Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease

Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD


Cardiovascular disease (CVD) continues to be the leading cause of death around the world and it is directly associated with blood levels of low-density lipoprotein cholesterol (LDL-C).1,2  In many clinical trials and in clinical practice, statins have been shown to be effective for lowering LDL-C, in both primary and secondary prevention, and to reduce the risk of future CVD events.3-6  The multi-society American College of Cardiology and American Heart Association guidelines for cholesterol management suggest that an adequate LDL-C lowering response with an intermediate-intensity statin is ≥30% and is  ≥50% with higher-intensity statins.5  The National Institute for Health and Care Excellence (NICE) guidelines defined sub-optimal responders as patients on treatment with statins for primary prevention of CVD who fail to achieve >40% reduction in LDL-C within the 24 months of statin initiation.6


Previous studies have identified individual biological and genetic variability of LDL-C response to statin therapy, as well as variation in treatment adherence, yet there is a paucity of literature on the variation of LDL-C response to statins in the general population.7,8  To address this issue, Akyea et al. examined the change in LDL-C and future risk of CVD in primary care patients over 24 months in response to initiation of statin therapy.9


This prospective cohort included 165,411 primary care patients, who were free of CVD at the initiation of statin therapy.  The data were collected from the UK Clinical Practice Research Datalink (CPRD), which is considered representative of the general population in the UK in terms of age, sex, and ethnicity.  Over half (51.2%, n=84,609) of patients had a sub-optimal LDL-C response to statin therapy within 24 months.  During the 1,077,299 person-years of follow-up (median follow-up 6.2 years) there were 22,798 CVD events.  Of these CVD events 12,142 were reported among the sub-optimal responders and 10,656 among the optimal responders (as defined by NICE).  The rates of CVD in the sub-optimal and optimal responders were 22.6 and 19.7/1000 person-years, respectively.


Compared to optimal responders, sub-optimal responders had a hazard ratio (HR) for incident CVD of 1.17 (95% CI 1.13-1.20).  After adjusting for age and baseline untreated LDL-C, the sub-optimal vs. optimal responders had a HR of 1.22 (95% CI 1.19-1.25).  Consideration of competing risks (e.g., patients transferring out of the practice, death) led to a lower HR for sub-optimal responders of 1.13 (95% CI 1.10-1.16) and an adjusted HR of 1.19 (95% CI 1.16-1.23).  It is worth noting that in this cohort, a higher proportion of patients with sub-optimal responses were prescribed lower potency statins than those with an optimal response.


Comment.  Overall the results show that over half of the patients in this general population cohort did not achieve >40% LDL-C reduction over 24 months with statin therapy.  Patients with suboptimal LDL-C responses were at higher risk for future CVD events.  These findings further support the view that “lower is better” for LDL-C and suggest that patients with a suboptimal response to statin therapy should be identified and evaluated for possible additional intervention, which might include intensification of lifestyle therapies, counseling regarding adherence to the prescribed statin regimen, dose escalation, switching to a higher-potency statin, or adjunctive pharmacotherapy such as ezetimibe or a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor.




  1. Nichols M, Townsend N, Scarborough P, et al. Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J. 2014;35:2950–9.

  2. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581–90.
  3. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ. 2003;326:1423.

  4. Cholesterol Treatment Trialists’ (CTT) collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010;376:1670–81.

  5. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. J Am Coll Cardiol. 2018;Epub ahead of print.
  6. National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modification. London: National Institute for Health and Care Excellence, 2016.
  7. Mega JL, Morrow DA, Brown A, et al. Identification of genetic variants associated with response to statin therapy. Arterioscler Thromb Vasc Biol. 2009;29:1310–5.

  8. Mann DM, Woodward M, Muntner P, et al. Predictors of nonadherence to statins: a systematic review and meta-analysis. Ann Pharmacother. 2010;44:1410–21.
  9. Akyea RK, Kai J, QUreshi N, Iyen B, Weng SF. Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease. Heart. 2019;Epub ahead of print.


Photo by Hush Naidoo

Associations of Dietary Cholesterol and Egg Consumption with Incident Cardiovascular Disease and Total Mortality

Associations of Dietary Cholesterol and Egg Consumption with Incident Cardiovascular Disease and Total Mortality

Associations of Dietary Cholesterol and Egg Consumption with Incident Cardiovascular Disease and Total Mortality


By Kevin C. Maki, PhD and Heather Nelson Cortes, PhD


Despite decades of research, the association between dietary cholesterol consumption, cardiovascular disease (CVD) and mortality remains controversial.  Adding to this controversy are the confusing recommendations in the 2015-2020 Dietary Guidelines for Americans.1,2  The Guidelines state that cholesterol is not a nutrient of concern for overconsumption, but also recommend that individuals should consume as little dietary cholesterol as possible while following a healthy eating pattern.  A meta-analysis of prospective cohort studies published in 2015 did not show statistically significant associations between dietary cholesterol consumption and incident CVD, coronary artery disease or stroke, although higher dietary cholesterol intake was associated with an increased level of low-density-lipoprotein cholesterol (LDL-C).3  Because a large chicken egg (~50 g) contains roughly 186 mg of cholesterol,4 limiting egg consumption has been recommended as a way to decrease dietary cholesterol and to possibly reduce the risk of CVD.


Zhong et al. recently published an analysis of the associations between intakes of dietary cholesterol and eggs with incident CVD and total mortality from the Lifetime Risk Pooling Project.5  The Lifetime Risk Pooling Project contains data from 6 cohorts in which usual dietary intake, fatal and nonfatal coronary heart disease, stroke, heart failure and CVD from other causes were assessed. The 6 cohorts were the Atherosclerosis Risk in Communities (ARIC) Study,6 Coronary Artery Risk Development in Young Adults (CARDIA) Study,7 Framingham Heart Study (FHS),8  Framingham Offspring Study (FOS),9 Jackson Heart Study (JHS)10 and the Multi-Ethnic Study of Atherosclerosis (MESA).11  The analysis included 29,615 participants (mean [standard deviation] age at baseline, 51.6 [13.5] years).5  There were 13,299 (44.9%) men and 9,204 (31.1%) subjects were black.  The median follow-up was 17.5 years (interquartile limits, 13.0-21.7; maximum, 31.3) during which there were 5,400 incident CVD events and 6,132 all-cause deaths. 


Dietary cholesterol and egg consumption showed linear associations with incident CVD and all-cause mortality (all P values for nonlinear terms, 0.19-0.83).  The addition of each 300 mg of dietary cholesterol per day was associated with higher risk of incident CVD (adjusted hazard ratio [HR] 1.17, 95% confidence interval [CI], 1.09-1.26 and adjusted absolute risk difference [ARD] 3.24%, 95% CI 1.39%-5.08%).  The same increment of dietary cholesterol per day was also associated with higher risk of all-cause mortality (adjusted HR 1.18, 95% CI 1.10-1.26 and adjusted ARD 4.43%, 95% CI 2.51%-6.36%). Consumption of each additional half egg per day was associated with higher risk of incident CVD:  adjusted HR 1.06, 95% CI 1.03-1.10; adjusted ARD 1.11%, 95% CI 0.32%-1.89% and all-cause mortality:  adjusted HR 1.08, 95% CI 1.04-1.11; adjusted ARD 1.93%, 95% CI 1.10%-2.76%.


The associations between egg consumption and incident CVD (adjusted HR 0.99, 95% CI 0.93-1.05) and all-cause mortality (adjusted HR 1.03, 95% CI 0.97-1.09) were no longer significant after adjusting for dietary cholesterol consumption.  The associations between dietary cholesterol intake and incident CVD, as well as mortality, remained statistically significant after adjusting for traditional CVD risk factors (including non-high-density lipoprotein cholesterol [non-HDL-C] concentration), various nutrient intakes and measures of diet quality.


Comment.  This new analysis by Zhong et al. has several strengths, including a long follow-up period and the availability and analysis of a great deal of dietary information, such as indices of diet quality, including the Alternative Healthy Eating Index, a Dietary Approaches to Stop Hypertension score and a Mediterranean Diet index.  The supplemental material for the paper includes extensive information from sensitivity analyses.


Despite these strengths, the results are difficult to interpret, in our view, for several reasons.  First, adjustment for non-HDL-C level did not materially alter the association between dietary cholesterol intake and incident CVD.  This is curious because the presumed mechanistic link between dietary cholesterol intake and incident CVD is through the effect of dietary cholesterol to raise the circulating concentrations of LDL-C and non-HDL-C, which are well-established major CVD risk factors that are believed to be causally related to CVD incidence.  In a communication with the authors, we were told that adjustment for non-HDL-C and HDL-C levels had virtually no impact on the point estimates for CVD risk.  Data were missing for LDL-C for 900 subjects, so this was not assessed separately.  Given the lack of effect of adjustment for lipid levels, if the association between dietary cholesterol intake and CVD risk is causal, one must hypothesize mechanisms other than the effect of dietary cholesterol to raise atherogenic cholesterol (LDL-C and non-HDL-C) levels.


A second issue is that within the range of typical cholesterol intakes in the United States (<300 mg/d), no significant increases in risk for incident CVD or all-cause mortality were observed.  For example, for intakes of 200 to <300 mg/d compared to <100 mg/d, the HR for CVD in model 3 (adjusted for CVD risk factors and medication use) was 0.99, 95% CI 0.87-1.12 and for mortality was 0.95, 95% CI 0.84-1.06.  Therefore, the traditional recommendation to limit dietary cholesterol intake to <300 mg/d is supported by these analyses.


Finally, the relationship between cholesterol intake and non-CVD mortality is similar to that for all-cause mortality, with model 3 HR for all-cause mortality of 1.15 (95% CI 1.07-1.23) compared with 1.13 (95% CI 1.04-1.22) for non-CVD mortality (eFigure 5 in the supplemental material).  We are not aware of biologically plausible mechanisms that would explain an increase in non-CVD mortality as a consequence of higher dietary cholesterol intake.  Therefore, the possibility of residual confounding must be considered.


It is also notable that two other recent publications have reported on the association between egg consumption and incident CVD.  In the EPIC-Norfolk cohort,12 the top quintile of egg consumption (median 40 g/d) was associated with a non-significantly lower adjusted incidence of ischemic heart disease compared with the lowest quintile (HR 0.93, 95% CI 0.86-1.01), with a p-value for trend across quintiles of 0.37.  Also, in a large study in China with nearly 500,000 participants,13 those who consumed eggs daily had lower risks for incident CVD (HR 0.89, 95% CI 0.87-0.92) and ischemic heart disease (HR 0.88, 95% CI 0.84-0.93) than those who rarely or never consumed eggs, with significant inverse trends (p < 0.001) over the range of egg intake categories.  So, within the space of one year we have seen publications from observational studies reporting associations ranging from a significant inverse association, to no significant relationship, to a significant positive association of egg intake with incident CVD and/or ischemic heart disease.


Our view is that the available data show convincingly that higher dietary cholesterol intake modestly raises the level of LDL-C, a major CVD risk factor, with linear models indicating a rise of ~2 mg/dL of LDL-C for each increment of 100 mg/d of dietary cholesterol.3,14,15  The results from the Zhong et al. study do not suggest elevations in CVD incidence or mortality risk for intakes of dietary cholesterol below the traditional recommendation of <300 mg/d (i.e., for intake of 200-299 mg/d compared with <100 mg/d).5  Their results also showed that the relationship between egg consumption and CVD and mortality risk could be accounted for by the cholesterol content of eggs.  Therefore, we believe it is reasonable to suggest that whole eggs can be a part of a healthy dietary pattern, provided that total dietary cholesterol intake is not excessive, with the traditional recommendation being not to exceed 300 mg/d.  For those with hypercholesterolemia, it may be reasonable to further restrict dietary cholesterol intake.  The National Lipid Association recommendations for management of dyslipidemia suggest that dietary cholesterol be limited to <200 mg/d for those with hypercholesterolemia, and further restriction may be prudent for those who are known to be hyperresponders, i.e., those who have a larger than average increase in LDL-C in response to an increase in dietary cholesterol.16  Additional research will be needed to determine whether a dietary cholesterol intake >300 mg/d is causally related to adverse health outcomes, and, if so, what mechanisms account for these relationships.



  1. US Department of Health and Human Services and US Department of Agriculture. 2015-2020 Dietary Guidelines for Americans. 8th Edition. December 2015. guidelines/2015/guidelines/.
  2. Dietary Guidelines Advisory Committee. Scientific Report of the 2015 Dietary Guidelines Advisory Committee: Advisory Report to the Secretary of Health and Human Services and the Secretary of Agriculture. Washington, DC: US Dept of Agriculture, Agricultural Research Service; 2015.
  3. Berger S, Raman G, Vishwanathan R, et al. Dietary cholesterol and cardiovascular disease. Am J Clin Nutr. 2015;102:276-294.
  4. US Department of Agriculture. Agricultural Research Service, Nutrient Data Laboratory. USDA National Nutrient Database for Standard Reference, Release 28. Version Current: September 2015.
  5. Zhong VW, Van Horn L, Cornelis MC, et al. Associations of dietary cholesterol or egg consumption with incident cardiovascular disease and mortality. JAMA. 2019;321:1081-1095.
  6. The ARIC Investigators. The Atherosclerosis Risk in Communities (ARIC) study: design and objectives. Am J Epidemiol. 1989;129:687-702.
  7. Friedman GD, Cutter GR, Donahue RP, et al. CARDIA: study design, recruitment, and some characteristics of the examined subjects. J Clin Epidemiol. 1988;41:1105-1116.
  8. Wong ND, Levy D. Legacy of the Framingham Heart Study: rationale, design, initial findings, and implications. Glob Heart. 2013;8:3-9.
  9. Feinleib M, Kannel WB, Garrison RJ, et al. The Framingham Offspring Study: design and preliminary data. Prev Med. 1975;4:518-525.
  10. Taylor HA Jr, Wilson JG, Jones DW, et al. Toward resolution of cardiovascular health disparities in African Americans. Ethn Dis. 2005;15(suppl 6):4-17.
  11. Bild DE, Bluemke DA, Burke GL, et al. Multi-Ethnic Study of Atherosclerosis: objectives and design. Am J Epidemiol. 2002;156:871-881.
  12. Key TJ, Appleby PN, Bradbury KE, et al. Consumption of meat, fish, dairy products, eggs and risk of ischemic heart disease: a prospective study of 7198 incident cases among 409,885 participants in the Pan-European EPIC cohort. Circulation. 2019; Epub ahead of print.
  13. Qin C, Lv J, Bian Z, et al. Associations of egg consumption with cardiovascular disease in a cohort study of 0.5 million Chinese adults. Heart. 2018;104:1756-1763.
  14. Vincent MJ, Allen B, Palacios OM, Haber LT, Maki KC. Meta-regression analysis of the effects of dietary cholesterol intake on LDL and HDL cholesterol. Am J Clin Nutr. 2019;109:7-
  15. Clarke R, Frost C, Collins R, Appleby P, Peto R. Dietary lipids and blood cholesterol: quantitative meta-analysis of metabolic ward studies. BMJ. 1997;314:112-117.
  16. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 2. J Clin Lipidol. 2015;9(6 Suppl):S1-S122.e1.


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Bempedoic acid in conjunction with statin therapy for dyslipidemia management

Bempedoic acid in conjunction with statin therapy for dyslipidemia management

By Aly Becraft, MS; Kevin C. Maki, PhD

Use of statins to reduce risk of cardiovascular disease is an effective treatment strategy,1 but the statin doses required to adequately reduce low density lipoprotein cholesterol (LDL-C) and non-high-density-lipoprotein cholesterol (non-HDL-C) levels and achieve optimal cardiovascular disease risk reduction are not well tolerated by some patients, and even maximal statin therapy may be inadequate to achieve sufficient cholesterol-lowering in some patients.2-8  Bempedoic acid is a promising prodrug that may be useful as an adjunct therapy to stains for lowering LDL-C. Its activation is reliant on very-long-chain acyl-CoA synthetase 1, which is present in the liver, but absent from most other tissues.8 Once activated, it is thought to act via the same cholesterol biosynthesis pathway as statins; however, its target, ATP citrate lyase (ACL), is further upstream in the pathway than the target for statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase.8 The liver specific activation of bempedoic acid differentiates it from statins. Because muscle cells do not express the activating enzyme for bempedoic acid, it is less likely to have skeletal muscle-related side effects.  This makes it an attractive adjunct therapy to statins since the most commonly reported side effects with statins include myalgias and other muscle-related complaints.8 Bempedoic acid has also been studied in combination with ezetimibe in patients with and without statin intolerance.9,10 It was shown to reduce LDL-C more than ezetimibe alone, and to have a similar tolerability profile. In a trial of patients with a history of statin intolerance and LDL-C ≥100 mg/dL, bempedoic acid added to background lipid-modifying therapy that included ezetimibe reduced LDL-C by 28.5% more than the addition of placebo (p < 0.001).10 Until recently, the efficacy and safety of bempedoic acid had been evaluated in relatively small groups and in trials of short duration.9-13

Ray et al.14 published results from the Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Harmony trial. This 52-week, randomized, double-blind, placebo-controlled trial evaluated the safety and efficacy of bempedoic acid for reducing LDL-C. In this phase 3, parallel group trial, a total of 2230 patients were enrolled; 1488 were assigned to receive bempedoic acid and 742 received a placebo. Patients qualified for the study if they had either atherosclerotic cardiovascular disease (97.6% of subjects) or heterozygous familial hypercholesterolemia (3.5% of subjects), were taking stable doses of maximally tolerated statin therapy, and had fasting LDL-C levels of at least 70 mg/dL (mean ± standard deviation 103.2 ± 29.4 mg/dL) . The primary end points were safety-related, including incidence of adverse events and changes in laboratory variables. Secondary end points included changes from baseline to 12 weeks in LDL-C, non-HDL-C, total cholesterol, apolipoprotein B and high-sensitivity C-reactive protein.

Of the enrolled patients, 78.1% completed the intervention and 94.6% continued the trial through week 52, providing a total of 1248 patient-years of exposure to bempedoic acid. Adverse events were reported in approximately 79% of both treatment groups, with a majority of events (>80%) graded as mild to moderate in severity. Common adverse event incidence and major adverse events occurred with similar frequency in both groups; however, the number of patients who discontinued treatment due to adverse events was higher in the bempedoic acid group compared to the placebo group (10.9% vs 7.1%; p = 0.005). Incidence of gout in the bempedoic acid group was modestly increased compared to placebo (1.3% vs 0.3%; p = 0.03). Interestingly, the incidence of new-onset diabetes or worsening diabetes was lower among subjects receiving bempedoic acid compared to placebo (3.3% vs. 5.4%; p = 0.02), although the total number of events was low.

Treatment with bempedoic acid significantly (p < 0.001) reduced LDL-C levels compared to placebo at week 12 (18.1% from baseline) and week 24 (16.1% from baseline). All other measured cardiometabolic risk factors were also significantly reduced (p < 0.001 for all comparisons) from baseline at week 12 with bempedoic acid compared to placebo. The effects of bempedoic acid were sustained with minimal attenuation through the end of the trial (week 52). Efficacy was observed to be greater among women than men (p = 0.03) but was not significantly different across other subgroups, including type or intensity of background lipid-lowering therapy.

Comment: The present trial provides evidence for the safe and efficacious longer term (1-year) , use of bempedoic acid as an adjunct therapy to statins. Although discontinuation of the trial was higher among subjects in the bempedoic acid group, adverse events appeared to occur at similar frequency in both groups. Increased gout occurrence with the bempedoic acid treatment may be related to metabolite competition with uric acid for renal transporters involved in their excretion14 and the incidence of gout in this trial was modest.

Compared to placebo, use of bempedoic acid in conjunction with statin therapy modestly reduced the levels of LDL-C and other lipoprotein lipid and biomarker levels from baseline to week 12 and throughout the remainder of the 52-week trial. Bempedoic acid works via the same cholesterol synthesis pathway as statins;8 however, doubling statin dosage reduces LDL-C levels by ~6%,15 less than half of the reported effect from the present trial. Furthermore, bempedoic acid treatment did not appear to cause or exacerbate skeletal muscle-related side effects associated with statin use, further signifying its efficacy and tolerability as a prospective statin adjunct. Of note, the trial population was predominantly white (~96%), and more racial diversity is needed in future evaluations of bempedoic acid safety and efficacy. In addition, 73% of patients were male; therefore, the present findings of greater treatment efficacy in women should also be explored in future studies with a greater proportion of women subjects.

In February 2019, the manufacturer, Esperion Therapeutics, Inc. (Ann Arbor, MI), submitted two New Drug Applications to the US Food and Drug Administration for approval of bempedoic acid and a bempedoic acid/ezetimibe combination tablet as once daily oral therapies for the treatment of patients with elevated LDL-C who need additional LDL-C lowering despite the use of currently accessible therapies. Esperion expects to receive notification on whether the submissions have been accepted for review in May of 2019.


  1. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980–2000. N Engl J Med. 2007;356:2388-98.
  2. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.
  3. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res. 2016;118:547–563.
  4. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:Suppl 2:S1-S45.
  5. Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: full report. J Clin Lipidol. 2015;9:129-69.
  6. Danese MD, Gleeson M, Kutikova L, et al. Management of lipid-lowering therapy in patients with cardiovascular events in the UK: a retrospective cohort study. BMJ Open. 2017;7:e013851.
  7. Steen DL, Khan I, Ansell D, Sanchez RJ, Ray KK. Retrospective examination of lipid-lowering treatment patterns in a real world high-risk cohort in the UK in 2014: comparison with the National Institute for Health and Care Excellence (NICE) 2014 lipid modification guidelines. BMJ Open. 2017;7:e013255.
  8. Pinkosky SL, Newton RS, Day EA, et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016;7:13457.
  9. Thompson PD, MacDougall DE, Newton RS, et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J Clin Lipidol. 2016;10:556-67.
  10. Ballantyne CM, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study. Atherosclerosis. 2018;277:195-203.
  11. Ballantyne CM, Davidson MH, Macdougall DE, et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J Am Coll Cardiol. 2013;62:1154-62.
  12. Thompson PD, Rubino J, Janik MJ, et al. Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance. J Clin Lipidol. 2015;9:295-304.
  13. Ballantyne CM, McKenney JM, MacDougall DE, et al. Effect of ETC-1002 on serum low-density lipoprotein cholesterol in hypercholesterolemic patients receiving statin therapy. Am J Cardiol. 2016;117:1928-33.
  14. Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, Robinson PL, Ballantyne CM. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019;380:1022-32.
  15. Nicholls SJ, Brandrup-Wognsen G, Palmer M, Barter PJ. Meta-analysis of comparative efficacy of increasing dose of atorvastatin versus rosuvastatin versus simvastatin on lowering levels of atherogenic lipids (from VOYAGER). Am J Cardiol. 2010;105:69-76.
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