Statin Intolerance and FH: GAUSS-3 Finds Benefit With Evolocumab, While Another Study Exposes Lifetime Risks of FH

CHICAGO, IL—Among patients unable to tolerate multiple statins because of muscle-related adverse events, treatment with evolocumab (Repatha, Amgen) and ezetimibe (Zetia, Merck/Sanofi) significantly lowered LDL cholesterol levels. That reduction was significantly larger with PCSK9 inhibitor than with ezetimibe.

Presenting the results of the GAUSS-3 study at the American College of Cardiology 2016 Scientific Sessions in Chicago, IL, lead investigator Steven Nissen, MD (Cleveland Clinic, OH), said the study revealed that approximately 40% of statin-intolerant individuals rechallenged with a statin were unable to take atorvastatin. These patients, he said, required lipid-lowering therapy given that their LDL cholesterol levels were in the “stratosphere.” 

“Good physicians recognize that statins have a time-honored beneficial effect on morbidity and mortality and we should do everything possible to get them onto statins,” said Nissen. “That’s what was done here. Yet we still have this group of people who could not tolerate statins. I think we try as hard as we can, but we need alternatives. Our goal was to understand [intolerance] better and to develop alternatives that would be tolerated by those patients.”

Published in JAMA to coincide with the late-breaking clinical trials session, the GAUSS-3 study was a two-stage randomized clinical trial that included 511 patients with uncontrolled LDL cholesterol levels. Importantly, all patients had a documented history of intolerance to atorvastatin 10 mg and another statin at any dose, or intolerance to three or more statins, including at least one drug used at the lowest possible dose.

‘Let Me Be as Clear as I Can Be . . . ’

In phase A of the study, the statin-intolerant individuals were enrolled in a 24-week crossover study with atorvastatin 20 mg or placebo to identify only those who developed muscle-related symptoms on statin therapy (and not on placebo). In total, intolerable muscle symptoms developed in 42.6% of individuals taking atorvastatin during the crossover study while another 19 subjects had significant elevations in creatinine kinase (10x the upper limit of normal while on statin therapy). These 218 individuals were then randomized to treatment with evolocumab 420 mg (subcutaneous injection once per month) or daily ezetimibe 10 mg. Prior to randomization, the baseline LDL cholesterol level was 222 mg/dL and 219 mg/dL in the ezetimibe- and evolocumab-treatment arms, respectively.

By 24 weeks of treatment, ezetimibe reduced LDL cholesterol levels 16.7% from baseline while evolocumab reduced LDL cholesterol levels 52.8%, a between-group difference that was statistically significant. Treatment with evolocumab also significantly reduced lipoprotein(a) and increased HDL cholesterol levels. Nearly one-third of those treated with evolocumab achieved LDL-cholesterol levels less than 70 mg/dL.

Evolocumab is approved by the US Food and Drug Administration for use in addition to diet and maximally tolerated statin therapy in adults with heterozygous and homozygous familial hypercholesterolemia (FH) or in those with clinical evidence of atherosclerotic cardiovascular disease who require further LDL-cholesterol lowering. It does not have a specific indication for patients intolerant to statins. Despite this, Nissen said he would be willing to treat very-high-risk patients who have tried and failed multiple statins.     

“Let me be as clear as I can be,” said Nissen. “If somebody is sitting across from you and they have multiple risk factors for coronary disease—they have LDL cholesterol levels of 210 or 220 mg/dL—they are an accident waiting to happen. To say, well it’s not cost-effective to treat that patient with the most effective alternative available to us. It doesn’t make any sense at all to me.”

Frederick Masoudi, MD (University of Colorado Anschutz Medical Center, Denver), who was not involved in the trial, said statin intolerance is a vexing clinical problem, in large part of the lack of a diagnostic test to confirm the physical finding. For him, the first part of GAUSS-3—where more than 80% of patients were intolerant to three statins—was the most interesting part of the trial, given that nearly 60% of these individuals didn’t have intolerable muscle-related symptoms when re-challenged with atorvastatin 20 mg. 

“It’s a very important finding because these data suggest that in terms of identifying statin intolerance, it pays to be patient,” said Masoudi. “Statins remain the mainstay of cardiovascular prevention in terms of cholesterol lowering in patients with the appropriate risk profiles. It will be important to try multiple statins over time before throwing in the towel on these drugs and considering other alternatives to therapy.”  

In an editorial accompanying the study, David Waters, MD, and Priscilla Hsue, MD (San Francisco General Hospital, CA), and Sripal Bangalore, MD (New York University School of Medicine), raise the question whether statin-intolerant patients should be treated with PCSK9 inhibitors at all, noting there are several arguments against doing so, not the least of which is cost. 

The drugs, as has been widely reported, cost more than $14,000 USD per year, and some have argued are not cost-effective at the current price. The editorialists don’t believe the financial analysis should mean no statin-intolerant patient receives evolocumab or alirocumab (Praluent, Sanofi/Regeneron), but they suspect only 1% of individuals at high risk for cardiovascular disease would have intolerable muscle symptoms using very-low-dose statins and would require a PCSK9 inhibitor. 

“[The] legacy effect of statins is impressive,” Waters et al write. “ PCSK9 inhibitors are just starting out. Whether PCSK9 inhibitors will have the same impressive long-term outcomes will not be known for many years.” 

In GAUSS-3, both ezetimibe and evolocumab were well tolerated, with 20.7% of patients in the evolocumab arm reporting muscle-related adverse events. In total, 4.8% of patients treated with the PCSK9 inhibitor discontinued treatment for any reason, with just one patient stopping because of muscle-related reasons. In the ezetimibe arm, 7.6% of patients discontinued the drug for muscle-related symptoms.  

Genetics of FH and Lifetime Exposure

In a second study presented during the late-breaking clinical trials session, Amit Khera, MD (Massachusetts General Hospital, Boston), and colleagues attempted to determine how many patients with LDL cholesterol ≥ 190 mg/dL had one of the mutations for FH and whether or not the risk of coronary artery disease varied according to FH mutation status for any given LDL cholesterol level.

In total, they screened for three genes known to cause FH—LDLR, APOB, and PCSK9—in 26,025 individuals from seven case-control studies and five prospective cohort studies. Among 8,577 individuals without coronary artery disease who served as controls in the case-control studies, 430 had an LDL cholesterol level ≥ 190 mg/dL but only 8 (1.9%) of these people carried a mutation for FH. Among 11,908 individuals from the prospective cohort studies, 956 had an LDL cholesterol ≥ 190 mg/dL but only 16 (1.7%) carried the FH mutation. Overall, 1.7% of 1,386 individuals with LDL cholesterol ≥ 190 mg/dL were FH-mutation positive. 

Individuals with the FH mutation were at a significantly increased risk of coronary artery disease, even when compared against those with the same LDL cholesterol level. For example, among those with an LDL cholesterol level ranging from 190 to 220 mg/dL, those with an FH mutation had a 17-fold higher risk of coronary disease compared with the reference group (individuals with LDL cholesterol < 130 mg/dL and no FH mutation). In contrast, those without the mutation only had a five-fold increased risk of coronary disease. 

To TCTMD, senior investigator Sekar Kathiresan, MD (Massachusetts General Hospital), said the researchers believe the incremental risk conferred by FH-mutation status is caused by a higher cumulative exposure to LDL cholesterol. They tested the hypothesis using data from the ARIC and FHS Offspring studies, where they had access to genetic data and serial measurements of LDL cholesterol. In 25 individuals with an FH mutation and an LDL cholesterol ≥ 130 mg/dL, those with an FH mutation had an 18-mg/dL higher average LDL cholesterol in the 8 years preceding the last visit. 

Jennifer Robinson, MD (University of Iowa Carver College of Medicine, Iowa City), one of the panelists during the late-breaking clinical trial session, cautioned physicians against erroneously interpreting the data given the excess risk conferred by FH mutation status. Regardless of the genetic fingerprint, individuals with an LDL cholesterol ≥ 190 mg/dL need to be treated, she stressed. Kim Eagle, MD (University of Michigan, Ann Arbor), said the diagnostic yield of genetic testing is quite low at 1.7%, making widespread genetic screening unfeasible, but questioned whether it might become more cost-effective as the costs come down.

To TCTMD, Kathiresan and Khera both said they imagine genetic screening might benefit those who fall into an “intermediate category,” such as a 35-year-old male with an LDL cholesterol level of 170 mg/dL. “If you have somebody between 30 and 50 years of age, and you’re wondering if they should get a statin, because their LDL is 160 mg/dL and they had a family history of disease—if I knew that person had a mutation, I would make a much bigger push to have them on a statin,” Kathiresan said.  

Commenting on the potential clinical implications of the FH findings, Stephen Nicholls, MD (University of Adelaide, Australia), adopted a wait-and-see approach.

“We’re just kind of discovering that FH is a much bigger issue,” he said. “I think that’s been one of the gifts of the PCSK9 inhibitor development program. There’s been a lot more attention focused there. There’s been a lot more interest in cascade screening. The question will be, would you be more aggressive in the way you ‘hunt’ relatives if you knew they had a monogenic mutation? But until we have a better grasp on what the cost implications are and how it actually changes the management, I think it remains a question mark for widespread use.”


  • Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance. JAMA. 2016; Epub ahead of print.
  • Waters DD, Hsue PY, Bangalore S. PCSK9 Inhibitors for Statin Intolerance. JAMA. 2016; Epub ahead of print. 
  • Khera AV, Won HH, Peloso GM, et al. Diagnostic yield of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol. 2016; Epub ahead of print. 


  •  Khera reports research support from an ACC/Merck Fellowship award and consulting for Merck and Amgen. Kathiresan has received research grants from Bayer Healthcare, Aegerion, and Regeneron and reports consulting fees from Merck, Quest Diagnostics, Genomics PLC, and Eli Lilly.
  • GAUSS-3 was sponsored by Amgen. 
  •  Nissen reports conducting clinical trials sponsored by Amgen, AstraZeneca, Cerenis, Eli Lilly, Novartis, Novo Nordisk, The Medicines Company, Orexigen, Takeda, and Pfizer. He reports consulting for multiple pharmaceutical companies but honoraria, speaking or consulting fees are paid directly to charity (for which he receives neither income nor a tax deduction). 

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