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Update - Week 27, 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

Statins + metformin a dream team?
Statins have proven their added value in CVD risk reduction but also revealed risks for muscle related complaints and increasing the chances of developing new onset diabetes (NOD), in patients that display pre-diabetic features. In this review the authors discuss the role that metformin could play in neutralizing the dysglycemic effects as well as triggering synergistic actions with statins. The authors provide an in-depth overview of potential intracellular processes where metformin and statins cross paths when combined and where synergy between the two drugs can have an impact on both plasma lipid and glucose levels. Statins decrease insulin release from pancreatic beta cells, by interacting with several insulin secretion related metabolic pathways as well as negatively affecting insulin sensitivity and increasing BMI. Metformin use is associated with a decrease in BMI, increased energy metabolism and was shown to increase GLP-1 production in the intestine. In the liver gluconeogenesis is inhibited These effects would account for the increase in insulin sensitivity as well as promoting insulin synthesis and release. Metformin’s effects on lipid metabolism are likely to take place in the intestine as well. It reduces intestinal bile acid uptake and force the liver to increase cholesterol production as well upregulate LDL-receptors to compensate for the lack of intestinal cholesterol flux. Benefits of this combination have been observed in patients with NAFLD, polycystic ovarium syndrome (PCOS) and diabetic retinopathy. With the introduction of a 1 tablet formulation (atorvastatin + metformin) trials will provide more detailed insights into the benefits of this synergistic combination.
van Stee MF, de Graaf AA, Groen AK. Actions of metformin and statins on lipid and glucose metabolism and possible benefit of combination therapy. Cardiovascular diabetology 2018; 17:94. http://www.ncbi.nlm.nih.gov/pubmed/?term=29960584
Contradictory effects of statins and low cholesterol on ICH
Can statins/low plasma cholesterol increase the risk for intracerebral hemorrhage? This question was addressed by evaluating a large Israeli health care provider registry that included 345 531 patients. Over a period of 5 years (2005 – 2010), 1304 ICH patients were sub-divided in to groups that used comparable average atorvastatin equivalent daily dose (AAEDD) and had a median follow-up of 9.5 years (interquartile range: 7.6-11.0 years). AAEDD categories were <10 mg/day, 10-19.9 mg/day and ≥20 mg/day. In patients that suffered an ICH, the statin use for the different AAEDD’s, were 81.0%, 15.0% and 4.0% respectively. In patients without ICH the use of the different AAEDD were 75.3%, 19.0% and 5.7%, respectively. Hazzard ratio’s (HR) for ICH I patients using statins, compared to patients with the <10 mg/day AAED, were HR 0.68 (0.58-0.79) for an AEDD 10-19,99 mg/day) and HR 0.62 (0.47-0.81) for an AAEDD >20 mg/day. When examining the impact of low cholesterol on ICH, the HR’s increased with decreasing cholesterol levels. Comparing the lowest baseline cholesterol level to the second third and fourth quartiles: OR: 0.71 (0.62–0.82), 0.55 (0.47–0.64), and 0.57 (0.49–0.67) respectively. The authors concluded that statin use was not associated with an increased risk of ICH, instead they observed a dose-dependent effect showing a reduced incidence of ICH’s. Low cholesterol did however show a relationship with an increased ICH risk.
Saliba W, Rennert HS, Barnett-Griness O et al. Association of statin use with spontaneous intracerebral hemorrhage: A cohort study. Neurology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29970405
Clinicians have a hard time catching up with the Guidelines
The trend for LDL-c targets continues downwards, the latest release of the AACE/ACE guidelines for lipid management added a new risk category: “extreme-risk”. Patient allocated to this level of CHD risk, are suggested to aim for an LDL- c target of < 55mg/dl. To evaluate how achievable this new LDL-c target is, the authors followed 1629 consecutive post ACS (>6 months), stable CAD, and that participate in the prospective Lipoprotein- Associated phospholipasE A2 in stable coronary aRTEry diSease (LAERTES) Study. Of the patients that were assigned to the extreme CVD risk category 32% had diabetes mellitus, 33% premature CAD and 9.2% HeFH. In total, 895 (55%) patients had at least one of those risk factors/characteristics. Lipid lowering therapy was used by 87%; an LDL-c <70mg/dl was observed in 20.3%, and LDL-c <55 mg/dl in 5.3%! Based on this sub analysis of the prospective Greek LAERTES study, more than half of the stable CAD patients were at extreme CVD risk. Only a very small percentage (∼5%) reached and LDL-c <55mg/dl. Promoting maximized traditional lipid lowering interventions e.g. high dose, high intensity statins + ezetimibe will need to be maximized to bridge the treatment gap, adding novel LDL-c lowering interventions by introducing PCSK9ab seems to be the next logical step, but cost-effectiveness of this approach will need to be addressed before successful implementation can become mainstream.
Rallidis LS, Kiouri E, Katsimardos A, Kotakos C. Extreme-risk category: High prevalence among stable coronary patients and an emerging widening treatment gap in achieving LDL-cholesterol less than 55mg/dL. Atherosclerosis 2018; 275:262-264. http://www.ncbi.nlm.nih.gov/pubmed/?term=29980053
Comparing the recent Taiwanese lipid guidelines to Western recommendations
The recently updated Taiwanese’s lipid guidelines resemble the commonly used European and US recommendations but have been slightly adapted to address specific Asian context. In this review the authors point out the similarities as well as highlighting some of the salient differences. For secondary prevention, including ACS, similar targets are embraced, including the LDL-c <55 mg/dl for Taiwanese patients with ASCVD + diabetes. Stroke patients should aim for an LDL-c <100 mg/dl. This contrasts with the other guidelines that advocate an LDL-c target of <70mg/dl. The rationale for this less aggressive approach is the higher incidence of hemorrhagic stroke (HS) in Asians compared to Caucasians and the increased HS risk observed in post-stroke patient that participated in the SPARCL trial. For diabetics without and with CVD similar LDL-c targets are advised, <100 mg/dl and <70 mg/dl respectively. In the later an LDL-c reduction of 30-40% is an alternative target if goals cannot be reached, this is less stringent as the >50% reduction other guidelines would aim for. For CKD patients the Taiwanese guidelines recommend starting statins if LDL-c > 100 mg/dl, but do not suggest a target. This should be implemented in patients with an EGFR <60 ml/min/1.73m2, not on dialysis. For FH patients without CVD and with CVD targets of < 100 mg/dl and < 70 mg/dl are recommended and are in line with other recent guidelines. The authors of the Taiwanese guidelines point out that their recommendations are in line with Western Guidelines but have added a few tweaks to accommodate the different genetic and physical characteristic of their Asian/Chinese patients.
Li YH, Yeh HI, Jeng JS, Charng MJ. Comparison of the 2017 Taiwan Lipid Guidelines and the Western Lipid Guidelines for High Risk Patients. Journal of the Chinese Medical Association : JCMA 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29980360
Predicting SAMS by means of a simple real time PCR commercial test
Predicting and or/confirming statin related muscle side effects is a challenging clinical dilemma. The role of SLCO1B1 c.521T>C polymorphism, as a harbinger of statin induced myopathy is gaining interests as so are the tests to confirm this relatively frequent genotype. The authors of this article analyzed the DNA of 181 healthy Austrian volunteers to estimate the prevalence of this polymorphism in Austria, as well as comparing two commercially available real time PCR assays to test for this genotype.  A total of 10 (5.5%) and 44 (24.3%) out of 181 individuals were SLCO1B1 c.521T>C C/C-homo and C/ T-heterozygotes. The SLCO1B1 c.521C allele frequency rate was 17.7%, pointing out that this is not an uncommon genetic finding in the Austrian population, potentially increasing the chances of developing SAM in the carriers of this genetic signature. Both tests provided robust, reliable and equal results and would make their use in clinical practice quite attractive.
Enko D, Harringer S, Oberkanins C et al. SLCO1B1 c.521T>C Genotyping in the Austrian Population Using 2 Commercial Real-Time Polymerase Chain Reaction Assays: An Implementation Study. Pharmacology 2018; 102:88-90. http://www.ncbi.nlm.nih.gov/pubmed/?term=29969773
Relevant publications
  1. Ruscica M, Ferri N, Macchi C et al. Lipid Lowering Drugs and Inflammatory Changes: an Impact on Cardiovascular Outcomes? Annals of medicine 2018:1-46. http://www.ncbi.nlm.nih.gov/pubmed/?term=29976096
  2. Zhang J, Liu N, Yang C. Effects of Rosuvastatin in combination with Nimodipine in patients with mild cognitive impairment caused by CSVD. Panminerva medica 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29962180
  3. Wang L, Wang Y, Wang H et al. The influence of the intestinal microflora to the efficacy of Rosuvastatin. Lipids Health Dis 2018; 17:151. http://www.ncbi.nlm.nih.gov/pubmed/?term=29960598
  4. Vithayathil M, Phung A. Near-Fatal Statin-Associated Autoimmune Myositis. Journal of clinical neurology (Seoul, Korea) 2018; 14:426-427. http://www.ncbi.nlm.nih.gov/pubmed/?term=29971985
  5. Ozkan B, Orscelik O, Uyar H et al. Awareness of Pleiotropic and Cardioprotective Effect of Statins in Patients with Coronary Artery Disease. BioMed research international 2018; 2018:8961690. http://www.ncbi.nlm.nih.gov/pubmed/?term=29977920
  6. Roberts R, Campillo A. Genetic stratification for primary prevention of coronary artery disease. Current opinion in cardiology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29979201
  7. Psarros C, Economou EK, Koutsilieris M, Antoniades C. Statins as Pleiotropic Modifiers of Vascular Oxidative Stress and Inflammation. Journal of critical care medicine (Universitatea de Medicina si Farmacie din Targu-Mures) 2015; 1:43-54. http://www.ncbi.nlm.nih.gov/pubmed/?term=29967815
  8. Mortensen MB, Nordestgaard B. Comparison of Five Major Guidelines for Statin Use in Primary Prevention. Annals of internal medicine 2018; 169:67-68. http://www.ncbi.nlm.nih.gov/pubmed/?term=29971420
  9. Lindblad AJ, Korownyk C. Comparison of Five Major Guidelines for Statin Use in Primary Prevention. Annals of internal medicine 2018; 169:66-67. http://www.ncbi.nlm.nih.gov/pubmed/?term=29971419
  10. Lee JY, Cha BS. Effects of Combination Therapy of Statin and Thiazolidinedione on Vascular Inflammation. Korean Circ J 2018; 48:602-604. http://www.ncbi.nlm.nih.gov/pubmed/?term=29968432
  11. Kerut EK, Hall ME, Turner MC, McMullan MR. Coronary risk assessment using traditional risk factors with CT coronary artery calcium scoring in clinical practice. Echocardiography (Mount Kisco, N.Y.) 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29974506
  12. Jeyamalar R, Wan Azman WA, Nawawi H et al. Updates in the management of Dyslipidaemia in the high and very high-risk individual for CV risk reduction. The Medical journal of Malaysia 2018; 73:154-162. http://www.ncbi.nlm.nih.gov/pubmed/?term=29962499
  13. Giral P. Comparison of Five Major Guidelines for Statin Use in Primary Prevention. Annals of internal medicine 2018; 169:67. http://www.ncbi.nlm.nih.gov/pubmed/?term=29971418
  14. Alzghari SK. An Unnecessary Pain: Using Pharmacogenetics for Statin-related Skeletal Muscle Toxicity. Cureus 2018; 10:e2557. http://www.ncbi.nlm.nih.gov/pubmed/?term=29974012
  15. Nose D, Shiga Y, Ueda Y et al. Association between plasma levels of PCSK9 and the presence of coronary artery disease in Japanese. Heart Vessels 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29974199
  16. Lorenzatti AJ, Eliaschewitz FG, Chen Y et al. Rationale and design of a randomized study to assess the efficacy and safety of evolocumab in patients with diabetes and dyslipidemia: the BERSON clinical trial. Clin Cardiol 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29962050
  17. Liu ZJ, Hu GP, Fei MY et al. Effects of Short-term High Dose Atorvastatin on Left Ventricular Remodeling in Patients with First Time Attack of Anterior Acute Myocardial Infarction. Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih / Chinese Academy of Medical Sciences 2018; 33:84-90. http://www.ncbi.nlm.nih.gov/pubmed/?term=29976277
  18. Lind PM, Salihovic S, Stubleski J et al. Changes in plasma levels of perfluoroalkyl substances (PFASs) are related to increase in carotid intima-media thickness over 10 years - a longitudinal study. Environmental health : a global access science source 2018; 17:59. http://www.ncbi.nlm.nih.gov/pubmed/?term=29970113
  19. Kroger K, Espinola-Klein C, Hoffmann U et al. [Peripheral Arterial Disease: When is a PCSK9 Inhibitor Useful?]. Deutsche medizinische Wochenschrift (1946) 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29972852
  20. Kaltoft MK, Nielsen JB, Dowie J. Risk Thresholds and Risk Classifications Pose Problems for Person-Centred Care. Studies in health technology and informatics 2018; 251:19-22. http://www.ncbi.nlm.nih.gov/pubmed/?term=29968591
  21. Arima R, Marttila M, Hautakoski A et al. Antidiabetic Medication, Statins and the Risk and Prognosis of Non-endometrioid Endometrial Cancer in Women with Type 2 Diabetes. Anticancer research 2018; 38:4169-4178. http://www.ncbi.nlm.nih.gov/pubmed/?term=29970546
  22. Al Sifri S, Al Shammeri O, Al Jaser S et al. Prevalence of lipid abnormalities and cholesterol target value attainment in patients with stable coronary heart disease or an acute coronary syndrome in Saudi Arabia. Saudi medical journal 2018; 39:697-704. http://www.ncbi.nlm.nih.gov/pubmed/?term=29968891
  23. Akbari H, Asadikaram G, Jafari A et al. Atorvastatin, losartan and captopril may upregulate IL-22 in hypertension and coronary artery disease; the role of gene polymorphism. Life sciences 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29981321
Miscellaneous publications
  1. Zhang T, Lu D, Yang W et al. HMG-CoA Reductase Inhibitors Relieve Endoplasmic Reticulum Stress by Autophagy Inhibition in Rats With Permanent Brain Ischemia. Frontiers in neuroscience 2018; 12:405. http://www.ncbi.nlm.nih.gov/pubmed/?term=29970982
  2. Yaghobee S, Ghahroudi A, Khorsand A et al. Radiographic Comparison of Bovine Bone Substitute Alone Versus Bovine Bone Substitute and Simvastatin for Human Maxillary Sinus Augmentation. Journal of dentistry (Tehran, Iran) 2018; 15:20-29. http://www.ncbi.nlm.nih.gov/pubmed/?term=29971118
  3. Ma YR, Wu YF, Duan YQ et al. [Effects of metoprolol or/and pravastatin on the pharmacokinetics of metformin in rats]. Yao xue xue bao = Acta pharmaceutica Sinica 2017; 52:253-257. http://www.ncbi.nlm.nih.gov/pubmed/?term=29979507
  4. Karimi B, Ashrafi M, Shomali T, Yektaseresht A. Therapeutic effect of simvastatin on DMBA-induced breast cancer in mice. Fundamental & clinical pharmacology 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29962034
  5. Husain I, Akhtar M, Madaan T et al. Rosuvastatin alleviates high-salt and cholesterol diet-induced cognitive impairment in rats via Nrf2-ARE pathway. Redox report : communications in free radical research 2018; 23:168-179. http://www.ncbi.nlm.nih.gov/pubmed/?term=29961403
  6. Einbond LS, Soffritti M, Esposti DD et al. A transcriptomic analysis of black cohosh: Actein alters cholesterol biosynthesis pathways and synergizes with simvastatin. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 2018. http://www.ncbi.nlm.nih.gov/pubmed/?term=29969672
  7. Choo EH, Han EJ, Kim CJ et al. Effect of Pioglitazone in Combination with Moderate Dose Statin on Atherosclerotic Inflammation: Randomized Controlled Clinical Trial Using Serial FDG-PET/CT. Korean Circ J 2018; 48:591-601. http://www.ncbi.nlm.nih.gov/pubmed/?term=29968431
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