there was no change in median EPC number [SAX: 35 (28-38) vs 33 (19-44) cells/HPF, p=0.9 and GLC: 39 (28-46) vs 25 (22-46) cells/ HPF, p=0.24] or adhesion capacity [SAX: 0.3 (0.17 – 0.65) vs 0.22(0.17 – 0.86), p=1.0, GLC: 0.32 (0.14 – 0.84) vs 0.27 (0.1 – 0.67) fluorescence units, p=0.88] after 6 months treatment in either group. In summary, we found no difference in EPC number or function in participants treated with SAX versus GLC for 6 months. These results may suggest a similar cardiovascular safety profile of SAX to GLC, a well-established treatment for T2DM.

Abstract Study 2

The Effect of Taurine on Endothelial Dysfunction In Type 2 Diabetes Mellitus: A Pilot Study

There is a two- to three-fold increase in cardiovascular (CVD) mortality in T2DM patients compared to aged-matched non-diabetic subjects(5). Endothelial dysfunction characterized by arterial stiffness predicts this CVD risk(6). Endothelial Progenitor Cells (EPCs) are bone marrow derived cells responsible for cardiovascular repair, act as a surrogate biological marker for vascular dysfunction, and predict cumulative future cardiovascular risk(7). Taurine is a sulfur-containing amino acid, synthesized in the body in limited amounts, and is present mainly in seafood(8, 9) which has been shown to have a beneficial effect in hypertension(10, 11), hypercholesterolaemia(12, 13), and endothelial function (14, 15). Taurine supplementation for 2 weeks improves arterial stiffness in patients with T1DM(16). We carried out a pilot study examining the effects of taurine on 11 T2DM patients in a randomized, double blind, cross-over placebo design. We evaluated any changes to EPC numbers and function. We also compared the degree of arterial stiffness using PWV. There was a trend towards an improvement in the number of EPC/hpf following taurine (40 ± 7 cells) and placebo (37 ± 10 cells) when compared to baseline (32 ± 8 cells, p=0.08). Similarly, there was a trend towards improvement in DBP following taurine (78.6 ± 7.4 mmHg) and placebo (79.3 ± 7.5 mmHg) when compared to baseline (86.3 ± 10.2mmHg, p=0.08). There were no differences in the EPC adhesion capacity between baseline (n=10, 0.66 ± 0.4 fluorescence unit), taurine (10, 0.97 ± 0.8 fluorescence unit) and placebo (11, 0.94 ± 0.5, p=0.43 fluorescence unit) group. There were also no differences in the measurements of PWV baseline [8.7 (8.0-8.4) m/s], taurine [9.1 (8.3-9.6) m/s] and placebo [8.9 (8.8-9.1) m/s, p=1.0]. These results may be interpreted as an absence of benefit of Taurine in modulating known markers of endothelial dysfunction in T2DM. The downward trend in DBP and an upward trend in the numbers of EPC seen in this pilot study, however, will require further evaluation in a larger cohort.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

19.1 MB

Comments

A thesis submitted for the degree of Doctor of Medicine from the Royal College of Surgeons in Ireland in 2016.

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