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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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.

 

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