Efficacy and safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, a post-commercialization study

Joshua Choi, Amir M Khan, Michael Jarmin, Naila Goldenberg, Charles J Glueck, Ping Wang, Joshua Choi, Amir M Khan, Michael Jarmin, Naila Goldenberg, Charles J Glueck, Ping Wang

Abstract

Background: Efficacy-safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab (ALI) and evolocumab (EVO), have previously been evaluated through controlled clinical trials with selective patient groups. Post-commercially, in 69 patients with heterozygous familial hypercholesterolemia (HeFH) and/or cardiovascular disease (CVD) with suboptimal LDL cholesterol (LDLC) lowering on maximal tolerated LDLC therapy, we assessed efficacy and safety of ALI and EVO.

Methods: Post-commercially, we started 29 patients on ALI 75 mg, 18 on ALI 150 mg, and 22 on EVO 140 mg every 2 weeks added to a maximally tolerated LDLC-lowering regimen. Since LDLC lowering did not differ between ALI 150 and EVO 140 mg, ALI 150-EVO 140 data were pooled (ALI-EVO). Changes in LDLC and AHA and NIH calculated 10-year CVD risks were assessed.

Results: Of the 69 patients, 25 had HeFH, 25 CVD, and 19 had both. At entry, 23 (33%) took statins and 46 (67%) were statin-intolerant. Mean ± SD and median follow-up were 49 ± 13 and 49 weeks on ALI 75 mg, and 37 ± 12 and 33 weeks on ALI-EVO. In the ALI-EVO group (n = 40), median LDLC fell from 165 mg/dl at entry to 70 mg/dl (median - 59%, p < .0001). AHA 10-year calculated CVD risk fell from 10.2 to 5.5% (median - 28%, p < .0001), and by the NIH calculator from 14.2 to 3.6% (median - 78%, p < .0001). In the ALI 75 mg group (n = 29), entry LDLC fell from 115 to 68 mg/dl (median - 39%, p < .0001). AHA 10-year calculated CVD risk fell from 11.5 to 7.3% (median - 20%, p = .004), and NIH 10-year risk from 12.9 to 5.1% (median 67%, p < .0001). Absolute and percent change in LDLC was independent of statin use. There were flu-like symptoms in 14% of patients. Adverse events did not differ (p > 0.05) between ALI 75 mg and ALI-EVO.

Conclusion: In patients with HeFH and/or CVD, LDLC decreased from 115 to 68 mg/dl (39%) on ALI 75 mg with mean follow-up of 49 weeks, and from 165 to 70 mg/dl (59%) on ALI-EVO over 37 weeks, p < .0001 for both. Adverse events were minimal and tolerable. ALI and EVO represent paradigm shifts in LDLC lowering.

Keywords: Alirocumab; Cardiovascular risk; Efficacy; Evolocumab; Hypercholesterolemia; Low-density lipoprotein; PCSK9 inhibitor; Safety.

Figures

Fig. 1
Fig. 1
Change in LDLC from entry to 28, 42, and 52 weeks on Alirocumab 75 mg every 2 weeks in 29 patients; median, 25th and 75th LDLC percentiles displayed
Fig. 2
Fig. 2
Change in LDLC from entry to 28, 42, and 52 weeks on Alirocumab 150 mg (n = 18) and Evolocumab 140 mg (n = 22) every 2 weeks (data pooled); median, 25th and 75th LDLC percentiles displayed

References

    1. Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of Evolocumab vs Ezetimibe in patients with muscle-related Statin intolerance: the GAUSS-3 randomized clinical trial. JAMA. 2016;315(15):1580–90. doi: 10.1001/jama.2016.3608.
    1. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J med. 2015;372(16):1489–1499. doi: 10.1056/NEJMoa1501031.
    1. Robinson JG, Kastelein JJ. PCSK9 inhibitors and cardiovascular events. N Engl J med. 2015;373(8):774.
    1. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J med. 2015;372(16):1500–1509. doi: 10.1056/NEJMoa1500858.
    1. Sabatine MS, Wasserman SM, Stein EA. PCSK9 inhibitors and cardiovascular events. N Engl J med. 2015;373(8):774–775.
    1. Marks D, Thorogood M, Neil HA, et al. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis. 2003;168(1):1–14. doi: 10.1016/S0021-9150(02)00330-1.
    1. Austin MA, Hutter CM, Zimmern RL, et al. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol. 2004;160(5):407–420. doi: 10.1093/aje/kwh236.
    1. Glueck CJ, Shah P, Goldenberg N, et al. Eligibility for PCSK9 treatment in 734 Hypercholesterolemic patients referred to a regional cholesterol treatment center with LDL cholesterol >/=70 mg/dl despite maximal tolerated cholesterol lowering therapy. Lipids Health Dis. 2016;15(1):55. doi: 10.1186/s12944-016-0227-2.
    1. Shah P, Glueck CJ, Jetty V, et al. Pharmacoeconomics of PCSK9 inhibitors in 103 hypercholesterolemic patients referred for diagnosis and treatment to a cholesterol treatment center. Lipids Health Dis. 2016;15(1):132. doi: 10.1186/s12944-016-0302-8.
    1. Roth EM. Alirocumab for hyperlipidemia: ODYSSEY phase III clinical trial results and US FDA approval indications. Futur Cardiol. 2016;12(2):115–128. doi: 10.2217/fca.15.78.
    1. Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I study. Am Heart J. 2015;169(6):906–915. doi: 10.1016/j.ahj.2015.03.004.
    1. Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36(19):1186–1194. doi: 10.1093/eurheartj/ehv028.
    1. Stroes E, Guyton J R, Lepor N, et al. Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients With Hypercholesterolemia Not on Statin Therapy: The ODYSSEY CHOICE II Study. J Am Heart Assoc. 2016;5(9):E003421.
    1. Colhoun HM, Ginsberg HN, Robinson JG, et al. No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY phase 3 studies. Eur Heart J. 2016;37(39):2981–9. doi: 10.1093/eurheartj/ehw292.
    1. Robinson JG, Rosenson RS, Farnier M, et al. Safety of very low low-density lipoprotein cholesterol levels with Alirocumab: pooled data from randomized trials. J am Coll Cardiol. 2017;69(5):471–482. doi: 10.1016/j.jacc.2016.11.037.
    1. Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. Jama. 2014;311(18):1870–1882. doi: 10.1001/jama.2014.4030.
    1. Koren MJ, Sabatine MS, Giugliano RP, et al. Long-term Low-Density Lipoprotein Cholesterol–Lowering Efficacy, Persistence, and Safety of Evolocumab in Treatment of Hypercholesterolemia. JAMA Cardiol. 2017;2(6):598–607. doi: 10.1001/jamacardio.2017.0747.
    1. Giugliano RP, Wiviott SD, Blazing MA, et al. Long-term Safety and Efficacy of Achieving Very Low Levels of Low-Density Lipoprotein Cholesterol: A Prespecified Analysis of the IMPROVE-IT Trial. JAMA Cardiol. 2017;2(5):547–555. doi: 10.1001/jamacardio.2017.0083.
    1. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713–1722. doi: 10.1056/NEJMoa1615664.
    1. Nicholls SJ, Puri R, Anderson T, et al. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016;316(22):2373–2384. doi: 10.1001/jama.2016.16951.
    1. Shah P, Glueck CJ, Goldenberg N, et al. Efficacy, safety, low density lipoprotein cholesterol lowering, and calculated 10-year cardiovascular risk reduction of alirocumab and evolocumab in addition to maximal tolerated cholesterol lowering therapy: a post-commercialization study. Lipids Health Dis. 2017;16(1):19. doi: 10.1186/s12944-017-0416-7.
    1. Banach M, Rizzo M, Toth PP, et al. Statin intolerance - an attempt at a unified definition. Position paper from an international lipid expert panel. Expert Opin Drug Saf. 2015;14(6):935–955. doi: 10.1517/14740338.2015.1039980.
    1. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European atherosclerosis society consensus panel statement on assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012–1022. doi: 10.1093/eurheartj/ehv043.
    1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J am Coll Cardiol. 2014;63(25 Pt B):2889–2934. doi: 10.1016/j.jacc.2013.11.002.
    1. Goff DC, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S49–S73. doi: 10.1161/01.cir.0000437741.48606.98.
    1. Hsia SH, Desnoyers ML, Lee ML. Differences in cholesterol management among states in relation to health insurance and race/ethnicity across the United States. J Clin Lipidol. 2013;7(6):675–682. doi: 10.1016/j.jacl.2013.03.010.
    1. Mann D, Reynolds K, Smith D, et al. Trends in statin use and low-density lipoprotein cholesterol levels among US adults: impact of the 2001 National Cholesterol Education Program guidelines. Ann Pharmacother. 2008;42(9):1208–1215. doi: 10.1345/aph.1L181.
    1. Waters DD, Brotons C, Chiang CW, et al. Lipid treatment assessment project 2: a multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals. Circulation. 2009;120(1):28–34. doi: 10.1161/CIRCULATIONAHA.108.838466.
    1. Jones PH, Nair R, Thakker KM. Prevalence of dyslipidemia and lipid goal attainment in statin-treated subjects from 3 data sources: a retrospective analysis. J am Heart Assoc. 2012;1(6):e001800. doi: 10.1161/JAHA.112.001800.
    1. Glueck CJ, Budhani SB, Masineni SS, et al. Vitamin D deficiency, myositis-myalgia, and reversible statin intolerance. Curr med res Opin. 2011;27(9):1683–1690. doi: 10.1185/03007995.2011.598144.
    1. Khayznikov M, Hemachrandra K, Pandit R, et al. Statin intolerance because of Myalgia, Myositis, Myopathy, or Myonecrosis can in most cases be safely resolved by vitamin D supplementation. N am J med Sci. 2015;7(3):86–93. doi: 10.4103/1947-2714.153919.
    1. Knickelbine T, Lui M, Garberich R, et al. Familial hypercholesterolemia in a large ambulatory population: Statin use, optimal treatment, and identification for advanced medical therapies. J Clin Lipidol. 2016;10(5):1182–1187. doi: 10.1016/j.jacl.2016.05.007.
    1. Lakey WC, Greyshock NG, Kelley CE, et al. Statin intolerance in a referral lipid clinic. J Clin Lipidol. 2016;10(4):870–879. doi: 10.1016/j.jacl.2016.03.004.
    1. Sabatine MS, Underberg JA, Koren M, et al. Focus on PCSK9 inhibitors: from genetics to clinical practice. Postgrad med. 2016;128(Suppl 1):31–39. doi: 10.1080/00325481.2016.1208895.
    1. Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation. 2013;127(1):96–103. doi: 10.1161/CIRCULATIONAHA.112.136101.
    1. Wei MY, Ito MK, Cohen JD, et al. Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education. J Clin Lipidol. 2013;7(5):472–483. doi: 10.1016/j.jacl.2013.03.001.
    1. Everett BM, Smith RJ, Hiatt WR. Reducing LDL with PCSK9 inhibitors--the clinical benefit of lipid drugs. N Engl J med. 2015;373(17):1588–1591. doi: 10.1056/NEJMp1508120.
    1. Shrank WH, Barlow JF, Brennan TA. New therapies in the treatment of high cholesterol: an argument to return to goal-based lipid guidelines. Jama. 2015;314(14):1443–1444. doi: 10.1001/jama.2015.10017.
    1. Stein EA, Raal FJ. Lipid-lowering drug therapy for CVD prevention: looking into the future. Curr Cardiol rep. 2015;17(11):104. doi: 10.1007/s11886-015-0659-8.
    1. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2012;380(9858):1995–2006. doi: 10.1016/S0140-6736(12)61771-1.
    1. McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J am Coll Cardiol. 2012;59(25):2344–2353. doi: 10.1016/j.jacc.2012.03.007.
    1. Rallidis LS, Triantafyllis AS, Tsirebolos G, et al. Prevalence of heterozygous familial hypercholesterolaemia and its impact on long-term prognosis in patients with very early ST-segment elevation myocardial infarction in the era of statins. Atherosclerosis. 2016;249:17–21. doi: 10.1016/j.atherosclerosis.2016.03.023.
    1. Farnier M, Gaudet D, Valcheva V, et al. Efficacy of alirocumab in high cardiovascular risk populations with or without heterozygous familial hypercholesterolemia: pooled analysis of eight ODYSSEY phase 3 clinical program trials. Int J Cardiol. 2016;223:750–757. doi: 10.1016/j.ijcard.2016.08.273.
    1. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388(10059):2532–2561. doi: 10.1016/S0140-6736(16)31357-5.
    1. Kent SM, Coyle LC, Flaherty PJ, et al. Marked low-density lipoprotein cholesterol reduction below current national cholesterol education program targets provides the greatest reduction in carotid atherosclerosis. Clin Cardiol. 2004;27(1):17–21. doi: 10.1002/clc.4960270105.
    1. Taylor AJ, Kent SM, Flaherty PJ, et al. ARBITER: arterial biology for the investigation of the treatment effects of reducing cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation. 2002;106(16):2055–2060. doi: 10.1161/01.CIR.0000034508.55617.65.
    1. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. Jama. 2006;295(13):1556–1565. doi: 10.1001/jama.295.13.jpc60002.
    1. Ference BA, Yoo W, Alesh I, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J am Coll Cardiol. 2012;60(25):2631–2639. doi: 10.1016/j.jacc.2012.09.017.
    1. D'Agostino RB, Sr, Grundy S, Sullivan LM, et al. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. Jama. 2001;286(2):180–187. doi: 10.1001/jama.286.2.180.
    1. US Food and Drug Administration. Highlights of prescribing information: REPATHA™. 2015. . Accessed April 2017.
    1. Sanofi/Regeneron . Highlights of prescribing information Praluent. 2015.
    1. Zhang XL, Zhu QQ, Zhu L, et al. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC med. 2015;13:123. doi: 10.1186/s12916-015-0358-8.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel