Lipophilic versus hydrophilic statin therapy for heart failure: a protocol for an adjusted indirect comparison meta-analysis

Abstract

BackgroundStatins are known to reduce cardiovascular morbidity and mortality in primary and secondary prevention studies. Subsequently, a number of nonrandomised studies have shown statins improve clinical outcomes in patients with heart failure (HF). Small randomised controlled trials (RCT) also show improved cardiac function, reduced inflammation and mortality with statins in HF. However, the findings of two large RCTs do not support the evidence provided by previous studies and suggest statins lack beneficial effects in HF. Two meta-analyses have shown statins do not improve survival, whereas two others showed improved cardiac function and reduced inflammation in HF. It appears lipophilic statins produce better survival and other outcome benefits compared to hydrophilic statins. But the two types have not been compared in direct comparison trials in HF.Methods/designWe will conduct a systematic review and meta-analysis of lipophilic and hydrophilic statin therapy in patients with HF. Our objectives are:1. To determine the effects of lipophilic statins on (1) mortality, (2) hospitalisation for worsening HF, (3) cardiac function and (4) inflammation.2. To determine the effects of hydrophilic statins on (1) mortality, (2) hospitalisation for worsening HF, (3) cardiac function and (4) inflammation.3. To compare the efficacy of lipophilic and hydrophilic statins on HF outcomes with an adjusted indirect comparison meta-analysis.We will conduct an electronic search of databases for RCTs that evaluate statins in patients with HF. The reference lists of all identified studies will be reviewed. Two independent reviewers will conduct the search. The inclusion criteria include:1. RCTs comparing statins with placebo or no statin in patients with symptomatic HF.2. RCTs that employed the intention-to-treat (ITT) principle in data analysis.3. Symptomatic HF patients of all aetiologies and on standard treatment.4. Statin of any dose as intervention.5. Placebo or no statin arm as control.The exclusion criteria include:1. RCTs involving cerivastatin in HF patients.2. RCTs with less than 4 weeks of follow-up.DiscussionWe will perform an adjusted indirect comparison meta-analysis of lipophilic versus hydrophilic statins in patients with HF using placebo or no statin arm as common comparator.

The Effect of Locally Delivered Statins on Treating Periodontal Intrabony Defects: A Systematic Review and Meta‐Analysis

“…SMV is a natural, mevalonic acid‐derived statin, and ATV is a synthetic, heptenoic acid‐derived statin. SMV and ATV are both lipophilic, which is why they passively diffuse through the cell membrane and are transported by specific carriers 42 . RSV is a hydrophilic statin that has prolonged effects compared with other statins.…”

Statins in therapy: Understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies

“…There are many clinical studies focussing on the differences between so-called hydrophilic and hydrophobic statins. Lipophilic versus hydrophilic statin therapy for heart failure has been assessed [8][9], and some of the pleiotropic (properties independent of cholesterol lowering outcomes) effects of statins including effects on malignancies [4][5][6][7] may be related to use of hydrophobic statins.…”

Effect of atorvastatin and rosuvastatin on glucose intolerance in low dose streptozotocin induced hyperglycemic Albino rats

“…14 The presence or absence of polar moieties on their largely hydrophobic structures influence solubility and localisation due to which metabolic differences among the statins occur. 15,16 Atorvastatin, fluvastatin, pitavastatin, simvastatin, cerivastatin and lovastatin are lipophilic, while pravastatin and rosuvastatin are hydrophilic. 16 Hydrophilic statins are more hepatocyte specific and less likely to enter extrahepatic cell membranes such as β cells of pancreas, adipocytes or skeletal muscles whereas lipophilic statins can more readily penetrate these tissues therefore it has been hypothesized that the latter might be more diabetogenic.…”

“…15,16 Atorvastatin, fluvastatin, pitavastatin, simvastatin, cerivastatin and lovastatin are lipophilic, while pravastatin and rosuvastatin are hydrophilic. 16 Hydrophilic statins are more hepatocyte specific and less likely to enter extrahepatic cell membranes such as β cells of pancreas, adipocytes or skeletal muscles whereas lipophilic statins can more readily penetrate these tissues therefore it has been hypothesized that the latter might be more diabetogenic. 17 Lipophilic statins enter into cells by passive diffusion, whereas hydrophilic statins employ carrier-mediated mechanisms for uptake.…”