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Additional CLEAR Outcomes Trial analyses

Primary Prevention Subgroup

Prespecified exploratory analysis of primary prevention patients1

Time to First Occurrence of MACE-4 in Primary Prevention Patients2,3
(nonfatal MI, coronary revascularization, nonfatal stroke, or CV death)

a chart, with a KM curve, showing the incidence of MACE-4 in primary prevention patients taking NEXLETOL vs placebo

MACE-34

(nonfatal MI, nonfatal
stroke, or CV death)

39 %
RRR

HR, 0.61
(95% CI: 0.46-0.80;
83 vs 134 placebo)

Nonfatal MI5

37 %
RRR

HR, 0.63
(95% CI: 0.39-1.01;
28 vs 44 placebo)

Coronary
Revascularization4

27 %
RRR

HR, 0.73
(95% CI: 0.50-1.05;
50 vs 68 placebo)

Methods2,4

Although prespecified, this study reports on outcomes in a subgroup within a larger clinical trial. Therefore, the results should be interpreted as hypothesis-generating rather than definitive evidence of benefits.

This exploratory subgroup analysis of primary prevention patients enrolled 2100 patients to bempedoic acid and 2106 patients to placebo. Criteria for primary prevention were based on meeting at least one of the following: presence of either type 1 or 2 diabetes in women older than 65 years or men older than 60 years, Reynolds risk score >30% or SCORE risk score >7.5% over 10 years, or coronary artery calcium score >400 Agatston units at any time in the past. Enrollment of primary prevention patients was capped at 30% of the total population (which included a mixed population of primary and secondary prevention patients).

Study Limitations2

  • This is a secondary analysis of a subpopulation in a larger randomized trial. Such analyses can result in false-positive findings due to the testing of multiple subgroups and may represent the play of chance
  • The sample size represented a fraction of the total enrolled population, and the number of events was smaller, resulting in wider confidence intervals
  • The inclusion of patients who reported inability to tolerate statins resulted in a high mean baseline LDL-C level. The effects of cholesterol lowering on cardiovascular events in populations with lower pretreatment LDL-C levels was not studied
  • The trial selected patients using specific criteria for a high level of risk of a first cardiac event. Whether outcomes would be similar in patients identified using other criteria for an increased risk remains uncertain

Total Events Analysis

Prespecified exploratory analysis of time to occurrence of first and all subsequent CV events with NEXLETOL6

Total Events Analysis: First and Subsequent MACE-4 Events6
(nonfatal MI, coronary revascularization, nonfatal stroke, or CV death)

a chart, with a KM curve, showing the difference between the first event and the total number of events among patients taking NEXLETOL vs placebo in the CLEAR Outcomes Trial

Total Events:
MACE-36

(nonfatal MI, nonfatal stroke, or CV death)

17 %
RRR

HR, 0.83
(95% CI: 0.73-0.93;
660 vs 793 placebo)

Total Events:
Nonfatal MI6

31 %
RRR

HR, 0.69
(95% CI: 0.58-0.83;
264 vs 379 placebo)

Total Events:
Coronary
Revascularization6

22 %
RRR

HR, 0.78
(95% CI: 0.68-0.89;
530 vs 678 placebo)

Methods6

Prespecified exploratory analysis of the ITT population evaluating the total number of events experienced during the treatment period of 6992 NEXLETOL-treated patients and 6978 placebo patients. The assessment included patients with no events, 1 event, or at least 2 events.

Total Events Limitations6

  • Comparisons between post hoc groups defined by the number of events should be interpreted with caution as recurrent events may correlate and reflect an imbalance in other clinical factors
  • The first incidence of a fatal event also prevents the subsequent risk of other events
  • The trial selected patients using specific criteria for statin-intolerant patients. Whether outcomes would be similar in patients identified using other criteria for an increased risk remains uncertain
  • A disproportionately greater increase in the use of additional lipid-modifying therapies was observed in the placebo group during the trial, which may have attenuated the potential clinical benefits observed with bempedoic acid
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INDICATION AND IMPORTANT SAFETY INFORMATION

Indication

NEXLIZET and NEXLETOL are indicated:

  • The bempedoic acid component of NEXLIZET and NEXLETOL is indicated to reduce the risk of myocardial infarction and coronary revascularization in adults who are unable to take recommended statin therapy (including those not taking a statin) with:
    • established cardiovascular disease (CVD), or
    • at high risk for a CVD event but without established CVD.
  • As an adjunct to diet:
    • NEXLIZET, alone or in combination with other LDL-C lowering therapies, to reduce LDL-C in adults with primary hyperlipidemia, including HeFH.
    • NEXLETOL, in combination with other LDL-C lowering therapies, or alone when concomitant LDL-C lowering therapy is not possible, to reduce LDL-C in adults with primary hyperlipidemia, including HeFH.

IMPORTANT SAFETY INFORMATION

NEXLIZET and NEXLETOL are contraindicated in patients with a prior hypersensitivity to bempedoic acid or ezetimibe or any of the excipients. Serious hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported.

Hyperuricemia : Bempedoic acid, a component of NEXLIZET and NEXLETOL, may increase blood uric acid levels, which may lead to gout. Hyperuricemia may occur early in treatment and persist throughout treatment, returning to baseline following discontinuation of treatment. Assess uric acid levels periodically as clinically indicated. Monitor for signs and symptoms of hyperuricemia, and initiate treatment with urate-lowering drugs as appropriate.

Tendon Rupture : Bempedoic acid, a component of NEXLIZET and NEXLETOL, is associated with an increased risk of tendon rupture or injury. Tendon rupture may occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders. Discontinue NEXLIZET or NEXLETOL at the first sign of tendon rupture. Consider alternative therapy in patients who have a history of tendon disorders or tendon rupture.

The most common adverse reactions in the primary hyperlipidemia trials of bempedoic acid, a component of NEXLIZET and NEXLETOL, in ≥2% of patients and greater than placebo were upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, and elevated liver enzymes.

Adverse reactions reported in ≥2% of patients treated with ezetimibe (a component of NEXLIZET) and at an incidence greater than placebo in clinical trials were upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza.

In the primary hyperlipidemia trials of NEXLIZET, the most commonly reported adverse reactions (incidence ≥3% and greater than placebo) observed with NEXLIZET, but not observed in clinical trials of bempedoic acid or ezetimibe, were urinary tract infection, nasopharyngitis, and constipation.

The most common adverse reactions in the cardiovascular outcomes trial for bempedoic acid, a component of NEXLIZET and NEXLETOL, at an incidence of ≥2% and 0.5% greater than placebo were hyperuricemia, renal impairment, anemia, elevated liver enzymes, muscle spasms, gout, and cholelithiasis.

Concomitant use of NEXLIZET or NEXLETOL with greater than 20 mg of simvastatin or 40 mg of pravastatin should be avoided due to the potential for increased risk of simvastatin- or pravastatin-related myopathy.

Discontinue NEXLIZET or NEXLETOL when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. Because of the potential for serious adverse reactions in a breast-fed infant, breastfeeding is not recommended during treatment with NEXLIZET or NEXLETOL.

Report pregnancies to Esperion Therapeutics, Inc. Adverse Event reporting line at at 1-833-377-7633.

Please see full Prescribing Information for NEXLIZET and NEXLETOL.

View Safety
▾

INDICATION AND IMPORTANT SAFETY INFORMATION

Indication

NEXLIZET and NEXLETOL are indicated:

  • The bempedoic acid component of NEXLIZET and NEXLETOL is indicated to reduce the risk of myocardial infarction and coronary revascularization in adults who are unable to take recommended statin therapy (including those not taking a statin) with:
    • established cardiovascular disease (CVD), or
    • at high risk for a CVD event but without established CVD.
  • As an adjunct to diet:
    • NEXLIZET, alone or in combination with other LDL-C lowering therapies, to reduce LDL-C in adults with primary hyperlipidemia, including HeFH.
    • NEXLETOL, in combination with other LDL-C lowering therapies, or alone when concomitant LDL-C lowering therapy is not possible, to reduce LDL-C in adults with primary hyperlipidemia, including HeFH.

IMPORTANT SAFETY INFORMATION

NEXLIZET and NEXLETOL are contraindicated in patients with a prior hypersensitivity to bempedoic acid or ezetimibe or any of the excipients. Serious hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported.

Hyperuricemia : Bempedoic acid, a component of NEXLIZET and NEXLETOL, may increase blood uric acid levels, which may lead to gout. Hyperuricemia may occur early in treatment and persist throughout treatment, returning to baseline following discontinuation of treatment. Assess uric acid levels periodically as clinically indicated. Monitor for signs and symptoms of hyperuricemia, and initiate treatment with urate-lowering drugs as appropriate.

Tendon Rupture : Bempedoic acid, a component of NEXLIZET and NEXLETOL, is associated with an increased risk of tendon rupture or injury. Tendon rupture may occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders. Discontinue NEXLIZET or NEXLETOL at the first sign of tendon rupture. Consider alternative therapy in patients who have a history of tendon disorders or tendon rupture.

The most common adverse reactions in the primary hyperlipidemia trials of bempedoic acid, a component of NEXLIZET and NEXLETOL, in ≥2% of patients and greater than placebo were upper respiratory tract infection, muscle spasms, hyperuricemia, back pain, abdominal pain or discomfort, bronchitis, pain in extremity, anemia, and elevated liver enzymes.

Adverse reactions reported in ≥2% of patients treated with ezetimibe (a component of NEXLIZET) and at an incidence greater than placebo in clinical trials were upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza.

In the primary hyperlipidemia trials of NEXLIZET, the most commonly reported adverse reactions (incidence ≥3% and greater than placebo) observed with NEXLIZET, but not observed in clinical trials of bempedoic acid or ezetimibe, were urinary tract infection, nasopharyngitis, and constipation.

The most common adverse reactions in the cardiovascular outcomes trial for bempedoic acid, a component of NEXLIZET and NEXLETOL, at an incidence of ≥2% and 0.5% greater than placebo were hyperuricemia, renal impairment, anemia, elevated liver enzymes, muscle spasms, gout, and cholelithiasis.

Concomitant use of NEXLIZET or NEXLETOL with greater than 20 mg of simvastatin or 40 mg of pravastatin should be avoided due to the potential for increased risk of simvastatin- or pravastatin-related myopathy.

Discontinue NEXLIZET or NEXLETOL when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. Because of the potential for serious adverse reactions in a breast-fed infant, breastfeeding is not recommended during treatment with NEXLIZET or NEXLETOL.

Report pregnancies to Esperion Therapeutics, Inc. Adverse Event reporting line at at 1-833-377-7633.

Please see full Prescribing Information for NEXLIZET and NEXLETOL.

CI=confidence interval; CTT=Cholesterol Treatment Trialists’ Coalition; CV=cardiovascular; GLP-1=glucagon-like peptide-1; HR=hazard ratio; hsCRP=high-sensitivity C-reactive protein; ITT=intent to treat; LDL-C=low-density lipoprotein cholesterol; LS=least squares; MACE=major adverse cardiovascular event; MI=myocardial infarction; NNT=number needed to treat; non-HDL-C=non-high-density lipoprotein cholesterol; RRR=relative risk reduction; SGLT2=sodium-glucose cotransporter-2.

REFERENCES

1. Nissen SE, Lincoff DB, Ray KK, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388:1353-1364. 2. Nissen SE, Menon V, Nicholls SJ, et al. Bempedoic acid for primary prevention of cardiovascular events in statin-intolerant patients. JAMA. 2023;330(2):131-140. 3. Nissen SE, Lincoff DB, Ray KK, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388(suppl):1353-1364. 4. Nissen SE, Menon V, Nicholls SJ, et al. Bempedoic acid for primary prevention of cardiovascular events in statin-intolerant patients. JAMA. 2023;330(suppl 2):131-140. 5. Data on file. 1002-043 MACE-4, MACE-3, and MACE components for primary prevention patients (full analysis set). March 2024. 6. Ray KK, Nicholls SJ, Li N, et al. Efficacy and safety of bempedoic acid among patients with and without diabetes: prespecified analysis of the CLEAR Outcomes randomised trial. Lancet Diabetes Endocrinol. 2024;12:19-28.