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

Summaries of Late-breaking Science Presentations at the 2018 American Heart Association meeting in Chicago, IL

Summaries of Late-breaking Science Presentations at the 2018 American Heart Association meeting in Chicago, IL

Summaries of Late-breaking Science Presentations at the 2018 American Heart Association meeting in Chicago, IL

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

 Dapagliflozin and Cardiovascular Events in the DECLARE-TIMI 58 Trial

The Dapagliflozin Effect on Cardiovascular Events—Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) Trial was designed to assess the safety and efficacy of dapagliflozin (10 mg/d), a selective sodium-glucose cotransporter (SGLT)-2 inhibitor, in the reduction of cardiovascular events in patients with type 2 diabetes mellitus.  This was a phase 3b, randomized, double-blinded, placebo-controlled trial in 17,160 patients ≥40 y of age with type 2 diabetes and either cardiovascular disease (CVD) or multiple CVD risk factors.  The primary efficacy endpoints were major adverse cardiovascular events (MACE; defined as cardiovascular death, myocardial infarction or ischemic stroke) and a composite of heart failure hospitalization (HHF) or cardiovascular death.  Median follow-up was 4.5 y.  The results for the outcomes including the hazard ratios (HR) and 95% confidence intervals (CI) are shown in the table below.

 

Outcome

Dapagliflozin

(n = 8582)

Placebo

(n = 8578)

HR (95% CI)

p-value

 

Rate/1000 patient-y

 

 

MACE

22.6

24.2

0.93 (0.84 to 1.03)

0.17

CVD/HHF

12.2

14.7

0.83 (0.73 to 0.95)

0.005

HHF

6.2

8.5

0.73 (0.61 to 0.88)

Cardiovascular death

7.0

7.1

0.98 (0.82 to 1.17)

All-cause mortality

15.1

16.4

0.93 (0.82 to 1.04)

Renal composite1

10.8

14.1

0.76 (0.67 to 0.87)

1Renal outcome was described as a 40% decrease in estimated glomerular filtration rate to <60 mL/min/1.73 m2, end-stage renal disease or death from renal or cardiovascular cause.

 

Conclusion:  Compared to placebo, dapagliflozin was safe and reduced the composite of cardiovascular death or HHF, but did not significantly reduce the incidence of MACE.

 Reference:

Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2018; Epub ahead of print.

 

 

Ezetimibe and Cerebro- and Cardiovascular Events in the EWTOPIA Trial
The role of lipid-lowering therapy in elderly (≥75 y of age) Japanese men and women with elevated low-density lipoprotein cholesterol (LDL-C) levels, but no history of coronary artery disease had not been well studied previously.  The Ezetimibe Lipid Lowering Trial on Prevention of Atherosclerosis in 75 or Older (EWTOPIA 75) investigation was a prospective, multi-center, open-label, blinded endpoint, randomized controlled trial conducted between 2009-2016 in Japanese men and women whose LDL-C level was ≥140 mg/dL and who had one or more cardiovascular risk factors (diabetes, hypertension, smoking, low high-density lipoprotein cholesterol, high triglycerides, previous history of cerebral infarction or peripheral artery disease). 

The primary endpoint was MACE, defined as a composite of sudden cardiac death, myocardial infarction, coronary revascularization, and/or stroke.  Secondary outcomes included cardiac events, cerebrovascular events, and all-cause mortality.  Eligible patients were randomized to either an ezetimibe group (10 mg/d plus dietary counseling; n = 1716) or a control group (dietary counseling alone; n = 1695).  LDL-C levels were reduced significantly more among patients taking ezetimibe (from 161 to 120 mg/dL) compared to subjects in the control group (from 162 to 131 mg/dL) (p < 0.001 for interaction).  The results for the outcomes are shown in the table below.

 

Outcome

HR (95% CI)

p-value

MACE

0.66 (0.50 to 0.86)

0.002

Cardiac events

0.60 (0.37 to 0.98)

0.04

Cerebrovascular events

0.78 (0.55 to 1.11)

>0.05

All-cause mortality

1.09 (0.89 to 1.34)

 

Conclusions:  In an elderly (≥75 y) Japanese population, ezetimibe (10 mg/d) plus dietary counseling compared to dietary counseling alone for primary prevention (elevated LDL-C, no history of CVD), was shown to help prevent cerebro- and cardiovascular events. 

 References:

Kumbhani DJ.  Ezetimibe in prevention of cerebro- and cardiovascular events in middle- to high-risk, elderly (75 years old or over) patients with elevated LDL-cholesterol – EWTOPIA 75.   https://www.acc.org/latest-in-cardiology/clinical-trials/2018/11/08/22/56/ewtopia75#references-for-article.

Ouchi Y. Ezetimibe in prevention of cerebro- and cardiovascular events in middle-to high-risk, elderly (75 years old or over) patients with elevated LDL-cholesterol: a multicenter, randomized, controlled, open-label trial. Presented at AHA 2018. November 10, 2018. Chicago, IL.

 

 

The Cardiovascular Inflammation Reduction Trial (CIRT): Low Dose Methotrexate for the Prevention of Atherosclerotic Events
CIRT was a randomized, double-blind trial of low-dose methotrexate (LD-MTX; target dose 15-20 mg/week) or placebo in patients with a prior myocardial infarction or multi-vessel coronary disease who also had either type 2 diabetes or metabolic syndrome.  It was designed to investigate whether inhibiting inflammation with LD-MTX might provide a similar cardiovascular benefit to that shown previously by treatment with canakinumab, an anti-inflammatory agent.  At the outset of CIRT, the primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death.  Towards the end of the trial, but before the trial was unblinded, hospitalization for unstable angina that led to urgent revascularization was added to the composite primary endpoint.

Eligible patients were randomly assigned to either LD-MTX (n = 2391) or placebo (n = 2395), and all patients also received 1 mg folate/day.  The trial was stopped after a median follow-up of 2.3 years (maximum 5.1 years) because it had crossed a pre-specified boundary for futility for both the original and final endpoints, and due to the lack of evidence for a reduction in C-reactive protein (CRP) with LD-MTX.  Median changes in inflammatory markers from enrollment to eight months in the LD-MTX and placebo groups, respectively, were 0.09 and 0.05 mg/L for CRP, -0.24 and -0.31 pg/mL for interleukin (IL)-1ß and 0.30 and 0.04 pg/mL for IL-6 (all p >0.05).  Results for the cardiovascular endpoints are shown below.

 

Outcome

LD-MTX

(n = 2391)

Placebo

(n = 2395)

HR (95% CI)

p-value

 

Rate/100 patient-y

 

 

Original MACE

3.46

3.43

1.01 (0.82 to 1.25)

0.91

Final MACE

4.13

4.31

0.96 (0.79 to 1.16)

0.67

Conclusions:  In patients with prior myocardial infarction or multivessel CVD with either type 2 diabetes or metabolic syndrome, LD-MTX did not reduce inflammatory markers or cardiovascular events when compared to placebo.

 Reference:

Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2018; Epub ahead of print.

Photo by Aaron Bean