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.

 

 

References

  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.

 

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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.

 

References

  1. US Department of Health and Human Services and US Department of Agriculture. 2015-2020 Dietary Guidelines for Americans. 8th Edition. December 2015. https://health.gov/dietary 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. https://ndb.nal.usda.gov/ndb/.
  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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Association of Long-term Consumption of Sugar-Sweetened and Artificially Sweetened Beverages with Total and Cause-specific Mortality

Association of Long-term Consumption of Sugar-Sweetened and Artificially Sweetened Beverages with Total and Cause-specific Mortality

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

In the United States, sugar sweetened beverages (SSBs) account for the largest source of added sugar in the diet 1,2.  These types of drinks (e.g., carbonated, noncarbonated, fruit, sports) have added caloric sweeteners like high fructose corn syrup, sucrose, or fruit juice concentrates.  Currently it is recommended that adults consume no more than 10% of their total energy intake from added sugar 3.

While consumption rates of SSBs had been declining in the US over the past 10 years, recent research has suggested a reversal in that trend, with increased consumption among adults of all ages averaging around 145 kcal/day (6% of energy)4.  In younger adults, SSBs are responsible for 9.3% of daily calories in men and 8.2% of daily calories in women 5-7.

Studies have shown a positive association between intake of SSBs and weight gain, as well as higher risks of type 2 diabetes, coronary heart disease and stroke 8-11.  Artificially sweetened beverages (ASBs) are used as alternatives to the calorically heavy SSBs, yet there has been little research on the long-term health effects of ASBs or on the relationship between SSB consumption and total mortality.

In an analysis of two ongoing prospective cohort studies, Malik et al. examined the association between intakes of SSBs and ASBs with total and cause-specific mortality 12.  The analysis included data from the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS).  The NHS study has been collecting data since 1976 and includes 121,700 female nurses, age 30-55 years at study entry.  The HPFS began in 1986 and includes 51,529 male health professionals, age 40-75 years at entry. 

Mean consumption of SSBs decreased in both cohorts over the follow-up periods, which were 34 years in the NHS and 28 years in the HPFS.  Intakes of SSBs and ASBs were inversely correlated in both the NHS (r = −0.06, P < 0.001) and the HPFS (r = −0.16, P < 0.001).  Overall, there were 36,436 deaths, including 7,896 from cardiovascular disease (CVD) and 12,380 from cancer during a total of 3,415,564 person-years of follow-up.

After adjusting for major diet and lifestyle factors, consumption of SSBs was associated with a higher risk of total mortality (Table).  SSBs were also associated with increased CVD mortality (hazard ratio comparing extreme categories of 1.31 [95% confidence interval, 1.15-1.50], P trend < 0.0001) and cancer mortality (1.16 [1.04-1.29], P trend = 0.0004).  ASB intake was associated with increased risk for total and CVD mortality only in the highest intake group (Table).  Interestingly, intake of ASBs was associated with total mortality in the NHS, but not the HPFS (P interaction = 0.01).  ASBs were not associated with cancer mortality in either cohort.

 

 

Table:  SSB and ASB Consumption and Mortality Risk (Total, CVD, Cancer)

Pooled Hazard Ratios (95% confidence intervals) from NHS and HPFS

 

<1/month

1-4/month

2-6/week

1-<2/d

>2/d

P trend

Total Mortality

SSB

1.0

 

1.01

(0.98, 1.04)

1.06

(1.03, 1.09)

1.14

(1.09, 1.19)

1.21

(1.13, 1.28)

<0.0001

ASB

1.0

 

0.96

(0.93, 0.99)

0.97

(0.95, 1.00)

0.98

(0.94, 1.03)

1.04

(1.02, 1.12)

0.01

CVD Mortality

SSB

1.0

1.06

(1.00, 1.12)

1.10

(1.04, 1.17)

1.19

(1.08, 1.31)

1.31

(1.15, 1.50)

<0.0001

ASB

1.0

0.93

(0.87, 1.00)

0.95

(0.89, 1.00)

1.02

(0.94, 1.12)

1.13

(1.02, 1.25)

0.02

Cancer Mortality

SSB

1.0

1.03 

(0.98, 1.08)

1.06

(1.01, 1.11)

1.12

(1.03, 1.21)

1.16

(1.04, 1.29)

0.0004

ASB

1.0

1.01

(0.96, 1.07)

0.99

(0.94, 1.04)

1.00

(0.93, 1.07)

1.04

(0.96, 1.12)

0.58

 

Comment.  Results from this study highlight the importance of minimizing SSB intake because consumption of SSBs has been consistently associated with adverse health outcomes and a less favorable cardiometabolic risk factor profile.8-11  Substituting ASBs for SSBs will help decrease added sugar intake, but it is important to note that the possible health impacts of long-term consumption have not been well documented.  It is uncertain whether the modest increases in total (4%) and CVD (13%) mortality associated with consuming ≥2 ASBs per day represent causal relationships.  Nevertheless, it is reasonable to recommend moderation in the consumption of these products.

 

References

  1. Hu FB, Malik VS. Sugar-sweetened beverages and risk of obesity and type 2 diabetes: epidemiologic evidence. Physiol Behav. 2010;100:47–54.
  2. National Cancer Institute: Division of Cancer Control & Population Sciences. Epidemiology and Genomics Research Program. Sources of Calories from Added Sugars among the US population, 2005–2006. Updated April 20, 2018. http://riskfactor.cancer.gov/diet/foodsources/added_sugars/.
  3. S. Department of Health and Human Services and U.S. Department of 
Agriculture. 2015–2020 Dietary Guidelines for Americans. 8th Edition. December 2015. http://health.gov/dietaryguidelines/2015/guidelines/.
  4. Welsh JA, Sharma AJ, Grellinger L, Vos MB. Consumption of added sugars is decreasing in the United States. Am J Clin Nutr. 2011;94:726–734.
  5. Ogden CL, Kit BK, Carroll MD, Park S. Consumption of sugar drinks in the United States, 2005–2008. NCHS Data Brief. 2011:1–8. 

  6. Rosinger A, Herrick K, Gahche J, Park S. Sugar-sweetened beverage consumption among U.S. adults, 2011–2014. NCHS Data Brief. 2017:1–8. 

  7. Malik VS, Pan A, Willett WC, Hu FB. Sugar-sweetened beverages and weight gain in children and adults: a systematic review and meta-analysis. Am J Clin Nutr. 2013;98:1084–1102.
  8. Malik VS, Popkin BM, Bray GA, Després JP, Willett WC, Hu FB. Sugar- sweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis. Diabetes Care. 2010;33:2477–2483.
  9. Fung TT, Malik V, Rexrode KM, Manson JE, Willett WC, Hu FB. Sweetened beverage consumption and risk of coronary heart disease in women. Am J Clin Nutr. 2009;89:1037–1042.
  10. de Koning L, Malik VS, Kellogg MD, Rimm EB, Willett WC, Hu FB. Sweetened beverage consumption, incident coronary heart disease, and biomarkers of risk in men. Circulation. 2012;125:1735–41, S1.
  11. Bernstein AM, de Koning L, Flint AJ, Rexrode KM, Willett WC. Soda consumption and the risk of stroke in men and women. Am J Clin Nutr. 2012;95:1190–1199.
  12. Malik VS, Li Y, Pan A, De Koning L, Schernhammer E, Willett WC, Hu FB. Long-term consumption of sugar-sweetened and artificially sweetened beverages and risk of mortality in US adults.  2019;139: doi: 10.1161/circulationaha.118.037401.

 

 

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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.

References

  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.
Photo by Louis Reed

The Effects of Icosapent Ethyl on Total Ischemic Events: An Analysis from REDUCE-IT

The Effects of Icosapent Ethyl on Total Ischemic Events: An Analysis from REDUCE-IT

By Aly Becraft, MS and Kevin C Maki, PhD

 

Statin therapy is highly effective for lowering low-density lipoprotein cholesterol (LDL-C), but many patients remain at risk for ischemic events, despite statin therapy.1 Elevated levels of triglycerides (TG) and TG-rich lipoproteins are independent risk factors for cardiovascular events and may play a casual role in the development of cardiovascular disease.2

 

Icosapent ethyl (VascepaÒ) is a highly purified derivative of EPA that is currently approved by the Food and Drug Administration for use as an adjunctive therapy in the treatment of hypertriglyceridemia in patients with TG levels ≥500 mg/dL.3 It has been shown to lower TG levels without raising LDL-C4,5 and may have anti-inflammatory, antioxidative, plaque-stabilizing, and membrane-stabilizing properties.6-9

 

Earlier this year, Bhatt et al. published results from the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) indicating that icosapent ethyl reduced risk for the first occurrence of the primary endpoint (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization or hospitalization for unstable angina) by 25% in patients with elevated TG levels (≥500 mg/dL) receiving statin therapy during a median follow-up of 4.9 y.3 In this randomized, double-blind, placebo-controlled trial, a total of 8,179 statin-treated patients were given 4 g/day icosapent ethyl or a mineral oil-based placebo with meals. At baseline, patients had a median TG level of 216 mg/dL and a median LDL-C of 75 mg/dL. Seventy-nine percent of patients had history of atherosclerosis and 29% had a history of diabetes.

 

Recently, the REDUCE-IT investigators sought to determine the effect of icosapent ethyl on total ischemic events in the trial.10 For this analysis, the primary outcome was the total of first plus subsequent ischemic events (defined the same as for the primary outcome in the main analysis).  There were 1,606 first primary endpoint events and 1,303 additional primary endpoint events (727 second events, 272 third events, and 269 fourth or more events). Total ischemic event rate for the primary outcome was reduced by 30% with icosapent ethyl compared to placebo (rate ratio [RR] 0.70, 95% confidence interval [CI] 0.62-0.78, P < 0.0001). First events were reduced by 25%, second events by 32%, third events by 31%, and fourth or more events by 48%. The key secondary endpoint, defined for this analysis as hard major adverse cardiac outcome (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke), was also significantly reduced with icosapent ethyl compared to placebo (RR 0.72, 95% CI 0.63-0.82, P < 0.0001). Several statistical models were used, and each demonstrated consistent effects of icosapent ethyl for reducing total ischemic events.

 

Comment: The results from this analysis demonstrate the benefit of icosapent ethyl as a therapy for the reduction of first and subsequent ischemic events in statin-treated patients. The present analysis of REDUCE-IT included patients from 11 different countries, yielding more conclusive outcomes for cardiovascular benefit than for interventions conducted in single countries.11-13

 

The efficacy of icosapent ethyl was numerically larger for second and higher events, which illustrates two important points.  First, those who have had a recent cardiovascular event are at high risk for subsequent events.  Second, the traditional analysis method of focusing only on first events markedly underestimates the impact of cardiovascular disease and often the benefit of the therapy under study.  Related to the second point, cost effectiveness analyses generally only consider first event reduction and may therefore underestimate cost effectiveness. 

 

Future analyses of biomarkers collected from REDUCE-IT patients may provide further insight into the mechanisms of action of icosapent ethyl and help to better explain the mechanisms responsible for the effects and identify additional potential clinical applications for this new therapy.

 

References:

  1. 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.
  2. Nordestgaard BG . Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res. 2016;118:547-63.
  3. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22.
  4. Bays HE, Ballantyne CM, Kastelein JJ, et al. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am J Cardiol. 2011;108:682-90.
  5. Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110:984-92.
  6. Bays HE, Ballantyne CM, Braeckman RA, et al. Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies. Am J Cardiovasc Drugs. 2013;13:37-46.
  7. Nelson JR, Wani O, May HT, Budoff M. Potential benefits of eicosapentaenoic acid on atherosclerotic plaques. Vascul Pharmacol. 2017;91:1-9.
  8. Mason RP, Jacob RF, Shrivastava S, et al. Eicosapentaenoic acid reduces membrane fluidity, inhibits cholesterol domain formation, and normalizes bilayer width in atherosclerotic-like model membranes. Biochim Biophys Acta. 2016;1858:3131-40.
  9. Sherratt SCR, Mason RP. Eicosapentaenoic acid and docosahexaenoic acid have distinct membrane locations and lipid interactions as determined by X-ray diffraction. Chem Phys Lipids. 2018;212:73-9.
  10. Bhatt DL, Steg PG, Miller M, et al.; REDUCE-IT Investigators. Effects of icosapent ethyl on total ischemic events: from REDUCE-IT. J Am Coll Cardiol. 2019; Epub ahead of print.
  11. Yokoyama M, Origasa H, Matsuzaki M, et al.; JELIS Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis [published correction appears in Lancet. 2007;370:220]. Lancet. 2007;369:1090-8.
  12. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico [published corrections appear in Lancet. 2001;357:642 and 2007;369:106]. Lancet. 1999;354:447-55.
  13. Tavazzi L, Maggioni AP, Marchioli R, et al.; GISSI-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1223-30.

 

 

 

 

Photo by Kendal James

Suboptimal Triglyceride Levels Among Statin Users in the National Health and Nutrition Examination Survey

Suboptimal Triglyceride Levels Among Statin Users in the National Health and Nutrition Examination Survey

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

 

Statin therapy is the primary treatment for dyslipidemia, even in those with moderately elevated triglycerides (TG).1  Hypertriglyceridemia, an independent risk factor of coronary heart disease (CHD), is defined as fasting TG >150 mg/dL.2  Meta-analyses have shown a 1.7-fold greater risk for CHD in those in the highest TG tertile compared to those in the lowest tertile.2,3  In a more recent longitudinal, real-world administrative database analysis, increased cardiovascular disease risk and direct healthcare costs were associated with hypertriglyceridemia, despite statin therapy and controlled low-density lipoprotein cholesterol (LDL-C) when compared to those with TG <150 mg/dL.4,5  Another study has also reported that approximately one-third of patients treated for dyslipidemia still have suboptimal TG levels.6

In the US population, limited data have been available on the prevalence and impact of hypertriglyceridemia in patients treated for dyslipidemia or with normal LDL-C levels, especially given the increase in statin use.  To help address this gap, Fan et al. analyzed National Health and Nutrition Examination Surveys (NHANES) from 2007-2014 to determine the prevalence of elevated TG levels in adults with and without statin use, as well as the associated 10-year predicted atherosclerotic cardiovascular disease (ASCVD) risk.7  The study included 9,593 US adults aged 20 years (219.9 million projected) and determined the proportion of persons with TG levels according to the categories of <150, 150-199, 200-499, and 500 mg/dL for both non-statin and statin users.

Proportion of US adults According to TG Category7

 

<150 mg/dL

150-199 mg/dL

≥ 200 mg/dL

Non-statin users

75.3%

12.8%

11.9%

Statin Users

68.4%

16.2%

15.4%

 

Among those with LDL-C <100 mg/dL (or <70 mg/dL in those with ASCVD), 27.6% had TG 150 mg/dL, despite statin use.  Significantly greater odds of TG 150 mg/dL in statin users were associated with higher age, higher body mass index, lower high-density lipoprotein cholesterol, higher LDL-C, and diabetes.  The estimated mean 10-year ASCVD risk from TG <150 to 500 mg/dL, ranged from 6.0-15.6% in those not taking statins, and 11.3-19.1% in statin users. This translates to a predicted 3.4 million ASCVD events over the next 10 years in those with TG 150 mg/dL.

Comment.  Based on these results in US adults, suboptimal TG levels are found in ~25% of the overall population and nearly one-third of adults on statin therapy.  TG elevation is associated with increased ASCVD risk, even when the LDL-C level is low.8  Lifestyle therapies are key in the management of an elevated TG level, including increased physical activity, weight loss, reduced glycemic load and alcohol restriction.1,9  The recently published results from the Reduction of Cardiovascular Events with Icosapent Ethyl (REDUCE-IT) trial demonstrated that ASCVD event risk was lowered by an impressive 25% in statin-treated high-risk patients with elevated TG by the addition of 4 g/d of icosapent ethyl (eicosapentaenoic acid [EPA] ethyl esters).10  Two additional large-scale trials are underway with TG-lowering drug therapies (Outcomes Study to Assess Statin Residual Risk Reduction with Epanova in High CV Risk Patients [STRENGTH] and Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes [PROMINENT]), which are evaluating effects of EPA + docosahexaenoic acid (DHA) carboxylic acids and pemafibrate, respectively.11,12  The results from the present survey suggest that the population-attributable risk due to elevated TG in the US is substantial, which underscores the importance of recognizing hypertriglyceridemia as a marker for ASCVD risk that can be addressed through lifestyle and pharmacologic therapies.

References

 

  1. Stone NJ, Robinson JG, Lichtenstein AH, et al. American College of Cardiology/American Heart Association task force on practice guidelines. 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. J Am Coll Cardiol. 2014;63(25 Pt B):2889–2934
  2. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;115(4): 450–458.
  3. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996;3(2):213–219.
  4. Toth PP, Granowitz C, Hull M, et al. High triglycerides are associated with increased cardiovascular events, medical costs, and resource use: a real-world administrative claims analysis of statin-treated patients with high residual cardiovascular risk. J Am Heart Assoc. 2018;7:e008740.
  5. Nichols GA, Philip S, Reynolds K, et al. Increased cardiovascular risk in hypertriglyceridemic patients with statin-controlled LDL cholesterol. J Clin Endocrinol Metab. 2018;103:3019–3027.
  6. Wong ND, Chuang J, Wong K, et al. Residual dyslipidemia among United States adults treated with lipid modifying therapy (Data from National Health and Nutrition Examination Survey 2009-2010). Am J Cardiol. 2013;112:373–379.
  7. Fan W, Philip S, Granowitz C, et al. Hypertriglyceridemia in statin-treated US adults: the National Health and Nutrition Examination Survey. J Clin Lipidol. 2019;13:100–108.
  8. Miller M, Cannon CP, Murphy SA, et al. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2008;51:724–730.
  9. Jacobson A, Savji N, Blumenthal RS, Martin SS. American College of Cardiology Expert Analysis. Hypertriglyceridemia management according to the 2018 AHA/ACC guideline. January 11, 2019. Available at https://www.acc.org/latest-in-cardiology/articles/2019/01/11/07/39/hypertriglyceridemia-management-according-to-the-2018-aha-acc-guideline.
  10. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11–22.
  11. Nicholls SJ, Lincoff AM, Bash D, et al. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: rationale and design of the STRENGTH trial. Clin Cardiol. 2018;41:1281–1288.
  12. Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J. 2018;206:80–93.

 

 

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Association of Statin Adherence with Mortality in Patients with Atherosclerotic Cardiovascular Disease

Association of Statin Adherence with Mortality in Patients with Atherosclerotic Cardiovascular Disease

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

 

There is little doubt of the role that statins play in the reduction of mortality risk, mainly attributable to a benefit on death from cardiovascular causes.  A meta-analysis of statin clinical trials reported a 12% proportional reduction in all-cause mortality per mmol/L reduction in low-density lipoprotein cholesterol (LDL-C) with the use of statins (rate ratio [RR] 0.88, 95% confidence interval [CI] 0.84-0.91; p < 0.0001).1  In a systematic review, De Vera et al. reported an increased risk of adverse outcomes with poor statin therapy adherence.2  With such a strong link between statin adherence and decreased mortality, it is unclear why so many patients stop taking their statins or what the long-term effects on health and healthcare costs will be.  Results from surveys of statin adherence suggest that as many as 50% of patients for whom statin therapy is prescribed stop taking the medication within 12 months.3,4  Rates of discontinuation and poor adherence are high even among those with known atherosclerotic cardiovascular disease (ASCVD).3,4

 

To further assess the association between statin adherence and all-cause mortality, Rodriguez et al. conducted a retrospective cohort analysis of patients between the ages of 21-85 years with one or more International Classification of Diseases, Ninth Revision, Clinical Modification codes for ASCVD on two or more dates in the previous two years without intensity changes to their statin prescription.5  All patients were treated within the Veterans Affairs Health System between January 1, 2013 and April 2014.

 

The primary outcome was death from all causes adjusted for demographic and clinical characteristics, and adherence to other cardiac medications.  Secondary outcomes included 1-year mortality, 1-year hospitalization for ischemic heart disease or ischemic stroke.  A sensitivity analysis was also conducted to investigate an association between statin adherence and hospitalization for gastrointestinal bleeding and pneumonia.  Finally, the researchers sought to determine if the association between statin adherence and mortality was modified by statin intensity (low, medium, high) or by patient-level or system-level characteristics.

 

The medication possession ratio (MPR) was used to measure patient medication adherence.  The MPR is the number of days of outpatient statin supplied during a 12- month period divided by the number of days the patient was not hospitalized and alive in the same 12-month time frame.  Medication adherence was categorized as <50% MPR, 50-69% MPR, 70-89% MPR and ≥90% MPR.

 

The study included 347,104 patients with ASCVD on stable statin prescriptions.  The overall mean statin adherence in this population was ~88%; ~6% had a MPR of <50% and ~64% had a MPR of ≥90%.  Overall, women were less adherent than men (odds ratio, 0.89; 95% CI, 0.84-0.94), as were minority groups, while younger and older patients were less likely to be adherent compared with those aged 65-74 years.  During a mean (standard deviation) follow up of 2.9 (0.8) years there were 85,930 deaths (24.8%).  Compared to the most adherent patients (MPR ≥90%), patients with a MPR <50% had a hazard ratio (HR) adjusted for clinical characteristics and adherence to other cardiac medications of 1.30 (95% CI, 1.27-1.34), while those with a MPR of 50-69% had a HR of 1.21 (95% CI, 1.18-1.24), and those with an MPR of 70-89% had a HR of 1.08 (95% CI, 1.06-1.09).

 

After one year, hospitalizations for ischemic heart disease and stroke were more frequent in patients who were less adherent to their statin therapy.  The proportion of patients with a hospitalization for ischemic heart disease or ischemic stroke was 13.4% (n = 2653) for an MPR<50%, 13.1% (n = 4018) for an MPR of 50-69%, 11.5% (n = 8729) for an MPR of 70-89%, and 11.5% (n = 25434) for an MPR of ≥90% (p < 0.001).  This association remained even after adjusting for baseline characteristics.  There was no association between MPR and hospitalization for gastrointestinal bleeding or pneumonia.

 

Finally, in this cohort 42,010 (12%) patients were on low-intensity therapy, 217,570 (63%) were on moderate-intensity therapy, and 87,524 (25%) were on high-intensity treatment.  Patients on moderate-intensity statin therapy were more likely to adhere to statin therapy compared to patients in the low- and high-intensity therapy groups.  Patients with the highest MPR had lower LDL-C values (77.2 mg/dL for MPR ≥90% compared with 92.1 mg/dL for MPR <50%).

 

Comment.  The role that statins play in the reduction of mortality is not surprising.  When a patient consistently takes the statin as prescribed, their risk of cardiovascular mortality will likely decrease.  What is surprising is the lack of adherence by patients, especially over time, given the evidence supporting statin effectiveness.  Further research should focus on how to improve patient adherence to statin therapy.6

 

Another important consideration that is illustrated by the present study is that it is important to consider the effects of healthy and unhealthy user bias in observational studies.  Ann Marie Navar makes this point in an editorial accompanying the paper.6  Those with the poorest adherence to statin therapy (MPR <50%) had a 30% increase in mortality.  Adjustment for follow-up LDL-C levels reduced the mortality hazard by 10%.  Thus, only one third of the effect appears to be attributable to the main pathway through which statins alter risk.  This suggests the presence of residual confounding by other factors.  People who are adherent to therapy recommendations differ in numerous ways relevant to health outcomes from those who do not.  It is difficult, if not impossible, to fully account for differences in potential confounders through statistical modeling.  Thus, while a portion of the higher mortality risk among those with poor adherence is likely due to less impact of the drug itself, other factors also likely contribute to a similar or even larger degree.

 

This concept was recently illustrated in an analysis from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.7,8  Healthy 55- to74-year old participants were randomly assigned to receive usual care or a more intensive screening program.  Among those randomized to more intensive screening, 10.8% did not complete any of the recommended screening tests.  After 10 years, those non-adherent subjects had 50% higher mortality compared to those with full adherence who completed all recommended tests.  However, the increased mortality was not attributable only to cancers, but to a wide range of causes.  Thus, non-adherence to recommended screening (or to prescribed medication) is likely a marker for an array of behaviors associated with increased mortality risk.  This unhealthy or healthy user bias should be kept in mind when evaluating the results from observational studies of behaviors associated with health outcomes.  Those who choose to engage in a behavior they view as health-promoting, such as taking prescribed medication, undergoing recommended screening tests, following a diet or exercise program, or taking a dietary supplement, may differ in important ways from those who choose not to engage in the behavior, resulting in healthy user bias.  Conversely, those who engage in behaviors they know are unhealthy, such as cigarette smoking, may also engage in other unhealthy behaviors (unhealthy user bias).  Thus, estimates of the effects of behavioral exposures from observational studies should be interpreted with caution and should ideally be verified in prospective, randomized, controlled trials.

 

References

 

  1. Baigent C, Keech A, Kearney PM, et al. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-1278.
  2. DeVera MA, Bhole V, Burns LC, Lacaille D. Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review. Br J Clin Pharmacol. 2014;78:684-698.
  3. Maddox TM, Chan PS, Spertus JA, et al. Variations in coronary artery disease secondary prevention prescriptions among outpatient cardiology practices: insights from the NCDR (National Cardiovascular Data Registry). J Am Coll Cardiol. 2014;63:539-546.
  4. Hirsh BJ, Smilowitz NR, Rosenson RS, et al. Utilization of and adherence to guideline-recommended lipid-lowering therapy after acute coronary syndrome: opportunities for improvement. J Am Coll Cardiol. 2015;66:184-192.
  5. Rodriguez F, Maron DJ, Knowles JW, et al. Association of statin adherence with mortality in patients with atherosclerotic cardiovascular disease. JAMA Cardiol. 2019; Epub ahead of print.
  6. Navar AM. Statins work, but only in people who take them. JAMA Cardiol. 2019; Epub ahead of print.
  7. Pierre-Victor D, Pinsky PF. Association of nonadherence to cancer screening examinations with mortality from unrelated causes: a secondary analysis of the PLCO Cancer Screening trial. JAMA Intern Med. 2019;179:196-203.
  8. Grady D. Why is nonadherence to cancer screening associated with increased mortality? JAMA Intern Med. 2018; Epub ahead of print.

 

OLYMPUS DIGITAL CAMERA

More Evidence that Low-density Lipoprotein Cholesterol and Triglyceride-lowering Genetic Variants Reduce Risk of Coronary Heart Disease

More Evidence that Low-density Lipoprotein Cholesterol and Triglyceride-lowering Genetic Variants Reduce Risk of Coronary Heart Disease

By Kevin C Maki, PhD and Mary R Dicklin, PhD

 

The total cholesterol concentration in circulation is comprised of cholesterol carried by three main types of lipoproteins:  low-density lipoproteins (LDL), very-low-density lipoproteins (VLDL) and high-density lipoproteins (HDL).  VLDL particles are the main carriers of triglycerides (TG), and the Friedewald equation estimates the VLDL cholesterol (VLDL-C) level in mg/dL as TG/5.  LDL and VLDL particles each contain a single molecule of apolipoprotein B (Apo B).  Non-HDL cholesterol (non-HDL-C) is the sum of the cholesterol carried by all particles that contain Apo B, i.e., LDL-C + VLDL-C.  Note for purists:  this ignores a quantitatively small contribution of cholesterol carried by chylomicron remnants and it includes cholesterol carried by lipoprotein (a) particles, which are generally in the LDL density range.

 

Non-HDL-C has been found to be a more consistent predictor of coronary heart disease (CHD) risk than LDL-C (Liu 2005, Robinson 2009).  Prior studies have shown that genetic variants that modify each of the components of non-HDL-C are associated with modification of cardiovascular disease risk, particularly incidence of CHD.

 

Ference and colleagues recently published a large-scale analysis of data from a group of 654,783 subjects, in 63 case-control or cohort studies, to investigate two sets of lipid-lowering genetic variants for the LDL receptor gene and the lipoprotein lipase (LPL) gene that predominantly affect LDL-C and TG, respectively (Ference 2019, Navar 2019).  The analysis included 91,129 cases of CHD.  Their investigation showed that both genetically-induced LDL-C reduction through the LDL receptor gene score and TG reduction through the LPL gene score were associated with significantly reduced CHD risk, findings which agree with those from prior investigations.

 

The authors then extended their analysis by investigating 168 genetic variants associated with either LDL-C or TG modification.  In order to make an “apples to apples” comparison, the associations were standardized to a 10 mg/dL difference in genetically-induced LDL-C reduction and a 50 mg/dL reduction in TG, which is equivalent to a 10 mg/dL reduction in VLDL-C (TG/5 = VLDL-C).  Each 10 mg/dL reduction in LDL-C was associated with 15.4% lower odds for CHD (odds ratio = 0.846) and each 10 mg/dL reduction in VLDL-C (50 mg/dL reduction in TG) was associated with 18.5% lower odds for CHD (odds ratio = 0.815).

 

Since LDL and VLDL particles each contain Apo B, the authors also investigated the effects of a 10 mg/dL genetically-induced reduction in Apo B.  The resulting odds ratio was 0.770, indicating 23% lower odds for CHD.  When 10 mg/dL reductions in all three (LDL-C, VLDL-C and Apo B) were included in the same model, only Apo B remained significant (odds ratio = 0.761). 

 

Comment on clinical implications.  The Apo B concentration represents the total number of circulating particles with atherogenic potential.  Most investigations have shown that Apo B predicts CHD risk slightly better than non-HDL-C, which is, in turn, a better predictor than LDL-C.  The present study extends those findings by showing that genetic modification of Apo B concentration is strongly associated with CHD risk, supporting a causal relationship.  The non-HDL-C concentration correlates strongly with the Apo B level because it represents cholesterol carried by the two main types of Apo B-containing lipoproteins, LDL and VLDL.

 

The National Lipid Association’s Recommendations for Patient-centered Management of Dyslipidemia identified non-HDL-C and LDL-C as co-primary targets of therapy for lipid modification (Jacobson 2014).  The recent American Heart Association/American College of Cardiology Guideline on the Management of Blood Cholesterol (Grundy 2018) also acknowledges the importance of non-HDL-C by identifying thresholds for either LDL-C or non-HDL-C for consideration of adding adjunctive therapy to a statin as a way of identifying patients who could potentially benefit from additional Apo B-containing lipoprotein reduction.  The results from this new study by Ference and colleagues suggest that a 10 mg/dL decline in VLDL-C has similar predictive value to that of a 10 mg/dL decline in LDL-C and that the predictive value of each is contained within the Apo B concentration.

 

In the US, Apo B measurement is not commonly completed.  Since non-HDL-C correlates strongly with the Apo B concentration, it can serve as a reasonable surrogate.  The National Lipid Association recommendations suggest goals for LDL-C of <70 mg/dL for those at very high risk and <100 mg/dL for others (Jacobson 2014).  The corresponding goals for non-HDL-C are <100 and <130 mg/dL, respectively.  It should be emphasized that the relationships show no evidence of thresholds, so reductions to levels of LDL-C and non-HDL-C well below 70 and 100 mg/dL, respectively, may be justified for some of the highest risk patients.  Such an approach is supported by results from studies of adjunctive therapies, including those with proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors and ezetimibe. 

 

Another important point with clinical relevance is that the reduction in CHD (or cardiovascular disease) risk with genetic variants is consistently larger than that observed in clinical trials of lipid-altering therapies.  For example, in a Cholesterol Treatment Trialists’ Collaboration analysis (2010), each mmol/L (38.7 mg/dL) reduction in LDL-C was associated with a 24% reduction in major CHD event risk, which means that a 10 mg/dL reduction induced by statin therapy would reduce CHD event risk by 6.8% (1 – 0.76(10/38.7) = 0.068 or 6.8%), considerably less than the 15.4% lower odds for CHD in the Ference investigation.  This likely reflects the greater length of time that individuals with genetic variants are exposed to altered levels of lipoproteins.  The implication is that even modestly lower levels of LDL-C and VLDL-C can have important impacts on CHD risk if maintained over an extended period, which highlights the importance of healthy diet and adequate physical activity.

 

The recently published results from the Reduction of Cardiovascular Events with EPA – Intervention Trial (REDUCE-IT) with eicosapentaenoic acid (EPA) ethyl esters showed an impressive reduction of 25% for major adverse cardiovascular events in patients with low baseline LDL-C (median 74 mg/dL) and elevated TG (median 216 mg/dL) (Bhatt 2019).  The placebo-corrected reductions in non-HDL-C and Apo B in the active treatment group were 10 mg/dL and 5-8 mg/dL, respectively.  The cardiovascular disease benefit was much larger than would be predicted based on the observed effects on non-HDL-C and Apo B over a period of ~5 years.  Similarly, studies of other TG-lowering drug therapies such as fibrates have shown substantial reductions in risk among subsets of patients with elevated TG, especially if accompanied by low HDL-C (Sacks 2010, Maki 2016).  In a meta-analysis completed by our group, cardiovascular disease risk reductions were 18% and 29% in studies of TG-lowering therapies in subgroups with elevated TG and elevated TG plus low HDL-C, respectively (Maki 2016).  It appears unlikely that these results can be explained entirely by changes in non-HDL-C or Apo B levels.  Therefore, additional research is needed to investigate pathways through which TG-lowering therapies affect cardiovascular risk.

 

In summary, genetically-induced reduction in LDL-C and VLDL-C (estimated as TG/5) are each associated with similar reductions in CHD risk.  The predictive value of each of these is contained within Apo B.  Since Apo B concentration is rarely measured in the US, non-HDL-C can serve as a surrogate marker and is a preferable target of therapy to LDL-C, because changes in both components of non-HDL-C (LDL-C and VLDL-C) appear to contribute similarly to risk alteration when compared on an “apples to apples” basis.  Thus, a 50 mg/dL reduction in TG (equivalent to a 10 mg/dL reduction in VLDL-C) should be expected to produce the same benefit for CHD risk as a 10 mg/dL lowering of LDL-C.

 

References

Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11-22.

Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. 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;376:1670-1681.

Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL variants and LDL-C lowering LDLR variants with risk of coronary heart disease. JAMA. 2019;321:364-373.

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. Circulation. 2018 [Epub ahead of print].

Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 – executive summary. J Clin Lipidol. 2014;8:473-488.

Liu J, Sempos C, Donahue RP, et al. Joint distribution of non-HDL and LDL cholesterol and coronary heart disease risk prediction among individuals with and without diabetes. Diabetes Care. 2005;28:1916-1921.

Maki KC, Guyton JR, Orringer CE, et al. Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia. J Clin Lipidol. 2016;10:905-914.

Navar AM. The evolving story of triglycerides and coronary heart disease risk. JAMA. 321:347-349.

Robinson JG. Are you targeting non-high-density lipoprotein cholesterol? J Am Coll Cardiol. 2009;55:42-44.

Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med. 2010;363:692-694.

Closeup of doctor checking patient daily report checklist

Comparing the Effectiveness of Second-line Antidiabetic Medications on Cardiovascular Events in Patients with Type 2 Diabetes Mellitus

Comparing the Effectiveness of Second-line Antidiabetic Medications on Cardiovascular Events in Patients with Type 2 Diabetes Mellitus

By Mary R Dicklin, PhD and Kevin C Maki, PhD, CLS, FNLA

 

Cardiovascular disease is the leading cause of morbidity and mortality among patients with type 2 diabetes (T2D).1  Metformin is widely recommended as first-line therapy, but metformin alone may be inadequate for achieving glycemic control, or may not be tolerated, in which case clinicians have several second-line antidiabetic medication (ADM) prescription options.2  The second-line ADMs include sulfonylureas (SFUs), thiazolidinediones (TZDs), insulin, glucagon-like peptide 1 (GLP-1) receptor agonists, sodium-glucose-cotransporter 2 (SGLT-2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors.3  Understanding how these ADMs differ in their effects on cardiovascular outcomes may assist clinicians in preventing comorbidities in patients with diabetes.

 

Results were recently published from a large, retrospective cohort study that examined major adverse cardiovascular events among insured adults with T2D who had recently started therapy with a second-line ADM after either taking metformin alone or not having received prior ADM.4  Nationwide U.S. administrative claims data were used from 2011-2015.  The primary outcome of the study was time to first cardiovascular event (defined as the composite of hospitalization for congestive heart failure, stroke, ischemic heart disease or peripheral artery disease) after starting a second-line ADM.  Patients were censored after either their first cardiovascular event, discontinuation of insurance coverage, transition of medical claims data coding from the International Classification of Diseases 9th revision to the 10th revision, or two years of follow up.

 

Among the 132,737 adults evaluated in this study, SFUs were used by 47.6%, DPP-4 inhibitors by 21.8%, basal insulin by 12.2%, GLP-1 receptor agonists by 8.6%, TZDs by 5.6% and SGLT-2 inhibitors by 4.3%.4  During the 169,384 person-years of follow-up there were 3480 incident cardiovascular events.  After adjusting for patient, prescriber and health plan characteristics, the risk of composite cardiovascular events according to second-line ADM was determined.  DPP-4 inhibitors were considered to have a neutral effect on cardiovascular outcomes, based on previous clinical trial evidence.5-7  Thus, DPP-4 inhibitor use was the referent (1.0) in the Cox proportional hazard regression analysis.4  The hazard ratios (95% confidence intervals) were:

  • DPP-4 inhibitors: 1.00 (reference)
  • GLP-1 receptor agonists: 0.78 (0.63-0.96)
  • SGLT-2 inhibitors: 0.81 (0.57-1.53)
  • TZDs: 0.92 (0.76-1.11)
  • SFUs: 1.36 (1.23-1.49)
  • Basal insulin: 2.03 (1.81-2.27)

 

Higher cardiovascular risk was associated with use of SFUs or basal insulin.  The risk associated with GLP-1 receptor agonist use was lower than with DPP-4 inhibitor use, but this finding was not statistically significant in all of the sensitivity analyses.  The risks associated with SGLT-2 inhibitors and TZDs were not significantly different from DPP-4 inhibitors.

 

Recent randomized clinical trials that have evaluated the cardiovascular risk associated with newer ADMs have also suggested reduced cardiovascular events.8,9  Unlike those randomized trials, in which most of the participants already had cardiovascular disease, just 5.5% of participants in this observational study had a history of prior cardiovascular events, although cardiovascular risk factors, such as dyslipidemia (61.6%) and hypertension (70.1%), were present in the majority of subjects.

 

In summary, these results suggest that, with regard to managing cardiovascular comorbidity in their patients with T2D, after metformin, clinicians may consider prescribing any of the newer ADMs (i.e., GLP-1 receptor agonists, SGLT-2 inhibitors and DPP-4 inhibitors) that were shown to be similarly associated with lower cardiovascular risk, instead of SFUs or basal insulin, which were associated with greater cardiovascular risk.

 

References:

  1. American Diabetes Association. 10. Cardiovascular disease and risk management: Standard of medical care in diabetes – 2019. Diabetes Care. 2019;42(Suppl 1):S102-S123.
  2. American Diabetes Association. 3. Prevention or delay of type 2 diabetes: Standards of medical care in diabetes – 2019. Diabetes Care. 2019;42(Suppl 1):S29-S33.
  3. Thrasher J. Pharmacologic management of type 2 diabetes mellitus: available therapies. Am J Cardiol. 2017;120:S4-S16.
  4. O’Brien MJ, Karam SL, Wallia A, et al. Association of second-line antidiabetic medications with cardiovascular events among insured adults with type 2 diabetes. JAMA Network Open. 2018;1:e1816125.
  5. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-1326.
  6. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232-242.
  7. White WB, Kupfer S, Zannad F, et al. Cardiovascular mortality in patients with type 2 diabetes and recent acute coronary syndromes from the EXAMINE trial. Diabetes Care. 2016;39:1267-1273.
  8. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2018; Epub ahead of print.
  9. Sposito AC, Berwanger O, de Carvalho LSG, Saraiva JFK. GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data. Cardiovasc Diabetol. 2018;17:157.
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2018 American College of Cardiology/American Heart Association Cholesterol Clinical Practice Guidelines

2018 American College of Cardiology/American Heart Association Cholesterol Clinical Practice Guidelines

2018 American College of Cardiology/American Heart Association Cholesterol Clinical Practice Guidelines

 By Heather Nelson Cortes, PhD, Mary R Dicklin, PhD and Kevin C Maki, PhD

 

The American College of Cardiology (ACC) and the American Heart Association (AHA) recently released their 2018 Guideline on the Management of Blood Cholesterol during the 2018 AHA meeting in Chicago, IL and simultaneously in Circulation1 and the Journal of the American College of Cardiology.1 The authors listed the top 10 take-home messages from the guidelines (see below, taken from the publication):

  1. In all individuals, emphasize a heart-healthy lifestyle across the life course.
  2. In patients with clinical atherosclerotic cardiovascular disease (ASCVD), reduce low-density lipoprotein cholesterol (LDL-C) with high-intensity statin therapy or maximally tolerated statin therapy.
  3. In very high-risk ASCVD, use a LDL-C threshold of 70 mg/dL (1.8mmol/L) to consider addition of non-statins to statin therapy.
  4. In patients with severe primary hypercholesterolemia (LDL-C level ≥190 mg/dL [≥4.9 mmol/L]), without calculating 10-year ASCVD risk, begin high-intensity statin therapy without calculating 10-year ASCVD risk.
  5. In patients 40 to 75 years of age with diabetes mellitus and LDL-C ≥70 mg/dL (≥1.8 mmol/L), start moderate-intensity statin therapy without calculating 10-year ASCVD risk.
  6. In adults 40 to 75 years of age evaluated for primary ASCVD, have a clinician-patient risk discussion before starting statin therapy.
  7. In adults 40 to 75 years of age without diabetes mellitus and with LDL-C ≥70 mg/dL (≥1.8 mmol/L), at a 10-year ASCVD risk of ≥7.5%, start a moderate-intensity statin if a discussion of treatment options favors statin therapy.
  8. In adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 7.5% to 19.9% (intermediate risk), risk-enhancing factors favor initiation of statin therapy (see No. 7).
  9. In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL-189 mg/dL (≥1.8-4.9 mmol/L), at a 10-year ASCVD risk of ≥7.5% to 19.9%, if a decision about statin therapy is uncertain, consider measuring coronary artery calcium (CAC).
  10. Assess adherence and percentage response to LDL-C-lowering medications and lifestyle changes with repeat lipid measurement 4 to 12 weeks after statin initiations or dose adjustment, repeated every 3 to 12 months as needed.

 

Comment: The previous ACC/AHA guidelines released in 2013 sparked a considerable amount of debate.2,3  Major areas of controversy at that time included the use of a new risk calculator for assessing 10-year ASCVD, and, notably, abandoning the use of lipid goals.3 Those guidelines were exceedingly statin-centric, and did not provide guidance for managing cholesterol with non-statin lipid-altering drugs.  Another set of national recommendations released shortly after the 2013 ACC/AHA guidelines, the National Lipid Association (NLA) recommendations for the patient-centered management of dyslipidemia, employed a more traditional approach of titrating lipid-lowering therapy to achieve patient-specific LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) goals.4  The NLA also recommended combination of statin and non-statin drugs to achieve atherogenic cholesterol goals when maximum tolerated statin therapy was inadequate.  Both sets of recommendations emphasized lifestyle management, and the importance of patient-clinician discussions in managing elevated cholesterol.

 

Noteworthy changes in the new ACC/AHA guidelines include goals by using percentage reductions to monitor adequacy of response to LDL-C-lowering therapy.  They also lower the CAC score for enhanced risk, and include lipoprotein(a) as a risk-enhancing factor that can be considered when the decision to use statin therapy is otherwise uncertain.1  The new ACC/AHA guidelines recommend that a CAC score of 1-99 favors statin use (especially after age 55 years), and that a CAC score of 100+ and/or ≥75th percentile is an indication to initiate statin therapy.  If measured in selected individuals, a lipoprotein(a) level of >50 mg/dL or >125 nmol/L indicates enhanced risk.  The new guidelines also recommend using non-statin drugs, specifically ezetimibe or a proprotein convertase subtilisin kexin type 9 inhibitor, but suggest that their use is limited mainly to secondary prevention in patients at very high-risk of new ASCVD events.

 

The new ACC/AHA guidelines close much of the gap between the 2013 guidelines and the NLA recommendations on issues that previously were either handled differently or had been unaddressed by the ACC/AHA.  We expect that these new guidelines will be readily incorporated into clinical practice and improve patient outcomes.

 

References:

  1. 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2018; Epub ahead of print and J Am Coll Cardiol. 2018; Epub ahead of print.
  2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guidelines 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. J Am Coll Cardio. 2014;63 (Pt B):2889-2934.
  3. Phillips E, Sasseen JJ. Current controversies with recent cholesterol treatment guidelines. J Pharm Pract. 2016;29:15-25.
  4. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 – executive summary. J Clin Lipidol. 2014;8:473-488.

 

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