Development of proprotein convertase subtilisin/kexin type 9 inhibitors and the clinical potential of monoclonal antibodies in the management of lipid disorders

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rosuvastatin 1 endocrinologydiseasesdrugs
Alirocumab 36 endocrinologydiseasesdrugs
Evolocumab 48 endocrinologydiseasesdrugs
atorvastatin 2 endocrinologydiseasesdrugs
ezetimibe 23 endocrinologydiseasesdrugs
familial hypercholesterolemia 7 endocrinologydiseases
hyperlipidemia 2 endocrinologydiseases
mixed hyperlipidemia 1 endocrinologydiseases

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Alirocumab 830 cholesterol and other atherogenic lipid fractions was studied in various Phase 2 and Phase 3 trials of Alirocumab , Evolocumab, and Bococizumab. The results of published long-term ODYSSEY and OSLER studies are summarized.
Alirocumab 1280 report (ICER-2015) is summarized herewith. The cardiovascular outcome trials with Evolocumab (FOURIER), Alirocumab (ODYSSEY OUTCOME) and Bococizumab (SPIRE-1 and SPIRE-2) are the ongoing clinical trials, and their results
Alirocumab 8374 antibodies have undergone extensive trials for their efficacy and safety. These are as follows: Praluent® ( Alirocumab ; REGN 727): manufactured by Regeneron (Tarrytown, NY, USA)/Sanofi Aventis (Paris, France); Rapatha®
Alirocumab 8625 by Amgen (Thousand Oaks, CA, USA); and Bococizumab (RN 316): developed by Pfizer (New York, NY, USA). Alirocumab and Evolocumab have been the front-runners of PCSK9 inhibitors recognized by the FDA and European Medicines
Alirocumab 8751 have been the front-runners of PCSK9 inhibitors recognized by the FDA and European Medicines Agency. Alirocumab was approved by the FDA on 24 July 2015 to be used in addition to diet and maximally tolerated statin
Alirocumab 9017 clinical ASCVD such as heart attack or stroke who require additional lowering of LDLc. The cost of Alirocumab in the USA is $14,600 per year.Evolocumab was approved by the FDA on 27 August 2015 to be used in addition
Alirocumab 11773 LDL(R)-defective patients. There was good response to Evolocumab in statin-intolerant patients (GAUSS trial). Alirocumab has been investigated in ROTH study,[25] Stein study[26] and McKenney study.[27] LDLc reduced by 31–72%
Alirocumab 11915 study,[25] Stein study[26] and McKenney study.[27] LDLc reduced by 31–72% in various studies. Both Alirocumab and Evolocumab also significantly reduced Apo-B, total cholesterol, triglyceride and non-HDLc. There
Alirocumab 13742 adverse reactions included injection-site reactions, mild neurocognitive impairment of memory and anemia. Alirocumab has undergone Phase 3 trials such as ODYSSEY LONG TERM,[36] ODYSSEY COMBO II,[37] ODYSSEY FH,[38] ODYSSEY
Alirocumab 15746 17,000 patients. SPIRE-2 is fully enrolled. The results are expected in 2018.Long-term trials with Alirocumab and EvolocumabTwo recent studies presented at ACC-15, ODYSSEY LONG TERM (for Alirocumab) and OSLER-1
Alirocumab 15834 trials with Alirocumab and EvolocumabTwo recent studies presented at ACC-15, ODYSSEY LONG TERM (for Alirocumab ) and OSLER-1 and OSLER-2 trials (for Evolocumab), have evaluated the benefits of PCSK9 inhibitors with
Alirocumab 16107 5).ODESSEY LONG TERM trialODESSEY LONG TERM trial[36] included 2,341 high-risk patients with LDLc >70 mg/dL ( Alirocumab , 1,553; placebo, 788). The baseline mean LDLc in Alirocumab group was 122.7±42.6 mg/dL, while in placebo
Alirocumab 16167 high-risk patients with LDLc >70 mg/dL (Alirocumab, 1,553; placebo, 788). The baseline mean LDLc in Alirocumab group was 122.7±42.6 mg/dL, while in placebo group, it was 121.9±41.4 mg/dL. The LDLc at 24 and 48
Alirocumab 16288 122.7±42.6 mg/dL, while in placebo group, it was 121.9±41.4 mg/dL. The LDLc at 24 and 48 weeks in Alirocumab vs placebo groups was 48.3 and 57.9 vs 118.9 and 122.6 mg/dL. At week 24, the difference between Alirocumab
Alirocumab 16396 Alirocumab vs placebo groups was 48.3 and 57.9 vs 118.9 and 122.6 mg/dL. At week 24, the difference between Alirocumab and placebo groups in the mean percent change from baseline was 62% points (P<0.001), and reduction
Alirocumab 16961 the two groups in a post hoc analysis which showed ~50% reduction of adverse clinical outcomes with Alirocumab vs placebo (1.7% vs 3.3%, hazard ratio 0.52, 95% CI 0.31–0.90, P=0.02). The Alirocumab group as compared
Alirocumab 17050 outcomes with Alirocumab vs placebo (1.7% vs 3.3%, hazard ratio 0.52, 95% CI 0.31–0.90, P=0.02). The Alirocumab group as compared with placebo group had a higher rate of injection-site reaction (5.9% vs 4.2%), myalgia
Alirocumab 17334 impairment and confusion (1.2% vs 0.5%) and ophthalmic events (2.9% vs 1.9%). The authors concluded that Alirocumab when added to statin therapy at the maximum tolerated dose significantly reduced LDLc and the rate of
Alirocumab 19199 patients were included in the study[42] to determine the safety and efficacy of anti-PCSK9 antibodies ( Alirocumab and Evolocumab). The primary efficacy end points were the percent and absolute reductions in LDLc and
Alirocumab 19870 Evolocumab generated significant reduction in total cholesterol, non-HDLc and VLDLc.The efficacy outcome for Alirocumab was on similar lines. LDLc reduced by over 50% (mean reduction −52.6%, 95% CI −58.2 to 47.0%) vs
Alirocumab 20885 more common in patients receiving anti-PCSK9 antibodies. The authors concluded that Evolocumab and Alirocumab were safe, well tolerated and showed no significant differences in rates of adverse events compared
Alirocumab 25031 by long-term CVOTs.Cost-effectiveness of monoclonal antibodies (PCSK9 inhibitors)The present cost of Alirocumab and Evolocumab is $14,600 and $14,100 per year in the USA. This is in contrast to the cost of high-intensity
Alirocumab 30175 ED Silverman (April 2016), there were 9,500 prescriptions of Evolocumab and 11,800 prescriptions for Alirocumab with the FDA-approved indications from August 2015 to February 2016 with a refusal rate of 75% by insurance
Alirocumab 35114 prospective CVOTs include FOURIER evaluating Evolocumab in 27,500 patients, ODYSSEY OUTCOME evaluating Alirocumab in 18,000 patients and SPIRE-1 and SPIRE-2 evaluating Bococizumab in 17,000 patients (Table 7). The
Alirocumab 36347 high cost.Table 1Standard doses of monoclonal antibodiesDrugOnce in 2 weeks (mg)Once in 4 weeks (mg) Alirocumab 75–150300Evolocumab140420Bococizumaba75/150300Note:aDose may be reduced if LDLc is <25 mg/dL.Abbreviation:
Alirocumab 37177 mg/dL12 weeksEvolocumab44–56%ROTHRoth et al[25]92LDLc >100 mg/dLOn atorvastatin 80 mg/day16 weeks Alirocumab 73.5±3.5%STEINStein et al[26]HeFH: 77LDLc >100 mg/dLOn statin ± ezetimibe12 weeksAlirocumab31.4–67.9%
Alirocumab 37270 mg/day16 weeksAlirocumab73.5±3.5%STEINStein et al[26]HeFH: 77LDLc >100 mg/dLOn statin ± ezetimibe12 weeks Alirocumab 31.4–67.9% (depending upon dose of Alirocumab)McKENNEYMcKenney et al[27]183LDLc ≥100 mg/dLOn statins12
Alirocumab 37317 al[26]HeFH: 77LDLc >100 mg/dLOn statin ± ezetimibe12 weeksAlirocumab31.4–67.9% (depending upon dose of Alirocumab )McKENNEYMcKenney et al[27]183LDLc ≥100 mg/dLOn statins12 weeksAlirocumab43–72% (mean=57%)BALLANTYNEBallantyne
Alirocumab 37392 (depending upon dose of Alirocumab)McKENNEYMcKenney et al[27]183LDLc ≥100 mg/dLOn statins12 weeks Alirocumab 43–72% (mean=57%)BALLANTYNEBallantyne et al[28]351LDLc <80 mg/dLOn statins24 weeksBococizumab28–53%Abbreviations:
Alirocumab 39023 lipoprotein; TG, triglyceride; HeFH, heterozygous familial hypercholesterolemia.Table 4Phase 3 trials (with Alirocumab )Trial/studyReferencePatientsDuration of trialDrug (SC)Results: reduction in LDLcODYSSEY LONG TERMRobinson
Alirocumab 40177 trialsTrial/studyReferencePatientsDrug and dosesMean LDLc reductionClinical eventsODYSSEY LONG TERMRobinson et al[36]Number2,341 Alirocumab 75–150 mg biweeklyGroupBasalAfter 48 weeksControl3.3%Alirocumab1,553Duration 78 weeksControl121.9
Alirocumab 40243 TERMRobinson et al[36]Number2,341Alirocumab 75–150 mg biweeklyGroupBasalAfter 48 weeksControl3.3% Alirocumab 1,553Duration 78 weeksControl121.9 mg/dl122.6 mg/dlAlirocumab1.7%Control788Alirocumab122.7 mg/dl57.9
Alirocumab 40304 biweeklyGroupBasalAfter 48 weeksControl3.3%Alirocumab1,553Duration 78 weeksControl121.9 mg/dl122.6 mg/dl Alirocumab 1.7%Control788Alirocumab122.7 mg/dl57.9 mg/dlReduction48.5%Reduction 52.8% (P<0.001)COMBINED OSLER-1
Alirocumab 40328 weeksControl3.3%Alirocumab1,553Duration 78 weeksControl121.9 mg/dl122.6 mg/dlAlirocumab1.7%Control788 Alirocumab 122.7 mg/dl57.9 mg/dlReduction48.5%Reduction 52.8% (P<0.001)COMBINED OSLER-1 and OSLER-2Sabatine et al[41]Number4,465Evolocumab
Alirocumab 41078 analyzed242517Total number of patients10,15912,20013,083Lipid profile changes LDLc ↓47.5%Evolocumab57%54.6% Alirocumab 52.6% Total cholesterol ↓31.5%36.6%36% Triglyceride ↓↓15.7%↓ Non-HDL ↓↓↓↓ Lipoproteins
Alirocumab 42371 1663402 (2014)N=18,000Maximally tolerated statinLDLc ≥70 mg/dl,non-HDL ≥100 mg/dl,Apo-B ≥80 mg/dl Alirocumab 75–150 mg biweeklyAs above64 months–SPIRE-1Clin Trials/Govt/CT2/show/NCT 01975376N=17,000High CV
Evolocumab 842 other atherogenic lipid fractions was studied in various Phase 2 and Phase 3 trials of Alirocumab, Evolocumab , and Bococizumab. The results of published long-term ODYSSEY and OSLER studies are summarized. There
Evolocumab 1258 (ICER). The draft report (ICER-2015) is summarized herewith. The cardiovascular outcome trials with Evolocumab (FOURIER), Alirocumab (ODYSSEY OUTCOME) and Bococizumab (SPIRE-1 and SPIRE-2) are the ongoing clinical
Evolocumab 8487 REGN 727): manufactured by Regeneron (Tarrytown, NY, USA)/Sanofi Aventis (Paris, France); Rapatha® ( Evolocumab ; AMBG 1451): manufactured by Amgen (Thousand Oaks, CA, USA); and Bococizumab (RN 316): developed by
Evolocumab 8640 (Thousand Oaks, CA, USA); and Bococizumab (RN 316): developed by Pfizer (New York, NY, USA).Alirocumab and Evolocumab have been the front-runners of PCSK9 inhibitors recognized by the FDA and European Medicines Agency.Alirocumab
Evolocumab 9059 stroke who require additional lowering of LDLc. The cost of Alirocumab in the USA is $14,600 per year. Evolocumab was approved by the FDA on 27 August 2015 to be used in addition to diet and maximally tolerable statin
Evolocumab 9327 clinical ASCVD such as heart attack or stroke who require additional lowering of LDLc. The cost of Evolocumab in the USA is $14,100 per year.Bococizumab developed by Pfizer is under consideration for the FDA approval.
Evolocumab 11257 (2–8%).Phase 2 trialsAll three monoclonal antibodies have been evaluated in Phase 2 trials (Table 2). Evolocumab has undergone trials such as LAPLACE-TIMI 56,[20] MENDEL-1,[21] GAUSS,[22] TESLA-A[23] and RUTHERFORD.[24]
Evolocumab 11718 LDL(R)-negative patients and partial response in LDL(R)-defective patients. There was good response to Evolocumab in statin-intolerant patients (GAUSS trial).Alirocumab has been investigated in ROTH study,[25] Stein
Evolocumab 11930 study[26] and McKenney study.[27] LDLc reduced by 31–72% in various studies. Both Alirocumab and Evolocumab also significantly reduced Apo-B, total cholesterol, triglyceride and non-HDLc. There were no clear
Evolocumab 13284 events were nasopharyngitis, diarrhea, bronchitis, arthralgia and injection-site reactions.Phase 3 trials Evolocumab has been evaluated in MENDEL-2,[29] GAUSS-2,[30] OSLER-2,[31] TESLA-B,[32] LAPLACE-2,[33] DESCARTES[34]
Evolocumab 15761 patients. SPIRE-2 is fully enrolled. The results are expected in 2018.Long-term trials with Alirocumab and Evolocumab Two recent studies presented at ACC-15, ODYSSEY LONG TERM (for Alirocumab) and OSLER-1 and OSLER-2 trials
Evolocumab 15882 studies presented at ACC-15, ODYSSEY LONG TERM (for Alirocumab) and OSLER-1 and OSLER-2 trials (for Evolocumab ), have evaluated the benefits of PCSK9 inhibitors with a longer follow-up duration of ≥52 weeks (Table
Evolocumab 17565 reduced.OSLER-1 and OSLER-2This study[41] enrolled 4,465 patients which included 2,976 patients as Evolocumab group and 1,489 patients as placebo/standard therapy group. The patients were followed for ~11 months
Evolocumab 17776 months with periodic assessment of lipid levels, safety and adjusted CV events. Mean LDLc at baseline in Evolocumab and standard therapy groups was 120 (97–149) and 121 (97–151) mg/dL, respectively. After 11.1 months,
Evolocumab 17893 standard therapy groups was 120 (97–149) and 121 (97–151) mg/dL, respectively. After 11.1 months, Evolocumab reduced LDLc from a mean of 120 to 48 mg/dL (P<0.001), while there was no significant change in LDLc
Evolocumab 18081 significant change in LDLc in standard therapy group (121–120 mg/dL). Thus, the reduction in LDLc by Evolocumab was by 61% (95% CI 59–63, P<0.01). In addition, there was reduction in non-HDLc (−52%), Apo-B (−47.3%),
Evolocumab 18437 infarction, unstable angina and stroke) at 1 year was reduced from 2.18% in the standard group to 0.95% in Evolocumab group (hazard ratio in Evolocumab group 0.47, 95% CI 0.28–0.78, P=0.003). Most adverse reactions occurred
Evolocumab 18471 at 1 year was reduced from 2.18% in the standard group to 0.95% in Evolocumab group (hazard ratio in Evolocumab group 0.47, 95% CI 0.28–0.78, P=0.003). Most adverse reactions occurred with almost similar frequency
Evolocumab 18630 adverse reactions occurred with almost similar frequency in the two groups. The adverse reactions in Evolocumab vs standard group, respectively, were as follows: serious adverse reactions, 222 (7.5%) vs 111 (7.5%);
Evolocumab 18932 neurocognitive events, 27 (0.9%) vs 4 (0.3%). The authors concluded that during 1 year of therapy, Evolocumab significantly reduced LDLc and also the incidence of CV events.Meta-analysis studyMeta-analysis study
Evolocumab 19214 included in the study[42] to determine the safety and efficacy of anti-PCSK9 antibodies (Alirocumab and Evolocumab ). The primary efficacy end points were the percent and absolute reductions in LDLc and other lipid profile
Evolocumab 19466 The safety outcomes were the rates of adverse events (Table 6).The percent LDLc reduction following Evolocumab treatment was 54.6% (95% CI −58.7 to 50.5%) and absolute mean reduction was −78.9 mg/dL (95% CI
Evolocumab 19761 ezetimibe. HDLc increased by 7.6% (95% CI 5.7–9.5%) vs placebo and 6.4% (95% CI 4.3–8.4%) vs ezetimibe. Evolocumab generated significant reduction in total cholesterol, non-HDLc and VLDLc.The efficacy outcome for Alirocumab
Evolocumab 20703 40.6–49.8%) with placebo. Serious TEATs occurred in 1.9%, leading to discontinuation of treatment with Evolocumab in 1.6% of patients at 12 weeks. Injection-site reactions were slightly more common in patients receiving
Evolocumab 20870 reactions were slightly more common in patients receiving anti-PCSK9 antibodies. The authors concluded that Evolocumab and Alirocumab were safe, well tolerated and showed no significant differences in rates of adverse events
Evolocumab 24789 memory impairment. There were no differences in adverse effects due to different doses/regimens of Evolocumab . Whether PCSK9 inhibitors leading to remarkable reduction in LDLc will translate into improved CV outcome
Evolocumab 25046 CVOTs.Cost-effectiveness of monoclonal antibodies (PCSK9 inhibitors)The present cost of Alirocumab and Evolocumab is $14,600 and $14,100 per year in the USA. This is in contrast to the cost of high-intensity statin
Evolocumab 30135 “Frontiers of Health and Medicine” by ED Silverman (April 2016), there were 9,500 prescriptions of Evolocumab and 11,800 prescriptions for Alirocumab with the FDA-approved indications from August 2015 to February
Evolocumab 30957 (UK), but the exact discount is not disclosed. The NICE, a cost-effectiveness body in the UK, has found Evolocumab cost-effective from the NHS resources and has specified following LDLc levels for use of Evolocumab
Evolocumab 31057 Evolocumab cost-effective from the NHS resources and has specified following LDLc levels for use of Evolocumab by the NHS (NICE Draft 2016).[52]HeFH with existing ASCVD: LDLc >3.5 mmol/L (>135 mg/dL)HeFH without
Evolocumab 32507 meantime, pricey PCKS9 inhibitors require careful patient selection.Gandra et al[55] have hypothesized that Evolocumab when added to SOC vs SOC alone is cost-effective in patients with HeFH and ASCVD with or without statin
Evolocumab 32942 incremental cost $158,307, incremental QALY 1.2 and incremental cost-effectiveness ratio 141,699/QUALY. Thus, Evolocumab met the ACC/AHA and World Health Organization thresholds in this population.Safety, patient acceptability
Evolocumab 35056 the key to evaluate new class of medication. The ongoing prospective CVOTs include FOURIER evaluating Evolocumab in 27,500 patients, ODYSSEY OUTCOME evaluating Alirocumab in 18,000 patients and SPIRE-1 and SPIRE-2
Evolocumab 36368 1Standard doses of monoclonal antibodiesDrugOnce in 2 weeks (mg)Once in 4 weeks (mg)Alirocumab75–150300 Evolocumab 140420Bococizumaba75/150300Note:aDose may be reduced if LDLc is <25 mg/dL.Abbreviation: LDLc, low-density
Evolocumab 36686 inhibitorResults: reduction in LDLcLAPLACE-TIMI-56Giugliano et al[20]631LDLc ≥100 mg/dLOn statin12 weeks Evolocumab 41.8–66.1%MENDEL-1Koren et al[21]406LDLc 100–190 mg/dL12 weeksEvolocumab43.0–50.9% (depending on
Evolocumab 36762 ≥100 mg/dLOn statin12 weeksEvolocumab41.8–66.1%MENDEL-1Koren et al[21]406LDLc 100–190 mg/dL12 weeks Evolocumab 43.0–50.9% (depending on dose of Evolocumab)GAUSSSullivan et al[22]160Statin intolerance12 weeksEvolocumab43–63%TESLA-AStein
Evolocumab 36807 weeksEvolocumab41.8–66.1%MENDEL-1Koren et al[21]406LDLc 100–190 mg/dL12 weeksEvolocumab43.0–50.9% (depending on dose of Evolocumab )GAUSSSullivan et al[22]160Statin intolerance12 weeksEvolocumab43–63%TESLA-AStein et al[23]HoFH 812
Evolocumab 36870 weeksEvolocumab43.0–50.9% (depending on dose of Evolocumab)GAUSSSullivan et al[22]160Statin intolerance12 weeks Evolocumab 43–63%TESLA-AStein et al[23]HoFH 812 weeksEvolocumabLDL(R)-negative: no response (2)LDLc ≥130 mg/dLLDL(R)-positive
Evolocumab 36924 Evolocumab)GAUSSSullivan et al[22]160Statin intolerance12 weeksEvolocumab43–63%TESLA-AStein et al[23]HoFH 812 weeks Evolocumab LDL(R)-negative: no response (2)LDLc ≥130 mg/dLLDL(R)-positive but defective (6)TG ≤400 mg/dL19–26%RUTHERFORDRaal
Evolocumab 37091 mg/dLLDL(R)-positive but defective (6)TG ≤400 mg/dL19–26%RUTHERFORDRaal et al[24]169LDLc ≥100 mg/dL12 weeks Evolocumab 44–56%ROTHRoth et al[25]92LDLc >100 mg/dLOn atorvastatin 80 mg/day16 weeksAlirocumab73.5±3.5%STEINStein
Evolocumab 37802 receptor; TG, triglyceride; HeFH, heterozygous familial hypercholesterolemia.Table 3Phase 3 trials (with Evolocumab )Trial/studyReferencePatientsDuration of trialMode of administration of EvolocumabResults: reduction
Evolocumab 37884 3Phase 3 trials (with Evolocumab)Trial/studyReferencePatientsDuration of trialMode of administration of Evolocumab Results: reduction in LDLcMENDEL-2Koren et al[29]61412 weeksBiweekly or monthlyCompared with placebo:
Evolocumab 40455 mg/dlReduction48.5%Reduction 52.8% (P<0.001)COMBINED OSLER-1 and OSLER-2Sabatine et al[41]Number4,465 Evolocumab 140 mg biweekly or 420 mg monthlyGroupBasalAfter 11.1 monthsPlacebo2.18%Evolocumab2,976Duration: 11.1
Evolocumab 40538 al[41]Number4,465Evolocumab 140 mg biweekly or 420 mg monthlyGroupBasalAfter 11.1 monthsPlacebo2.18% Evolocumab 2,976Duration: 11.1 monthsControl121 mg/dl120 mg/dlEvolocumab0.95%HeFH247Evolocumab120 mg/dl48 mg/dlReduction56.4%Statin
Evolocumab 40599 monthlyGroupBasalAfter 11.1 monthsPlacebo2.18%Evolocumab2,976Duration: 11.1 monthsControl121 mg/dl120 mg/dl Evolocumab 0.95%HeFH247Evolocumab120 mg/dl48 mg/dlReduction56.4%Statin intolerance254Reduction 61% (P<0.01)Placebo1,489Abbreviations:
Evolocumab 40621 monthsPlacebo2.18%Evolocumab2,976Duration: 11.1 monthsControl121 mg/dl120 mg/dlEvolocumab0.95%HeFH247 Evolocumab 120 mg/dl48 mg/dlReduction56.4%Statin intolerance254Reduction 61% (P<0.01)Placebo1,489Abbreviations:
Evolocumab 41060 trials analyzed242517Total number of patients10,15912,20013,083Lipid profile changes LDLc ↓47.5% Evolocumab 57%54.6%Alirocumab52.6% Total cholesterol ↓31.5%36.6%36% Triglyceride ↓↓15.7%↓ Non-HDL
Evolocumab 42060 (2014)N=27,500Age 40–85 yearsHigh CV riskLDLc ≥70 mg/dl, non-HDL ≥100 mg/dl, TG ≤400 mg/dlStatin therapy Evolocumab 140 mg biweekly or 420 mg monthly% fall in LDLcCV death, nonfatal MI, stroke, hospitalization for unstable
atorvastatin 28665 intolerance are often managed successfully with reduction of statin dose or change to rosuvastatin from atorvastatin or other brand of statin. However, in severe statin intolerance, this policy may not be successful.
atorvastatin 37147 mg/dL19–26%RUTHERFORDRaal et al[24]169LDLc ≥100 mg/dL12 weeksEvolocumab44–56%ROTHRoth et al[25]92LDLc >100 mg/dLOn atorvastatin 80 mg/day16 weeksAlirocumab73.5±3.5%STEINStein et al[26]HeFH: 77LDLc >100 mg/dLOn statin ± ezetimibe12
ezetimibe 3101 therapy may be required to meet LDLc targets. IMPROVE-IT[9] has recently concluded that addition of ezetimibe to statin therapy produces further reduction of LDLc with better CV results. However, under the circumstances
ezetimibe 3385 alternative lipid-lowering drug may be required. PCSK9 inhibitors are recent additions to statins (and ezetimibe ) as potent lipid-lowering drugs for the treatment of elevated LDLc and ASCVD.[10]–[13]ObjectivesThe
ezetimibe 10490 reduce LDLc to 25–40 mg/dL (50–75% reduction) and are more potent and effective than statins and ezetimibe .Clinical trials and efficacy studiesMany clinical trials with PCSK9 monoclonal antibodies have demonstrated
ezetimibe 10927 Some of the prominent trials are summarized in Tables 2–4. The reductions in LDLc vs placebo/statin/ ezetimibe have ranged 45–70%. In addition, there has been reduction in total cholesterol (26–38%), Apo-B (34–52%),
ezetimibe 19653 was −78.9 mg/dL (95% CI −88.9 to −68.9 mg/dL) vs placebo and −36.3% (95% CI 38.86–33.9%) vs ezetimibe . HDLc increased by 7.6% (95% CI 5.7–9.5%) vs placebo and 6.4% (95% CI 4.3–8.4%) vs ezetimibe. Evolocumab
ezetimibe 19750 vs ezetimibe. HDLc increased by 7.6% (95% CI 5.7–9.5%) vs placebo and 6.4% (95% CI 4.3–8.4%) vs ezetimibe . Evolocumab generated significant reduction in total cholesterol, non-HDLc and VLDLc.The efficacy outcome
ezetimibe 20052 −52.6%, 95% CI −58.2 to 47.0%) vs placebo. A less marked reduction of LDLc was found when compared with ezetimibe (−29.9%, 95% CI −32.9 to −26.95%). HDLc level increased by a mean of 8% (95% CI 4.2–11.7%).
ezetimibe 20373 essentially did not reveal significant differences between anti-PCSK9 antibodies and the placebo (or ezetimibe ) except slightly increased rate of injection-site reactions (relative risk 1.48, 95% CI 1.5–2.09,
ezetimibe 21012 tolerated and showed no significant differences in rates of adverse events compared with placebo or ezetimibe controls.Meta-analysis by Navarese et alNavarese et al[43] evaluated 24 trials (eight, Phase 2; 16,
ezetimibe 21628 larger reduction when compared with placebo (−58.77%, 95% CI 56.5–61.5%) than when compared with ezetimibe (−36.17%, 95% CI 33.1–39.3%). There was reduction in total cholesterol by 31.9% and in lipoprotein
ezetimibe 22883 meta-analyzed a total of 17 trials involving 13,083 patients (8,250 given PCSK9 inhibitors, 846 given ezetimibe and 3,987 placebo). PCSK9 inhibition alone led to 57% lower LDLc, 36% lower total cholesterol, 46% lower
ezetimibe 23085 cholesterol, 46% lower Apo-B, 24.3% lower Lp (a) and 47% lower PCSK9 levels. Compared with placebo, PCSK9 and ezetimibe resulted in reduction of LDLc by 69% and 21%, respectively. Maximum reduction of LDLc of 57.8% was seen
ezetimibe 25162 $14,600 and $14,100 per year in the USA. This is in contrast to the cost of high-intensity statin and ezetimibe therapy which is ~$1,000 per year. The incremental cost per clinical outcome achieved by PCSK9 inhibitors
ezetimibe 28993 hypercholesterolemiaNon-FH associated with existing ASVD need intensive statin therapy with/without ezetimibe . However, substantial heterogeneity in response to statin therapy has been reported in a meta-analysis
ezetimibe 29544 with inadequate LDLc reduction by statin therapy may benefit with an additional therapy, for example, ezetimibe or PCSK9 inhibitors. However, PCSK9 inhibitors are costly. Their use may be considered by lipid experts
ezetimibe 34484 benefits.[1]–[5] LDLc reduction was the basis of the FDA approval of statins in 1987. IMPROVE-IT (statin with ezetimibe ) study further strengthened this concept.[9] CTT meta-analysis of over 170,000 patients in 26 randomized
ezetimibe 35419 inhibitors of PCSK9 and prevent destruction of LDL(R) with marked reduction of LDLc compared to statin and ezetimibe . A target LDLc of 40–60 mg/dL is possible with PCSK9 inhibitors. Health care benefits with monoclonal
ezetimibe 35916 ASCVD and uncontrolled hypercholesterolemia in spite of maximally tolerated statin with or without ezetimibe .PCSK9 inhibitors are indicated for treatment of FH, and it may be considered cost-effective in HoFH
ezetimibe 37253 atorvastatin 80 mg/day16 weeksAlirocumab73.5±3.5%STEINStein et al[26]HeFH: 77LDLc >100 mg/dLOn statin ± ezetimibe 12 weeksAlirocumab31.4–67.9% (depending upon dose of Alirocumab)McKENNEYMcKenney et al[27]183LDLc ≥100
ezetimibe 38065 monthlyCompared with placebo: 52–57%LDL 100–190 mg/dLFramingham risk factor ≤10Compared with ezetimibe 38–40% (P<0.001)GAUSS-2Stroes et al[30]307LDLc 193±59 mg/dL12 weeksBiweekly or monthlyCompared with
ezetimibe 38208 et al[30]307LDLc 193±59 mg/dL12 weeksBiweekly or monthlyCompared with placebo 53–56%Compared with ezetimibe 37–39% (P<0.001)OSLER-2Koren et al[31]1,10452 weeksMonthly52.3% (mean) (P<0.0001)TESLA-BRaal et al[32]49LDLc
ezetimibe 39474 monthlyOngoing trialODYSSEY COMBO IICannon et al[37]720On maximally tolerated statinHigh CV riskOn ezetimibe 12 weeks75–150 mg biweekly30% (P<0.0001)ODYSSEY FHKastelein et al[38]249HeFH24 weeks75–150 mg biweekly49%
ezetimibe 39664 weeks75–150 mg biweekly49% (P<0.0001)ODYSSEY ALTERNATIVEMoriarty et al[39]314Statin intoleranceOn ezetimibe 12 weeks75–150 mg biweeklyOngoing trialODYSSEY MONORoth et al[40]103LDL 100–190 mg/dlNo lipid-lowering
rosuvastatin 28647 with mild statin intolerance are often managed successfully with reduction of statin dose or change to rosuvastatin from atorvastatin or other brand of statin. However, in severe statin intolerance, this policy may not
Select Disease Character Offset Disease Term Instance
familial hypercholesterolemia 28884 inhibitors may be an effective alternative in patients with severe ASCVD with statin intolerance.Non familial hypercholesterolemia Non-FH associated with existing ASVD need intensive statin therapy with/without ezetimibe. However, substantial
familial hypercholesterolemia 37634 proprotein convertase subtilisin/kexin type 9; LDLc, low-density lipoprotein cholesterol; HoFH, homozygous familial hypercholesterolemia ; LDL(R), low-density lipoprotein receptor; TG, triglyceride; HeFH, heterozygous familial hypercholesterolemia.Table
familial hypercholesterolemia 37744 hypercholesterolemia; LDL(R), low-density lipoprotein receptor; TG, triglyceride; HeFH, heterozygous familial hypercholesterolemia .Table 3Phase 3 trials (with Evolocumab)Trial/studyReferencePatientsDuration of trialMode of administration
familial hypercholesterolemia 38965 low-density lipoprotein cholesterol; LDL, low-density lipoprotein; TG, triglyceride; HeFH, heterozygous familial hypercholesterolemia .Table 4Phase 3 trials (with Alirocumab)Trial/studyReferencePatientsDuration of trialDrug (SC)Results:
familial hypercholesterolemia 39937 SC, subcutaneous; LDLc, low-density lipoprotein cholesterol; CV, cardiovascular; HeFH, heterozygous familial hypercholesterolemia ; FH, familial hypercholesterolemia; LDL, low-density lipoprotein.Table 5Long-term trialsTrial/studyReferencePatientsDrug
familial hypercholesterolemia 39972 lipoprotein cholesterol; CV, cardiovascular; HeFH, heterozygous familial hypercholesterolemia; FH, familial hypercholesterolemia ; LDL, low-density lipoprotein.Table 5Long-term trialsTrial/studyReferencePatientsDrug and dosesMean
familial hypercholesterolemia 40794 61% (P<0.01)Placebo1,489Abbreviations: LDLc, low-density lipoprotein cholesterol; HeFH, heterozygous familial hypercholesterolemia .Table 6Comparison of three meta-analyses on PCSK9 inhibitorsStudy parameterNavarese et al[43]Zhang et
hyperlipidemia 14462 double-blind, placebo-controlled, randomized, parallel-group, multicenter trial on 299 patients with hyperlipidemia receiving statin therapy and with LDL ≥70 mg/dL. Bococizumab was administered subcutaneously at doses
hyperlipidemia 15397 and triglycerides.SPIRE-SI will evaluate the role of Bococizumab in patients with primary or mixed hyperlipidemia who are intolerant to statin and have high CV risk with LDLc >70 mg/dL and triglyceride ≤400 mg/dL.
mixed hyperlipidemia 15391 Apo-B, HDLc and triglycerides.SPIRE-SI will evaluate the role of Bococizumab in patients with primary or mixed hyperlipidemia who are intolerant to statin and have high CV risk with LDLc >70 mg/dL and triglyceride ≤400 mg/dL.

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