Effect of Targeting Inflammation With Salsalate

Hauser, Thomas H.; Salastekar, Ninad; Schaefer, Ernst J.; Desai, Tanvi; Goldfine, Harvey; Fowler, Kristen; Weber, Griffin M; Welty, Francine K.; Clouse, Melvin E.; Shoelson, Steven E.; Goldfine, Allison B.

doi:10.1001/jamacardio.2016.0605

Cited by 50 publications

(17 citation statements)

References 36 publications

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“…Imaging methods, analytical methods, and study materials have been made available to other researchers for purposes of reproducing the results or replicating the procedures 14, 15…”

Section: Methodsmentioning

confidence: 99%

“…The protocol for performance of CCTA, plaque identification, and quantification has been previously published14, 15 with image acquisition details and references in Appendix 1 in Supplement 2 of Hauser et al 15…”

Section: Methodsmentioning

confidence: 99%

“…Representative images have been previously published (Supplement 2 in Hauser et al) 15. Segments with past revascularization or significant calcification causing calcium‐bloom artifact were excluded.…”

Section: Methodsmentioning

confidence: 99%

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Effect of Eicosapentaenoic and Docosahexaenoic Acids Added to Statin Therapy on Coronary Artery Plaque in Patients With Coronary Artery Disease: A Randomized Clinical Trial

Alfaddagh

Elajami

Ashfaque

et al. 2017

JAHA

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BackgroundAlthough statins reduce cardiovascular events, residual risk remains. Therefore, additional modalities are needed to reduce risk. We evaluated the effect of eicosapentaenoic acid and docosahexaenoic acid in pharmacologic doses added to statin treatment on coronary artery plaque volume.Methods and ResultsA total of 285 subjects with stable coronary artery disease on statins were randomized to omega‐3 ethyl‐ester (1.86 g of eicosapentaenoic acid and 1.5 g of docosahexaenoic acid daily) or no omega‐3 (control) for 30 months. Coronary plaque volume was assessed by coronary computed tomographic angiography. Mean (SD) age was 63.0 (7.7) years; mean low‐density lipoprotein cholesterol ≤80 mg/dL. In the intention‐to‐treat analysis, our primary endpoint, noncalcified plaque volume, was not different between groups (P=0.14) but approached significance in the per protocol analysis (P=0.07). When stratified by age in the intention‐to‐treat analysis, younger omega‐3 subjects had significantly less progression of the primary endpoint, noncalcified plaque (P=0.013), and fibrous, calcified and total plaque. In plaque subtype analysis, controls had significant progression of fibrous plaque compared to no change in the omega‐3 ethyl‐ester group (median % change [interquartile range], 5.0% [−5.7, 20.0] versus −0.1% [−12.3, 14.5], respectively; P=0.018). Among those on low‐intensity statins, omega‐3 ethyl‐ester subjects had attenuation of fibrous plaque progression compared to controls (median % change [interquartile range], 0.3% [−12.8, 9.0] versus 4.8% [−5.1, 19.0], respectively; P=0.032). In contrast, those on high‐intensity statins had no difference in plaque change in either treatment arm.ConclusionsHigh‐dose eicosapentaenoic acid and docosahexaenoic acid provided additional benefit to statins in preventing progression of fibrous coronary plaque in subjects adherent to therapy with well‐controlled low‐density lipoprotein cholesterol levels. The benefit on low‐intensity statin, but not high‐intensity statin, suggests that statin intensity affects plaque volume.Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01624727.

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“…Imaging methods, analytical methods, and study materials have been made available to other researchers for purposes of reproducing the results or replicating the procedures 14, 15…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Effect of Eicosapentaenoic and Docosahexaenoic Acids Added to Statin Therapy on Coronary Artery Plaque in Patients With Coronary Artery Disease: A Randomized Clinical Trial

Alfaddagh

Elajami

Ashfaque

et al. 2017

JAHA

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“…Study design, inclusion details for obese statin-treated persons with stable CHD, exclusion criteria, randomization and follow-up are available 5 (Supplement). Participants with established diabetes at baseline were excluded from analysis a priori due to potential confounding from change in concomitant diabetes medications 6 , and insufficient numbers with diabetes in the parent trial for adequate power to evaluate this sub-population.…”

Section: Methodsmentioning

confidence: 99%

Salsalate improves glycaemia in overweight persons with diabetes risk factors of stable statin‐treated cardiovascular disease: A 30‐month randomized placebo‐controlled trial

Salastekar

Desai

Hauser

et al. 2017

Diabetes Obesity Metabolism

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Objective To assess long‐term efficacy and safety of salsalate to improve glycemia in persons with diabetes risk, who are overweight with statin‐treated, stable coronary heart disease. Methods Glycemic status was assessed in 192 persons without diabetes at baseline in a pre‐specified secondary analysis from Targeting INflammation Using SALsalate in CardioVascular Disease (TINSAL‐CVD), a multi‐center, double‐masked, randomized (1:1), placebo‐controlled, parallel clinical trial. Results Participants were mostly Caucasian males, age 60±7 years, BMI 31.4±3.0 kg/m2, fasting glucose 92.8±11.0 mg/dL, and HbA1c 5.8±0.3%. Reductions in mean fasting glucose ‐5.70 mg/dL (95%CI: ‐7.44 to ‐3.97 mg/dL, P<0.001), HbA1c ‐0.11% (95%CI: ‐0.210 to ‐0.002%, P=0.046) and glycated serum protein ‐81.8 μg/mL (95%CI: ‐93.7 to ‐69.9 μg/mL, P<0.001) were demonstrated in salsalate compared to placebo‐assigned groups over 30 months. Reductions in fasting glucose and glycated serum protein were greater with salsalate compared to placebo in participants with prediabetes compared to a normoglycemic sub‐group (Pinteraction=0.018). Salsalate lowered total white blood cell counts (mean difference ‐0.7x103/μL, 95%CI: ‐1.0 to ‐0.4 x103/μL, P<0.001) and increased adiponectin (mean difference 1.8 μg/mL, 95%CI: 0.9 to 2.6 μg/mL, P<0.001) and albuminurea (16.7 μg/mg, 95%CI: 6.4 to 27.1 μg/mg, P<0.001) compared to placebo, consistent with previous results for patients with type 2 diabetes taking salsalate for shorter times. Conclusions Salsalate improves glycemia in obese persons at increased risk for diabetes, and hence may decrease risk of incident type 2 diabetes. Salsalate may inform new therapeutic approaches for diabetes prevention, but renal safety may limit clinical utility.

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“…In an ancillary study of 75 patients from the overall trial (TINSAL-FMD), there was also no difference in flow-mediated dilation, a marker of endothelial dysfunction (51). More recently, in TINSAL-CVD, 257 patients with stable coronary artery disease were randomized to 30 months of salsalate or placebo (52). At 30 months, there was no difference in hsCRP or coronary plaque volume measured by computed tomography angiography.…”

Section: Strategies To Target Residual Inflammatory Riskmentioning

confidence: 99%

Targeting Residual Inflammatory Risk: A Shifting Paradigm for Atherosclerotic Disease

Aday

Ridker

2019

Front. Cardiovasc. Med.

118

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As biologic, epidemiologic, and clinical trial data have demonstrated, inflammation is a key driver of atherosclerosis. Circulating biomarkers of inflammation, including high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6), are associated with increased risk of cardiovascular events independent of cholesterol and other traditional risk factors. Randomized trials have shown that statins reduce hsCRP, and the magnitude of hsCRP reduction is proportional to the reduction in cardiovascular risk. Additionally, these trials have demonstrated that many individuals remain at increased risk due to persistent elevations in hsCRP despite significant reductions in low-density lipoprotein cholesterol (LDL-C) levels. This “residual inflammatory risk” has increasingly become a viable pharmacologic target. In this review, we summarize the data linking inflammation to atherosclerosis with a particular focus on residual inflammatory risk. Additionally, we detail the results of Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), which showed that directly reducing inflammation with an IL-1β antagonist reduces cardiovascular event rates independent of LDL-C. These positive data are contrasted with neutral evidence from CIRT in which low-dose methotrexate neither reduced the critical IL-1β to IL-6 to CRP pathway of innate immunity, nor reduced cardiovascular event rates.

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Effect of Targeting Inflammation With Salsalate

Abstract: clinicaltrials.gov Identifier: NCT00624923.

Cited by 50 publications

References 36 publications

Effect of Eicosapentaenoic and Docosahexaenoic Acids Added to Statin Therapy on Coronary Artery Plaque in Patients With Coronary Artery Disease: A Randomized Clinical Trial

Effect of Eicosapentaenoic and Docosahexaenoic Acids Added to Statin Therapy on Coronary Artery Plaque in Patients With Coronary Artery Disease: A Randomized Clinical Trial

Salsalate improves glycaemia in overweight persons with diabetes risk factors of stable statin‐treated cardiovascular disease: A 30‐month randomized placebo‐controlled trial

Targeting Residual Inflammatory Risk: A Shifting Paradigm for Atherosclerotic Disease

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