That Myalgia of Yours Is Not From Statin Intolerance

Background: Drugs mimicking natural beneficial mutations, including that for familial hypercholesterolemia (FH), might represent the future of hypolipidemic drug treatment. Objective: The aim of this review is to review the properties and the effects of these drugs, which are either already commercially available or are in the process to be approved for the treatment of dyslipidemia. Results: More than a decade ago, it was accidentally discovered that proprotein convertase subtilisin/kexin type 9 (PCSK9) loss-of-function mutations resulted in marked lifelong reduction of LDL-C and the incidence of cardiovascular disease (CVD). This provided the idea for a human anti-PCSK9 antibody. Along with dozens of phase II and III studies demonstrating unprecedented reductions in LDL-C levels, two large clinical trials established the substantial benefits of evolocumab and alirocumab on cardiovascular morbidity and mortality, on top of standard treatment. Evolocumab and alirocumab are now approved and used in clinical practice for the treatment of FH, statin intolerance, and high risk patients not achieving LDL-C targets. Anti RNA, small molecules, peptides and also protein fragments against PCSK9 are in phase 1 trials. Angiopoietin-like protein 3 (ANGPTL3) regulates lipid metabolism increasing triglycerides (TGs), remnants, and LDL-C. In a huge study, ANGPTL3 deficiency due to gene(s) loss-of-function was associated with substantial reductions in circulating TGs, LDL-C, and CVD. Evinacumab, an ANGPTL3 antibody, caused a dose-dependent reduction in fasting TG levels of up to 76% and LDL-C of up to 23% and CVD risk by 41%. There is also antisense oligonucleotide and micro-RNA- 27b (miR-27b) against ANGPTL3. Two naturally occurring mutations in apo3 gene, A23T and K58E, reduce TGs and CVD risk. A monoclonal antibody targeting apoC-III has the same effect. Conclusion: Mimicking the beneficial naturally happening mutations in lipid metabolism pathways with biological drugs is probably the future of hypolipidemic drug treatment.

Download Full-text

Pooled safety and efficacy of inclisiran in patients with statin intolerance (ORION-10 and ORION-11)

European Heart Journal ◽

10.1093/ehjci/ehaa946.3009 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

R.S Wright ◽

D Kallend ◽

F.J Raal ◽

R Stoekenbroek ◽

W Koenig ◽

...

Keyword(s):

Statin Therapy ◽

Therapeutic Option ◽

Lipid Lowering ◽

Funding Source ◽

Lipid Lowering Therapy ◽

Statin Intolerance ◽

Private Company ◽

Phase 3 ◽

Absolute Reduction ◽

Secondary Endpoints

Abstract Introduction Statin-associated side effects prevent a substantial proportion of patients from being adequately treated with statin therapy and achieving adequate LDL-C reductions. Phase 3 trials showed that inclisiran, a new siRNA, durably lowers LDL-C by ≥50% on top of maximally tolerated statin therapy. Purpose To evaluate inclisiran's tolerability and LDL-C lowering effects among individuals who were not receiving statin therapy mainly because of statin intolerance. Methods The Phase 3 ORION-10 and ORION-11 trials randomized patients with established ASCVD (or risk-equivalents) with LDL-C >70 mg/dl despite maximally tolerated statins to inclisiran or placebo (1:1). Inclisiran sodium 300 mg was administered s.c. at baseline, three months later, then every six months. The primary efficacy endpoints were % change in LDL-C from baseline to Day 510 and time adjusted % change in LDL-C from baseline after Day 90 and up to Day 540. Absolute LDL-C reductions were secondary endpoints. This analysis included individuals who were not on statin therapy at baseline. Results The trials included 252 (7.9% of the pooled trial populations; mean age 68; male 62%; lipid-lowering therapy 28%). AE rates and LDL-C reductions are shown in the Table. Overall, 12 (4.7%) patients had myalgia (4.8% in the inclisiran groups, 4.7% in the placebo groups). There were 8 discontinuations in the inclisiran groups (6.5%) and 3 in the placebo groups (2.3%). The placebo-adjusted mean reduction in LDL-C at Day 510 was 45.8%, an absolute reduction of 68.0 mg/dL (p<0.0001). Conclusion Among statin intolerant individuals in ORION-10 and 11, inclisiran potently and durably lowered LDL-C with an adverse event profile comparable to placebo. Inclisiran may represent a new and potent therapeutic option for patients with elevated LDL-C unable to tolerate statins. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The Medicines Company

Download Full-text

Abstract 280: Defining Statin Intolerance Among High Cardiovascular Risk Patients: Do US Administrative Databases Lend Themselves to Identification Of Statin Intolerance?

Circulation Cardiovascular Quality and Outcomes ◽

10.1161/circoutcomes.8.suppl_2.280 ◽

2015 ◽

Vol 8 (suppl_2) ◽

Author(s):

Joanne M Foody ◽

Lois E Lamerato ◽

Mehul R Dalal ◽

Jennifer Sung ◽

Irfan Khan ◽

...

Keyword(s):

Adverse Events ◽

Administrative Databases ◽

Administrative Database ◽

Statin Intolerance ◽

Mixed Dyslipidemia ◽

Henry Ford ◽

Risk Patients ◽

Artery Disease ◽

Measures Of Concordance ◽

Sensitivity Specificity

Introduction: The clinical and economic impact of statin intolerance (SI) in high CV risk patients is unknown due, in part, to a lack of consensus in its definition. We sought to define and validate an SI algorithm for use in an administrative database (AD) among high-CV risk patients Methods: Adults with ≥1 qualifying change (See Table 1) in statin therapy and ≥1 prior diagnosis of hyperlipidemia, hypercholesterolemia, or mixed dyslipidemia were identified from the AD of the Health Alliance Plan at Henry Ford Health System (HFHS). A sample of 1000 patients was drawn from the pool of eligible adults and stratified by high CV risk based on presence of comorbid conditions including diabetes, coronary heart disease, and peripheral artery disease. Statin utilization and adverse events data were abstracted both from the AD and the HFHS electronic medical record (EMR). SI was defined using both a primary definition inclusive of all possible statin related adverse events and a secondary definition that included only musculoskeletal events. SI was categorized as absolute (AI) or titration (TI) intolerance. The performance of the AD algorithm was assessed using measures of concordance (Cohen’s kappa [κ]) and accuracy (sensitivity, specificity, positive predictive value [PPV]) with the EMR as reference. Results: A total of 353 patients (48% female, 44% Caucasian, mean (SD) age 63 (12) years) were identified as high CV risk with 33% having a history of CHD, 77% diabetes and 2% PAD. Forty-two percent of patients were on simvastatin, 35% atorvastatin, 11% lovastatin, 7% rosuvastatin and 6% pravastatin/fluvastatin. Table 1 characterizes the validation sample. SI was identified in 19.3% and 20.7%, AI in 3.1% and 2.8%, and TI in 16.7% and 18.7% of patients in the EMR and AD, respectively. The algorithm identifying any SI had robust concordance (κ=0.73), good sensitivity (80.9%) and PPV (75.3%). The TI algorithm performed better (κ=0.78, sensitivity=86.4%, PPV=77.3%) than the AI algorithm (κ=0.56, sensitivity=54.5%, PPV=60.0%). Specificity was high (>94%) across all 3 algorithms. Conclusion: This study successfully defined SI among high-CV risk patients using an evidence-based validated algorithm. To our knowledge, this is the first such algorithm for use in AD to be made available to decision-makers.

Download Full-text