Hypertension Journal

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Statin Update: Intolerance, Benefit, and Beyond
  JOHTN
REVIEW ARTICLE
Statin Update: Intolerance, Benefit, and Beyond
Aaron Y. Kluger1,2, Kristen M. Tecson1,2, Sivakumar Sudhakaran3,4, Jun Zhang1, Peter A. McCullough1,3,4
1Baylor Heart and Vascular Institute, Dallas, Texas, USA
2Baylor Scott and White Research Institute, Dallas, Texas, USA
3Baylor University Medical Center, Dallas,Texas, USA
4Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, Texas
Address for correspondence: Peter A. McCullough, Baylor Heart and Vascular Institute, 621 N. Hall St., H030, Dallas 75226, Texas, USA.
Phone: 248-444-6905
Fax: 214.820.3793.
E-mail: peteramccullough@gmail.com
Received: 12-12-2018; Accepted: 27-12-2018
doi: 10.15713/ins.johtn.0141

 
ABSTRACT
Statins (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors) comprise a class of lipid-lowering therapy (LLT) withdemonstrated effects on reducing cholesterol synthesis so that less very low-density lipoprotein cholesterol (LDL-C) are secretedinto plasma by the liver, ultimately reducing the concentration of plasma LDL-C. An additional effect of statins is upregulation ofsterol regulatory element-binding protein 2, upregulation of this protein increases the density of LDL-receptors on the cell surfaceof hepatocytes and causes greater clearance of LDL-C. Therefore, because statins reduce the creation and increase the clearanceof a family of atherogenic particles (particularly LDL-C), there is a clear biologic rationale for the reduction in atheroscleroticcardiovascular disease (ASCVD) events shown in multiple large-scale clinical trials. This makes statins well-suited as the base oftherapy in the prevention and treatment of ASCVD. Real and perceived intolerance is the greatest detractor of statins from thepotential public health benefits of broad-scale use. Up to one-third of patients who are prescribed statins fail to take them over thelong-term and thus derive no benefit. About half of these patients have "perceived statin intolerance," in which they believe theyhave stain intolerance due to conflated chronic symptoms or concern for adverse effects. Randomized, placebo-controlled blindedtrials including such patients demonstrate that approximately 85% can, in fact, tolerate a statin during the blinded period. The otherhalf of the statin-intolerant population is believed to have "real statin-intolerance" due to reproducible legitimate adverse effectssuch as myalgias, increases in hepatic transaminases, and malaise; there is a pharmacoepidemiologic explanation for this 15% ofthe patient population. The full public health benefit of statins can only be accomplished through improved patient education andpublic awareness. This paper will provide an update on statins and their position in clinical lipidology, especially given advances inother forms of LLT.
Keywords: Cardiovascular death, intolerance, lipids, low-density lipoprotein cholesterol, myalgia, myocardial infarction, statin, stroke
How to cite this article: Kluger AY, Tecson KM, Sudhakaran S,Zhang J, McCullough PA. Statin update: Intolerance, benefit,and beyond. Hypertens 2019;5(1): 2-7.
Source of support: This work was partially funded by the BaylorHealth Care System Foundation,
Conflict of interest: None
 
 

Introduction

Statins, also known as 3-hydroxy-3-methyl-glutaryl-coenzyme A(HMG-CoA) reductase inhibitors, are a class of lipid-loweringtherapy (LLT) that has proven effects in reducing the synthesisof cholesterol and as a result, less very low-density lipoproteincholesterol (VLDL-C) is secreted by the liver into plasma.[1]With less VLDL, there is less conversion to intermediate densitylipoprotein (IDL) cholesterol and ultimately LDL-C. Thus, onaverage, administration of moderate intensity statins can resultin a 30-50% reduction in LDL-C; similarly, high-intensity statinscan result in a >50% reduction.[2] In addition, statins upregulatesterol-regulatory element binding protein-2 transcription factors,increasing the density of LDL receptors (LDL-R) on the cellsurface of hepatocytes allowing for greater clearance of LDL-C.[3]

 
There are several explanations for why some patients may havea lower than expected reduction in LDL-C. First and foremost, highintake of dietary saturated fat, which stimulates the production ofVLDL can partially negate the statin effect on LDL-C.[4] There areknown gain-of-function mutations of HMG-CoA-reductase whichrender statins less effective.[5-8] Patients with normal alleles forLDL-R stand to have the greatest LDL-C reduction and conversely,those with polymorphisms for this complex 839 amino acid proteinreceptor are likely to have less LDL-C clearance and less of a statinbenefit. This form of familial hypercholesterolemia (FH) is animportant clinical condition to consider when the treated LDL-Cremains >145 mg/dl. Other forms of heterozygous FH (HeFH)can result in defects in the production of apoprotein B-100 (apoB),the signal protein on VLDL, IDL, and LDL.[9] Rarely, HeFH canresult from a gain-of-function mutation for proprotein convertasesubtilisin kexin-9 (PCSK-9), which regulates the density of LDL-Ron the hepatocyte surface.

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Thus, by reducing the production of a family of atherogenicparticles particularly LDL-C - and increasing its clearance,statins have a strong biologic rationale for the reductionin atherosclerotic cardiovascular disease (ASCVD) eventsdemonstrated in a multitude of large-scale clinical trials. Thissupports statins as the base of therapy in the prevention andtreatment of ASCVD as well as additional therapy as indicated.

Statin Intolerance

The single greatest detractor to statin use and its observedbenefit is statin-intolerance. A unified definition of statinintolerance has been proposed: The inability to tolerate at leasttwo different statins - one statin at the lowest starting averagedaily dose and the other statin at any dose.[10,11] In addition,this statin intolerance should meet these additional conditions:(1) Characterized by inability to use statins due to significantsymptoms and/or biomarker abnormalities which can betemporally attributed to the initiation or dose escalation of statins,supported with appropriate drug withdrawal and rechallenge;(2) either "complete" (intolerant to any statin at any dose) or"partial" (intolerant to some statins at some doses); and (3) notattributable to established predispositions such as drug-druginteractions and untreated chronic disease (hypothyroidism,fibromyalgia, and osteoarthritis). Up to one-third of patients whoare prescribed statins do not take them over the long-term andhence derive no benefit. Approximately half of such individualshave "perceived statin intolerance" in which conflated chronicsymptoms or concern for adverse effects cause them to believethey have statin intolerance. When these individuals participatein randomized, placebo-controlled blinded trials, approximately85% can tolerate a statin during the blinded period. The other halfof the statin-intolerant population is believed to have "real statinintolerance" due to reproducible bona fide adverse effects; mostcommonly myalgias, increases in hepatic transaminases, andmalaise. Data from the Statin Response Examined by GeneticHaplotype Markers study and the Study of the Effectiveness ofAdditional Reductions in Cholesterol and Homocysteine studyfound that polymorphisms for the organic anion transporter 1,which is responsible for clearance of statins and stain alcoholsby the liver, were associated with statin intolerance as definedby a composite adverse event of discontinuation for any sideeffect, myalgia, or a creatine phosphokinase >3× upper limit ofnormal during follow-up (occurred in 19%).[12] The SLCO1B1*5mutation was associated with intolerance of pravastatin andmore so with simvastatin, which requires cytochrome P450 3A4detoxification before the OATP1 step. Furthermore, there wasevidence supporting a gene-dose effect (rates of statin intolerancein those with 0, 1, or 2 alleles were 19%, 27%, and 50%, respectively,P = 0.01). When these data are considered together with what isknown about statin clearance with glucuronidation, cytochromeP450, and now OATP1 systems, it is reasonable to infer thatimpaired drug clearance and high drug levels (genetically and/ordue to drug-drug interactions) play a role in the pathogenesis ofstatin intolerance in at least half of those who are unwilling totake this class of agents.[13] Importantly, Vitamin D deficiency,ubiquinone depletion, coenzyme Q10, and low lipid levels areunlikely to play pathogenic roles in statin toxicity.[14] In summary,there is a pharmacoepidemiologic explanation for this 15% of thepopulation and only through improved patient education andpublic awareness can the maximal public health benefit of statinsbe realized.[15,16]

 
Justification for the Use of Statins in Prevention: An
Intervention Trial Evaluating Rosuvastatin (JUPITER)
Trial as a Working Example of CV Benefit


There have been many analyses of the CV benefits of statins. Ingeneral, the higher the LDL-C and greater risk, the greater thebenefit of statins on coronary heart disease (CHD) events. Themost striking example is the JUPITER trial [Table 1].[17] Thistrial recruited n = 18,702 statin-naive men >50 years and women>60 years without diabetes, LDL-C < 130 mg/dl, and highsensitivity C-reactive protein (hs-CRP) >2.0 mg/L (present in2/3 who were screened) and randomized them to rosuvastatin20 mg daily versus placebo. Rosuvastatin reduced LDL-C from108 to 55 mg/dl (48% reduction), and this was associated with a44% reduction in the primary endpoint of myocardial infarction,stroke, revascularization, hospitalization for unstable angina,and cardiac death, P < 0.00001. There was a 47% risk reductionin the traditional tripartite endpoint of nonfatal myocardialinfarction, stroke, or CV death, P < 0.00001. Finally, there wasa 20% reduction in all-cause death, P = 0.02. From a relativerisk reduction standpoint, the JUPITER trial stands as the mostsuccessful primary prevention study of statins. The success ofthis trial is partly ascribed to the use of a high-potency statinand recruiting statin-naive patients, with the results of patientswith hs-CRP > 2.0 mg/dl implying that multiple confoundingrisk factors that raise hs-CRP were present (adiposity, metabolicsyndrome, hypertension, smoking, etc.).

Beyond Statins

In the United States, the entry of generic ezetimibe into themarketplace will allow much greater use of this adjunctivemedication. Ezetimibe (when used in addition to a statin) lowersLDL-C by an additional ∼18% by impairing enterohepaticreabsorption of cholesterol.[18] This is roughly 3 timesgreater efficacy than a strategy of doubling the statin dose.[19]The Improved Reduction of Outcomes: Vytorin EfficacyInternational (IMPROVE-IT) Trial [Table 1] randomized18,144 participants with acute coronary syndromes to ezetimibe10 mg daily in addition to simvastatin 40 mg p.o. q.d. orsimvastatin alone. The combination therapy produced anachieved LDL-C of 53.7 mg/dl as compared to 69.5 mg/dl inthe simvastatin-only group.[20] This additional 22.7% reductionin LDL-C attributable to ezetimibe was associated with a 2.0%absolute risk reduction in the primary endpoint of a majorcoronary event (nonfatal myocardial infarction, hospitalizationfor unstable angina, or coronary revascularization), stroke, orCV death, P = 0.016. IMPROVE-IT - considering JUPITER -suggests that (1) the larger relative benefit is due to the statinand (2) the addition of ezetimibe to statin is associated withfurther LDL-C lowering. The modest relative benefit in thereduction of events in IMPROVE-IT may be partly due to thelimited percent LDL-C lowering and the patient populationpost-acute coronary syndromes where other factors includingprothrombotic and procedural may have introduced variation inthe natural occurrence of CHD events.[21]

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Table 1: Comparison of three contemporary seminal trials of LLT: The JUPITER, IMPROVE-IT, and further cardiovascular outcomesresearch with PCSK9 inhibition in subjects with elevated risk (FOURIER) trials

Resistant Hypertension 2018
MI: Myocardial infarction, MACE: Major adverse cardiovascular event, CV: Cardiovascular, LDL-C: Low-density lipoprotein cholesterol, RRR: Relativerisk reduction, HR: Hazard ratio, CI: Confidence interval, N/A: Not available. LLT: Lipid-lowering therapies, JUPITER: Justification for the use of statins inprevention: An intervention trial evaluating rosuvastatin, IMPROVE-IT: Improved reduction of outcomes: Vytorin efficacy international trial

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The advent of PCSK-9 inhibitors has raised an entirely newset of issues with respect to lipid management and reduction inCHD events. These monoclonal antibodies to PCSK-9 allowLDL-R to recycle to the cell surface and clear LDL-C with greaterefficiency and have been associated with an additional 60%reduction in LDL-C. The further CV Outcomes Research withPCSK9 Inhibition in Subjects with Elevated Risk (FOURIER)trial [Table 1] randomized 27,564 patients with stable coronarydisease on maximally tolerated statin therapy and LDL-C of92 mg/dl to evolocumab in standard doses or placebo and theresultant LDL-C values were 30 mg/dl (59% reduction).[22] Thiswas associated with a 15% relative risk reduction in the primaryendpoint of nonfatal myocardial infarction, ischemic stroke,coronary revascularization, hospitalization for unstable angina,or CV death, P < 0.001.

Thus, when a statin is used at baseline, the addition ofezetimibe (22.7% additional lowering LDL-C and 2.0% absoluterisk reduction in CHD) and monoclonal antibodies againstPCSK-9 (59% additional LDL-C lowering and 15% relative riskin CHD) improve outcomes significantly. The largest relativebenefit appears to be with the statin positioned as the foundationof therapy (up to ∼50% reduction in CHD risk), likely due toits mechanism of action in reducing the production of all theatherogenic particles while upregulating LDL-R at the sametime. It is entirely possible that whichever drug is positioned asthe first form of LLT may have the largest role in reducing CHDevents; however, given the mechanism of action and the resultsof recent clinical trials, it is unlikely there will be a departure fromstatins as first-line LLT in patients at risk for and with CHD.

Mechanism of Action for Statins, Ezetimibe, and
Monoclonal Antibodies Against PCSK-9


While statins, ezetimibe, and monoclonal antibodies againstPCSK9 all contribute to the reduction of LDL-C levels, themechanism of action for each LLT is different [Figure 1].[17,19,20]

 
Thus, the use of these agents is complementary to one anotherand is attractive both mechanistically and clinically.

Statins reduce cholesterol biosynthesis in the liver; this isassociated with a reduction in LDL cholesterol and decreasing theincidence of CV events. These beneficial effects make it possible forstatins to act as primary and secondary prevention of CV events.[1]The mechanism of action for statins is dependent on the inhibitionof HMG-CoA reductase, an enzyme that converts HMG-CoAinto mevalonic acid, a cholesterol precursor that catalyzes the ratelimitingstep in cholesterol production.[1,23,24] Statins reduce serumcholesterol by reducing the synthesis of cholesterol in the liverthrough HMG-CoA inhibition.[24] The reduction of cholesterolin hepatocytes leads to the increase of hepatic LDL-R (thesedetermine the reduction of circulating LDL and its precursors,IDL, and VLDL), leading to LDL-C being taken from the bloodinto the liver.[1,24] Interestingly, cholesterol reduction by statinsleads to a significant increase in endothelial function.[1] In addition,statins inhibit transendothelial migration and chemotaxis ofneutrophils, producing an anti-inflammatory effect.[1]

Ezetimibe is an intestinal and biliary cholesterol absorptioninhibitor. Its primary target of action is to inhibit the delivery ofintestinal cholesterol to the liver through the transport proteinNiemann-pick C1 like 1 protein (NPC1L1). Therefore, themechanism of action for ezetimibe is dependent on the inhibitionof NPC1L1. By binding to the NPC1L1 receptor, ezetimibeprevents uptake of intestinal luminal micelles - which containcholesterol - into enterocytes.[24,25]

Because cholesterol uptake is reduced and hepatic cholesterolis decreased, ezetimibe causes a depletion of hepatic LDL-Cstores, leading to upregulation of hepatic LDL-R, thereby causingLDL-C to be taken up by the liver from the blood.[24,25] In additionto inhibition of intestinal cholesterol absorption, ezetimibe is alsoable to interact with hepatic NPC1L1, and thus reduces biliarycholesterol absorption. The dual absorption further reduces serumcholesterol levels.[25] As demonstrated in IMPROVE-IT, combiningezetimibe with simvastatin provides greater reductions in LDL-Clevels than those achieved with either agent used as monotherapy;this incremental CV benefit is presumably due to reductions of bothintestinal and hepatic sources of cholesterol.[17,26,27]

This benefit is consistent with the LDL hypothesis in thatlowering LDL acts as a primary target of therapy for the primaryand secondary prevention of CV events.[25,28] It is noteworthythat the NPC1L1 receptor (the target of ezetimibe) and HMGCoAreductase (the target of statins) are roughly the same bypolymorphisms, indicating that the efficacy of LDL-C loweringthrough the NPC1L1 receptor is comparable to that through theHMG-CoA reductase.[28]

PCSK9 plays an important role in LDL-C/LDL-Rmetabolism.[29] Therefore, anti-PCSK9 monoclonal antibodyinducedreduction of LDL-C is dependent on the inhibitionof PCSK9, which increases LDL-C metabolism by recyclingLDL-R on the surface of hepatocytes. Under conditions of highlevels of PCSK9, the degradation of the PCSK9-LDL-R complexin lysosomes is increased. In contrast, when PCSK9 levels arelow, hepatic surface LDL-R levels become high because LDL-Rcan be recycled to the hepatic surface after delivery of LDL-Cparticles to endosomes, thus resulting in lower circulatingLDL-C levels.[29] PCSK9 activity can be inhibited by monoclonalantibodies against PCSK9 through the extracellular pathway.[29]

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Resistant Hypertension 2018
Figure 1: Mechanisms of action for statins, ezetimibe, and monoclonal antibodies against PCSK-9

Data from the JUPITER trial demonstrate that rosuvastatintreatedpatients achieved both LDL-C and hs-CRP reduction,thereby leading to a reduction in ASCVD events.[20] Theresults indicate that the direct linkage between cholesteroland inflammation in the atherosclerotic plaque exists, and thebeneficial impact of statins on inflammation is proportional tothe reduction of levels of LDL-C.[22] Recently, it has becomeclear that hs-CRP is not a causal factor for atherosclerosis, butrather a powerful risk biomarker for ASCVD events. In fact, bothrosuvastatin and ezetimibe have the ability to decrease CRP andimprove CV outcomes.[22] However, the relationship between thereduction of LDL-C and CRP has not been observed in clinicaltrials of anti-PCSK9 monoclonal antibodies, perhaps due to theexclusion of patients with systemic inflammation.[22] Anotherpostulated mechanism of action by which statins and ezetimibedecrease CV risk is by improving vascular endothelial dysfunctionand by reducing pro-inflammatory cytokines, CRP, and damageof the arterial wall.[22] A recent clinical trial comparing simvastatinat a high dose of 80 mg to simvastatin 10 mg/ezetimibe 10 mgfound that the decrease in LDL-C and improvement ofendothelial function (assessed by flow-mediated vasodilation)were similar between the groups.[30] The results suggest thatthe improvement in endothelial function with statins is likelydependent on a reduction in LDL-C, independent of the dose ofstatin administered, without evidence of a pleiotropic action.[30]

Conclusions

There remains a large opportunity to improve CHD event ratesacross the globe with the use of statins in primary and secondarycare. Approximately half of "statin intolerance" is perceived andis amenable to another trial of statin therapy in the well-preparedpatient. The other half of statin intolerance has a genetic basisin impaired clearance of statins and their metabolic breakdownproducts which are toxic to skeletal myocytes when theyremain in high concentrations in plasma over time. The use ofrosuvastatin in a primary prevention population at risk for CHDresulted in a 48% reduction in LDL-C and a corresponding 44%reduction of CHD, conferring a 20% reduction in mortality.The addition of ezetimibe or PCSK-9 inhibition therapy tomaximally tolerated statins further lowers LDL-C by 24% and50%, respectively. However, this corresponds to a much smallerrelative risk reduction of CHD events (6% and 15%, respectively)and neither ezetimibe nor PCSK-9 inhibitors have demonstrateda mortality benefit. Therefore, at this time, statins should remainfoundational LLT in the prevention of CHD events.

 
  • The mechanism of action for statins: By reducing thesynthesis of cholesterol in the liver through the HMG-CoAinhibition, statin-reduced cholesterol in hepatocytes convertsVLDL to IDL to LDL, and results in the increase of hepaticLDL-R, thereby leading to LDL-C being up taken from bloodinto the liver (upper left corner of figure).
  • The mechanism of action for ezetimibe: By binding to theNPC1L1 receptor, ezetimibe prevents uptake of intestinalluminal micelles, which contain cholesterol, into enterocytes.Due to reduced cholesterol uptake and decreased hepaticcholesterol, ezetimibe leads to upregulation of hepaticLDL-R, causing LDL-C to be taken up by the liver from theblood (upper right corner of figure).
  • The mechanism of action for anti-PCSK9 monoclonalantibodies: By inhibition of PCSK9 on the surface ofhepatocytes, anti-PCSK9 monoclonal antibodies interruptthe degradation of the PCSK9-LDL receptor complex inlysosomes, and recycle LDL-R on the hepatic cell surface,thus resulting in lower circulating LDL-C levels (bottom offigure).

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