Abstract
Nonadherence to statin guidelines is common. The solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotype is associated with simvastatin myopathy risk and is proposed for clinical implementation. The unintended harms of using pharmacogenetic information to guide pharmacotherapy remain a concern for some stakeholders. To determine the impact of delivering SLCO1B1 pharmacogenetic results to physicians on the effectiveness of atherosclerotic cardiovascular disease (ASCVD) prevention (measured by low-density lipoprotein cholesterol [LDL-C] levels) and concordance with prescribing guidelines for statin safety and effectiveness. This randomized clinical trial was performed from December 2015 to July 2019 at 8 primary care practices in the Veterans Affairs Boston Healthcare System. Participants included statin-naive patients with elevated ASCVD risk. Data analysis was performed from October 2019 to September 2020. SLCO1B1 genotyping and results reporting to primary care physicians at baseline (intervention group) vs after 1 year (control group). The primary outcome was the 1-year change in LDL-C level. The secondary outcomes were 1-year concordance with American College of Cardiology-American Heart Association and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for statin therapy and statin-associated muscle symptoms (SAMS). Among 408 patients (mean [SD] age, 64.1 [7.8] years; 25 women [6.1%]), 193 were randomized to the intervention group and 215 were randomized to the control group. Overall, 120 participants (29%) had a SLCO1B1 genotype indicating increased simvastatin myopathy risk. Physicians offered statin therapy to 65 participants (33.7%) in the intervention group and 69 participants (32.1%) in the control group. Compared with patients whose physicians did not know their SLCO1B1 results at baseline, patients whose physicians received the results had noninferior reductions in LDL-C at 12 months (mean [SE] change in LDL-C, -1.1 [1.2] mg/dL in the intervention group and -2.2 [1.3] mg/dL in the control group; difference, -1.1 mg/dL; 90% CI, -4.1 to 1.8 mg/dL; P < .001 for noninferiority margin of 10 mg/dL). The proportion of patients with American College of Cardiology-American Heart Association guideline-concordant statin prescriptions in the intervention group was noninferior to that in the control group (12 patients [6.2%] vs 14 patients [6.5%]; difference, -0.003; 90% CI, -0.038 to 0.032; P < .001 for noninferiority margin of 15%). All patients in both groups were concordant with CPIC guidelines for safe statin prescribing. Physicians documented 2 and 3 cases of SAMS in the intervention and control groups, respectively, none of which was associated with a CPIC guideline-discordant prescription. Among patients with a decreased or poor SLCO1B1 transporter function genotype, simvastatin was prescribed to 1 patient in the control group but none in the intervention group. Clinical testing and reporting of SLCO1B1 results for statin myopathy risk did not result in poorer ASCVD prevention in a routine primary care setting and may have been associated with physicians avoiding simvastatin prescriptions for patients at genetic risk for SAMS. Such an absence of harm should reassure stakeholders contemplating the clinical use of available pharmacogenetic results. ClinicalTrials.gov Identifier: NCT02871934.
Highlights
Most patients carry 1 or more genetic variants deemed actionable for their association with either the effectiveness or safety of at least 1 medication.[1,2] High-quality evidence for such pharmacogenetic associations derives from decades of knowledge about candidate genes involved in pharmacokinetic pathways and from more recent developments in genome-wide association studies and large-scale phenotyping of drug response.[3]
The proportion of patients with American College of Cardiology–American Heart Association guideline-concordant statin prescriptions in the intervention group was noninferior to that in the control group (12 patients [6.2%] vs 14 patients [6.5%]; difference, −0.003; 90% CI, −0.038 to 0.032; P < .001 for noninferiority margin of 15%)
Clinical testing and reporting of SLCO1B1 results for statin myopathy risk did not result in poorer atherosclerotic cardiovascular disease (ASCVD) prevention in a routine primary care setting and may have been associated with physicians avoiding simvastatin prescriptions for patients at genetic risk for statin-associated muscle symptoms (SAMS). Such an absence of harm should reassure stakeholders contemplating the clinical use of available pharmacogenetic results
Summary
Most patients carry 1 or more genetic variants deemed actionable for their association with either the effectiveness or safety of at least 1 medication.[1,2] High-quality evidence for such pharmacogenetic associations derives from decades of knowledge about candidate genes involved in pharmacokinetic pathways and from more recent developments in genome-wide association studies and large-scale phenotyping of drug response.[3]. 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, are cholesterol-lowering medications used by millions of patients for the primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD).[6] In 2008, a genome-wide association study[7] identified an association between the common nonsynonymous c.521T>C variant in SLCO1B1 (rs4149056) and severe simvastatin-related myopathy, and subsequent studies[8,9,10] have reported an association between this variant and milder phenotypes of statin intolerance The association between this genetic variant and SAMS appears strongest for simvastatin ; as a result, the Clinical Pharmacogenetics Implementation Consortium (CPIC) has published guidelines for simvastatin prescribing and dosing when a patient’s SLCO1B1 genotype is known.[11] whether integrating SLCO1B1 testing into routine clinical care improves patient outcomes is unknown.[12] Of particular relevance to statins is the question of whether pharmacogenetic results might influence physician and patient behavior around initiation of and adherence to therapy, given that concordance with recommended guidelines is suboptimal in many real-world clinical settings.[13,14,15] In an era when patients increasingly have information about their genetic make-up, including SLCO1B1 genotype, from clinical or commercial sources, it might be more important to demonstrate that the clinical use of that information does not have the unintended consequence of worsening ASCVD prevention efforts than to demonstrate that it prevents simvastatin myopathy
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