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Update - Week 14, 2019
 
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

IMNM – an uncommon statin side effect
A rare but serious complication in patients using statins is an auto-immune mediated necrotizing myopathy (IMNM), with an estimated incidence of 2-3 per 100 000 patients. This compact case review aims to familiarize lipid specialists with symptoms and diagnostic features as well as therapeutic options. This review was based on a retrospective analysis of 5 cases with an average of 2-3-year follow up. Common symptoms shared by all patients was proximal muscle weakness that persisted after statin cessation. Muscle biopsies showed necrotizing myopathy but absent inflammatory infiltrates. MRI confirmed the presence of edema as well as inflammation of the subcutis and muscular fasciae of arms and legs plus fatty muscle replacements. Positive HMGCR antibodies, MRI and biopsies were determined to be fundamental for the diagnosis of IMNM. These diagnostic features distinguish IMNM from the more common toxic myopathy All patients were treated with combined immunomodulatory treatments, initially with IV steroids, followed by high-dose oral steroid therapy and additional immunosuppressive drugs. All patients were able to achieve clinical remission, attributed to these regimens. With an estimated 200 million statin users worldwide, there are potentially 4000 – 6000 patients prone to develop these serious adverse events. Awareness of these distinctive characteristics will increase the odds of a timely diagnosis and improve the chances of complete remission using a combined immunosuppressive therapeutic approach.
Villa L, Lerario A, Calloni S et al. Immune-mediated necrotizing myopathy due to statins exposure. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology 2018; 37:257-262. http://www.ncbi.nlm.nih.gov/pubmed/?term=30944904
 
Should statins be used post TAVR procedures?
Statins have shown protective benefits in patients that had invasive cardiac procedures such as PTCA and CABG. In this retrospective analysis of 3956 participants of the PARTNER and Sapiens 3 trial/registry, who had transcatheter aortic valve replacements (TAVR), 626 post procedure patients using statins were matched to 626 patients not using a statin. Endpoints of the study all proved to be favorable in the statin-treated patients. All-cause mortality, HR: 0.65 (0.49-0.87, P=0.001); cardiovascular mortality, HR: 0.66 (0.46-0.96, P=0.030), and non-cardiovascular mortality, HR: 0.64 (0.44-0.99, P=0.045). Separation of the curves started at 3 months and continued to separate even more, over the 2.1 years follow up period of the study. The observed mortality benefits were not driven by reduced AMI or strokes in patients on a statin and anti-inflammatory or pleiotropic effects of statins were proposed an explanation. The investigators used so-called falsification endpoints to test for healthy selection bias. These endpoints were similar in both groups; e.g. urinary infection (P=0.66) and hip fracture (P=0.64). The authors concluded that statins used by patients discharged after TAVR, reduced cardiovascular and non-cardiovascular mortality, compared with no statin use. Although pleiotropic effects of statins could be responsible for the observed early benefits, residual confounding, despite propensity-matching, cannot be ruled out and prospective randomized studies will need to confirm these observations.
Peri-Okonny PA, Liu Y, Malaisrie SC et al. Association of Statin Use and Mortality After Transcatheter Aortic Valve Replacement. J Am Heart Assoc 2019; 8:e011529. http://www.ncbi.nlm.nih.gov/pubmed/?term=30947591
 
2018 cholesterol management guidelines – a secondary prevention perspective  
The updated cholesterol management guidelines have incorporated data from the recent major clinical trials that used non-statins as add-on therapy to statins in high CVD risk secondary patients. This review highlights the trials that impacted and changed the previous guidelines, as well as the proposed assessments before therapeutic decisions are made and executed. The 3 major endpoint trials responsible for changing the high-intensity high dose statin monotherapy approach were the IMPROVE-IT (ezetimibe 10 mg + simvastatin 40 mg vs simvastatin 40 mg) FOURIER (evolocumab + statin vs statin) and ODYSSEY OUTCOMES (alirocumab + statin vs statins). These trials proved the CV benefits of this non-statin lipid lowering drugs, as well as pointing out that incremental lower targets, compared to the LDL-c < 70 mg/dl of the previous guidelines, provided additional protection. In the 2018 guideline high dose – high-intensity statins remain the first choice and risk stratification for secondary prevention patients is introduced. Not very high-risk patients are contrasted with very high-risk patients, in the latter group additional non-statin lipid-lowering drugs can be used. No absolute LDL-c treatment targets are advocated except a > 50% LDL-c reduction when using high-intensity statins and 30-49% reduction with moderate intensity statins, in patients that cannot tolerate high-intensity statins. In very high-risk patients with an LDL-c > 70 mg/dl, despite maximum tolerated statin therapy, a stepwise approach, advising a first-line therapy with ezetimibe, followed by PCSK9ab if a patient’s LDL-c remains > 70 mg/dl. A major driving force this directive is the price for PCSK9ab, they failed to be cost-effective in most simulation models, when compared to ezetimibe; currently available in generic formulations. Prudent use is advocated, targeting only very high-risk patients, that failed to respond adequately to high-intensity statins -/+ ezetimibe. The 2018 cholesterol guidelines support the initiation of high-to moderate intensity statins or continuation of high-intensity statins for those adults >75 with clinical ASCVD who tolerate it well. However, treatment decisions should be made after a clinician-patient risk discussion, evaluating the competing risk of other comorbidities, incorporating patient preferences, values, and cost of therapy.
Jia X, Al Rifai M, Birnbaum Y et al. The 2018 Cholesterol Management Guidelines: Topics in Secondary ASCVD Prevention Clinicians Need to Know. Curr Atheroscler Rep 2019; 21:20. http://www.ncbi.nlm.nih.gov/pubmed/?term=30941517
 
Statin adherence post-AMI significantly impacts survival
Statin adherence remains a hurdle that is important to address. Using data collected in a Medicare administrative claims registry, a retrospective analysis was performed in 101 101 post-AMI patients (≥66 years) hospitalized between 2008 – 2010. Statin adherence was evaluated 180 days prior to the event and 180 days post AMI. Patients were categorized as adherent, moderately non-adherent and severely non-adherent. Change in adherence status was compared with findings prior and post AMI hospitalization. Patients were followed for 18 months to evaluate all-cause mortality. Increase in adherence after the AMI was noted in 20% of the participants; 16% decreased in adherence and 14% remained non-adherent pre- and post AMI event. Reduced mortality was observed in patients that improved adherence; from severely non-adherent to adherent, after suffering an AMI, HR: 0.83 (0.75–0.92). This was similar in patients that remained adherent prior and post AMI, HR: 0.88 (0.82-0.94). Patients were less likely to survive if they changed from adherent or moderately non-adherent prior to the AMI to severely non-adherent post-AMI, HR: 1.09 (0.99-1.20) and HR: 1.11 (1.01-1.22) respectively. This is compared with patients that were severely non-adherent pre- and post-AMI. The authors emphasized that nonadherence was associated with increased mortality over a relatively short period of 18 months. What was a re-assuring finding is that non-adherent patients that became adherent after the AMI enjoyed a similar risk reduction as patients that were adherent prior- as well as post-AMI. Never too late to improve statin adherence. Underlining the importance of not stopping with statins after an ASCVD event as well as adhering to this class of lipid-lowering drugs after an AMI, even if adherence was less then ideal before hospitalization.
Hickson RP, Robinson JG, Annis IE et al. It's Not Too Late to Improve Statin Adherence: Association Between Changes in Statin Adherence from Before to After Acute Myocardial Infarction and All-Cause Mortality. J Am Heart Assoc 2019; 8:e011378. http://www.ncbi.nlm.nih.gov/pubmed/?term=30929542
 
Impact of LDL-c levels in secondary prevention - real-world data  
The Rochester Epidemiology Project (REP), is a records-linkage system capturing health care utilization and outcomes of the Olmsted County (Minnesota) residents. Starting in 1966, the REP collected data of more 500 000 people and 6 million person-years of follow-up. For these analysis persons included were diagnosed with ASCVD (2005 -2012), had an LDL-c measurement < 90 days post event and used moderate or high-intensity statins. Using a Cox regression model the relationship between LDL-c and a composite endpoint of CV event and all-cause death was evaluated. In the 1854 patients, with an ASCVD index event, 1241 new events were recorded during the median follow-up period of 5.9 years. The event rate per 100 person-years was 11.26 (10.64-11.91). Follow-up event rates after 90 days post ASCVD diagnosis for patients with LDL-c < 70 mg/dl; 70-100 mg/dl and > 100 mg/dl were 10.51 (9.57 to 11.52), 9.57 (8.66 to 10.55), and 11.40 (9.96 to 12.98) respectively. After multivariate adjustments the HR for CV event and/or death was 1.31 (1.08-1.59), when comparing the patients with an LDL-c > 100 mg/dl with an LDL-c < 70 mg/dl. These observations re-enforce the importance of lowering LDL-c adequately but also show that a significant ASCVD burden remains even in patients able to achieve an LDL-c <70 mg/dl.
Chamberlain AM, Cohen SS, Weston SA et al. Relation of Cardiovascular Events and Deaths to Low-Density Lipoprotein Cholesterol Level Among Statin-Treated Patients With Atherosclerotic Cardiovascular Disease. Am J Cardiol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30948001
Relevant publications
  1. Schade DS, Obenshain SS, Eaton RP. Prevention of Statin Overtreatment and Increased Patient Compliance in High Cardiovascular Risk Individuals. Am J Med 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30953634
  2. Rosenson RS, Daviglus ML, Handelsman Y et al. Efficacy and safety of evolocumab in individuals with type 2 diabetes mellitus: primary results of the randomised controlled BANTING study. Diabetologia 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30953107
  3. Poli A. Primary prevention and hypercholesterolaemia: 'Doc, please, give me the natural statin'. European heart journal supplements : journal of the European Society of Cardiology 2019; 21:B71-b72. http://www.ncbi.nlm.nih.gov/pubmed/?term=30948955
  4. Petit C, Batool F, Bugueno IM et al. Contribution of Statins towards Periodontal Treatment: A Review. Mediators Inflamm 2019; 2019:6367402. http://www.ncbi.nlm.nih.gov/pubmed/?term=30936777
  5. Patel C, Thompson C, Copley-Harris M, Hattab Y. Sitagliptin and Simvastatin Interaction Causing Rhabdomyolysis and AKI. Case reports in medicine 2019; 2019:2601537. http://www.ncbi.nlm.nih.gov/pubmed/?term=30936920
  6. Olmos-Martinez JM, Molina H, Salas C et al. Acute Colchicine-induced Neuromyopathy in a Patient Treated with Atorvastatin and Clarithromycin. European journal of case reports in internal medicine 2019; 6:001066. http://www.ncbi.nlm.nih.gov/pubmed/?term=30931282
  7. Lowe K, Kubra KT, He ZY, Carey K. Vitamin D Supplementation to Treat Statin-Associated Muscle Symptoms: A Review. The Senior care pharmacist 2019; 34:253-257. http://www.ncbi.nlm.nih.gov/pubmed/?term=30935447
  8. Klein-Szanto AJP, Bassi D. Keep recycling going: new approaches to reduce LDL-C. Biochem Pharmacol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30953636
  9. Jensen JS, Weeke PE, Bang LE et al. Clinical characteristics and lipid lowering treatment of patients initiated on proprotein convertase subtilisin-kexin type 9 inhibitors: a nationwide cohort study. BMJ Open 2019; 9:e022702. http://www.ncbi.nlm.nih.gov/pubmed/?term=30940751
  10. Corsini A. Statin-associated muscle symptoms: is Proprotein convertase subtilisin/kexin type 9 inhibitors a therapeutic option? European heart journal supplements : journal of the European Society of Cardiology 2019; 21:B48-b49. http://www.ncbi.nlm.nih.gov/pubmed/?term=30948945
  11. Chao TH, Hsiao PJ, Liu ME et al. A subanalysis of Taiwanese patients from ODYSSEY South Korea and Taiwan study evaluating the efficacy and safety of alirocumab. Journal of the Chinese Medical Association : JCMA 2019; 82:265-271. http://www.ncbi.nlm.nih.gov/pubmed/?term=30946207
  12. Bundy JD, Cai X, Scialla JJ et al. Serum Calcification Propensity and Coronary Artery Calcification Among Patients With CKD: The CRIC (Chronic Renal Insufficiency Cohort) Study. American journal of kidney diseases : the official journal of the National Kidney Foundation 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30935773
  13. Rieder SC, Huber LC, Trachsler J, Herberger E. [CME: Nephrotic Syndrome in Adults: Presentation, Diagnosis, Therapy]. Praxis 2019; 108:347-355. http://www.ncbi.nlm.nih.gov/pubmed/?term=30940036
  14. Merlant M, Fite C, Kottler D et al. [Dermatomyositis-like syndrome revealing statin-induced necrotizing autoimmune myopathy with anti-HMGCR antibodies]. Annales de dermatologie et de venereologie 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30929872
  15. Mehrabani S, Askari G, Miraghajani M et al. Effect of coenzyme Q10 supplementation on fatigue: A systematic review of interventional studies. Complementary therapies in medicine 2019; 43:181-187. http://www.ncbi.nlm.nih.gov/pubmed/?term=30935528
  16. Jeong SM, Jang W, Shin DW. Association of statin use with Parkinson's disease: Dose-response relationship. Movement disorders : official journal of the Movement Disorder Society 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30938893
  17. Hoffmann U, Lu MT, Olalere D et al. Rationale and design of the Mechanistic Substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE): Effects of pitavastatin on coronary artery disease and inflammatory biomarkers. Am Heart J 2019; 212:1-12. http://www.ncbi.nlm.nih.gov/pubmed/?term=30928823
  18. Henry C, Zaizafoun M, Stock E et al. Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia. Proceedings (Baylor University. Medical Center) 2018; 31:419-423. http://www.ncbi.nlm.nih.gov/pubmed/?term=30948970
  19. Grinspoon SK, Fitch KV, Overton ET et al. Rationale and design of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE). Am Heart J 2019; 212:23-35. http://www.ncbi.nlm.nih.gov/pubmed/?term=30928825
  20. Fransgaard T, Hallas J, Thygesen LC, Gogenur I. Association of Statin Use and Oncological Outcomes After Neoadjuvant Radiotherapy in Patients With Rectal Cancer. Anticancer research 2019; 39:2177-2182. http://www.ncbi.nlm.nih.gov/pubmed/?term=30952765
  21. Davila-Fajardo CL, Diaz-Villamarin X, Antunez-Rodriguez A et al. Pharmacogenetics in the Treatment of Cardiovascular Diseases and Its Current Progress Regarding Implementation in the Clinical Routine. Genes 2019; 10. http://www.ncbi.nlm.nih.gov/pubmed/?term=30939847
  22. Christie CF, Fang D, Hunt EG et al. Statin-dependent modulation of mitochondrial metabolism in cancer cells is independent of cholesterol content. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2019:fj201802723R. http://www.ncbi.nlm.nih.gov/pubmed/?term=30951369
  23. Chacra APM, Ferrari MC, Rocha VZ, Santos RD. Case report: The efficiency and safety of lomitapide in a homozygous familial hypercholesterolemic child. J Clin Lipidol 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30948303
Basic Science publications
 
 
  1. Yin N, Zhang H, Ye R et al. Fluvastatin Sodium Ameliorates Obesity through Brown Fat Activation. Int J Mol Sci 2019; 20. http://www.ncbi.nlm.nih.gov/pubmed/?term=30939798
  2. Paseban M, Mohebbati R, Niazmand S et al. Comparison of the Neuroprotective Effects of Aspirin, Atorvastatin, Captopril and Metformin in Diabetes Mellitus. Biomolecules 2019; 9. http://www.ncbi.nlm.nih.gov/pubmed/?term=30934759
  3. Lin CK, Liu ST, Chang CC, Huang SM. Regulatory mechanisms of fluvastatin and lovastatin for the p21 induction in human cervical cancer HeLa cells. PLoS One 2019; 14:e0214408. http://www.ncbi.nlm.nih.gov/pubmed/?term=30939155
  4. Boulate G, Amazit L, Naman A et al. Potentiation of mitotane action by rosuvastatin: New insights for adrenocortical carcinoma management. International journal of oncology 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30942448
  5. Ansari S, Jalili H, Bizukojc M, Amrane A. Influence of the construction of porous spargers on lovastatin production by Aspergillus terreus ATCC 20,542 in a laboratory bubble column. Bioprocess and biosystems engineering 2019. http://www.ncbi.nlm.nih.gov/pubmed/?term=30949844
  6. Ali I, Alharbi OML, ZA AL et al. Preparation of a carboxymethylcellulose-iron composite for uptake of atorvastatin in water. International journal of biological macromolecules 2019; 132:244-253. http://www.ncbi.nlm.nih.gov/pubmed/?term=30930264
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