Shruti Daga

Cardiovascular Effects of a Novel SIRT1 Activator, SRT2104, in Otherwise Healthy Cigarette Smokers

Background We examined the effect of the oral SIRT1 activator SRT2104 on cardiovascular function in otherwise healthy cigarette smokers. Methods and Results Twenty‐four otherwise healthy cigarette smokers participated in a randomized double‐blind, placebo‐controlled crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Plasma SRT2104 concentrations, serum lipid profile, plasma fibrinolytic factors, and markers of platelet and monocyte activation were measured at baseline and at the end of each treatment period together with an assessment of forearm blood flow during intra‐arterial bradykinin, acetylcholine, and sodium nitroprusside infusions. Three hours postdose, mean plasma SRT2104 concentration was 1328±748 ng/mL after 28 days of active treatment. Compared with placebo, serum lipid profile improved during SRT2104 administration, with reductions in serum total cholesterol (−11.6±20 versus 6±21 mg/dL), low‐density lipoprotein cholesterol (−10±17 versus 3±21 mg/dL), and triglyceride (−39.8±77 versus 13.3±57 mg/dL) concentrations (P<0.05 for all). All vasodilators produced a dose‐dependent increase in blood flow (P<0.0001) that was similar during each treatment period (P>0.05 for all). No significant differences in fibrinolytic or blood flow parameters were observed between placebo and SRT2014. Conclusions SRT2104 appears to be safe and well tolerated and associated with an improved lipid profile without demonstrable differences in vascular or platelet function in otherwise healthy cigarette smokers. Clinical Trial Registration http://www.clinicaltrials.gov. Unique identifier: NCT01031108.

P-selectin antagonism reduces thrombus formation in humans

Summary.  Background: Interaction of P‐selectin with its glycoprotein ligand (P‐selectin glycoprotein ligand type 1) mediates inflammatory processes that may also include vascular thrombosis. Platelet P‐selectin expression is increased in patients with coronary heart disease, and its antagonism represents a potential future therapeutic target for the prevention and treatment of atherothrombosis. Aim: To investigate the effects of the novel small molecule P‐selectin antagonist PSI‐697 on thrombus formation in humans. Methods and Results: In a double‐blind randomized crossover study, thrombus formation was measured in 12 healthy volunteers, using the Badimon ex vivo perfusion chamber under conditions of low and high shear stress. Saline placebo, low‐dose (2 m) and high‐dose (20 m) PSI‐697 and the glycoprotein IIb–IIIa receptor antagonist tirofiban (50 ng mL−1) were administered into the extracorporeal circuit prior to the perfusion chamber. As compared with saline placebo, blockade of platelet glycoprotein IIb–IIIa receptor with tirofiban produced 28% and 56% reductions in thrombus formation in the low‐shear and high‐shear chambers, respectively. PSI‐697 caused a dose‐dependent, but more modest, reduction in thrombus formation. Low‐dose PSI‐796 (2 m) reduced total thrombus area by 14% (P = 0.04) and 30% (P = 0.0002) in the low‐shear and high‐shear chambers, respectively. At the high dose (20 m), PSI‐697 reduced total thrombus area by 18% (P = 0.0094) and 41% (P = 0.0008) in the low‐shear and high‐shear chambers, respectively. Conclusions: P‐selectin antagonism with PSI‐697 reduces ex vivo thrombus formation in humans. These findings provide further evidence that P‐selectin antagonism may be a potential target for the prevention and treatment of cardiovascular disease.

Platelet receptor polymorphisms do not influence Staphylococcus aureus-platelet interactions or infective endocarditis

Cardiac vegetations result from bacterium–platelet adherence, activation and aggregation, and are associated with increased morbidity and mortality in infective endocarditis. The GPIIb/IIIa and FcγRIIa platelet receptors play a central role in platelet adhesion, activation and aggregation induced by endocarditis pathogens such as Staphylococcus aureus, but the influence of known polymorphisms of these receptors on the pathogenesis of infective endocarditis is unknown. We determined the GPIIIa platelet antigen PlA1/A2 and FcγRIIa H131R genotype of healthy volunteers (n = 160) and patients with infective endocarditis (n = 40), and investigated the influence of these polymorphisms on clinical outcome in infective endocarditis and S. aureus–platelet interactions in vitro. Platelet receptor genotype did not correlate with development of infective endocarditis, vegetation characteristics on echocardiogram or the composite clinical end-point of embolism, heart failure, need for surgery or mortality (P > 0.05 for all), even though patients with the GPIIIa PlA1/A1 genotype had increased in vivo platelet activation (P = 0.001). Furthermore, neither GPIIIa PlA1/A2 nor FcγRIIa H131R genotype influenced S. aureus-induced platelet adhesion, activation or aggregation in vitro (P > 0.05). Taken together, our data suggest that the GPIIIa and FcγRIIa platelet receptor polymorphisms do not influence S. aureus–platelet interactions in vitro or the clinical course of infective endocarditis.

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

Objective 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. Methods 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). Results 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. Conclusions 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. Trial registration number NCT01031108.

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

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.

Predictors of Nonuse of a High‐Potency Statin After an Acute Coronary Syndrome: Insights From the Stabilization of Plaques Using Darapladib‐Thrombolysis in Myocardial Infarction 52 (SOLID‐TIMI 52) Trial

Background High‐potency statins reduce cardiovascular events after acute coronary syndromes but remain underused in clinical practice. We examined predictors of nonuse of high‐potency statins after acute coronary syndromes. Methods and Results The Stabilization of pLaques usIng Darapladib‐Thrombolysis in Myocardial Infarction (SOLID‐TIMI 52) trial enrolled patients after an acute coronary syndrome in 36 countries between 2009 and 2011. Statin use was strongly encouraged throughout the trial, and statin potency was at the discretion of the treating physician. A high‐potency statin was defined as ≥40 mg atorvastatin, ≥20 mg rosuvastatin, or 80 mg simvastatin daily. Predictors of nonuse of high‐potency statins were examined using logistic regression. Of the patients included (n=12 446), 11 850 (95.2%) were treated with a statin at baseline after acute coronary syndrome (median 14 days), but only 5212 (41.9%) were on a high‐potency statin. Selected patient factors associated with nonuse of high‐potency statins included age ≥75 years (odds ratio 1.39, 95% CI 1.24–1.56), female sex (odds ratio 1.11, 95% CI 1.02–1.22), renal dysfunction (odds ratio 1.17, 95% CI 1.03–1.32), and heart failure during hospital admission (odds ratio 1.43, 95% CI 1.27–1.62). At 3 months after baseline, only 49% of patients had low‐density lipoprotein cholesterol <70 mg/dL. Among the 5490 patients (59%) who were not on a high‐potency statin at 3 months, lower low‐density lipoprotein cholesterol was a predictor of nonuse of a high‐potency statin after a median of 2.3 years (odds ratio 1.15 for 10 mg/dL decrease, 95% CI 1.11–1.19). Conclusion Despite the widespread use of statins after acute coronary syndromes, most patients are not treated with high‐potency statins early and late after the event, including patients at the highest risk of recurrent cardiovascular events. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01000727.

Efficacy and safety of monotherapy with sirukumab compared with adalimumab monotherapy in biologic-naïve patients with active rheumatoid arthritis (SIRROUND-H): a randomised, double-blind, parallel-group, multinational, 52-week, phase 3 study.

Objective This randomised, double-blind, parallel-group, phase 3 study compared monotherapy with sirukumab, an anti–interleukin-6 cytokine monoclonal antibody, with adalimumab monotherapy in patients with rheumatoid arthritis (RA). Methods Biologic-naïve patients with active RA who were inadequate responders or were intolerant to, or inappropriate for, methotrexate were randomised to subcutaneous sirukumab 100 mg every 2 weeks (n=187), sirukumab 50 mg every 4 weeks (n=186) or adalimumab 40 mg every 2 weeks (n=186). Primary endpoints at week 24 were change from baseline in Disease Activity Score in 28 joints (DAS28) using erythrocyte sedimentation rate (ESR) and proportion of patients achieving an American College of Rheumatology (ACR) 50 response; these endpoints were tested in sequential order. This study is registered at EudraCT (number: 2013-001417-32) and ClinicalTrials.gov (number: NCT02019472). Results Significantly greater improvements from baseline in mean (SD) DAS28 (ESR) were observed at week 24 with sirukumab 100 mg every 2 weeks (−2.96 (1.580)) versus adalimumab 40 mg every 2 weeks (−2.19 (1.437); P<0.001). Sirukumab 50 mg every 4 weeks also showed significantly greater improvement from baseline at week 24 in DAS28 (ESR) (−2.58 (1.524)) compared with adalimumab (P=0.013). The ACR50 response rates with the 100 mg (35.3%) and 50 mg (26.9%) doses of sirukumab were comparable to that with adalimumab (31.7%) at week 24. The safety profile of sirukumab was consistent with that observed with anti–interleukin-6 receptor antibodies. A dose-related effect on the incidence of injection-site reactions was observed with sirukumab. Conclusion Sirukumab monotherapy showed greater improvements in DAS28 (ESR), but similar ACR50 response rates, versus adalimumab monotherapy.