The CLEAR (Cholesterol Lowering via Bempedoic Acid [ETC-1002], an ACL-Inhibiting Regimen) Outcomes trial was approved by multiple local institutional review boards and randomized 13,970 statin-intolerant patients at high risk of cardiovascular events to bempedoic acid or placebo.1 Bempedoic acid reduced low-density lipoprotein cholesterol by 21% and major adverse cardiovascular events (MACE)-4 by 13%.1 Bempedoic acid use was associated with mean increases in serum uric acid (UA) from baseline to month 6 of approximately 0.8 mg/dL, which were stable overtime and reversible, due to modest inhibition of organic anion transporter-2, which mediates renal UA transport.2,3 Gout adverse events (AEs) were reported in 3.1% and 2.1% of bempedoic acid and placebo patients,1 with elevated serum UA levels at baseline associated with increased gout incidence (7.7% bempedoic acid and 5.2% placebo).3 It is not known whether use of UA-lowering medications helps mitigate gout incidence in patients receiving bempedoic acid.
This post hoc analysis using the safety analysis data set evaluated the use and timing of UA-lowering medications (baseline use and/or new medication added post randomization) on the incidence of gout, and whether baseline elevated serum UA, prior history of gout, or both influenced incidence of gout reported as AEs by investigators. The effect of bempedoic acid vs placebo on MACE-4 (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization) was assessed in those without or with a history of gout using a proportional hazard model in the full analysis data set. At baseline 375/7,001 (5.4%) bempedoic acid and 345/6,964 (5.0%) placebo patients reported having prior gout or gouty arthritis; 2,158 (30.8%) and 2,162 (31.0%), respectively, had UA levels greater than the upper limit of normal. During the trial, UA-lowering medications were used in 16.4% bempedoic acid and 10.7% placebo patients: the majority (∼96%) being allopurinol. Of patients on a UA-lowering medication at baseline, 90.0% were still on a UA-lowering medication at the end of the study. Table 1 presents data for patients without prior gout and normal UA, with either prior gout or elevated UA, or both. The use of UA-lowering medications at baseline and/or during the trial was used to assess timing relative to the incidence of gout among different patient groups.
What is the clinical question being addressed?
Does uric acid–lowering medication use impact gout adverse events in patients receiving bempedoic acid, with or without prior gout and/or baseline elevated uric acid?
What is the main finding?
Gout incidence was lower with uric acid–lowering medication use during CLEAR Outcomes.
Table 1.
Uric Acid–Lowering Medication Use and Incidence of Gout Adverse Events by History of Gout or Elevated Uric Acid Level at Baseline
| No History of Gout/Baseline Uric Acid Normal |
History of Gout Only |
Baseline Uric Acid >ULN Only |
Both (Baseline Uric Acid > ULN and History of Gout) |
|||||
|---|---|---|---|---|---|---|---|---|
| Use of Uric Acid–Lowering Med | Bempedoic Acid (n = 4658) |
Placebo (n = 4648) | Bempedoic Acid (n = 185) |
Placebo (n = 154) | Bempedoic Acid (n = 1968) |
Placebo (n = 1971) | Bempedoic Acid (n = 190) |
Placebo (n = 191) |
| Gout AE irrespective of uric acid–lowering med use | 44 (0.9) | 22 (0.5) | 16 (8.6) | 17 (11) | 128 (6.5) | 63 (3.2) | 39 (20.5) | 50 (26.2) |
| Baseline use of uric acid–lowering med | 137 (2.9) | 129 (2.8) | 128 (69.2) | 102 (66.2) | 84 (4.3) | 92 (4.7) | 83 (43.7) | 78 (40.8) |
| Gout AE during the triala | 0 | 1 (<0.1) | 6 (3.2) | 14 (9.1) | 5 (0.3) | 2 (0.1) | 13 (6.8) | 21 (11.0) |
| Started uric acid–lowering med during the trial | 236 (5.1) | 82 (1.8) | 15 (8.1) | 5 (3.2) | 414 (21.0) | 216 (11.0) | 48 (25.3) | 38 (19.9) |
| Gout AE at any time during the triala | 30 (0.6) | 10 (0.2) | 6 (3.2) | 2 (1.3) | 90 (4.6) | 47 (2.4) | 22 (11.6) | 17 (8.9) |
| Gout AE after uric acid–lowering med started | 0 | 1 (<0.1) | 1 (0.5) | 0 | 17 (0.9) | 3 (0.2) | 6 (3.2) | 4 (2.1) |
| No use of uric acid–lowering med during the trial | 4,285 (92.0) | 4,437 (95.5) | 42 (22.7) | 47 (30.5) | 1470 (74.7) | 1,663 (84.4) | 59 (31.1) | 75 (39.3) |
| Gout AE at any time during the triala | 14 (0.3) | 11 (0.2) | 4 (2.2) | 1 (0.6) | 33 (1.7) | 14 (0.7) | 4 (2.1) | 12 (6.3) |
AE = adverse event; ULN = upper limit of normal.
Values are n (%). Gout AE could have occurred at any time during the trial regardless of timing of uric acid–lowering medication
Among patients without prior gout or elevated UA, gout was infrequent in both treatment groups (<1%). For patients with prior gout who never received UA-lowering medications during follow-up, 2.2% of bempedoic acid patients and 0.6% of placebo patients experienced gout. When a UA-lowering medication was used, either at baseline or after a gout event, the incidence of gout was similar to or lower in bempedoic acid–treated patients vs placebo (3.2% vs 9.1% and 0.5% vs 0%, respectively). In patients with elevated UA but no history of gout, incidence of gout among those who never received UA-lowering therapies occurred twice as often with bempedoic acid (1.7%) vs placebo (0.7%) but occurred less often with any use of UA-lowering therapies either at baseline or after an episode of gout (<1%) in both bempedoic acid and placebo patients. Patients with both a prior history of gout and elevated UA had the highest use of UA-lowering medications at baseline (43.7% for bempedoic acid and 40.8% for placebo) and the highest overall incidence of gout in both treatment groups (20.5% in bempedoic acid and 26.2% in placebo). In this subset of patients, gout occurred less frequently when UA-lowering medications were used at baseline for both bempedoic acid (6.8%) and placebo (11.0%), and after these medications were initiated during the study (3.2% and 2.1%, respectively). The adjusted hazard ratios for the effect of bempedoic acid on MACE-4 was 0.87 (95% CI: 0.63-1.21) in those with a prior history of gout (n = 720) and was 0.87 (95% CI: 0.79-0.96) among those without (n = 13,245) (P interaction = 1.00).
Gout is associated with a 17% higher incidence of all-cause mortality mostly attributed to cardiovascular death, compared to those without gout.4 Episodes of gout are largely preventable with lifestyle changes and use of UA-lowering medications.4 Many patients with a prior history of gout have hypercholesterolemia and require lipid-lowering therapy. If statins are not tolerated, other options are required to reduce cardiovascular risk. In CLEAR Outcomes patients with a prior history of gout derived similar cardiovascular benefits with bempedoic acid as those without. Data from the phase 3 bempedoic acid clinical development program consistently demonstrated a 0.8 mg/dL mean increase in UA and 1.1% increase in gout with bempedoic acid vs placebo and may result in some patients not being offered this potentially cardioprotective therapy. In this regard, the present study which assessed both incidence of gout and its potential mitigation provides evidence for practical management. Firstly, gout occurred infrequently with bempedoic acid and was comparable to placebo in those without a prior history of gout and with normal UA. In patients without prior gout, elevated UA levels at baseline were associated with a greater incidence of gout, consistent with phase 3 data for bempedoic acid.5 The highest frequency of gout occurred in those with both elevated UA levels at baseline and prior history of gout, but use of UA-lowering therapies lowered incidence of gout in this subpopulation either when used prior to commencing bempedoic acid or after a first event. For those not on UA-lowering therapies at baseline, the initiation of a UA-lowering medication after a gout AE reduced incidence of subsequent episodes.
Limitations of this study include post hoc nature and use of UA-lowering medication which is the main exposure of interest and is in itself a confounder in the relationship between bempedoic acid and gout. Prior gout, higher baseline UA levels, and prior UA medications all influence medication use during the trial while also affecting gout occurrence. Moreover, because bempedoic acid increases UA levels, that arm has a higher chance of receiving UA medications during the study which limits comparisons involving post randomization UA medication use.
In conclusion, this post hoc analysis showed similar cardiovascular benefits of bempedoic acid in patients with and without prior gout. Incidence of gout with bempedoic acid was comparable to placebo in patients with no history of gout and a normal baseline UA level. While bempedoic acid was associated with higher incidence of gout in patients with elevated UA at baseline, gout was less pronounced when UA-lowering medications were used, suggesting that clinically indicated monitoring and treatment initiation may reduce potential risk of gout in patients receiving bempedoic acid.
Funding support and author disclosures
Funding for the CLEAR Outcomes study was provided by Esperion Therapeutics, Inc. Dr Ray has received grants to his institution from Amgen, Daiichi Sankyo, Ultragenix, and Sanofi; and has received consulting fees from Daiichi Sankyo, Esperion, Amgen, Novartis, Eli Lilly, Silence Therapeutics, Algorithm, Abbott, AstraZeneca, New Amsterdam, Sanofi, Mankind, Scribe, Vaxxinity, Novo Nordisk, and Boehringer Ingelheim. Dr Nicholls has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Eli Lilly, Esperion, Resverlogix, Novartis, InfraReDx, and Sanofi-Regeneron; and is a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron, Vaxxinity, CSL Sequiris, and Novo Nordisk. Dr Lincoff reports receipt of Honoraria/Consultancy from Novo Nordisk, Eli Lilly, Alnylam, Amgen, Ardelyx, Brainstorm Cell, Cadrenal, GlaxoSmithKline, Johnson & Johnson, Medtronic, Neovasc, ReCor, and TD Cowen; and has received research funding to Cleveland Clinic from AbbVie, AstraZeneca, CSL Behring, Eli Lilly, Esperion, and Novartis. Drs Li, Powell, Herout, and Ms Bloedon are compensated employees of Esperion Therapeutics, Inc, and may own shares of Esperion stock. Dr Nissen reports that the Cleveland Clinic Center for Clinical Research has received funding to perform clinical trials from Abbvie, AstraZeneca, Amgen, Bristol Myers Squibb, Eli Lilly, Esperion, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, Pfizer, and Silence Therapeutics; is involved in these clinical trials but receives no personal remuneration for his participation; and consults for these pharmaceutical companies but does not accept compensation.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
References
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