Exploring pleiotropic effects of lipid modifiers on coagulation and hemostasis with genetics

Background: Statins have long been suspected to have pleiotropic effects via thrombotic factors. Randomized controlled trials are too limited to be definitive. We examined the associations of genetically mimicking effects of statins, PCSK9 inhibitors and alternative lipid targets (in genes LDLR, APOC3, and LPL) on key indicators of coagulation system function, i.e., prothrombin time (PT) and activated partial thromboplastin time (aPTT). Methods: We assessed the effect of established genetic mimics of effects of lipid modifiers and alternative lipid treatment targets on PT (n=58,110) and aPTT (n=37,767), all transformed to z-scores, using Mendelian randomization taking advantage of Biobank Japan. Ischemic heart disease (IHD) was a control outcome. Results: Genetically mimicked effects of statins increased PT by 0.31 standard deviation (SD) per SD increase in LDL (95% confidence interval (CI) 0.10 to 0.51) based on rs12916 but did not affect aPTT. Genetically mimicking effects of targeting LDLR increased PT based on rs688 (0.33 SD per SD increase in TG, 95% CI 0.03 to 0.63) but did not affect aPTT. Genetically mimicking effects of PCSK9 inhibitors or targeting APOC3, or LPL had no effect on PT or aPTT. Genetically mimicking effects of statins, PCSK9 inhibitors and alternative lipid targets reduced risk of IHD in Biobank Japan. Conclusion: Statins, and possibly targeting LDLR, may also act via a coagulation cascade factor, likely specific to the extrinsic or common pathway. Further elucidation of the mechanistic pathway may facilitate development of new interventions and inform use of statins particularly in relation to use of other anticoagulants.

Predicting the effect of statins on cancer risk using genetic variants: a Mendelian randomization study in UK Biobank

Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. We here assess the potential effect of statin therapy on cancer risk in Mendelian randomization analyses. We obtained genetic associations with the risk of overall and 22 site-specific cancers for 367,703 individuals in UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (OR per 1 standard deviation increase in LDL-cholesterol 1.32, 95% CI 1.13-1.53, p=0.0003), but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9, LDLR, NPC1L1, APOC3, LPL) were not. Genetically-predicted LDL-cholesterol was not associated with overall cancer risk (OR 1.01, 95% CI 0.98-1.05, p=0.50). Our results predict that statins reduce cancer risk, but other lipid-lowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.

Nanoformulations for glioblastoma multiforme: a new hope for treatment

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, associated with a high mortality rate and a survival of between 12 and 15 months after diagnosis. Due to current treatment limitations involving surgery, radiotherapy and chemotherapy with temozolamide, there is a high rate of treatment failure and recurrence. To try to overcome these limitations nanotechnology has emerged as a novel alternative. Lipid, polymeric, silica and magnetic nanoparticles, among others, are being developed to improve GBM treatment and diagnosis. These nanoformulations have many advantages, including lower toxicity, biocompatibility and the ability to be directed toward the tumor. This article reviews the progress that have been made and the large variety of nanoparticles currently under study for GBM.

Quality and Consumer Acceptance of Meat from Rabbits Fed Diets in Which Soybean Oil is Replaced with Black Soldier Fly and Yellow Mealworm Fats

This trial investigated the effect of the dietary inclusion of Hermetia illucens (H) and Tenebrio molitor (T) fats as alternative lipid sources for growing rabbits, and assessed the carcass characteristics; proximate composition; lipid peroxidation, and fatty acid profile of the meat, as well as consumer acceptance. At weaning, 200 crossbred rabbits (1051 ± 138 g initial body weight) were allotted to five isolipidic (4% dry matter (DM)) dietary treatments: a control diet (C) containing 1.5% of soybean oil, and four experimental diets in which soybean oil was partially (50%) or totally (100%) substituted by H (H50 and H100) or T (T50 and T100) fats. The carcass characteristics, the meat quality traits, and the consumer acceptance of the cooked meat were not affected. The fat content of Longissimus thoracis et lumborum muscle of the rabbits was 1.1% on average. In the case of rabbit fed the H diets (average of diets H50 and H100), the same muscles revealed a higher saturated fatty acid proportion (47.1% vs. 39.7% and 40.8%, respectively) and a lower polyunsaturated fatty acid proportion than the rabbits fed the C and T diets (average of diets T50 and T100) (26.5% vs. 31.7% and 29.7%) (p < 0.001). The meat of the rabbits fed the diets containing insect fat (average for H and T diets) was less susceptible to oxidation (0.24 vs. 0.39 mg malondialdehyde/kg meat in the C group; p < 0.01).

Statin-Associated Bilateral Foot Myopathy

Objective: To report a case of statin-induced bilateral foot myopathy that resulted from 2 different statins. Case Summary: A 44-year-old Caucasian male with a history of ventricular fibrillation cardiac arrest, hyperlipidemia, and coronary artery disease experienced bilateral foot pain, weakness, and soreness while taking atorvastatin 20 mg daily. The pain subsided within weeks of discontinuing atorvastatin but returned years later after the initiation of rosuvastatin. The Naranjo probability scale indicates that this is a definite association between bilateral foot myopathy and statin use. Discussion: There is an association with statin use and lowering cardiovascular risk in patients with dyslipidemia and cardiovascular disease. However, statin metabolites can accumulate in the myocytes of muscle groups to cause a common side effect of myopathy. Statin myopathy typically occurs in large, bilateral, or proximal muscle groups, such as the thighs, back, calves, or buttocks. This patient was unusual in that his muscle symptoms only occurred in his feet and was severe enough to affect his ambulation. Conclusion: Stain-associated muscle symptoms have been reported to lessen medication adherence. There is also a risk with muscle symptoms that the patient could develop rhabdomyolysis, a rare but serious condition. Recognizing statin-associated muscle symptoms even in uncommon locations is important, so that alternative lipid-lowering strategies can be implemented to lower cardiovascular risk.

Statin-associated muscle symptoms: epidemiology, risk factors, mechanisms and treatment

Statins are widely prescribed and the risk of adverse drug reactions of lipid-lowering therapy is actively discussed, including muscle symptoms. This review synthesizes the knowledge about the clinical aspects of statin-associated muscle symptoms, which is important for the practitioner. Potential mechanisms of their development, risk factors, clinical manifestations, treatment and prevention are described. Timely detection the side effects of statins makes it possible to diagnose and eliminate, which is crucial for conducting lipid-lowering therapy for patients with atherosclerotic cardiovascular diseases. Management of statin-associated muscle symptoms requires altering (reduced dosages, use of another statin or alternative lipid-lowering drugs) or discontinuing the statin treatment.