Cardiometabolic effects of a novel SIRT1 activator, SRT2104, in people with type 2 diabetes mellitus

Noh, R. M., Venkatasubramanian, S., Daga, S., Langrish, J., Mills, N. L., Lang, N. N. , Hoffmann, E., Waterhouse, B., Newby, D. E. and Frier, B. M. (2017) Cardiometabolic effects of a novel SIRT1 activator, SRT2104, in people with type 2 diabetes mellitus. Open Heart, 4(2), e000647. (doi: 10.1136/openhrt-2017-000647) (PMID:28912956) (PMCID:PMC5588958)

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Abstract

Background: The cardiometabolic effects of SRT2104, a novel SIRT1 activator, were investigated in people with type 2 diabetes mellitus (T2DM). Methods: Fifteen adults with T2DM underwent a randomised, double-blind, placebo-controlled cross-over trial and received 28 days of oral SRT2104 (2.0 g/day) or placebo. Forearm vasodilatation (measured during intrabrachial bradykinin, acetylcholine and sodium nitroprusside infusions) as well as markers of glycaemic control, lipid profile, plasma fibrinolytic factors, and markers of platelet-monocyte activation, were measured at baseline and at the end of each treatment period. Results: Lipid profile and platelet-monocyte activation were similar in both treatment arms (p>0.05 for all). Forearm vasodilatation was similar on exposure to acetylcholine and sodium nitroprusside (p>0.05,respectively). Bradykinin-induced vasodilatation was less during treatment with SRT2104 versus placebo (7.753vs9.044, respectively, mean difference=−1.291,(95% CI −2.296 to −0.285, p=0.012)). Estimated net plasminogen activator inhibitor type 1 antigen release was reduced in the SRT2104 arm versus placebo (mean difference=−38.89 ng/100mL tissue/ min, (95%CI −75.47, to –2.305, p=0.038)). There were no differences in other plasma fibrinolytic factors (p>0.05 for all). After 28 days, SRT2104 exposure was associated with weight reduction (−0.93 kg (95% CI −1.72 to −0.15), p=0.0236), and a rise in glycated haemoglobin (5 mmol/ mol or 0.48% (0.26 to 0.70), p=0.004) Conclusions: In people with T2DM, SRT2104 had inconsistent, predominantly neutral effects on endothelial and fibrinolytic function, and no discernible effect on lipids or platelet function. In contrast, weight loss was induced along with deterioration in glycaemic control, suggestive of potentially important metabolic effects. Clinical trial registration: NCT01031108; Results.

Item Type:Articles
Additional Information:The study was funded and supported by Sirtris Pharmaceuticals Inc, Cambridge, Massachusetts.
Keywords:SIRT-1 activator, cardiovascular risk, endothelial dysfunction, lipids, platelet activation, sirtuins, type 2 diabetes mellitus, weight loss.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Newby, Professor David and Lang, Dr Ninian
Authors: Noh, R. M., Venkatasubramanian, S., Daga, S., Langrish, J., Mills, N. L., Lang, N. N., Hoffmann, E., Waterhouse, B., Newby, D. E., and Frier, B. M.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Open Heart
Publisher:BMJ Publishing Group
ISSN:2053-3624
ISSN (Online):2053-3624
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Open Heart 4(2): e000647
Publisher Policy:Reproduced under a Creative Commons license

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