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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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

More Recent Headlines from the Late-breaking Clinical Trial Presentations at the American Heart Association Scientific Sessions 2

More Recent Headlines from the Late-breaking Clinical Trial Presentations at the American Heart Association Scientific Sessions -

Less Pessimism Called for When Interpreting the Results from VITAL Regarding Cardiovascular Benefits with Omega-3

 

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

 The primary results from the Vitamin D and Omega-3 Trial (VITAL) were recently presented at the late-breaking clinical trial sessions of the American Heart Association (AHA) meeting in Chicago, IL and simultaneously published in the New England Journal of Medicine.1  VITAL was a randomized, placebo-controlled trial of a 1 g/d fish oil capsule (Lovaza®/Omacor®) and 2000 IU/day vitamin D3 administered to 25,871 men ≥50 y of age and women ≥55 y of age.  The primary endpoints were major cardiovascular events (a composite of myocardial infarction [MI], stroke or death from cardiovascular causes) and invasive cancer of any type.  The key secondary endpoints were individual components of the composite cardiovascular endpoint, the composite endpoint plus coronary revascularization, site-specific cancers and death from cancer.  Patients were followed for a median of 5.3 y.  A discussion of the findings from the omega-3 and cardiovascular disease portion of the trial follows.

A major cardiovascular event occurred in 386 subjects in the omega-3 group and 419 in the placebo group (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.80 to 1.06, p = 0.24).1  The HR (95% CI) for the key secondary endpoints were 0.93 (0.82 to 1.04) for the composite plus coronary revascularization, 0.72 (0.59 to 0.90) for total MI, 1.04 (0.83 to 1.31) for total stroke, and 0.96 (0.76 to 1.21) for death from cardiovascular causes.  There were no excess risks of bleeding or other serious adverse events with the interventions.

In our opinion, the response to the results from VITAL has been unnecessarily pessimistic.2  It is true that the 8% reduction in the primary composite endpoint was not statistically significant.  However, as we have previously written, we believe that the failure of many of the omega-3 cardiovascular outcomes trials to show clear evidence of benefit can likely be attributed, in part, to the low dosages of omega-3 administered (most <1 g/d eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) and the groups in which the studies have been conducted (without elevated triglycerides [TG] and not limited to subjects with low omega-3 dietary intake).3  This was also the case in VITAL, where subjects at relatively low cardiovascular risk were administered a 1g/d fish oil concentrate capsule (providing 840 mg/d EPA + DHA) and the median fish intake in the study sample at baseline was well above the average intake in the US general population.1

 Results from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), presented in the same late-breaking clinical trials session at AHA and published simultaneously in New England Journal of Medicine, demonstrated that Vascepa® at a higher dosage of 4 g/d (~3700 mg/d EPA as icosapent ethyl) administered to subjects at higher risk with elevated TG (median of 216 mg/dL) resulted in a significant 25% reduction in the primary endpoint, the composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization or unstable angina.4  Unfortunately, an editorial that accompanied VITAL did not acknowledge the findings from REDUCE-IT, and in fact stated “…in the absence of additional compelling data, it is prudent to conclude that the strategy of dietary supplementation with either n-3 fatty acids or vitamin D as protection against cardiovascular events or cancer suffers from deteriorating VITAL signs.”2  It would seem that we do have “additional compelling data” in REDUCE-IT and that we should not abandon the idea that omega-3 fatty acids, when administered at higher dosages and to higher risk populations, reduces cardiovascular risk.  This adds to the biologic plausibility of the secondary outcomes for which benefits were observed.

In VITAL, endpoints that achieved nominal statistical significance included reductions in total MI (HR 0.72, 95% CI 0.59 to 0.90), total coronary heart disease (composite of MI, coronary revascularization and death from coronary heart disease; HR 0.83, 95% CI 0.71 to 0.97) and death from MI (HR 0.50, 95% CI 0.26 to 0.97) with omega-3 fatty acids vs. placebo.1  However, the editorial that accompanied VITAL emphasized the strong need for caution in interpreting “positive” results from secondary endpoints.2  While we agree that statistically significant secondary endpoints should not outweigh the null findings from the primary endpoint, it is also important that findings from secondary endpoints are not overlooked, particularly when they are in general agreement with results from prior studies.3,5-7  It is also notable that the subgroup with below-median fish intake at baseline showed statistically significant reductions of 19% and 40% in the primary outcome variable and total MI, respectively.1  This observation further supports the possibility that a relatively low dosage of EPA + DHA may have benefits in those with lower omega-3 fatty acid intakes.8

Our group published a meta-analysis of 14 randomized controlled trials that investigated the effects of omega-3 fatty acid supplementation on cardiac death, and reported that there was an 8% lower risk with omega-3 fatty acids vs. controls (and ~29% lower risk when dosages >1 g/d EPA + DHA were evaluated).7  Death from CHD in VITAL was not statistically significantly lower (HR 0.76, 95% CI 0.49 to 1.16).1  However, to further assess the potential for fatal CHD reduction with omega-3 fatty acid supplementation, we added the results from VITAL,1 along with other recently published trials,4,6 to a previous meta-analysis published by Aung and colleagues.5  This analysis demonstrated a statistically significant reduction in fatal CHD with omega-3 fatty acid interventions (relative risk 0.901, 95% CI 0.841 to 0.965, p = 0.003).9

Thus, it is our opinion that the null findings for the primary cardiovascular endpoint in VITAL need to be interpreted alongside the favorable findings from REDUCE-IT.  These results suggest the need for additional studies with higher dosages of EPA + DHA administered to high-risk populations.  We eagerly await the results from the last of the large-scale omega-3 fatty acid trials that is underway, The Outcomes Study to Assess Statin Residual Risk Reduction with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH), which enrolled subjects with elevated TG and below-average high-density lipoprotein cholesterol levels.10

References:

  1. Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2018; Epub ahead of print.

 

  1. Keaney JF, Jr., Rosen CJ. VITAL signs for dietary supplementation to prevent cancer and heart disease. N Engl J Med. 2018; Epub ahead of print.

 

  1. Maki KC, Dicklin MR. Omega-3 fatty acid supplementation and cardiovascular disease risk: glass half full or time to nail the coffin shut? Nutrients. 2018;10(7).

 

  1. Bhatt DL, Steg G, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2018; Epub ahead of print.

 

  1. Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol. 2018;3:225-234.

 

  1. ASCEND Study Collaborative Group. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018; Epub ahead of print.

 

  1. Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: an updated meta-analysis and review of research gaps. J Clin Lipidol. 2018;11:1152-1160.

 

  1. Rimm EB, Appel LJ, Chiuve SE, et al. Seafood long-chain n-3 polyunsaturated fatty acids and cardiovascular disease: a science advisory from the American Heart Association. Circulation. 2018;138:e35-e47.

 

  1. Maki KC, Dicklin MR. Recent headlines from the late-breaking clinical trial presentations at the American Heart Association scientific sessions. REDUCE-IT – a landmark cardiovascular outcomes study of an omega-3 fatty acid. November 27, 2018. Available at https://mbclinicalacademy.com/headlines/.

 

  1. 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.

 

 

 

Medical equipment

ODYSSEY Outcomes Trial: Topline Results and Clinical Implications

ODYSSEY Outcomes Trial: Topline Results and Clinical Implications

By Kevin C Maki, PhD, CLS, FNLA; Kristen N Smith, PhD, RD, LD; Mary R Dicklin, PhD

 Background:

Cardiovascular disease (CVD) event risk is high in those with recent acute coronary syndromes (ACS), despite treatment with evidence-based preventive therapies. Prior research has shown that CVD event risk is lowered when low-density lipoprotein cholesterol (LDL-C) is lowered through various means, such as:

  • Statin therapy (compared with placebo)2
  • High-intensity statin therapy (compared with moderate-intensity statin therapy)3
  • Ezetimibe added to statin therapy (compared with placebo)4
  • Anacetrapib added to statin therapy (compared with placebo)5
  • Evolocumab added to statin therapy (compared with placebo)6

Alirocumab is a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), a validated target for risk reduction in patients with stable atherosclerotic CVD.7-8. Research outcomes on alirocumab show that it reduces LDL-C (sustained reductions) and other atherogenic lipoproteins7 with documented safety and tolerability.8

The hypothesis of the Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome During Treatment with Alirocumab (ODYSSEY Outcomes) trial was that alirocumab, versus placebo, reduces cardiovascular (CV) morbidity and mortality after recent ACS in patients with elevated levels of atherogenic lipoproteins despite intensive or maximum-tolerated statin therapy.9

 Methods:

This study was a randomized, double-blind, placebo-controlled, parallel group study of 18,924 patients randomized at 1315 sites in 57 countries between November 2, 2012 and November 11, 2017.1,9

Key inclusion criteria:

  • Age ≥40 years
  • ACS
    • 1 to 12 months prior to randomization [acute myocardial infarction (MI) or unstable angina]
  • High-intensity statin therapy
    • Atorvastatin 40 to 80 mg daily, or
    • Rosuvastatin 20 to 40 mg daily, or
    • Maximum tolerated dose of one of these agents for ≥2 weeks
    • Patients not taking statins were authorized to participate if tolerability issues were present and documented
  • Inadequate control of lipids
    • LDL-C ≥70 mg/dL (1.8 mmol/L), or
    • Non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL (2.6 mmol/L), or
    • Apolipoprotein B ≥80 mg/dL

 

Key exclusion criteria:

  • Uncontrolled hypertension
  • NYHA class III or IV heart failure; left ventricular ejection fraction <25% if measured
  • History of hemorrhagic stroke
  • Fasting triglycerides >400 mg/dL (4.52 mmol/L)
  • Use of fibrates, other than fenofibrate or fenofibric acid
  • Recurrent ACS within 2 weeks prior to randomization
  • Coronary revascularization performed within 2 weeks prior to or after randomization
  • Liver transaminases >3 x upper limit of normal; hepatitis B or C infection
  • Creatine kinase >3 x upper limit of normal
  • Estimated glomerular filtration rate <30 mL/min/1.73 m2
  • Positive pregnancy test

 

Primary Efficacy Outcome

Major Secondary Efficacy Endpoints

Other Secondary and Safety Endpoints

Time of first occurrence:

§  Coronary heart disease (CHD) death, or

§  Non-fatal MI, or

§  Fatal or non-fatal ischemic stroke, or

§  Unstable angina requiring hospitalization

Tested in the following hierarchical sequence:

§  CHD event: CHD death, non-fatal MI, unstable angina requiring hospitalization, or ischemia-driven coronary revascularization

§  Major CHD event: CHD death or non-fatal MI

§  CV event: CV death, non-fatal CHD event, or non-fatal ischemic stroke

§  All-cause death, non-fatal MI, non-fatal ischemic stroke

§  CHD death

§  CV death

§  All-cause death

Secondary endpoints:

§  Components of the primary endpoint considered individually:

·       CHD death

·       Non-fatal MI

·       Fatal and non-fatal ischemic stroke

·       Unstable angina requiring hospitalization

§  Ischemia-driven coronary revascularization

§  Congestive heart failure requiring hospitalization

 

Safety endpoints:

§  Adverse events

§  Laboratory assessments

Patients screened for this study completed a run-in period of 2 to 16 weeks on high-intensity or maximum-tolerated dose of atorvastatin or rosuvastatin. If at least one lipid entry criterion was met, then the subject was randomized to receive either subcutaneous alirocumab (75 or 150 mg) or placebo every 2 weeks. In order to maximize the number of patients in the target LDL-C range (25-50 mg/dL), alirocumab was blindly titrated or subjects were blindly switched to placebo if they were either substantially above or below (<15 mg/dL for LDL-C) the target range.

Results:

Of the 18,924 patients randomized for this study:

  • 9462 were assigned to alirocumab and 9462 received placebo
  • Median follow-up was 2.8 years (interquartile range limits 2.3-3.4 years)
  • 8242 (44%) patients with potential follow-up ≥3 years
  • 1955 patients experienced a primary endpoint; 726 patients died

Topline results showed that treatment with alirocumab was associated with significant reductions in LDL-C, and these reductions remained consistent over time.  Mean baseline and on-treatment LDL-C values are shown in the table below.

 

 

Placebo

(n = 9462)

Alirocumab

(n = 9462)

Baseline

  87.0 mg/dL

87.0 mg/dL

4 months

  93.3 mg/dL

39.8 mg/dL

12 months

  96.4 mg/dL

48.0 mg/dL

48 months

101.4 mg/dL

66.4 mg/dL

The “on-treatment” analysis showed that mean LDL-C was lowered by 55.7 mg/dL (-62.7%) in the alirocumab group vs. placebo at 4 months, 54.1 mg/dL (-61.0%) at 12 months and 48.1 mg/dL (-54.7%) at 48 months.

Several endpoints were significantly less frequent in the alirocumab group vs. placebo. Major adverse cardiac events (MACE; includes CHD death, non-fatal MI, ischemic stroke, or unstable angina requiring hospitalization) are shown in the table below, along with other endpoints.

 

Endpoint

Alirocumab

(n = 9462)

n (%)

Placebo

(n = 9462)

n (%)

Hazard Ratio (95% Confidence Interval)

Log-rank

P-value

MACE

903 (9.5)

1052 (11.1)

0.85 (0.78, 0.93)

0.0003

     CHD death

205 (2.2)

222 (2.3)

0.92 (0.76, 1.11)

0.38

     Non-fatal MI

626 (6.6)

722 (7.6)

0.86 (0.77, 0.96)

0.006

     Ischemic stroke

111 (1.2)

152 (1.6)

0.73 (0.57, 0.93)

0.01

     Unstable angina

37 (0.4)

60 (0.6)

0.61 (0.41, 0.92)

0.02

Secondary

       

     CHD event

1199 (12.7)

1349 (14.3)

0.88 (0.81, 0.95)

0.001

     Major CHD

     event

793 (8.4)

899 (9.5)

0.88 (0.80, 0.96)

0.006

     CV event

1301 (13.7)

1474 (15.6)

0.87 (0.81, 0.94)

0.0003

     Death, MI,

     ischemic stroke

973 (10.3)

1126 (11.9)

0.86 (0.79, 0.93)

0.0003

     CHD death

205 (2.2)

222 (2.3)

0.92 (0.76, 1.11)

0.38

     CV death

240 (2.5)

271 (2.9)

0.88 (0.74, 1.05)

0.25

     All-cause death

334 (3.5)

392 (4.1)

0.85 (0.73, 0.98)

0.026*

(nominal)

Several pre-specified subgroup analyses for the primary outcome variable were presented, including, notably, an analysis by baseline LDL-C categories of <80, 80-99, and ≥100 mg/dL.  Although the test for heterogeneity of response across subgroups was not statistically significant (p = 0.09), the hazard ratio (HR) for the comparison of alirocumab to placebo was numerically lower for the subgroup with baseline LDL-C ≥100 mg/dL [HR 0.76, 95% confidence interval (CI) 0.65 to 0.87] than for those with baseline LDL-C <80 mg/dL (HR 0.86, 95% CI 0.74 to 1.01) or 80-99 mg/dL (HR 0.96, 95% CI 0.92 to 1.14).

Comment by Kevin C Maki, PhD, CLS, FNLA:

When compared with placebo, the use of alirocumab 75 or 150 mg every two weeks, aiming for LDL-C levels of 25-50 mg/dL (and allowing levels as low as 15 mg/dL), led to reduced MACE, MI and ischemic stroke, and was associated with reduced all-cause death. Treatment was safe and well tolerated. CV and CHD death were not significantly reduced. Therefore, the results for total mortality should be viewed with caution, since roughly 70% of total mortality was attributable to CV causes. 

Subgroup analyses identified numerically larger benefits for the primary outcome in subjects with baseline levels of LDL-C ≥100 mg/dL (median LDL-C 118 mg/dL). However, the test for heterogeneity of effect across subgroups was not statistically significant (p = 0.09).  The proportional risk reductions for subjects with baseline LDL-C <80, 80-99 and ≥100 mg/dL were 14%, 4% and 24%, respectively. Only the subgroup with LDL-C ≥100 mg/dL showed a statistically significant reduction in the alirocumab group compared with placebo. That was also true for all-cause mortality, which was reduced by 29% in the alirocumab group vs. placebo in subjects with baseline LDL-C ≥100 mg/dL, but was not significantly reduced in the other subgroups. This finding should also be interpreted with caution because the test for heterogeneity was, again, not significant (p = 0.12). 

The US Institute for Clinical and Economic Review (ICER) provided new estimates of the price range that would be acceptable for the drug, based on the results of the ODYSSEY Outcomes trial.10 ICER calculated two updated value-based price benchmarks, net of rebates and discounts, for alirocumab in patients with a recent acute coronary event:  $2300-$3400 per year if used to treat all patients who meet trial eligibility criteria, and $4500-$8000 per year if used to treat higher-risk patients with LDL-C ≥100 mg/dL despite intensive statin therapy. The manufacturers of alirocumab (Sanofi and Regeneron Pharmaceuticals, Inc.) have announced plans for a reduced price for the drug that will be in the range of the $4500-$8000 identified by ICER, which is substantially below the “list price” of approximately $14,000 per year that had been charged initially.

A number of commentaries from experts in the field have suggested that this class of medications is appropriate for use mainly in patients in whom LDL-C is ≥100 mg/dL, based on the results from the analyses presented at the American College of Cardiology meeting (and not yet published in a peer reviewed journal), including the cost-effectiveness evaluation by ICER. For example, the highly respected cardiologist Milton Packer, MD wrote a piece in which he stated:11

“…the benefit in the entire trial was driven entirely by the effect seen in 5,629 patients who started with LDL cholesterol >100 mg/dL. There was no benefit in patients with lower values for baseline LDL cholesterol.”

With all due respect to Dr. Packer and others who hold this opinion, I view this conclusion as premature for several reasons. The test for heterogeneity (treatment by subgroup interaction) across baseline LDL-C categories was not significant at an alpha of 5%, showing a p-value of 0.09.  Moreover, the study was not designed with sufficient statistical power to reliably differentiate effects across baseline LDL-C categories. This lack of statistical power for tests of heterogeneity of treatment effects argues for caution in the clinical application of such findings, even when the test for heterogeneity is pre-specified and/or when it does reach statistical significance.

Sir Richard Peto, the eminent biostatistician and epidemiologist from the University of Oxford has quipped that only one thing is worse than doing subgroup analyses for a clinical trial, and that is believing the results! To demonstrate the potential unreliability, Peto reported on a set of subgroup analyses from the Second International Study of Infarct Survival (ISIS-2).12  In the trial overall, the survival advantage produced by aspirin for patients with suspected myocardial infarction was 23%, which was highly statistically significant (p < 0.000001).13 ISIS-2 patients were divided into 12 subgroups according to their astrological sign, and the treatment effect of aspirin compared with placebo was calculated in each subgroup. The results ranged from no apparent effect of aspirin in two subgroups (Libra and Gemini) to aspirin being associated with a halving of the mortality in another (Capricorn).

Results from subgroup analyses are useful for generating hypotheses to test prospectively, but should not, in most cases, be applied as the sole basis for clinical practice decisions without replication in other trials, and, ideally, prospective testing in one or more trials designed for the purpose of evaluating possible differences across subgroups in clinical response.  Regarding the results for the subgroup with baseline LDL-C <100 mg/dL in ODYSSEY Outcomes, it should be noted that the authors of the paper from the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial with the other approved PCSK9 inhibitor agent, evolocumab, report the following:6

“The benefits were also consistent across quartiles of baseline LDL cholesterol levels, from patients in the top quartile, who had a median LDL cholesterol level of 126 mg per deciliter (interquartile range, 116 to 143) (3.3 mmol per liter [interquartile range, 3.0 to 3.7]) at baseline, down to those in the lowest quartile, who had a median LDL cholesterol level of 74 mg per deciliter (interquartile range, 69 to 77) (1.9 mmol per liter [interquartile range, 1.8 to 2.0]) at baseline.”

Results from other trials such as the Improved Reduction of Outcomes: Vytorin Efficacy International Trial4 (IMPROVE-IT; statin plus ezetimibe) and the HPS3/TIMI55 Randomized Evaluation of the Effects of Anacetrapib through Lipid-modification5 (REVEAL; statin plus anacetrapib) have shown benefits with atherogenic cholesterol lowering that are generally consistent with the results observed in statin trials based on the Cholesterol Treatment Trialists’ (CTT) analyses,14 i.e., a HR of 0.78 (22% reduction) per mmol/L (38.7 mg/dL) reduction in LDL-C, despite average baseline LDL-C levels below 100 mg/dL (~94 mg/dL in IMPROVE-IT and 61 mg/dL in HPS2/TIMI55-REVEAL).  Notably, in both IMPROVE-IT and HPS3/TIMI55-REVEAL, the placebo and active treatment group Kaplan-Meier curves did not clearly separate for the first 2.0 to 2.5 years. In a prior study with evacetrapib [Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE)], no CVD event benefit (or harm) was observed over a median follow-up period of 2.2 years, despite modest lowering of LDL-C.15  The median follow-up period for both of the PCSK9 inhibitor trials (FOURIER, 2.2 years and ODYSSEY Outcomes, 2.8 years) was short compared with those from most trials of statins, which had median follow-up periods that averaged roughly 5 years.14 In fact, the FOURIER investigators reported that:

“… in FOURIER, the magnitude of the risk reduction with regard to the key secondary end point appeared to grow over time, from 16% during the first year to 25% beyond 12 months, which suggests that the translation of reductions in LDL cholesterol levels into cardiovascular clinical benefit requires time.”

Findings from studies of genetic variants that alter atherogenic cholesterol levels suggest that the benefits of maintaining lower levels may not be fully apparent after only a few years of intervention. The prototypical example of this is one of the findings that led to the development of the PCSK9 inhibitor class of lipid-altering agents. Cohen et al.16 reported that a nonsense loss-of-function mutation in the PCSK9 gene was associated with a 38 mg/dL (0.98 mmol/L) lower average level of LDL-C, and a missense mutation was associated with a 21 mg/dL (0.54 mmol/L) reduction in LDL-C. Based on the CTT relationship, the predicted reductions in CVD event risk would have been roughly 22% and 13%, respectively. However, the observed reductions in CVD (CHD and stroke) incidence were approximately 50% and 37%, respectively (estimated from data presented in the paper). The reductions in risk were most evident for CHD, where HRs were 0.11 (89% reduction) and 0.50 (50% reduction) for those with the nonsense and missense mutations, respectively. These results, and those from many other studies of lipid-altering genetic variants, suggest a greater CVD event risk reduction than would be predicted from the effects of statin and other lipid-altering therapies on risk.17 A likely explanation is that genetic variants produce differences that are maintained over decades, rather just a few years duration, as is the case in randomized, controlled intervention trials. 

Thus, there are reasons to believe that “lower is probably better” for atherogenic cholesterol levels with regard to CVD event reduction in high-risk patients, even if the baseline level of LDL-C is less than 100 mg/dL. Atherosclerosis is a disease that develops and progresses over decades. Thus, it seems possible, and indeed, likely, that benefits will be observed with therapy to further reduce atherogenic cholesterol among those with LDL-C less than 100 mg/dL over follow-up periods longer than the 2- to 3-year median durations in the ODYSSEY Outcomes and FOURIER trials. At present, this is a hypothesis that remains to be verified with additional clinical research. Given that the subgroup with baseline LDL-C <100 mg/dL who received placebo in the ODYSSEY Outcomes trial experienced an event rate above 3% per year, substantial residual risk is present in such patients. Dr. Packer ended his commentary by saying “The ODYSSEY trial shows that we may have reached the limits of what we can achieve by lowering lipids.” My view is that the potential for aggressive atherogenic cholesterol reduction to lower CVD event risk in those with recent ACS (and other high-risk patients) has not been fully evaluated. Accordingly, efforts to understand the effects of atherogenic cholesterol lowering in high-risk patients with LDL-C levels <100 mg/dL should remain an important priority.

References:

  1. Schwartz GG, Szarek M, Bhatt DL, et al. The ODYSSEY OUTCOMES trial: topline results. Alirocumab in patients after acute coronary syndrome. Presented at ACC.18 67th Annual Scientific Session & Expo. Acc.18 Joint ACC/JACC Late-breaking clinical trials. Accessed at https://accscientificsession.acc.org/features/2018/03/video-sanofi-regeneron on March 15, 2018.
  2. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285(13):1711-1718.
  3. 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(15):1495-1504.
  4. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397.
  5. HPS3/TIMI55-REVEAL Collaborative Group, Bowman L, Hopewell JC, et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med. 2017;377(13):1217-1227.
  6. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722.
  7. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489-1499.
  8. Robinson JG, Rosenson RS, Farnier M, et al. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: pooled data from randomized trials. J Am Coll Cardiol. 2017;69(5):471-482.
  9. Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J. 2014;168(5):682-689.
  10. Institute for Clinical and Economic Review, 2018. Alirocumab for treatment of high cholesterol: effectiveness and value. Preliminary New Evidence Update. March 10, 2018. Accessed at https://icer-review.org/wp-content/uploads/2018/03/Alirocumab-Preliminary-New-Evidence-Update_03102018.pdf on March 23, 2018.
  11. Packer, M. Confessions and omens from the ODYSSEY Trial - Milton Packer assesses his predictions in the future of lipid research. MEDPAGE TODAY, March 14, 2018. Accessed at https://www.medpagetoday.com/blogs/revolutionandrevelation/71755 on March 23, 2018.
  12. Peto R. Current misconception 3: that subgroup-specific trial mortality results often provide a good basis for individualising patient care. Br J Cancer. 2011;104:1057-1058.
  13. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2(8607):349-360.
  14. Baigent C, Keech A, Kearney PM, et al. 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(9493):1267-1278.
  15. Lincoff AM, Nicholls SJ, Riesmeyer JS, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017;376(20):1933-1942.
  16. Cohen JC, Boerwinkle E, Mosley TH, Jr., et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272.

17.       Ference BA. Mendelian randomization studies: using naturally randomized genetic data to fill evidence gaps. Curr Opin