What does the research show about pcsk9 inhibitors?

PCSK9 inhibitors

Added to statins, evolocumab and alirocumab injections lowered LDL cholesterol about 50 to 60% and cut heart attacks, strokes and related events by about 15 to 25% against placebo in FOURIER, ODYSSEY OUTCOMES and VESALIUS-CV. Inclisiran lowered LDL about half, with outcome trials not yet reported. Memory and thinking matched placebo in EBBINGHAUS. Injection-site reactions were slightly more common.

Add to Bio HackChecked 2026-11-14

Status: Prescription drugs in the US, injected under the skin. Repatha (evolocumab) is FDA-approved to reduce major cardiovascular events in adults at increased risk and, with diet and exercise, to lower LDL cholesterol in adults with high cholesterol and in people 10 and older with heterozygous or homozygous familial hypercholesterolemia. Praluent (alirocumab) is approved to reduce major cardiovascular events in adults at increased risk and to lower LDL cholesterol in adults, in heterozygous familial hypercholesterolemia from age 8, and in homozygous familial hypercholesterolemia in adults. Leqvio (inclisiran), given by a health professional at the start, at 3 months and then every 6 months, is approved to lower LDL cholesterol in adults with high cholesterol, in heterozygous familial hypercholesterolemia from age 12, and in homozygous familial hypercholesterolemia in children 12 and older. None carries a boxed warning.
Also called: evolocumab, Repatha, alirocumab, Praluent, inclisiran, Leqvio, PCSK9 monoclonal antibodies, PCSK9 antibody, small interfering RNA, siRNA cholesterol injection, cholesterol injection
Taken for: high cholesterol, LDL, familial hypercholesterolemia, heart attack prevention, stroke prevention, statin intolerance, lipoprotein(a)

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help5

StrongShown to cut major cardiovascular events by about 15% against placebo on top of statins in people with heart disease, about 1.5 percentage points over 2 to 3 years.
StrongShown to lower LDL cholesterol by about 47 to 59% against placebo or no antibody, to a median 30 mg/dL in FOURIER.
StrongShown to lower LDL cholesterol by about 45 to 52% against placebo on top of statins, with injections every 6 months after the first two.
ModerateShown to lower lipoprotein(a) against placebo across PCSK9 inhibitors, on low-certainty, mostly indirect comparisons between drugs.
LimitedOne trial found evolocumab cut coronary death, heart attack or stroke by 25% against placebo, 6.2% against 8.0% at 5 years, in people without a prior event.

Reported risks3

StrongShown to raise mild injection-site reactions slightly, about 2 to 8% against 1 to 5% on placebo injections, most often with inclisiran.Common
ModerateShown to slightly raise colds and upper respiratory infections on evolocumab, 9.3% against 6.3%, and joint pain and bronchitis on inclisiran, against placebo.Common
ModerateThe labels warn of allergic reactions, including angioedema and, for inclisiran, anaphylaxis. Allergic reactions on evolocumab were 5.1% against 4.7% on placebo.Common

What people take it for, and what was found

Shown to help5

Strong

Heart attack and stroke on top of statins, evolocumab and alirocumab

Shown to cut major cardiovascular events by about 15% against placebo on top of statins in people with heart disease, about 1.5 percentage points over 2 to 3 years.

Compared with placebo injections added to statin therapy [1][2]; placebo or active treatment, pooled [3]; placebo, in a network of trials [4]

The numbers and sources

Effect: In FOURIER, evolocumab under the skin lowered the primary composite (cardiovascular death, heart attack, stroke, hospitalization for unstable angina or revascularization) from 11.3% to 9.8% (HR 0.85, 95% CI 0.79 to 0.92) and cardiovascular death, heart attack or stroke from 7.4% to 5.9% (HR 0.80, 95% CI 0.73 to 0.88) over a median 2.2 years [1]. In ODYSSEY OUTCOMES, alirocumab lowered coronary death, heart attack, ischemic stroke or unstable angina from 11.1% to 9.5% (HR 0.85, 95% CI 0.78 to 0.93) over a median 2.8 years, with a larger absolute benefit when baseline LDL was 100 mg/dL or more [2]. The Cochrane review rated both drugs' effect on cardiovascular events against placebo as high certainty: alirocumab OR 0.87 (95% CI 0.80 to 0.94) and evolocumab OR 0.84 (95% CI 0.78 to 0.91), each about 2 percentage points [3]. A network meta-analysis of 8 trials in atherosclerotic disease found lower major events with evolocumab (RR 0.78) and alirocumab 150 mg (RR 0.47) [4].
Population: 27,564 people with atherosclerotic disease and LDL of 70 mg/dL or more on statins [1]; 18,924 people 1 to 12 months after an acute coronary syndrome on high-intensity or maximum tolerated statins [2]; 60,997 participants in 24 RCTs [3]; 49,847 patients in 8 trials [4].
Sources: [1], [2], [3], [4]
Caveats: The reviews pool largely the same large trials. Most participants already had heart disease or were at high risk [3].

Limited

Heart attack and stroke without a prior event, evolocumab

One trial found evolocumab cut coronary death, heart attack or stroke by 25% against placebo, 6.2% against 8.0% at 5 years, in people without a prior event.

Compared with placebo injections [5]

The numbers and sources

Effect: Over a median 4.6 years, the 5-year rate of coronary death, heart attack or ischemic stroke was 6.2% on evolocumab 140 mg every 2 weeks and 8.0% on placebo (HR 0.75, 95% CI 0.65 to 0.86). With ischemia-driven revascularization added, rates were 13.4% against 16.2% (HR 0.81). Adverse event rates did not differ between groups [5].
Population: 12,257 people with atherosclerosis or diabetes, no prior heart attack or stroke, and LDL of 90 mg/dL or more, median age 66, 43% women [5].
Sources: [5]
Caveats: One trial (VESALIUS-CV). The abstract does not state how many took statins [5].
Why limited: This rests on one trial, of 12,257 people. Strength counts independent studies that agree, so one trial is limited at any size.

Strong

LDL cholesterol, evolocumab and alirocumab

Shown to lower LDL cholesterol by about 47 to 59% against placebo or no antibody, to a median 30 mg/dL in FOURIER.

Compared with placebo injections added to statins [1]; no antibody [6]; placebo [7]

The numbers and sources

Effect: At 48 weeks in FOURIER, evolocumab lowered LDL cholesterol 59% against placebo, from a median 92 mg/dL to 30 mg/dL [1]. Across 24 RCTs, PCSK9 antibodies lowered LDL cholesterol by 47.49% against no antibody (95% CI 25.35 to 69.64) and lowered other atherogenic lipids [6]. A network meta-analysis of 62 trials also found lower LDL cholesterol and ApoB with PCSK9 inhibitors against placebo [7].
Population: 27,564 people on statins [1]; 10,159 patients in 24 RCTs [6]; 73,240 participants in 62 trials [7].
Sources: [1], [6], [7]
Caveats: [7] includes agents not sold in the US and gives LDL effects only in the full text.

Strong

LDL cholesterol, inclisiran

Shown to lower LDL cholesterol by about 45 to 52% against placebo on top of statins, with injections every 6 months after the first two.

Compared with placebo injections added to maximum tolerated statins [8]; placebo or control [9][10]

The numbers and sources

Effect: In ORION-10 and ORION-11, inclisiran 284 mg under the skin on day 1, day 90 and every 6 months lowered LDL cholesterol at day 510 by 52.3% and 49.9% against placebo [8]. Pooling 8 RCTs, inclisiran lowered LDL cholesterol by 50.42%, total cholesterol by 31.22% and ApoB by 41.47% against control [9]. Pooling 14 RCTs, LDL fell 44.9% against placebo (95% CI 39.54 to 50.25), with high heterogeneity (I² 90.3%) [10].
Population: 1,561 people with atherosclerotic disease and 1,617 with disease or equivalent risk, on statins [8]; 5,016 patients in 8 RCTs [9]; over 13,000 participants in 14 RCTs [10].
Sources: [8], [9], [10]
Caveats: The reviews pool largely the same ORION trials.

Moderate

Lipoprotein(a)

Shown to lower lipoprotein(a) against placebo across PCSK9 inhibitors, on low-certainty, mostly indirect comparisons between drugs.

Compared with placebo [7]

The numbers and sources

Effect: All six PCSK9 inhibitors studied lowered lipoprotein(a) against placebo. The largest estimates were for agents not sold in the US (ongericimab 46.36% and tafolecimab 41.12%). Adverse and serious adverse events did not differ from placebo [7].
Population: 73,240 participants in 62 RCTs [7].
Sources: [7]
Caveats: The abstract does not give separate figures for evolocumab, alirocumab or inclisiran. Whether lowering lipoprotein(a) itself cuts events is unknown [7].

Mixed results1

Strong

Death from any cause

Mixed results: alirocumab lowered all-cause death slightly against placebo in pooled trials, while evolocumab did not, and a network analysis found no regimen lowered deaths.

Compared with placebo injections added to statins [2][3]; placebo, in a network of trials [4]

The numbers and sources

Effect: In ODYSSEY OUTCOMES, deaths were 3.5% on alirocumab and 4.1% on placebo (HR 0.85, 95% CI 0.73 to 0.98) [2]. Pooled against placebo, alirocumab lowered mortality (OR 0.83, 95% CI 0.72 to 0.96, about 1 percentage point) and evolocumab did not (OR 1.04, 95% CI 0.91 to 1.19), both high certainty [3]. In atherosclerotic disease, no regimen significantly lowered cardiovascular or all-cause death [4].
Population: 18,924 people after an acute coronary syndrome [2]; up to 29,432 participants per comparison [3]; 49,847 patients in 8 trials [4].
Sources: [2], [3], [4]
Caveats: The ODYSSEY mortality result was not part of the primary end point [2]. Follow-up in most trials was 2 to 3 years.

Not shown to help1

Moderate

Heart attack and stroke, inclisiran

Not shown to change heart attacks, strokes or deaths against placebo in pooled lipid trials. No completed outcome trial was sourced.

Compared with placebo or control [9]

The numbers and sources

Effect: Pooling 8 RCTs, all-cause death, cardiovascular death, major adverse cardiovascular events, heart attack, stroke and serious adverse events did not differ from control (p above 0.05) [9].
Population: 5,016 patients in 8 RCTs, most lasting about 18 months [9].
Sources: [9]
Caveats: These trials were designed to measure LDL, not events, and were too short and small to show event differences [9]. The Leqvio label approves it for LDL lowering only [11].

Doses studied

FOURIER gave evolocumab 140 mg under the skin every 2 weeks or 420 mg monthly [1]. VESALIUS-CV gave 140 mg every 2 weeks [5]. ODYSSEY OUTCOMES gave alirocumab 75 mg every 2 weeks, adjusted under blinding to aim for LDL cholesterol of 25 to 50 mg/dL [2]. ORION-10 and ORION-11 gave inclisiran 284 mg under the skin on day 1, day 90 and every 6 months [8]. All three outcome trials enrolled people already on statins, except VESALIUS-CV, whose abstract does not say [1][2][5].

Risks

Reported risks3

StrongCommon

Injection-site reactions

Shown to raise mild injection-site reactions slightly, about 2 to 8% against 1 to 5% on placebo injections, most often with inclisiran.

The numbers and sources

How common: Common: between 1 in 100 and 1 in 10 people.
Effect: In FOURIER, injection-site reactions occurred in 2.1% on evolocumab and 1.6% on placebo [1]. In ODYSSEY OUTCOMES they occurred in 3.8% on alirocumab and 2.1% on placebo [2], leading 0.3% to stop [12]. In ORION-10 and ORION-11 they were 2.6% against 0.9% and 4.7% against 0.5%, none severe or persistent [8]. Across three inclisiran trials the label reports 8% against 2% [11]. In pooled alirocumab trials the label reports 7.2% against 5.1% [12], and in a 52-week evolocumab trial 5.7% against 5.0% [13].
Population: 27,564 people [1]; 18,924 people [2]; 3,178 people [8]; 3,655 people in inclisiran trials [11]; label pooled trials [13][12].
Sources: [1], [2], [8], [11], [12], [13]
Caveats: Definitions varied (redness, pain, bruising, itching, swelling).

ModerateCommon

Colds, flu and other common reactions

Shown to slightly raise colds and upper respiratory infections on evolocumab, 9.3% against 6.3%, and joint pain and bronchitis on inclisiran, against placebo.

The numbers and sources

How common: Common: between 1 in 100 and 1 in 10 people.
Effect: In a 52-week evolocumab trial, nasopharyngitis occurred in 10.5% against 9.6% on placebo, upper respiratory infection in 9.3% against 6.3%, influenza in 7.5% against 6.3% and back pain in 6.2% against 5.6% [13]. On inclisiran, joint pain occurred in 5% against 4% and bronchitis in 4% against 3% [11]. In ODYSSEY OUTCOMES, muscle pain occurred in 6% on alirocumab against 5% on placebo [12].
Population: 901 people in a 52-week evolocumab trial [13]; 3,655 people in inclisiran trials [11]; 18,894 people in ODYSSEY OUTCOMES [12].
Sources: [13], [11], [12]
Caveats: Label tables list reactions more common than placebo [13][12][11].

ModerateCommon

Allergic reactions

The labels warn of allergic reactions, including angioedema and, for inclisiran, anaphylaxis. Allergic reactions on evolocumab were 5.1% against 4.7% on placebo.

The numbers and sources

How common: Common: between 1 in 100 and 1 in 10 people.
Effect: In evolocumab trials, hypersensitivity reactions occurred in 5.1% against 4.7% on placebo, most often rash (1.0% against 0.5%) [13]. Allergic reactions led 0.6% on alirocumab to stop, against 0.2% on placebo [12]. Anaphylaxis and angioedema have been reported with inclisiran after approval [11].
Population: Label trial pools and reports after approval [13][12][11].
Sources: [13], [12], [11]
Caveats: Serious reactions were rare.

Checked, no increase found3

Strong

Thinking and memory

Not shown to change memory, executive function or processing speed against placebo over 19 months, and neurocognitive adverse events were as common as on placebo in pooled trials.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: In EBBINGHAUS, the spatial working memory strategy score changed by -0.21 on evolocumab and -0.29 on placebo (noninferior, P = 0.85 for superiority). Working memory, episodic memory and psychomotor speed did not differ, and LDL level was not linked to cognitive change [14]. Pooling 21 RCTs, neurocognitive adverse events did not differ from control (RR 1.01, 95% CI 0.86 to 1.19), for alirocumab (RR 0.88) or evolocumab (RR 1.42, 95% CI 0.74 to 2.73) [15]. FOURIER found no difference in neurocognitive events [1].
Population: 1,204 people from FOURIER tested with the Cambridge Neuropsychological Test Automated Battery [14]; 59,733 patients in 21 RCTs [15]; 27,564 people [1].
Sources: [14], [15], [1]
Caveats: EBBINGHAUS lasted a median 19 months and was funded by Amgen [14]. Longer effects of very low LDL on the brain were not tested.

Strong

New diabetes and blood sugar

Not shown to raise new diabetes, fasting glucose or HbA1c against control with evolocumab or alirocumab, in pooled trials and in FOURIER.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: Across 18 studies of people without diabetes, new diabetes (RR 1.05, 95% CI 0.95 to 1.16), fasting glucose (MD 0.00 mmol/L) and HbA1c (MD 0.00%) did not differ from control [16]. FOURIER found no difference in new-onset diabetes [1]. The Repatha label reports new diabetes in 8.1% on evolocumab and 7.7% on placebo among 16,676 people without diabetes at the start [13].
Population: 26,123 participants without diabetes in 18 RCTs [16]; 27,564 people [1][13].
Sources: [16], [1], [13]
Caveats: Trials lasted up to about 3 years.

Limited

Use in pregnancy

The Repatha label states data in pregnancy are too few to assess risk. Monkeys given up to 12 times the human exposure showed no effects on pregnancy or infants.

The numbers and sources

How common: How often is not known: the sources give no rate.
Effect: The label states clinical trial and postmarketing data on evolocumab in pregnancy are insufficient to evaluate risk of birth defects, miscarriage or other outcomes, and that monkey studies found no effects on pregnancy or infant development [13].
Population: Pregnant monkeys and limited human reports [13].
Sources: [13]
Caveats: Animal data and a label statement.

Claims tested and not found

That very low LDL on PCSK9 inhibitors harms memory or thinking. EBBINGHAUS found no difference from placebo in executive function, memory or speed over 19 months, and no link with LDL level [14].
That PCSK9 antibodies raise diabetes risk the way statins do. New diabetes, fasting glucose and HbA1c did not differ from control across 18 trials [16].
That evolocumab lowers deaths from any cause. Pooled against placebo, mortality did not differ (OR 1.04, 95% CI 0.91 to 1.19) [3].

Statins Ezetimibe and fenofibrate

Sources

Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. New England Journal of Medicine. 2017. https://doi.org/10.1056/nejmoa1615664
Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. New England Journal of Medicine. 2018. https://doi.org/10.1056/nejmoa1801174
Schmidt AF, Carter JL, Pearce LS, et al. PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews. 2020. https://doi.org/10.1002/14651858.cd011748.pub3
Raone L, Gritti V, Mandurino-Mirizzi A, et al. Efficacy of PCSK9 Inhibitors on Clinical Outcomes in Patients with Established Atherosclerotic Cardiovascular Disease: A Network Meta-analysis. American Journal of Cardiovascular Drugs. 2026. https://doi.org/10.1007/s40256-025-00778-1
Bohula EA, Marston NA, Bhatia AK, et al. Evolocumab in Patients without a Previous Myocardial Infarction or Stroke. New England Journal of Medicine. 2026. https://doi.org/10.1056/nejmoa2514428
Navarese EP, Kołodziejczak M, Schulze V, et al. Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Annals of Internal Medicine. 2015. https://doi.org/10.7326/m14-2957
Pu Y, Huang W, Tu Y, Zeng Q. Comparative efficacy and safety of PCSK9 inhibitors for lipoprotein(a) reduction: a systematic review and network meta-analysis. BMC Cardiovascular Disorders. 2026. https://doi.org/10.1186/s12872-026-06480-7
Ray KK, Wright RS, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. New England Journal of Medicine. 2020. https://doi.org/10.1056/nejmoa1912387
Basit J, Ahmed M, Singh P, et al. Safety and Efficacy of Inclisiran in Hyperlipidemia: An Updated Meta-Analysis of Randomised Controlled Trials. Endocrinology, Diabetes & Metabolism. 2025. https://doi.org/10.1002/edm2.70039
Satyam SM, El-Tanani M, Patni MA, et al. Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management. BMC Cardiovascular Disorders. 2026. https://doi.org/10.1186/s12872-026-05515-3
US Food and Drug Administration. Leqvio (inclisiran injection) prescribing information, revised August 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fc0afca-4513-4c35-b594-6544aee29a44
US Food and Drug Administration. Praluent (alirocumab injection) prescribing information, revised July 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=446f6b5c-0dd4-44ff-9bc2-c2b41f2806b4
US Food and Drug Administration. Repatha (evolocumab injection) prescribing information, revised October 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd61e902-166d-4aa6-9f3c-a18c1008d07e
Giugliano RP, Mach F, Zavitz K, et al. Cognitive Function in a Randomized Trial of Evolocumab. New England Journal of Medicine. 2017. https://doi.org/10.1056/nejmoa1701131
Hirsh Raccah B, Yanovsky A, Treves N, et al. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk for neurocognitive adverse events: A systematic review, meta-analysis and meta-regression. International Journal of Cardiology. 2021. https://doi.org/10.1016/j.ijcard.2021.04.025
Cao Y, Liu H, Dong Q, Li S, Li J. Effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies on new-onset diabetes mellitus and glucose metabolism: A systematic review and meta-analysis. Diabetes, Obesity and Metabolism. 2018. https://doi.org/10.1111/dom.13235

Everything in the library

Shown to help5

Reported risks3

What people take it for, and what was found

Shown to help5

Mixed results1

Not shown to help1

Doses studied

Risks

Reported risks3

Checked, no increase found3

Claims tested and not found

Related

Sources