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

Radzi M Noh; Sowmya Venkatasubramanian; Shruti Daga; Jeremy Langrish; Nicholas L Mills; Ninian N Lang; Ethan Hoffmann; Brian Waterhouse; David E Newby; Brian M Frier

doi:10.1136/openhrt-2017-000647

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

Radzi M Noh, Sowmya Venkatasubramanian, Shruti Daga, Jeremy Langrish, Nicholas L Mills, Ninian N Lang, Ethan Hoffmann, Brian Waterhouse, David E Newby, Brian M Frier

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	e000647
Journal	Open heart
Volume	4
Issue number	2
Early online date	2 Sep 2017
DOIs	https://doi.org/10.1136/openhrt-2017-000647
Publication status	E-pub ahead of print - 2 Sep 2017

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Journal Article

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@article{05229edca3154ac39feb0af98253ebd0,

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

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.",

keywords = "Journal Article",

author = "Noh, {Radzi M} and Sowmya Venkatasubramanian and Shruti Daga and Jeremy Langrish and Mills, {Nicholas L} and Lang, {Ninian N} and Ethan Hoffmann and Brian Waterhouse and Newby, {David E} and Frier, {Brian M}",

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doi = "10.1136/openhrt-2017-000647",

language = "English",

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TY - JOUR

T1 - Cardiometabolic effects of a novel SIRT1 activator, SRT2104, in people with type 2 diabetes mellitus

AU - Noh, Radzi M

AU - Venkatasubramanian, Sowmya

AU - Daga, Shruti

AU - Langrish, Jeremy

AU - Mills, Nicholas L

AU - Lang, Ninian N

AU - Hoffmann, Ethan

AU - Waterhouse, Brian

AU - Newby, David E

AU - Frier, Brian M

PY - 2017/9/2

Y1 - 2017/9/2

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1136/openhrt-2017-000647

DO - 10.1136/openhrt-2017-000647

M3 - Article

C2 - 28912956

VL - 4

SP - e000647

JO - Open heart

JF - Open heart

SN - 2053-3624

IS - 2

ER -

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

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