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Resistance and intolerance to statins.


Reiner Z.  


Nutr Metab Cardiovasc Dis. 2014 Oct;24(10):1057-1066

Commentary:  Statin resistance is inadequate LDL-C lowering with statin therapy.  The resistance to statins has been associated with polymorphisms in the  3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA-R), P-glycoprotein (Pg-P/ABCB1), breast cancer resistance protein (BCRP/ABCG2), multidrug resistance-associated proteins (MRP1/ABCC1 and MRP2/ABCC2), organic anion transporting polypeptides (OATP), RHOA, Nieman-Pick C1-like1 protein (NPC1L1),farnesoid X receptor (FXR), cholesterol 7alpha-hydroxylase (CYP7A1), Apolipoprotein E (ApoE), proprotein convertase subtilisin/kexin type 9 (PCSK9), low density lipoprotein receptor (LDLR), lipoprotein (a) (LPA), cholesteryl ester transfer protein (CETP), and tumor necrosis factor α (TNF-α) genes.  Resistance is not understood well enough to justify genetic testing before statin therapy in order to screen out possible hypo-responders.  LDL-C levels will still need to be followed.  -Michael Jones Ph.D.

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New cholesterol guidelines: Worth the wait?


Raymond C, Cho L, Rocco M, Hazen SL.


Cleveland Clinic Journal of Medicine 2014; 81:11-19


Commentary:  The authors reviewed the pros and cons of the ACC/AHA Guidelines, looking at the four major statin treatment groups, making a case for continued reliance on LDL-C goals for individual patients.  They suggest a hybrid approach using global risk assessment and high-intensity statin treatment while relying on ATPIII goals for monitoring individual patients.  -Michael Jones Ph.D.

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The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines  for the management of dyslipidaemias 2011. 

Ray KK, Kastelein JJ, Boekholdt SM, Nicholls SJ, Khaw KT, Ballantyne CM, Catapano AL, Reiner Ž, Lüscher TF

Eur Heart J. 2014 Apr;35(15):960-8. doi: 10.1093/eurheartj/ehu107. Epub 2014 Mar 17


Commentary:  The new ACC/AHA 2013 guidelines are compared with the ESC/EAS guidelines for the management of dyslipidemias 2011.    -Michael Jones Ph.D.

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Combination therapy in dyslipidemia: Where are we now?

Catapano AL, Farnier M, Foody JM, Toth PP, Tomassini  E, Brudi P, Tershakovec AM. 


Atherosclerosis. 2014 Sep 30;237(1):319-335.


Commentary:  This is a very thorough review of the literature on the use of other drugs (ezetimibe, bile acid sequestrants, niacin, and fibrates) in combination with statins.  The need for combination therapy is discussed for high risk patients (T2DM, metabolic syndrome, FH) as well as for statin intolerant and statin resistant patients.  The potential role of novel drugs recently approved or under development is reviewed.  -Michael Jones Ph.D.

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Atheroma Progression in Hyporesponders to Statin Therapy

Kataoka Y, St. John J, Wolski K, et   


Atherosclerosis, Thrombosis and Vascular Biology 2015; 35:990-995


Commentary:  In this study 647 patients from 7 clinical trials who had angiographic evidence of coronary artery disease were started on statin therapy and followed by IVUS. They were divided into statin responders (≥ 15% reduction in LDL-C) and hyporesponders (<15% reduction).  Twenty percent were found to be hyporesponders.  Hyporesponders had lower LDL-C at baseline (97 mg/dL) compared to responders (131 mg/dL). Non-responders also had lower systolic blood pressures than responders at baseline.   In responders, mean LDL-C was reduced from 131 to 73 mg/dL whereas in hyporesponders the mean LDL-C was essentially unchanged (97 to 100 mg/dL).  After adjustment for baseline differences in clinical parameters and plaque burden statin hyporesponders had an increase in % atheroma volume (0.83 ± 0.58 %) whereas responders had either no change or a decrease in (-0.21 ± 0.52%,p<0.006 between groups).  Some of the differences may have been due to the fact that rosuvastatin use was much less prevalent and the doses of atorvastatin used were lower in the hyporesponder group compared to the responder group.


There are several takeaway messages from this study:  (1) A significant percentage (20% in this study) of patients do not respond well to statin therapy, at least as it was employed in these studies; (2) Statin hyporesponders have either no regression or even progression of their CVD even with modest baseline elevations in LDL-C; (3) Alternative strategies are needed to reduce CVD risk in statin hyporesponders.  These findings have significance in light of recent changes in some guidelines for management. o-Michael Jones Ph.D.

The Lower the LDL-C, the Better. IMPROVE-IT shows positive results

Peggy Peck

MedPage Today, November 17th, 2014


Commentary: The long-awaited results of the IMPROVE-IT trial were reported today (Nov. 17) at AHA.  The study of 18,000 patients with acute coronary syndrome compared treatment with simvastatin plus ezetimibe to treatment with simvastatin alone.  LDL-C was lower with combination therapy compared to the statin alone (1-year LDL-C 53.2 mg/dL vs. 69.9 mg/dL with simvastatin alone).  The composite endpoint of cardiovascular death, myocardial infarction, or stroke was reduced from 34.7% for simvastatin alone to 32.7% for ezetimibe plus simvastatin.  Subjects were followed every 4 months until 5,250 CV events occurred, resulting in a 7-year duration for the trial.  This is the first study that has shown a non-statin drug to have a positive effect on clinical outcomes when given in combination with a statin.  The results indicate that there is room for improvement in patients treated with statins by the judicious use of ezetimibe to achieve further LDL-C reduction, i.e. the lower the LDL-C, the better.-Michael Jones P.h.D.

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Further Insight Into the Cardiovascular Risk Calculator:  The Roles of Statins, Revascularizations, and Underascertainment in the Women’s Health Study


Coo NR, Ridker  PM. 


JAMA Intern Med. Published online October 06, 2014


Commentary:  The authors used the pooled cohort equations from the recent American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Assessment of Cardiovascular to predict outcomes in 27 542 women ages 45 to 79 years in the Women’s Health Study.  The mortality predicted by the pooled cohort equations was 1.90 times the observed value in low risk women (5.0-<7.5% risk) and 1.4 times the observed value in women with risk of 7.5% or greater.  After correction for statin use and revascularization procedure, the relative risk ratios  (predicted:observed) were 1.8 and 1.3 for the two risk populations.  Underascertainment seemed unlikely as follow-up was 97.2% in WHS.   Risks may be lower than predicted in contemporary populations.  -Michael Jones Ph.D.

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Association of Low-Density Lipoprotein Cholesterol–Related Genetic Variants With Aortic Valve Calcium and Incident Aortic Stenosis


Smith JG, Luk K, Schulz C-A,  Engert JC, et al; for the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Extracoronary CalciumW orking Group.  


Jama Published online October 26, 2014.


Commentary: Although LDL-C has been associated with aortic stenosis in epidemiologic studies, interventional studies lowering cholesterol has not affected progression of the disease.  These investigators looked at relationships between lipid levels and aortic calcium in the CHARGE consortium and relationships between genetic risk scores (GRSs) for lipid abnormalities and incident aortic stenosis in the Malmö Diet and Cancer Study (MDCS,).  Plasma LDL-C, but not HDL-C or TG, was associated with incident aortic stenosis.  The GRS for LDL-C but not for HDL-C or TG, was associated with the presence of aortic valve calcium and with incident aortic stenosis. These associations suggest a causal relationship between LDL-C and aortic valve disease.  The authors hypothesize that LDL-C lowering  trials may have failed because the intervention was started after valve disease was already present, and thus earlier intervention might offer the possibility of preventing or slowing progression of aortic valve disease.  -Michael Jones Ph.D.

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Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. 

Boekholdt SM, Hovingh GK, Mora S, Arsenault BJ, Amarenco P, Pedersen TR, LaRosa JC, Waters DD, DeMicco DA, Simes RJ, Keech AC, Colquhoun D, Hitman GA, Betteridge DJ, Clearfield MB, Downs JR, Colhoun HM, Gotto AM Jr, Ridker PM, Grundy SM, Kastelein JJ


J Am Coll Cardiol.2014 Aug 5;64(5):485-94


Commentary:  This meta-analysis including 38,153 patients treated with high-intensity statin regimens has several significant findings:  (1) Outcomes were better the lower the LDL-C on treatment, with  no apparent lower limit; (2) Response to high-intensity statin therapy were highly variable; (3) Many patients were hypo-responsive and >40% did not achieve LDL-C <70 mg/dL.  - Michael Jones Ph.D.

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High-Intensity Statin Therapy Alters the Natural History of Diabetic Coronary Atherosclerosis: Insights From SATURN. 


Stegman B, Puri R, Cho L, Shao M, Ballantyne CM, Barter PJ, Chapman MJ, Erbel R, Libby P, Raichlen JS, Uno K, Kataoka Y, Nissen SE, Nicholls SJ


Diabetes Care. 2014 Nov;37(11):3114-20.


Commentary:  This subgroup analysis from the SATURN study shows that high-intensity statin therapy can decrease plaque atheroma volume (PAV)  in both diabetic and nondiabetic patients.  Reduction was similar when LDL-C was ≤70 mg/dL but at levels  >70mg/dL regression of PAV in diabetic patients was only about one-third that in nondiabetic patients.  This underscores the importance of LDL-C levels in the treatmebnt of patients with diabetes.  

-Michael Jones Ph.D.

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Application of New Cholesterol Guidelines to a Population-Based Sample

Pencina MJ, Navar-Boggan AM, D’Agostino RB, Williams K, Neel B, Sniderman AD, Peterson ED. 


N Eng J Med  2013;350:1422-1431


Commentary: The authors used data from NHANES 2005 to estimate the number of persons who would be qualified for statin therapy under the new ACC/AHA Guidelines as compared to the ATP-III Guidelines and extrapolated to a population of 115.4 million Americans aged 40-75.  The new Guidelines would increase the number of patients eligible for statin therapy by 12.8 million, primarily in older adults with no history of cardiovascular disease.  -Michael Jones Ph.D

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Atherogenic Dyslipidemia and Combination Pharmacotherapy in Diabetes: Recent Clinical Trials

Hamilton SJ, Watts GF.


The Review of Diabetic Studies 2013;10:191-203


Commentary: Patients with T2DM  may need drugs in addition to statins to reduce residual risk.  Recent studies with fenofibrate, niacin, ezetimibe, and n-3 fatty acids in combination with statins are reviewed.  The authors concluded that there is some evidence for benefit with fenofibrate, that further evidence is needed for ezetimibe and n-3 fatty acids, and that the use of niacin in combination with statins in patients with T2DM is not warranted.  -Michael Jones Ph.D. 

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Accuracy of statin assignment using the 2013 AHA/ACC Cholesterol Guideline versus the 2001 NCEP ATP III guideline: correlation with atherosclerotic plaque imaging.

Johnson KM, Dowe DA


J Am Coll Cardiol. 2014 Sep 2;64(9):910-9


Commentary:  The investigators reviewed computer tomographic angiograms on 3076 consecutive patients at a private outpatient radiology practice and determined the need for treatment using NCEP ATPIII guidelines (NCEP) and the recent ACC/AHA guideline on the assessment of cardiovascular risk (GACR).  The probability of being prescribed a statin rose sharply with plaque burden when GACR was used but not when the NCEP guideline was used.  Using NCEP criteria, 59% of patients with ≥50% left main artery stenosis and 40% of those with ≥50% stenosis of other branches would not have been prescribed statins, whereas using GACR only 19% and 10%, respectively would not have been treated.  Interestingly, when NCEP risk alone was used, without LDL-C targets, the percentage of patients treated would have been similar to that using GACR.  The authors conclude that the use of LDL-C targets degraded the ability to detect patients with serious plaque burden who might benefit from statins.  A limitation on the study was the fact that baseline LDL-C values were not available for patients who were already on statins, and the baseline values were estimated.  When patients who were on statins were removed from the analysis, the conclusions were the same.  This study was small and involved a select population of mostly Caucasian patients.  The results, however, are thought-provoking.  - Michael Jones Ph.D.

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