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Update - Week 50, 2018
 
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

It’s the LDL-c stupid! Or is there more?
Comparing the effects pf statins with genetic inhibition of PCSK9 showed some interesting differences. Using NMR spectroscopy 228 lipid and metabolic parameters were analyzed in 2659 statin allocated participants of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. These results were compared to participants of 8 cohorts (N=72 185), of which 3 135 (2.2%) had a PCSK9 loss of function allele (rs 11591147), used as a proxy to mimic PCSK9ab treatment. The effects on a wide range of lipid and metabolic parameters were consistent when scaled to similar LDL-c lowering outcomes (R2=0.88). No changes in glycolysis related parameters were associated with genetic variations in PCSK9. This contrasts with the pro-diabetogenic risk reported in Mendelian randomization studies; alternative mechanism will need to be explored to explain these observations. Significant weaker effects on VLDL lipids and GlycA, a marker associated with inflammation. A reduced VLDL-c lowering was observed in carriers of PCSK9 SNP compared to statin use (54% versus 77% reduction, relative to LDL-C lowering; P=2×10-7 for heterogeneity). The authors concluded that these differences could potentially translate into smaller CVD risk decline for equivalent LDL-c reductions.
Sliz E, Kettunen J, Holmes MV et al. Metabolomic Consequences of Genetic Inhibition of PCSK9 Compared With Statin Treatment. Circulation 2018; 138:2499-2512. http://www.ncbi.nlm.nih.gov/pubmed/?term=30525347
 
 
Personalized ethnic treatment, intriguing observations in HOPE-3
Ethnic and genetic difference can have a significant impact on expected outcomes of medications to reduce blood pressure and LDL-cholesterol. In this sub-analysis of the HOPE-3 study, Asian participants (N=6241) were compared to non -Asians (N=6464). Both group were considered at intermediate risk and absent CVD. They were randomized to candesartan 16 mg/hydrochlorothiazide 12.5 mg or placebo and rosuvastatin 10 mg or placebo; median follow-up was 5.6 years. There were two primary outcomes, the first was a composite of cardiovascular disease death, myocardial infarction and stroke. The second additionally included heart failure, cardiac arrest and revascularization. No difference for both primary outcomes in the two groups. All patients did not improve endpoints related to BB lowering but clear and consistent benefits in all patients using rosuvastatin. Asians responded less favorably to the BP lowering medication compared to the non-Asians. Systolic BP -4.3 vs. -7.7mmHg for non-Asians, P<0.0001). This was mainly due to a lesser effect in Chinese (-2.1 mmHg) than in other Asians (-7.3 mmHg). On a similar note rosuvastatin was less effective in Asians as well, -0.49 mmol/L (–19.1 mg/dL) compared with non-Asians -0.95 mmol/L (-36.7 mg/dL), Pinteraction <0.0004). Reported medication discontinuation due muscle related symptoms were similar in both groups. But more non-Asians developed new onset diabetes compared to Asians. Non-Asians:  4.70% rosuvastatin, 3.52% placebo, P=0.025), Asians: 3.02% rosuvastatin, 4.04% placebo, P=0.0342), Pinteraction<0021. The authors concluded that Asian participant in the HOPE-3 study experience similar benefits as non-Asians without increased intolerability or safety issues.
Pais P, Jung H, Dans A et al. Impact of blood pressure lowering, cholesterol lowering and their combination in Asians and non-Asians in those without cardiovascular disease: an analysis of the HOPE 3 study. Eur J Prev Cardiol 2018:2047487318819019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30537846
 
Can we predict SAMS?
Exploring characteristics of patients presenting with statin associated muscle symptoms (SAMS) was the aim of this multi-center US/Canadian study. Between 2004 and 2013 748 statins using patients were included from 5 centers. These were all Caucasians (392 males and 356 females). The statin intolerant (N=634), based on questionnaire information, were compared with 114 statin tolerant patients. The collected data included physical characteristics, statin type + dosage, concomitant drugs, muscle complaints, co-morbidities and family history. Associations with SAMS were identified using a logistic regression model. The following characteristics were more common in patients with SAMS; positive family history for CVD (OR: 3.60, 95% CI: 2.08-6.22), Obesity (OR=3.08, 95% CI: 1.18, 8.05), hypertension (OR=2.24, 95% CI: 1.33, 3.77), smoking (OR=2.08, 95% CI: 1.16, 3.74), and statin type. Intriguingly no associations for age or sex were observed. A direct causality could not be determined. However, the results suggest that individuals presenting with these SAMS related features in their personal and family histories, may be at higher risk for developing muscle related symptoms. Attention to patients presenting with one or more of these characteristics could be used to develop improved preventive strategies to ensure long term statin compliance.
Ochs-Balcom HM, Nguyen LM, Ma C et al. Clinical Features Related to Statin-Associated Muscle Symptoms. Muscle Nerve 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30549046
 
Is there something we missed with Co-Q10 suppletion?
The effects of Co-enzyme Q10 (Q10) in patients using statins has predominantly focused on muscle related side effects. Unfortunately, studies that examined the potential benefits, showed contradictory outcomes and the use of Q10 for statin related muscle problems remains controversial. The authors of this article examined the effects of Q10 on insulin secretion/production. In this rodent study, pravastatin treated LDLr-/- knockout mice were shown to have mitigated insulin secretion as well as increased islet cell death and oxidative stress. Adding Q10 to the diet resulted in reversal of fasting hyperglycemia, improved glucose tolerance (20%) and a >2-fold increase in insulin sensitivity. The pravastatin triggered impaired islet glucose-stimulated insulin secretion (-40%), was fully restored with Q10 as well. Using Invitro experiments with INS1E cells, they showed that cells co-treated with Q10, were safeguarded from pravastatin triggered cell death and oxidative stress. Compared to pravastatin, simvastatin and atorvastatin showed stronger (10- 15-fold increase), dose dependent INS1E cell death. Q10 suppletion was associated with attenuated harmful effects as well. The observed outcomes in this rodent + cell culture model not only confirm the detrimental effects of statin on glycemic regulation but also point towards potential protective effects of Q10 in the context of statin use. Examining Q10’s glycemic benefits in statin users by means of a properly designed RCT, should be less challenging than evaluating the hard to objectify, nefarious statin related muscle problems.
Lorza-Gil E, de Souza JC, Garcia-Arevalo M et al. Coenzyme Q10 protects against beta-cell toxicity induced by pravastatin treatment of hypercholesterolemia. Journal of cellular physiology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30536661
 
Should Chinese CAD patients be treated differently?
The use of high dose/high intensity statins in Asian patients was and remains a controversial topic. Better response and less tolerability were arguments commonly voiced, low- intermediate potency statin would protect Asian CAD patients comparable to Caucasian CAD patients, where high does-high intensity statins are preferred in most major guidelines. In this Chines cross-sectional multi-center study (March 2015 – December 2016) 1 994 STEMI and NSTEMI patients were evaluated 4-40 weeks after their ACS hospitalization. Included patients were treated with statins for >2 weeks. Intensive statins (atorvastatin 40-80 mg or rosuvastatin 20 mg) were used by 1493 (74.9%) of all patients. A maximum tolerated statin dose was used by 499 (25%) of the patients. The majority of the 1 994 eligible patients were unable to reach lipid goals of LDL-C <1.80 mmol/L (70 mg/dL), or ApoB <0.8 g/L, or non-HDL-C <2.59 mmol/L (100 mg/dL). This included 910 (71.5%) of the patients on intensive statin therapy. The mean LDLC, Non-HDL-c and Apo B plasma concentrations in the 721 patients not at target, were 2.46±0.71 mmol/L, 3.1±0.89 mmol/L, and 0.84±0.30 g/L, respectively. The authors reflect on the inadequate use of high dose/high intensity statins as well as pointing towards the need for non-statin add-on treatment options such as ezetimibe and PCSK9ab. This study illustrates the common finding in Chinese and Caucasian patients with respect to inadequate use of statins as well as an urgent need for add on LDL-c lowering therapeutic strategies in high risk patients unable to reach lipid targets.
Jiang J, Zhou YJ, Li JJ et al. Uncontrolled hyperlipidemia in Chinese patients who experienced acute coronary syndrome: an observational study. Therapeutics and clinical risk management 2018; 14:2255-2264. http://www.ncbi.nlm.nih.gov/pubmed/?term=30532548
Relevant publications
  1. Zhang H, Cui Y, Zhao Y et al. Effects of sartans and low-dose statins on cerebral white matter hyperintensities and cognitive function in older patients with hypertension: a randomized, double-blind and placebo-controlled clinical trial. Hypertension research : official journal of the Japanese Society of Hypertension 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30552406
  2. Yamaguchi K, Wakatsuki T, Niki T et al. Observation of short-term atorvastatin-induced changes in coronary arterial plaque properties using integrated backscatter intravascular ultrasound in a patient. Journal of cardiology cases 2011; 3:e111-e114. http://www.ncbi.nlm.nih.gov/pubmed/?term=30532851
  3. Yagi S, Fujimura M, Akaike M et al. Increase in serum triglyceride was associated with coronary plaque vulnerability in a patient with rheumatoid arthritis. Journal of cardiology cases 2014; 10:54-57. http://www.ncbi.nlm.nih.gov/pubmed/?term=30546505
  4. Wagner JB, Abdel-Rahman S, Gaedigk R et al. Impact of genetic variation on pravastatin systemic exposure in pediatric hypercholesterolemia. Clinical pharmacology and therapeutics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30549267
  5. Shiga Y, Miura SI, Nishikawa H et al. Regression of coronary plaque after coronary artery bypass graft. Journal of cardiology cases 2012; 5:e92-e95. http://www.ncbi.nlm.nih.gov/pubmed/?term=30532913
  6. Sahebkar A, Simental-Mendia LE, Pirro M et al. Impact of ezetimibe on plasma lipoprotein(a) concentrations as monotherapy or in combination with statins: a systematic review and meta-analysis of randomized controlled trials. Scientific reports 2018; 8:17887. http://www.ncbi.nlm.nih.gov/pubmed/?term=30552391
  7. Rinella ME, Trotter JF, Abdelmalek MF et al. Rosuvastatin improves the FGF19 analogue NGM282-associated lipid changes in patients with nonalcoholic steatohepatitis. J Hepatol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30529590
  8. Park MW, Park GM, Han S et al. Moderate-intensity versus high-intensity statin therapy in Korean patients with angina undergoing percutaneous coronary intervention with drug-eluting stents: A propensity-score matching analysis. PLoS One 2018; 13:e0207889. http://www.ncbi.nlm.nih.gov/pubmed/?term=30532220
  9. Lee SH, Choi JH. Involvement of inflammatory responses in the early development of calcific aortic valve disease: lessons from statin therapy. Animal cells and systems 2018; 22:390-399. http://www.ncbi.nlm.nih.gov/pubmed/?term=30533261
  10. Ladapo JA, Pfeifer JM, Pitcavage JM et al. Quantifying Sex Differences in Cardiovascular Care Among Patients Evaluated for Suspected Ischemic Heart Disease. Journal of women's health (2002) 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30543478
  11. Kim WH, Lee CH, Han JH et al. C/EBP homologous protein deficiency inhibits statin-induced myotoxicity. Biochem Biophys Res Commun 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30528737
  12. Hemo B, Shahar DR, Geva D, Heymann AD. Adherence to quality of care measurements among 58,182 patients with new onset diabetes and its association with mortality. PLoS One 2018; 13:e0208539. http://www.ncbi.nlm.nih.gov/pubmed/?term=30540832
  13. Gupta KK, Ali S, Sanghera RS. Pharmacological Options in Atherosclerosis: A Review of the Existing Evidence. Cardiology and therapy 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30543029
  14. Dyrbus K, Gasior M, Desperak P et al. Characteristics of lipid profile and effectiveness of management of dyslipidaemia in patients with acute coronary syndromes - Data from the TERCET registry with 19,287 patients. Pharmacol Res 2018; 139:460-466. http://www.ncbi.nlm.nih.gov/pubmed/?term=30527895
  15. Downs TN. Statins: The Burglar of Memory? The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists 2018; 33:706-710. http://www.ncbi.nlm.nih.gov/pubmed/?term=30545434
  16. Qamar A, Giugliano RP, Keech AC et al. Interindividual Variation in Low-Density Lipoprotein Cholesterol Level Reduction With Evolocumab: An Analysis of FOURIER Trial Data. JAMA cardiology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30540337
  17. Cho YK, Nam CW, Koo BK et al. Usefulness of baseline statin therapy in non-obstructive coronary artery disease by coronary computed tomographic angiography: From the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) study. PLoS One 2018; 13:e0207194. http://www.ncbi.nlm.nih.gov/pubmed/?term=30540755
  18. Buhse S, Kuniss N, Liethmann K et al. Informed shared decision-making programme for patients with type 2 diabetes in primary care: cluster randomised controlled trial. BMJ Open 2018; 8:e024004. http://www.ncbi.nlm.nih.gov/pubmed/?term=30552272
  19. Blais JE, Chan EW, Law SWY et al. Trends in statin prescription prevalence, initiation, and dosing: Hong Kong, 2004-2015. Atherosclerosis 2018; 280:174-182. http://www.ncbi.nlm.nih.gov/pubmed/?term=30529830
  20. Al-Taani GM, Al-Azzam SI, Alzoubi KH, Aldeyab MA. Which drugs cause treatment-related problems? Analysis of 10,672 problems within the outpatient setting. Therapeutics and clinical risk management 2018; 14:2273-2281. http://www.ncbi.nlm.nih.gov/pubmed/?term=30532550
  21. Akbari H, Asadikaram G, Vakili S, Masoumi M. Atorvastatin and losartan may upregulate renalase activity in hypertension but not coronary artery diseases: The role of gene polymorphism. Journal of cellular biochemistry 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30548657
  22. Aguiar A, Giaquinto PC. Low cholesterol is not always good: low cholesterol levels are associated with decreased serotonin and increased aggression in fish. Biology open 2018; 7. http://www.ncbi.nlm.nih.gov/pubmed/?term=30530746
  23. Ung MH, MacKenzie TA, Onega TL et al. Statins associate with improved mortality among patients with certain histological subtypes of lung cancer. Lung cancer (Amsterdam, Netherlands) 2018; 126:89-96. http://www.ncbi.nlm.nih.gov/pubmed/?term=30527197
  24. Rosenson RS, Colantonio LD, Burkholder GA et al. Trends in Utilization of Statin Therapy and Contraindicated Statin Use in HIV--Infected Adults Treated With Antiretroviral Therapy From 2007 Through 2015. J Am Heart Assoc 2018; 7:e010345. http://www.ncbi.nlm.nih.gov/pubmed/?term=30526249
  25. Pahor M, Anton SD, Beavers DP et al. Effect of losartan and fish oil on plasma IL-6 and mobility in older persons. The ENRGISE Pilot randomized clinical trial. J Gerontol A Biol Sci Med Sci 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30541065
  26. Pagidipati NJ, Coles A, Hemal K et al. Sex differences in management and outcomes of patients with stable symptoms suggestive of coronary artery disease: Insights from the PROMISE trial. Am Heart J 2018; 208:28-36. http://www.ncbi.nlm.nih.gov/pubmed/?term=30529930
  27. Mori D, Kashihara Y, Yoshikado T et al. Effect of OATP1B1 genotypes on plasma concentrations of endogenous OATP1B1 substrates and drugs, and their association in healthy volunteers. Drug metabolism and pharmacokinetics 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30528195
  28. Kruk PJ. Beneficial effect of additional treatment with widely available anticancer agents in advanced small lung cell carcinoma: A case report. Molecular and clinical oncology 2018; 9:647-650. http://www.ncbi.nlm.nih.gov/pubmed/?term=30546895
  29. Gachpazan M, Kashani H, Khazaei M et al. The impact of statin therapy on survival of patients with gastrointestinal cancer. Current drug targets 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30539694
  30. Dekkers CC, Westerink J, Hoepelman AIM, Arends JE. Overcoming Obstacles in Lipid-lowering Therapy in Patients with HIV - A Systematic Review of Current Evidence. AIDS reviews 2018; 20:205-219. http://www.ncbi.nlm.nih.gov/pubmed/?term=30548018
  31. de Las Marinas Alvarez MD, Lopez Calatayud V, Solaz Garrido B et al. Moderate Asymptomatic Subacute Eosinophilia Secondary to Simvastatin Therapy. J Investig Allergol Clin Immunol 2018; 28:434-436. http://www.ncbi.nlm.nih.gov/pubmed/?term=30530396
  32. Chen MJ, Bala A, Huddleston JI, 3rd et al. Statin use is associated with less postoperative cardiac arrhythmia after total hip arthroplasty. Hip international : the journal of clinical and experimental research on hip pathology and therapy 2018:1120700018816091. http://www.ncbi.nlm.nih.gov/pubmed/?term=30526117
  33. Basu S, Wagner RG, Sewpaul R et al. Implications of scaling up cardiovascular disease treatment in South Africa: a microsimulation and cost-effectiveness analysis. The Lancet. Global health 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30528531
  34. Anderson-Carter I, Posielski N, Liou JI et al. The impact of statins in combination with androgen deprivation therapyin patients with advanced prostate cancer: A large observational study. Urologic oncology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30528885
Miscellaneous publications
 
 
  1. Yang CN, Kok SH, Wang HW et al. Simvastatin alleviates bone resorption in apical periodontitis possibly by inhibition of mitophagy-related osteoblast apoptosis. International endodontic journal 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30537112
  2. Palko-Labuz A, Sroda-Pomianek K, Wesolowska O et al. MDR reversal and pro-apoptotic effects of statins and statins combined with flavonoids in colon cancer cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2019; 109:1511-1522. http://www.ncbi.nlm.nih.gov/pubmed/?term=30551403
  3. Nonaka K, Ozaki Y, Ito K et al. Endurance exercise increases the protein levels of PGC-1alpha and respiratory chain complexes in mouse skeletal muscle during atorvastatin administration. The journal of physiological sciences : JPS 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30536041
  4. Milenkovic U, Ilg MM, Zuccato C et al. Simvastatin and the Rho-kinase inhibitor Y-27632 prevent myofibroblast transformation in Peyronie's disease-derived fibroblasts via inhibition of YAP/TAZ nuclear translocation. BJU international 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30536599
  5. Leite ML, Soares DG, de Oliveira Duque CC et al. Positive influence of simvastatin used as adjuvant agent for cavity lining. Clinical oral investigations 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30552591
  6. Guo X, Wang L, Xia X et al. Effects of atorvastatin and/or probucol on recovery of atherosclerosis in high-fat-diet-fed apolipoprotein E-deficient mice. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2019; 109:1445-1453. http://www.ncbi.nlm.nih.gov/pubmed/?term=30551396
  7. Gao G, Jiang S, Ge L et al. Atorvastatin improves doxorubicin-induced cardiac dysfunction by modulating Hsp70, Akt and MAPK signalling pathways. Journal of cardiovascular pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30540688
  8. Farsani BE, Karimi S, Mansouri E. Pravastatin attenuates testicular damage induced by doxorubicin - a stereological and histopatological study. Journal of basic and clinical physiology and pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=30530881
  9. El-Seweidy MM, Sarhan Amin R, Husseini Atteia H et al. Dyslipidemia induced inflammatory status, platelet activation and endothelial dysfunction in rabbits: Protective role of 10-Dehydrogingerdione. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2018; 110:456-464. http://www.ncbi.nlm.nih.gov/pubmed/?term=30530048
  10. Dang H, Song B, Dong R, Zhang H. Atorvastatin reverses the dysfunction of human umbilical vein endothelial cells induced by angiotensin II. Experimental and therapeutic medicine 2018; 16:5286-5297. http://www.ncbi.nlm.nih.gov/pubmed/?term=30542486
  11. Baliga M, Chakraborty S, Kumari T et al. Is there a role for PRF with simvastatin in stage I osteoradionecrosis? Oral oncology 2018; 87:177-178. http://www.ncbi.nlm.nih.gov/pubmed/?term=30527236
  12. Wang L, Yuan M, Zheng J. Crystal structure of the condensation domain from lovastatin polyketide synthase. Synthetic and systems biotechnology 2019; 4:10-15. http://www.ncbi.nlm.nih.gov/pubmed/?term=30533541
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