Simvastatin reduces vaso‐occlusive pain in sickle cell anaemia: a pilot efficacy trial

Abstract

Summary Sickle cell anaemia (SCA) is a progressive vascular disease characterized by episodic vaso-occlusive pain. Despite the broad impact of inflammation on acute and chronic clinical manifestations of SCA, no directed anti-inflammatory therapies currently exist. Statins are cholesterol-lowering agents shown to confer protection from vascular injury by suppressing inflammation. We previously documented a reduction in soluble biomarkers of inflammation in patients with sickle cell disease treated with simvastatin. To determine the potential clinical efficacy of simvastatin, we treated 19 SCA patients with single daily dose simvastatin for 3 months and assessed changes from baseline in the frequency and intensity of diary-reported pain and levels of circulating nitric oxide metabolites (NOx), high sensitivity C-reactive protein (hs-CRP), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), ICAM-3, E-selectin, and vascular endothelial growth factor (VEGF). Treatment with simvastatin resulted in a significant reduction in the frequency of pain (p=0.0003), oral analgesic use (p=0.003) and circulating hs-CRP (p=0.003), soluble (s)E-selectin (p=0.01), sICAM-1 (p=0.02), sICAM-3 (p=0.02) and sVEGF (p=0.01). Simvastatin had no effect on pain intensity or levels of NOx, sP-selectin and sVCAM-1. The observed reductions in pain rate and markers of inflammation were greatest in subjects receiving hydroxycarbamide (HC), suggesting a synergistic effect of simvastatin. These results provide preliminary clinical data to support a larger trial of simvastatin in SCA.

Renal protection by atorvastatin in a murine model of sickle cell nephropathy

“…Although the effects of statins on the progression of kidney disease in human clinical trials remain controversial, studies have demonstrated significant improvement in proteinuria or albuminuria following treatment with statins as summarized in a recent meta‐analysis (Su et al , ). A small pilot study examining the effect of simvastatin in SCD patients found significant decreases in markers of inflammation and reduction in the frequency of pain episodes (Hoppe et al , ). In this study, treatment with simvastatin for 3 months resulted in decreased plasma levels of the endothelial marker soluble E‐selectin but not sVCAM‐1.…”

Inflammatory molecule reduction with hydroxyurea therapy in children with sickle cell anemia

“…Several new drugs with specific anti-inflammatory targets are currently in development. Anti-adhesion agents such as anti-E selectin (rivipansel, formerly GMI-1070), 17 anti-P selectin (crizanlizumab), 18 and broad anti-adhesives (simvastatin, AKT inhibitors), 19 used individually or in combination with hydroxyurea, have been shown to reduce VOEs. An opportunity now exists to further test new drugs in combination with hydroxyurea in order to potentiate the benefits provided by hydroxyurea therapy alone.…”

Sickle Cell Clinical Research and Intervention Program (SCCRIP): A lifespan cohort study for sickle cell disease progression from the pediatric stage into adulthood

“…Examples include, but are not limited to (1) the long‐term effects of hydroxyurea, hematopoietic stem cell transplantation, and transfusion therapy and the role of new interventions (e.g. anti‐inflammatory agents, Hb affinity modulators, anti‐oxidants, and gene therapy) in cumulative organ damage; (2) cognitive impairment, both its underlying mechanisms and the impact on social function; (3) the impact of the environment on the disease course, including poverty, which is prevalent in the SCD population; (4) pain control, particularly in patients who progress to chronic pain; (5) risk factors for bone mineral loss and osteonecrosis, including vitamin D deficiency, which is prevalent in SCD, and establishment of prevention and treatment guidelines; (6) risk factors for sickle nephropathy in older children and adults and the role of renal‐modifying therapies; (7) factors underlying the sharp increase in mortality in young adults, as compared to children; and (8) how biomarkers can be used to monitor treatment response and disease severity …”

“…SCCRIP participants have raised no significant concerns regarding the use of their biospecimens for future genetic studies, and most cite possibly contributing to the development of curative therapies as a motivation for study participation. Hb affinity modulators, [70][71][72] anti-oxidants, 73 and gene therapy 74 how biomarkers can be used to monitor treatment response and disease severity. 76 A major long-term goal of SCCRIP is to utilize genomic studies to predict SCD outcomes and guide treatment.…”