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Update - Week 50,  2017 
 
Curated by Peter Lansberg,
a Dutch lipidologist and educator, and
reviewed by prof. Philip Barter, Past President of the
International Atherosclerosis Society.
The IAS Statin Newsletter will keep you up-to-date with all recent statin publications, using a curated approach to select relevant articles.

Key publications

The two faces of plaque calcification
Statins effectively regress coronary plaques and reduce CV events. The increase in plaque calcifications has been a somewhat contradictory observation that is poorly understood. In this review, the authors provide an explanation of this seemingly conflicting observation. Calcification is an inflammation driven process, that can be observed in all phases of the atherosclerosis process, they make a distinction in the type of macrophages involved. Macrophages with the pro-inflammatory M1 phenotype produce cytokines such as  IL-1β, IL-6 TNF-alpha and oncostatin M (OSM) that stimulate mineralization of smooth muscle cells and promote micro calcifications.The M2 macrophages are involved in the healing response of plaque inflammation, and in response may facilitate macroscopic calcium deposits. This process is stimulated by the induction of osteoblastic differentiation and maturation of vascular smooth muscle cells. The authors suggest that macro calcification reflect plaque stability while micro calcifications are associated with plaque instability and rupture. Statins promote the healing processes in the AS plaques by enhancing M2 type macrophages, responsible for the observed macro calcifications. The reported increase in calcium deposits, observed in statin imaging trials, should be interpreted differently in contrast with the pro-inflammatory micro calcifications observed in the process of atherosclerosis progression and plaque destabilization. The precise molecular mechanisms of these two-different type of calcification processes need to be explored further and might provide us with new therapeutic strategies for patients with increased CVD risk.
Shioi A, Ikari Y. Plaque Calcification During Atherosclerosis Progression and Regression. J Atheroscler Thromb 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29238011

High throughput NMR metabolic lipoprotein profiling in 394 PREVEND IT participants
Using advanced lipid profiling techniques can provide new insights in the complexity of lipid metabolism and the effects lipid modulation by cholesterol lowering drugs such as statins. The authors of this study examined the effects of pravastatin in the participants of the PREVEND-IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial). Using a nuclear magnetic resonance–based metabolomics platform, they performed a metabolic profiling of 231 lipoproteins and metabolite measurements in 394 of the 964 participants. Measurements were assessed at baseline and after 3 months of treatment. The diameters of VLDL (6 subclasses), IDL, LDL (3 subclasses) and HDL (4 subclasses) were compared in the two treatment arms. Patients using pravastatin showed lower (change in SD units) LDL-C −1.01 (−1.14−0.88); remnant cholesterol −1.03 (−1.17, −0.89), and apoB −0.98 (−1.11, −0.86). Changes in the HDL subclasses less consistent, with significant increases across large HDL subclasses measures and a reduction in small and very large HDL, all VLDL, IDL and LDL subclasses were reduced and distinct changes in lipid composition were observed as well; pronounced cholesterol reductions in VLDL subclasses, lower concentrations of fatty acids but with limited effects on fatty acid ratios. The authors concluded that the distinct effects on lipoprotein sub classes as well as fatty acid profiles were observed in the participants using pravastatin. After confirming the results, this novel high throughput metabolic profiling technique could evolve into a valuable instrument to support he discovery of future therapeutic strategies.
Kofink D, Eppinga RN, van Gilst WH et al. Statin Effects on Metabolic Profiles: Data From the PREVEND IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial). Circ Cardiovasc Genet 2017; 10. http://www.ncbi.nlm.nih.gov/pubmed/?term=29237679
Ho JE. Harnessing the Power of Pharmacometabolomics: The Metabolic Footprint of Statins. Circ Cardiovasc Genet 2017; 10. http://www.ncbi.nlm.nih.gov/pubmed/?term=29237684
 
Adding ω-3 fatty acids to rosuvastatin, what can we expect?
Multi center RCT to explore benefits of ω-3 fatty acids as add on therapy to rosuvastatin in patients with elevated TG’s despite statin therapy. An 8-week multi-center(N=33) placebo controlled RCT (June 2014 –March 2016) in Korean high CVD risk patients (N=215). After a 4-week run in period with rosuvastatin 20 mg, patients in whom TG’s remained elevated, were randomized to placebo or ω-3 fatty acids 4 g/day. Final analysis was possible in 201 evaluable patients. Combination therapy showed superior reductions in TG’s and non-HDL-C; -26.3% vs -11.4% (p<0.001) and -10.7% vs -2.2% (p=0.001) respectively. These effects were more pronounced if baseline TG or non-HDL-C were high and BMI was low. No differences in reported side effects between the two treatment arms. The authors concluded that the addition of ω-3 fatty acids to rosuvastatin 20 mg provided superior control of TG’s and non-HDL-C, in patients that started with high baseline concentrations of these lipoprotein factions. If these cosmetic improvements translate to better CVD outcomes has not been addressed in this study. Only a prospective placebo controlled outcome trial can provide a convincing answer to this question.
Kim CH, Han KA, Yu J et al. Efficacy and Safety of Adding Omega-3 Fatty Acids in Statin-Treated Patients with Residual Hypertriglyceridemia: ROMANTIC (Rosuvastatin-OMAcor iN residual hyperTrIglyCeridemia), a Randomized, Double-blind, and Placebo-controlled Trial. Clinical therapeutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29223557

New lipid targets to address residual risk?
Addressing residual risk in patients that despite on-target LDL-C are insufficiently protected remains an ongoing quest in lipid management. In this subgroup analysis of the Jupiter trial (N=9 423) NMR analysis of VLDL subclasses (small, medium and large) as well as total VLDL cholesterol mass was measured to quantify CHD risk changes. Patients in Jupiter were randomized to rosuvastatin 20 mg or placebo. Risk of ASCVD (N=211). for this analysis, minimal (<median) or greater (≥median) marker reductions, applying adjusted Cox models, was used in the rosuvastatin allocated group. Changes in VLDL related parameters were only modestly related to changes in LDL-C (Spearman r≤0.29). The median achieved plasma LDL-C reached 54 mg/dl, triglycerides 101 mg/dl. ASCVD risk reduction were noted in patients with greater reductions in LDL-C, VLDL cholesterol mass and small VLDL particle concentrations. After incremental adjustment for LDL-C change the latter two remained significant predictors of ASCVD risk (P<0.006). Statin related lower concentrations of triglycerides, medium and large VLDL particles were not associated with further ASCVD risk reductions. The authors concluded that in the rosuvastatin treated Jupiter population further reduction of triglycerides were not related to ASCVD risk reduction. Additional lowering of small cholesterol-enriched, triglyceride depleted VLDL dis provide superior protection for ASCVD complications. The current findings in this Jupiter sub-study should be viewed as hypothesis generating and warrant further exploration. 
Lawler PR, Akinkuolie AO, Harada P et al. Residual Risk of Atherosclerotic Cardiovascular Events in Relation to Reductions in Very-Low-Density Lipoproteins. J Am Heart Assoc 2017; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=29223956
 
Real World setting of managing statin associated muscle symptoms
The knowledge and science addressing statin intolerance remains limited and lacks simple straightforward and most important uniform recommendations for primary health care providers. With recent updated guidelines, and expanding numbers of patients considered statin eligible, the numbers of statin intolerant patients will rise sharply as well. The authors of this article aimed to review and analyze how patients that presented with statin tolerability issues, were managed. Data was collected by sending surveys to 10 138 pre-selected individuals from the Ailment Panel of Lightspeed Online Research - Consumer Panel (2009). These participants had a history of high cholesterol and statin use. The survey consisted of 89 questions related to demographics, employment, disease severity and history, treatment history and satisfaction, adherence, attitudes toward statin treatment, sources of information, and health resource costs. Of the former statin users (n=1 220) 60% reported muscle related problems in contrast with 25% of current statin users (N=8 918 – P<0.01). Statins were stopped due to muscle complaints, more frequently by former statin users compared with current users; standard deviations 2.2 ± 1.7 vs 1.6 ± 1.5 (p<0.0001). Patients that experienced muscle symptoms received the following recommendations from their health care providers: switching to other statin (33.8%), stopping the statin (15.9%), continuing the statin with further monitoring of muscle symptoms (12.2%), reducing the statin dose (9.8%), or getting a blood test for signs of muscle damage (9.2%). A lower percentage were advised to add either vitamin D (7.0%) or coenzyme Q10 (5.8%), or to switch to non-statin therapy (6.1%) or red yeast rice (2.6%).. The authors suggested that this descriptive analysis highlights the importance of statin associated muscle symptoms as well as the most common responses of health care providers. They emphasized the need for more research in order to formulate patient centric and evidence based approaches.  These are urgently needed to ensure that patients continue using statins, and protect them from the CV complications, so frequently observed in non-adherent patients.
Jacobson TA, Khan A, Maki KC et al. Provider recommendations for patient-reported muscle symptoms on statin therapy: Insights from the Understanding Statin Use in America and Gaps in Patient Education survey. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29239815 
 
Can ACS patients reach an LDL-C <70 mg/dl? Real World data from 18 different countries.
In the observational prospective follow-up DYSIS-II ACS study, 3 867 patients from 18 countries in Europe, the Middle East, South-, Southeast- and East-Asia participated. Patients hospitalized for ACS in 2013 – 2014 were included, reflecting a contemporary approach to lipid management of very high-risk patients. Data collected at base-line and after 120 ± 15 days of the ACS admission were evaluated to determine type and dosage of lipid lowering medication as well as number of patients able to achieve an LDL-C target of <70 mg/dl.  At admission 2 521 (65%) were prescribed lipid lowering drugs, using an equipotent atorvastatin dosage of 22 mg/day; 68 (2.7%) patients used Ezetimibe 10 mg as an add-on treatment. At discharge lipid lowering drugs were used by 3 767 patients with an equipotent atorvastatin dosage of 37 mg/day and 181 (4.8%) used ezetimibe 10 mg as an add-on treatment. After 120 days, the equipotent atorvastatin dosage decreased to 32 mg/day and the number of patients using ezetimibe 10 mg as an add-on treatment, increased slightly to 185 (4.9%). Overall an LDL-C target of <70mg/dl was achieved by 37%; ranging from 5,6% (Egypt) to 62% in Korea (100% of the 40 Jordan participants!). Laboratory testing, during the 4-month follow-up, was performed in in only 32% of all participants. The outcomes of this multinational prospective follow up study in very high-risk patients re-affirms that 2/3 of ACS patients are not achieving the internationally accepted LDL-C targets of < 70mg/dl. These targets are not unrealistic and within reach of all or 2/3 of the ACS patients in Jordan and Korea respectively.
Gitt AK, Lautsch D, Ferrieres J et al. Contemporary data on treatment practices for low-density lipoprotein cholesterol in 3867 patients who had suffered an acute coronary syndrome across the world. Data in brief 2018; 16:369-375. http://www.ncbi.nlm.nih.gov/pubmed/?term=29234694
Relevant publications
  1. Sumi A, Nakamura U, Iwase M et al. The gene-treatment interaction of paraoxonase-1 gene polymorphism and statin therapy on insulin secretion in Japanese patients with type 2 diabetes: Fukuoka diabetes registry. BMC medical genetics 2017; 18:146. http://www.ncbi.nlm.nih.gov/pubmed/?term=29233102
  2. Ozdemir T, Sahin I, Avci, II et al. Assessment of factors related to statin non-adherence in patients with established coronary artery disease: A single-center observational study. Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir 2017; 45:723-730. http://www.ncbi.nlm.nih.gov/pubmed/?term=29226893
  3. Oh J, Lee CJ, Kim DI et al. Target achievement with maximal statin-based lipid-lowering therapy in Korean patients with familial hypercholesterolemia: A study supported by the Korean Society of Lipid and Atherosclerosis. Clin Cardiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29243274
  4. Ma Y, Gong Y, Garg A, Zhou H. Compound heterozygous familial hypercholesterolemia in a Chinese boy with a de novo and transmitted low-density lipoprotein receptor mutation. J Clin Lipidol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29233637
  5. Cicero AFG, Bove M, Borghi C. Pharmacokinetics, pharmacodynamics and clinical efficacy of non-statin treatments for hypercholesterolemia. Expert Opin Drug Metab Toxicol 2017:1-7. http://www.ncbi.nlm.nih.gov/pubmed/?term=29231064
  6. Van Wyhe RD, Rahal OM, Woodward WA. Effect of statins on breast cancer recurrence and mortality: a review. Breast cancer (Dove Medical Press) 2017; 9:559-565. http://www.ncbi.nlm.nih.gov/pubmed/?term=29238220
  7. Smith LE, Smith DK, Blume JD et al. High-Density Lipoprotein Cholesterol Concentration and Acute Kidney Injury After Cardiac Surgery. J Am Heart Assoc 2017; 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=29223955
  8. Shek AB, Kurbanov RD, Abdullaeva GJ et al. Simvastatin intolerance genetic determinants: some features in ethnic Uzbek patients with coronary artery disease. Archives of medical sciences. Atherosclerotic diseases 2017; 2:e68-e75. http://www.ncbi.nlm.nih.gov/pubmed/?term=29242847
  9. Issa OM, Roberts R, Mark DB et al. Effect of high-dose oral multivitamins and minerals in participants not treated with statins in the randomized Trial to Assess Chelation Therapy (TACT). Am Heart J 2018; 195:70-77. http://www.ncbi.nlm.nih.gov/pubmed/?term=29224648
  10. Groom KM, David AL. The role of aspirin, heparin, and other interventions in the prevention and treatment of fetal growth restriction. American journal of obstetrics and gynecology 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29229321
  11. Go AS, Fan D, Sung SH et al. Contemporary rates and correlates of statin use and adherence in nondiabetic adults with cardiovascular risk factors: The KP CHAMP study. Am Heart J 2017; 194:25-38. http://www.ncbi.nlm.nih.gov/pubmed/?term=29223433
  12. Delles C, Rankin NJ, Boachie C et al. Nuclear magnetic resonance-based metabolomics identifies phenylalanine as a novel predictor of incident heart failure hospitalisation: results from PROSPER and FINRISK 1997. European journal of heart failure 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29226610
  13. de Grijs D, Teixeira P, Katz S. The association of statin therapy with the primary patency of femoral and popliteal artery stents. Journal of vascular surgery 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29224939
  14. Chen MC, Tsai YC, Tseng JH et al. Simvastatin Inhibits Cell Proliferation and Migration in Human Anaplastic Thyroid Cancer. Int J Mol Sci 2017; 18. http://www.ncbi.nlm.nih.gov/pubmed/?term=29236027
  15. Barnett S, Ogungbenro K, Menochet K et al. Gaining mechanistic insight into coproporphyrin I as endogenous biomarker for OATP1B-mediated drug-drug interactions using population pharmacokinetic modelling and simulation. Clinical pharmacology and therapeutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29243231
Miscellaneous publications
  1. Yu R, Longo J, van Leeuwen JE et al. Statin-induced cancer cell death can be mechanistically uncoupled from prenylation of RAS family proteins. Cancer research 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29229608
  2. Yang B, Sun J, Yuan Y, Sun Z. Effects of atorvastatin on autophagy in skeletal muscles of diabetic rats. Journal of diabetes investigation 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29245171
  3. Wang P, Luo L, Shen Q et al. Rosuvastatin improves myocardial Hypertrophy after hemodynamic Pressure overload via regulating the Crosstalk of Nrf2/ARE and TGF-beta/ Smads Pathways in Rat Heart. Eur J Pharmacol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29225188
  4. Okoye I, Namdar A, Xu L et al. Atorvastatin downregulates co-inhibitory receptor expression by targeting Ras-activated mTOR signalling. Oncotarget 2017; 8:98215-98232. http://www.ncbi.nlm.nih.gov/pubmed/?term=29228684
  5. Infante-Garcia C, Ramos-Rodriguez JJ, Hierro-Bujalance C et al. Antidiabetic Polypill Improves Central Pathology and Cognitive Impairment in a Mixed Model of Alzheimer's Disease and Type 2 Diabetes. Mol Neurobiol 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29224179
  6. Haas MJ, Jurado-Flores M, Hammoud R et al. The Effects of Known Cardioprotective Drugs on Proinflammatory Cytokine Secretion From Human Coronary Artery Endothelial Cells. American journal of therapeutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29232287
  7. Miller BR, Kung Y. Structural features and domain movements controlling substrate binding and cofactor specificity in class II HMG-CoA reductase. Biochemistry 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29224355
  8. Manickavasagam D, Novak K, Oyewumi MO. Therapeutic Delivery of Simvastatin Loaded in PLA-PEG Polymersomes Resulted in Amplification of Anti-inflammatory Effects in Activated Microglia. The AAPS journal 2017; 20:18. http://www.ncbi.nlm.nih.gov/pubmed/?term=29243172
  9. Cetkovic Z, Cvijic S, Vasiljevic D. In vitro/in silico approach in the development of simvastatin-loaded self-microemulsifying drug delivery systems. Drug development and industrial pharmacy 2017:1-49. http://www.ncbi.nlm.nih.gov/pubmed/?term=29228833
  10. Bai X, Wang XP, He GD et al. Simultaneous Determination of Rosuvastatin, Rosuvastatin-5 S-lactone, and N-desmethyl Rosuvastatin in Human Plasma by UPLC-MS/MS and Its Application to Clinical Study. Drug research 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29232752
  11. Awad E, Othman EM, Stopper H. Effects of Resveratrol, Lovastatin and the mTOR-Inhibitor RAD-001 on Insulin-Induced Genomic Damage In Vitro. Molecules (Basel, Switzerland) 2017; 22. http://www.ncbi.nlm.nih.gov/pubmed/?term=29231877
  12. Ahmed IS, El Hosary R, Hassan MA et al. Efficacy and Safety Profiles of Oral Atorvastatin-Loaded Nanoparticles: Effect of Size Modulation on Biodistribution. Molecular pharmaceutics 2017. http://www.ncbi.nlm.nih.gov/pubmed/?term=29232954  
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