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Effects of the small molecule SIRT1 activator, SRT2104 on arterial stiffness in otherwise healthy cigarette smokers and subjects with type 2 diabetes mellitus.

ABSTRACT: Arterial stiffness increases with age, and is associated with adverse cardiovascular outcome including increased mortality. The effect of the oral small molecule SIRT1 activator, SRT2104, on arterial stiffness was examined in otherwise healthy cigarette smokers and participants with type 2 diabetes mellitus.24 otherwise healthy cigarette smokers and 15 people with stable type 2 diabetes were randomised in a double-blind placebo-controlled crossover trial and received 28?days of oral SRT2104 (2.0?g/day) or matched placebo. Blood pressure was measured using non-invasive oscillatory sphygmomanometry. Pulse wave analysis and velocity were measured using applanation tonometry at baseline and the end of each treatment period. Owing to the small sample size and similar trends for both groups, data for the two groups were pooled (post hoc analysis).Compared to placebo, treatment with SRT2104 was associated with a significant reduction in augmentation pressure (p=0.0273) and a trend towards improvement in the augmentation index and corrected augmentation index (p>0.05 for both). However, no changes were observed in pulse wave velocity and time to wave reflection (p>0.05). Systolic and diastolic blood pressures remained unchanged throughout the study. Treatment by cohort interaction was not significant for any of the pulse wave parameters, suggesting that the response to SRT2104 in otherwise healthy smokers and people with diabetes was consistent.SRT2104 may improve measures of arterial stiffness in otherwise healthy cigarette smokers and in participants with type 2 diabetes. Definitive conclusions are not possible given the small sample size and exploratory nature of this analysis.NCT01031108.

SUBMITTER: Venkatasubramanian S

PROVIDER: S-EPMC4879341 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Effects of the small molecule SIRT1 activator, SRT2104 on arterial stiffness in otherwise healthy cigarette smokers and subjects with type 2 diabetes mellitus.

Venkatasubramanian Sowmya S Noh Radzi M RM Daga Shruti S Langrish Jeremy P JP Mills Nicholas L NL Waterhouse Brian R BR Hoffmann Ethan E Jacobson Eric W EW Lang Ninian N NN Frier Brian M BM Newby David E DE

Open heart 20160517 1

<h4>Objective</h4>Arterial stiffness increases with age, and is associated with adverse cardiovascular outcome including increased mortality. The effect of the oral small molecule SIRT1 activator, SRT2104, on arterial stiffness was examined in otherwise healthy cigarette smokers and participants with type 2 diabetes mellitus.<h4>Methods</h4>24 otherwise healthy cigarette smokers and 15 people with stable type 2 diabetes were randomised in a double-blind placebo-controlled crossover trial and rec ...[more]

PMID: 27239324

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Project description:BackgroundIndividuals with type 1 diabetes mellitus are at high risk for the development of hypertension, contributing to cardiovascular complications. Hyperglycaemia-mediated neurohormonal activation increases arterial stiffness, and is an important contributing factor for hypertension. Since the sodium glucose cotransport-2 (SGLT2) inhibitor empagliflozin lowers blood pressure and HbA1c in type 1 diabetes mellitus, we hypothesized that this agent would also reduce arterial stiffness and markers of sympathetic nervous system activity.MethodsBlood pressure, arterial stiffness, heart rate variability (HRV) and circulating adrenergic mediators were measured during clamped euglycaemia (blood glucose 4-6 mmol/L) and hyperglycaemia (blood glucose 9-11 mmol/L) in 40 normotensive type 1 diabetes mellitus patients. Studies were repeated after 8 weeks of empagliflozin (25 mg once daily).ResultsIn response to empagliflozin during clamped euglycaemia, systolic blood pressure (111 ± 9 to 109 ± 9 mmHg, p = 0.02) and augmentation indices at the radial (-52% ± 16 to -57% ± 17, p = 0.0001), carotid (+1.3 ± 1 7.0 to -5.7 ± 17.0%, p < 0.0001) and aortic positions (+0.1 ± 13.4 to -6.2 ± 14.3%, p < 0.0001) declined. Similar effects on arterial stiffness were observed during clamped hyperglycaemia without changing blood pressure under this condition. Carotid-radial pulse wave velocity decreased significantly under both glycemic conditions (p ≤ 0.0001), while declines in carotid-femoral pulse wave velocity were only significant during clamped hyperglycaemia (5.7 ± 1.1 to 5.2 ± 0.9 m/s, p = 0.0017). HRV, plasma noradrenalin and adrenaline remained unchanged under both clamped euglycemic and hyperglycemic conditions.ConclusionsEmpagliflozin is associated with a decline in arterial stiffness in young type 1 diabetes mellitus subjects. The underlying mechanisms may relate to pleiotropic actions of SGLT2 inhibition, including glucose lowering, antihypertensive and weight reduction effects.Trial registrationClinical trial registrationNCT01392560.

Project description:Activation of Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, is an unexplored therapeutic approach for treatment of inflammatory diseases. The goal of this study was to evaluate the clinical activity and tolerability of multiple doses of SRT2104, a selective activator of SIRT1, in patients with moderate to severe psoriasis after day 84 of treatment. Forty patients were randomized 4:1 to three escalating doses of SRT2104 (250, 500, 1000 mg/d SRT2104 or placebo). Across all SRT2104 groups, 34.6% of patients (9 out of 26; 90% CI 18.0%-54.2%, p<0.0001) achieved good to excellent histological improvement based on skin biopsies taken at baseline and day 84. To evaluate the changes in expression profile with treatment and to identify pathways involved in histological improvement, a subset of 22 Pre and Post treatment biopsies from 11 patients (4 Placebo, 7 Active Treatment) were hybridized to hgu133plus2 chips. Improvement in histology was associated with modulation of IL-17 and TNF-_ signaling pathways and keratinocyte differentiation target genes. Various studies suggest a crucial role of TNF_ and IL-17 in psoriasis pathogenesis and IL-17/TNF_ synergism induces a strong induction of differentially expressed genes in psoriasis, thus advocating a crucial role of IL-17/TNF_ combination in the molecular basis of disease (Chiricozzi et al., 2010). In the current study, broad scale gene expression profiling revealed that SRT2104 significantly reduced known IL-17 and TNF_ responsive genes including SERPINB4, S100A12, SERPINB3, kynu etc. even though the sample size for this analysis was small. One of the most highly modulated genes by SRT2104 included Kynu, a gene that regulates tryptophan metabolism, known to confer antibacterial effector functions (Daubener and MacKenzie, 1999). Interestingly kynu is part of the etanercept residual genomic profile that is not modulated by etanercept therapy even though clinical efficacy is achieved. Possibly, SRT2104 may be modulating the lipid barrier of the epidermis of psoriatic skin via modulation of keratinocyte diferentiation genes, which would be consistent with the observed improvement in skin histology. These results indicate a combinatorial effect of SRT2104 on TNF_, and IL-17 inflammatory signaling pathways and keratinocyte differentiation that could be a contributing factor towards improvement in clinical scores by the SIRT1 activator, SRT2104.

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Effects of the small molecule SIRT1 activator, SRT2104 on arterial stiffness in otherwise healthy cigarette smokers and subjects with type 2 diabetes mellitus.

Publications

Effects of the small molecule SIRT1 activator, SRT2104 on arterial stiffness in otherwise healthy cigarette smokers and subjects with type 2 diabetes mellitus.

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