Statin intolerance and new lipid-lowering treatments

Article Figures & Data

TABLE 1

Nonstatin lipid-lowering medications

Medication	Mechanism of action	LDL-C reduction	Trials
Ezetimibe	Reduces absorption of cholesterol from small intestine	15%–25%	IMPROVE IT²⁷
Bempedoic acid	Inhibition of adenosine triphosphate citrate lyase	15%–20% (alone) 25%–30% (with ezetimibe)	CLEAR Outcomes study (pending)
PCSK9 inhibitors	Inhibition of PCSK9 protein resulting in more LDL receptors available, and increased uptake of LDL-C into cells	45%–60%	FOURIER, 2015³⁰ ODYSSEY Outcomes 2015¹⁹

LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9

TABLE 2

PCSK9 inhibitor trials

Trial^{^a}	PCSK9 inhibitor	Definition of statin intolerance	Statin rechallenge	LDL-C reduction with PCSK9 inhibitor	LDL-C reduction with ezetimibe^{^a}	Patients with muscle events during trial
GAUSS-2, 2014³²	Evolocumab	Intolerable muscle-related side effects to ≥ 2 statins; most participants unable to tolerate ≥ 3 statins	No	56.1% (140 mg every 2 weeks) 55.3% (420 mg per month)	19.2%	12% (evolocumab) 23% (ezetimibe)
GAUSS-3, 2016¹⁸	Evolocumab	Intolerance to atorvastatin 10 mg and another statin at any dose; or 3 or more statins, with 1 at the lowest daily dose and 2 others at any dose	Yes	52.8% (420 mg per month)	16.7%	20.7% (evolocumab) 28.8% (ezetimibe) HR 0.68; 95% CI 0.39-1.19
ODYSSEY ALTERNATIVE, 2015¹⁹	Alirocumab	Inability to tolerate 2 or more statins because of unexplained skeletal muscle-related symptoms with one of the 2 statins at the lowest-approved daily starting dose.	Yes	45.0% (75 mg every 2 weeks)	14.6%	32.5% (alirocumab) 41.1% (ezetimibe) HR 0.71; 95% CI 0.47 to 1.06

↵a All trials used ezetimibe 10 mg daily as the nonstatin comparator.
CI = confidence interval; HR = hazard ratio; LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9