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Basic and translational research
Original research article
Cardiometabolic effects of a novel SIRT1 activator, SRT2104, in people with type 2 diabetes mellitus
  1. Radzi M Noh1,
  2. Sowmya Venkatasubramanian2,
  3. Shruti Daga3,
  4. Jeremy Langrish2,
  5. Nicholas L Mills4,
  6. Ninian N Lang5,
  7. Ethan Hoffmann6,
  8. Brian Waterhouse6,
  9. David E Newby7 and
  10. Brian M Frier8
  1. 1 Department of Diabetes, Royal Infirmary of Edinburgh, Edinburgh, UK
  2. 2 Department of Cardiovascular Research, University of Edinburgh, Edinburgh, UK
  3. 3 Clinical Development, GSK, Surrey, UK
  4. 4 Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK
  5. 5 BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
  6. 6 Research and Development, GlaxoSmithKline, Philadelphia, Pennsylvania, USA
  7. 7 Division of Health Sciences, Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, Edinburgh, UK
  8. 8 Department of Diabetes, Royal Infirmary Edinburgh, NHS Lothian, Edinburgh, UK
  1. Correspondence to Dr Radzi M Noh; radzi.noh{at}doctors.org.uk

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/100 mL 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.

  • sirtuins
  • SIRT-1 activator
  • type 2 diabetes mellitus
  • weight loss
  • lipids
  • endothelial dysfunction
  • lipids
  • cardiovascular risk
  • platelet activation

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/openhrt-2017-000647

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    Footnotes

    • Contributors DEN is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. RMN and SV were the main researchers who recruited the volunteers and conducted the study. JL, SD and NLM had input in writing the study protocol. RMN prepared the main manuscript and all other authors reviewed and edited the contents.

    • Funding The study was funded and supported by Sirtris Pharmaceuticals Inc, Cambridge, Massachusetts. They also supplied the study drug SRT2104 and its matching placebo.

    • Disclaimer DEN has undertaken consultancy for GSK; SD is currently an employee ofGlaxoSmithKline, UK, and owns stock; EH is an employee of Sirtris Pharmaceuticals, Massachusetts, and owns stock; BW is an employee of GlaxoSmithKline, Pennsylvania, and owns stock. RMN, SV, NLM, NNL and BMF declare no conflicts of interest.

    • Competing interests None declared.

    • Ethics approval Lothian Regional Ethics Committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement All available data can be obtained by contacting the corresponding author.