Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial
Open accessAbstract
IMPORTANCE: Muscle-related statin intolerance is reported by 5% to 20% of patients. OBJECTIVE: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. DESIGN, SETTING, AND PARTICIPANTS: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. INTERVENTIONS: Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). MAIN OUTCOME AND MEASURES: Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. RESULTS: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7% (95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5% (95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, -16.7% (95% CI, -20.8% to -12.5%); absolute change, -31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, -52.8% (95% CI, -55.8% to -49.8%); absolute change, -102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was -37.8%; absolute difference, -75.8 mg/dL. For week 24, between-group difference in LDL-C was -36.1%; absolute difference, -71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). CONCLUSIONS AND RELEVANCE: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01984424.
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The trials comparing statin-based therapy to placebo showed similar between-group incidence of muscle symptoms and statin-discontinuation rate.
“The trials comparing statin-based therapy to placebo showed similar between-group incidence of muscle symptoms and statin-discontinuation rate. [20,21,25,26,43,47]”
From Safety outcomes of statin vs non-statin lipid-lowering interventions in patients with prior statin-associated muscle symptoms: A systematic review and meta-analysis (2025) · cites this paper as [20]
In Statin Rechallenge Outcomes, muscle symptoms were significantly more likely with atorvastatin than placebo in both treatment periods (HR 1.34 and 1.96). The same section reports intolerable symptoms with atorvastatin but not placebo in 42.6% of patients, versus 26.5% with placebo but not atorvastatin. The Discussion notes similar symptom rates only during the first 50 days, not across the full comparison. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn the GAUSS 3 trial after 24 weeks, LDL cholesterol reductions were 54.5% with evolocumab compared with 16.7% with ezetimibe, with slightly higher rates of musculoskeletal adverse events (20.7% with evolocumab and 28.8% with ezetimibe).
“Similar LDL cholesterol reductions were demonstrated in the GAUSS 3 trial after 24 weeks (54.5% with evolocumab compared with 16.7% with ezetimibe), with slightly higher rates of musculoskeletal adverse events (20.7% with evolocumab and 28.8% with ezetimibe).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [137]
Table 3 reports LDL-C reductions of 54.5% with evolocumab and 16.7% with ezetimibe for the mean of weeks 22 and 24. At week 24 alone, the reductions were 52.8% and 16.7%, respectively. The Safety and Tolerability Outcomes section confirms muscle-related adverse-event rates of 20.7% and 28.8%, with the higher rate in the ezetimibe group. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn GAUSS 3, after 24 weeks, LDL cholesterol reductions were 54.5% with evolocumab compared with 16.7% with ezetimibe.
“Similar LDL cholesterol reductions were demonstrated in the GAUSS 3 trial after 24 weeks (54.5% with evolocumab compared with 16.7% with ezetimibe), with slightly higher rates of musculoskeletal adverse events (20.7% with evolocumab and 28.8% with ezetimibe).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [131]
Table 3 (Coprimary End Points) reports LDL-C reductions of 54.5% with evolocumab and 16.7% with ezetimibe for the mean of weeks 22 and 24. At week 24 specifically, the reductions were 52.8% and 16.7%, respectively, so the claim assigns the evolocumab figure to a more specific time point than the paper does. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMost trials used statins with low to moderate intensity.
“Most trials used statins with low to moderate intensity [20,21,24–26,40,43,46,48,49]”
From Safety outcomes of statin vs non-statin lipid-lowering interventions in patients with prior statin-associated muscle symptoms: A systematic review and meta-analysis (2025) · cites this paper as [20]
The Abstract (page unavailable) says GAUSS-3 used atorvastatin 20 mg in its statin-rechallenge phase, consistent with moderate-intensity statin use in this trial. It does not establish that most of the trials cited used low- to moderate-intensity statins; its subsequent treatment phase compared two nonstatin drugs. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe outcomes of interest of our systematic review were not the main outcomes or the pre-specified outcomes of some studies.
“The quality of non-randomized study was generally poor and the outcomes of interest of our systematic review were not the main outcomes or the pre-specified outcomes of some studies [20,46,47].”
From Safety outcomes of statin vs non-statin lipid-lowering interventions in patients with prior statin-associated muscle symptoms: A systematic review and meta-analysis (2025) · cites this paper as [20]
The paper’s “Primary and Secondary End Points” section identifies LDL-C changes as the coprimary outcomes and says cardiovascular events were adjudicated rather than listing them among the primary efficacy outcomes. This supports the concern if those events were outcomes of interest to the review, but the cited paper cannot establish what outcomes the citing authors’ review sought or whether they were prespecified in other studies. (LLM, conf=0.73)
Experimental — accuracy not yet measured
In GAUSS 3, musculoskeletal adverse event rates were 20.7% with evolocumab and 28.8% with ezetimibe.
“Similar LDL cholesterol reductions were demonstrated in the GAUSS 3 trial after 24 weeks (54.5% with evolocumab compared with 16.7% with ezetimibe), with slightly higher rates of musculoskeletal adverse events (20.7% with evolocumab and 28.8% with ezetimibe).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [131]
New evidence on the management of SAMS has become available from randomized controlled trials and observational data.
“New evidence on the management of SAMS have since become available both from randomized control trials (RCTs) and from observational data [20–26].”
23 studies were included for data extraction, with 9 RCTs analyzed quantitatively.
“23 studies were included for data extraction [20–26,35–50], with 9 RCTs analyzed quantitatively.”
8 out of 13 RCTs were judged at low risk of bias.
“We judged 8 [20,22,23,25,26,40,48,49] out of 13 RCTs at low risk of bias (S2 File).”
13 RCTs conducted between 2006-2023 were included, of which five were parallel, five crossover, and three n-of-1.
“We included 13 RCTs conducted between 2006–2023, of which five were parallel RCTs [40,46–49], five were crossover RCTs [20,21,23,26,43] and three were n-of-1 RCTs [22,24,25] (S4 File, Table 1).”
Nine trials assessed statin against placebo.
“nine trials assessed statin against placebo [20–26,43]”
Ten trials provided data on incidence of muscle symptoms.
“Ten trials [20,21,25,26,40,43,46–49] provided data on incidence of muscle symptoms”
Data on incidence of muscle symptoms were available in five parallel-group RCTs and three crossover RCTs.
“Data on incidence of muscle symptoms were available in five parallel-group RCTs [40,46–49], and three crossover RCTs [20,21,43].”
Data on treatment discontinuation due to muscle symptoms were available in three parallel-group RCTs and two crossover RCTs.
“Data on treatment discontinuation were available in three parallel-group RCTs [40,46,48], and two crossover RCTs [20,43].”
The studies we analyzed utilized different definitions for SAMS, different comparators ranging from placebo to phytotherapeutics and newer lipid-lowering therapies such as PCSK-9 inhibitors.
“This variability is reflected in the studies we analyzed, which utilized different definitions for SAMS, different comparators ranging from placebo to phytotherapeutics and newer lipid-lowering therapies such as PCSK-9 inhibitors [20,40,46].”
The observed heterogeneity was mainly driven by two factors: the highly weighted study by Nissen et al. and the inclusion of a higher intensity statin in the Stein et al. trial.
“Overall, these findings suggest that the observed heterogeneity was mainly driven by two factors: the highly weighted study by Nissen et al. [20] and the inclusion of a higher intensity statin in the Stein et al. [48] trial.”
The risk of new-onset diabetes is higher with more potent statins at high doses, in the elderly, and in the presence of other diabetes risk factors such as overweight or insulin resistance.
“However, the risk is higher with the more potent statins at high doses [248], and is also higher in the elderly, and in the presence of other risk factors for diabetes such as overweight or insulin resistance [249].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [249]
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Aebi, P. S., Villoz, F., Bührer, J., Lyko, C., Abolhassani, N., Del Giovane, C., Gencer, B., Rodondi, N., & Blum, M. R. (2025) · PLOS One · doi:10.1371/journal.pone.0338575
- Authors
- Nissen, S. E., Stroes, E., Dent-Acosta, R. E., Rosenson, R. S., Lehman, S. J., Sattar, N., Preiss, D., Bruckert, E., Ceška, R., Lepor, N., Ballantyne, C. M., Gouni-Berthold, I., Elliott, M., Brennan, D. M., Wasserman, S. M., Somaratne, R., Scott, R., Stein, E. A., & for the GAUSS-3 Investigators
- Affiliations
- Cleveland Clinic (US)
- University of Amsterdam (NL)
- Amgen (United States) (US)
- Icahn School of Medicine at Mount Sinai (US)
- Flinders University (AU)
- University of Glasgow (GB)
- University of Oxford (GB)
- University Hospital of Paris 6, Paris, France
- Charles University in Prague, Prague, Czech Republic11General University Hospital in Prague, Prague, Czech Republic
- University of California, Los Angeles (US)
- Baylor College of Medicine (US)
- Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany
- Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio
- Corresponding author
- Nissen, Steven E.
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2016-04-19
- Volume
- 315
- Issue
- 15
- Pages
- 1580
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2314193179
- Cited by
- 522
- References
- 18
- Citations by year
- 2026: 19 · 2025: 35 · 2024: 34 · 2023: 34 · 2022: 53 · 2021: 41 · 2020: 65 · 2019: 61 · 2018: 55 · 2017: 75 · 2016: 50
- FWCI
- 89.09
- Type
- journal article
- Language
- en
- Open access
- green
- jama.jamanetwork.com
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
- HAL (submittedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- statin intolerance, evolocumab, ezetimibe, LDL cholesterol lowering, atorvastatin, statin rechallenge, PCSK9 inhibition, lipid-lowering therapy, tolerability, creatine kinase, coronary artery disease, hypercholesterolemia, statin-induced myopathy, crossover design
- MeSH terms
- Atorvastatin, Ezetimibe, Adult, Antibodies, Monoclonal, Anticholesteremic Agents, Creatine Kinase, Double-Blind Method, Female, Humans, Hypercholesterolemia, Cholesterol, LDL, Male, Middle Aged, Muscular Diseases, Myositis, Rhabdomyolysis, Time Factors, Biomarkers, Cross-Over Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Antibodies, Monoclonal, Humanized, Myalgia
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