Study analysis · British journal of clinical pharmacology · 2026
Cholesterol shots cut heart attacks and deaths — but were linked to a 44% higher relative risk of depression in a huge real-world study.
In people who already have heart disease, those who started PCSK9 inhibitor shots had fewer heart problems and deaths but more diagnoses of depression and anxiety than those who took only statins — though the study can’t prove cause and effect.
Overview
What the study found
The study in plain English — the bottom line, every takeaway we extracted, and what to do with them.
In simple terms
This study looked back at medical records to see if people who took certain cholesterol-lowering drugs had different health outcomes. It can show links, like 'people on these drugs had more anxiety diagnoses,' but it cannot prove the drug caused the difference because people were not randomly assigned. Other differences between the groups could explain the results.
What’s the bottom line?
Researchers looked at medical records of about 61,000 pairs of adults with heart and blood-vessel disease. One person in each pair started a PCSK9 inhibitor shot (alirocumab or evolocumab) and the other started a statin pill. They then compared what happened over the next 12 months.
How strong is this study?
The study used a very large number of people and tried to match patients who were similar in important ways, which is a strength. But it was not a randomized experiment, and we only have the summary, so we can't be sure all important differences were accounted for. That means the findings are clues for more research, not final proof.
0 / 100
- COI disclosureconflicts of interest not disclosed
- Data availabilitydata not shared
- Code availabilitycode not shared
56 / 100
- Randomizationnot randomized
- Blindingblinding unclear
- Control group+15/15
- Sample size (n=60885)+20/20
- Follow-up+10/10
100 / 100
54 / 100
- P-valuesno p-values reported
- Effect size+20/20
- Confidence intervals+15/15
- Pre-registrationnot pre-registered
Each component is scored out of 100 and then capped by the study design — a case series cannot reach the ceiling a randomised trial can, however well it is reported.
Where it sits
RCT reviewsReviews of RCTs (Meta-analyses)
Max 100Randomized TrialsRandomized Trials
Max 90Reviews of Cohort StudiesReviews of Cohort Studies
Max 85Cohort StudiesCohort Studies
Max 72Reviews of Case-Control StudiesReviews of Case-Control Studies
Max 63Case-Control StudiesCase-Control Studies
Max 58Cross-Sectional & Case SeriesCross-Sectional & Case Series
Max 50Expert OpinionExpert Opinion
Max 553 / 100
Probability of being correct
Groups of people are followed over time to see who develops an outcome. Strong for identifying risk factors and associations, but cannot prove causation as firmly as RCTs.
This design cannot establish causation — the findings describe an association, not a cause. Retrospective observational cohort with propensity score matching cannot prove causation. Lack of randomization leaves residual confounding, treatment selection, and surveillance bias possible; abstract-only prevents verification of methodology.
COI Unknown
Could not determine conflict of interest status
No conflicts of interest or funding disclosures were present in the provided text; potential conflicts cannot be assessed.
The provided text contains only the abstract (Aims, Methods, Results, Conclusions) and lacks any author affiliations, conflict of interest declarations, or funding information. Therefore, industry funding and author relationships are unknown.
Key takeaways
- 01
People on PCSK9 inhibitors had about a 16% lower relative risk of major heart problems (HR 0.84), about an 18% lower relative risk of heart attack (HR 0.82), about a 13% lower relative risk of heart failure (HR 0.87), and about a 60% lower relative risk of dying from any cause (HR 0.40).
- 02
Stroke risk was similar.
- 03
They had about a 33% higher relative risk of any psychiatric diagnosis (HR 1.33), about a 44% higher relative risk of depression (HR 1.44), and about a 39% higher relative risk of anxiety (HR 1.39).
- 04
All of these are relative risks; the study did not report absolute risks, so the number of extra or avoided cases per 1,000 people is not known.
- 05
All results are relative risks only — the study abstract does not give the baseline event rates, so we cannot say how many extra cases of depression or anxiety, or how many heart attacks avoided, that means per 1,000 people over the 12 months.
- 06
The absolute risk difference was not reported in this study.
- 07
Also, this was an observational record study, not a randomized trial, so it can show links but not prove that the drug causes the mental health differences.
Surprising findings
- PCSK9 inhibitors were associated with a 60% lower relative risk of all-cause mortality (HR 0.40, 95% CI 0.37–0.43), which is much larger than the reduction in MACE (HR 0.84).A mortality benefit that large is unusual and could be partly explained by unmeasured confounding, since this is observational and absolute risks were not reported.
- PCSK9 inhibitor use was associated with higher relative risks of any psychiatric diagnosis, depression and anxiety, even though negative control outcomes did not differ.Neuropsychiatric safety was previously uncertain, and a mental health signal from a cardiovascular drug is counterintuitive for many patients and clinicians.
Practical takeaways
Do not stop or avoid a prescribed PCSK9 inhibitor based on this abstract alone. If you notice new or worsening mood symptoms, discuss them with your clinician.
This is an observational association, not proof of causation. Absolute risks were not reported, and the authors describe the findings as hypothesis-generating. Full paper was not available.
low confidenceClinicians may consider asking patients on PCSK9 inhibitors about mood symptoms, especially depression and anxiety, while awaiting prospective data.
The study cannot establish causality, and surveillance bias could inflate diagnoses. No guideline change can be based on this abstract alone.
low confidenceWhen interpreting the mortality benefit, remember it is a relative risk (HR 0.40); the absolute number of deaths prevented per 1,000 patients is unknown.
Absolute risk reduction was not reported in the abstract, so the real-world magnitude remains uncertain.
low confidenceWhy this study matters
Heart benefits: 60% lower relative risk of death
Among 60,885 matched pairs, PCSK9 inhibitor therapy was associated with lower 12-month risks of MACE (HR 0.84, 95% CI 0.80–0.88; about 16% lower relative risk), heart attack (HR 0.82), heart failure (HR 0.87) and all-cause mortality (HR 0.40, 95% CI 0.37–0.43; about 60% lower relative risk). Ischaemic stroke did not differ. Absolute risks were not reported, so the number of events prevented per 1,000 patients is unknown.
A 60% lower relative risk of death is a huge signal that would make anyone pay attention — but without absolute risks, we don’t know how many deaths were actually prevented.
Mental health signal: depression and anxiety higher
PCSK9 inhibitor use was associated with higher 12-month relative risks of any psychiatric diagnosis (HR 1.33, 95% CI 1.25–1.42; about 33% higher), depression (HR 1.44, 95% CI 1.28–1.61; about 44% higher) and anxiety (HR 1.39, 95% CI 1.28–1.50; about 39% higher). These associations persisted in secondary analyses, while negative control outcomes did not differ.
People often focus on heart benefits and may not expect a mental health signal from a cholesterol drug. This could spark important conversations about monitoring mood.
Stroke and neurodegeneration: no clear harm
Ischaemic stroke did not differ between groups, and after Bonferroni correction no neurodegenerative association (dementia, Parkinson’s disease) remained significant.
Earlier concerns about neurocognitive effects of lipid-lowering drugs are not supported here, which may reassure some patients.
Observational design: hypothesis-generating only
This was a propensity score–matched retrospective cohort study using TriNetX, comparing PCSK9 inhibitor initiators to statin-monotherapy initiators. The authors note potential residual confounding, statin-intolerance-related treatment selection and surveillance bias, and describe the findings as hypothesis-generating.
It’s a reminder that real-world data can show links but cannot prove cause and effect — and treatment selection can bias results.
Comparator matters: statin monotherapy vs PCSK9 inhibitor
The comparison was PCSK9 inhibitor initiation versus statin monotherapy. People who start a PCSK9 inhibitor may differ from those who stay on statins — for example, statin intolerance, access, or disease severity — which could influence both heart and mental health outcomes.
The choice of comparator shapes the results. It’s not PCSK9 inhibitor vs placebo, so real-world differences between groups matter.
Want the whole report?
Detailed mode opens the full scientific breakdown — every score component, the methodology, conflicts of interest, the evidence analysis behind each claim, and the raw study data.
Overview
What the study found
The study in plain English — the bottom line, every takeaway we extracted, and what to do with them.
Not medical advice. For informational purposes only. Always consult a healthcare professional. Terms
Researchers looked at medical records of about 61,000 pairs of adults with heart and blood-vessel disease. One person in each pair started a PCSK9 inhibitor shot (alirocumab or evolocumab) and the other started a statin pill. They then compared what happened over the next 12 months.
Research results
People on PCSK9 inhibitors had about a 16% lower relative risk of major heart problems (HR 0.84), about an 18% lower relative risk of heart attack (HR 0.82), about a 13% lower relative risk of heart failure (HR 0.87), and about a 60% lower relative risk of dying from any cause (HR 0.40). Stroke risk was similar. They had about a 33% higher relative risk of any psychiatric diagnosis (HR 1.33), about a 44% higher relative risk of depression (HR 1.44), and about a 39% higher relative risk of anxiety (HR 1.39). All of these are relative risks; the study did not report absolute risks, so the number of extra or avoided cases per 1,000 people is not known.
What this means - more context
All results are relative risks only — the study abstract does not give the baseline event rates, so we cannot say how many extra cases of depression or anxiety, or how many heart attacks avoided, that means per 1,000 people over the 12 months. The absolute risk difference was not reported in this study. Also, this was an observational record study, not a randomized trial, so it can show links but not prove that the drug causes the mental health differences.
To assess real-world cardiovascular and neuropsychiatric safety of PCSK9 inhibitors (alirocumab or evolocumab) in adults with established atherosclerotic cardiovascular disease (ASCVD), since randomized trials showed cardiovascular benefit but real-world neuropsychiatric safety remained uncertain.
Propensity score–matched retrospective cohort study (TriNetX U.S. Federated Research Network) of 60,885 matched pairs of adults with established ASCVD (mean age 70 years; 61% male) initiating a PCSK9 inhibitor vs statin monotherapy, 2017–2024. Over 12 months, PCSK9 inhibitor use was associated with lower relative risks of MACE (HR 0.84), myocardial infarction (HR 0.82), heart failure (HR 0.87) and all-cause mortality (HR 0.40), with no difference in ischaemic stroke. No neurodegenerative association survived Bonferroni correction. PCSK9 inhibitor use was associated with higher relative risks of any psychiatric diagnosis (HR 1.33), depression (HR 1.44) and anxiety (HR 1.39). Absolute risks and absolute risk differences were not reported in the abstract, so the number of events prevented or added per 1,000 patients is unknown. Authors describe the findings as hypothesis-generating given observational design and potential residual confounding, statin-intolerance-related treatment selection, and surveillance bias.
Methods Used
Propensity score–matched retrospective cohort study using the TriNetX U.S. Federated Research Network. Adults with established ASCVD initiating alirocumab or evolocumab between 2017 and 2024 were matched 1:1 to statin-monotherapy initiators. The 12-month primary analysis assessed MACE (myocardial infarction, heart failure, ischaemic stroke, all-cause death), neurodegenerative disease (dementia, Parkinson's disease) and psychiatric disorders (psychosis, bipolar disorder, depression, anxiety), with Bonferroni correction and negative control outcomes. Secondary analyses examined individual agents, ASCVD subtypes, statin use, an intensified lipid-lowering comparator and extended follow-up.
Main Finding
Among 60,885 matched pairs, PCSK9 inhibitor therapy was associated with lower relative 12-month risks of MACE (HR 0.84, 95% CI 0.80–0.88; ~16% lower relative risk), myocardial infarction (HR 0.82, 0.79–0.86), heart failure (HR 0.87, 0.83–0.92) and all-cause mortality (HR 0.40, 0.37–0.43; ~60% lower relative risk); ischaemic stroke did not differ. No neurodegenerative association remained significant after Bonferroni correction. PCSK9 inhibitor use was associated with higher relative 12-month risks of any psychiatric diagnosis (HR 1.33, 1.25–1.42; ~33% higher relative risk), depression (HR 1.44, 1.28–1.61; ~44% higher relative risk) and anxiety (HR 1.39, 1.28–1.50; ~39% higher relative risk), persisting in secondary analyses; negative control outcomes did not differ. All effects are relative; absolute risk differences (events prevented or added per 1,000 patients) were not reported in the abstract.
Confidence Level
Limited — based on abstract only, full methodology not available. Large propensity-matched cohort with confidence intervals, Bonferroni correction and negative control outcomes strengthens internal validity, but the observational design and authors' own caveats about residual confounding, treatment selection and surveillance bias mean findings are hypothesis-generating, not causal.
Study Flags
Red Flags
- •Full text not available - methodology details cannot be verified
- •Observational retrospective design with potential residual confounding, statin-intolerance-related treatment selection and surveillance bias (as noted by authors)
- •Absolute risk differences not reported; only relative risks (HRs) available, limiting real-world interpretation
No biological mechanisms were identified in this study. This may be an epidemiological, observational, or survey-based study that reports associations rather than proposing causal biological pathways.
Surprising Findings
PCSK9 inhibitors were associated with a 60% lower relative risk of all-cause mortality (HR 0.40, 95% CI 0.37–0.43), which is much larger than the reduction in MACE (HR 0.84).
A mortality benefit that large is unusual and could be partly explained by unmeasured confounding, since this is observational and absolute risks were not reported.
Practical Takeaways
Do not stop or avoid a prescribed PCSK9 inhibitor based on this abstract alone. If you notice new or worsening mood symptoms, discuss them with your clinician.
RCT reviewsReviews of RCTs (Meta-analyses)
Max 100Randomized TrialsRandomized Trials
Max 90Reviews of Cohort StudiesReviews of Cohort Studies
Max 85Cohort StudiesCohort Studies
Max 72Reviews of Case-Control StudiesReviews of Case-Control Studies
Max 63Case-Control StudiesCase-Control Studies
Max 58Cross-Sectional & Case SeriesCross-Sectional & Case Series
Max 50Expert OpinionExpert Opinion
Max 553 / 100
Probability of being correct
Groups of people are followed over time to see who develops an outcome. Strong for identifying risk factors and associations, but cannot prove causation as firmly as RCTs.
Human Cohort Study
Subject
Moderate probability
on the GRADE evidence scale
This study looked back at medical records to see if people who took certain cholesterol-lowering drugs had different health outcomes. It can show links, like 'people on these drugs had more anxiety diagnoses,' but it cannot prove the drug caused the difference because people were not randomly assigned. Other differences between the groups could explain the results.
Strengths
- Large sample of 60,885 propensity score-matched pairs
- Propensity score matching to balance measured confounders
- Bonferroni correction for multiple comparisons
Weaknesses
- Full methodology not available - based on abstract only
- Retrospective observational cohort, not randomized
- Blinding status unknown
Methodology
Evidence Keywords
Statistical Reporting
Not medical advice. For informational purposes only. Always consult a healthcare professional. Terms
Researchers looked at medical records of about 61,000 pairs of adults with heart and blood-vessel disease. One person in each pair started a PCSK9 inhibitor shot (alirocumab or evolocumab) and the other started a statin pill. They then compared what happened over the next 12 months.
Research results
People on PCSK9 inhibitors had about a 16% lower relative risk of major heart problems (HR 0.84), about an 18% lower relative risk of heart attack (HR 0.82), about a 13% lower relative risk of heart failure (HR 0.87), and about a 60% lower relative risk of dying from any cause (HR 0.40). Stroke risk was similar. They had about a 33% higher relative risk of any psychiatric diagnosis (HR 1.33), about a 44% higher relative risk of depression (HR 1.44), and about a 39% higher relative risk of anxiety (HR 1.39). All of these are relative risks; the study did not report absolute risks, so the number of extra or avoided cases per 1,000 people is not known.
What this means - more context
All results are relative risks only — the study abstract does not give the baseline event rates, so we cannot say how many extra cases of depression or anxiety, or how many heart attacks avoided, that means per 1,000 people over the 12 months. The absolute risk difference was not reported in this study. Also, this was an observational record study, not a randomized trial, so it can show links but not prove that the drug causes the mental health differences.
To assess real-world cardiovascular and neuropsychiatric safety of PCSK9 inhibitors (alirocumab or evolocumab) in adults with established atherosclerotic cardiovascular disease (ASCVD), since randomized trials showed cardiovascular benefit but real-world neuropsychiatric safety remained uncertain.
Propensity score–matched retrospective cohort study (TriNetX U.S. Federated Research Network) of 60,885 matched pairs of adults with established ASCVD (mean age 70 years; 61% male) initiating a PCSK9 inhibitor vs statin monotherapy, 2017–2024. Over 12 months, PCSK9 inhibitor use was associated with lower relative risks of MACE (HR 0.84), myocardial infarction (HR 0.82), heart failure (HR 0.87) and all-cause mortality (HR 0.40), with no difference in ischaemic stroke. No neurodegenerative association survived Bonferroni correction. PCSK9 inhibitor use was associated with higher relative risks of any psychiatric diagnosis (HR 1.33), depression (HR 1.44) and anxiety (HR 1.39). Absolute risks and absolute risk differences were not reported in the abstract, so the number of events prevented or added per 1,000 patients is unknown. Authors describe the findings as hypothesis-generating given observational design and potential residual confounding, statin-intolerance-related treatment selection, and surveillance bias.
Methods Used
Propensity score–matched retrospective cohort study using the TriNetX U.S. Federated Research Network. Adults with established ASCVD initiating alirocumab or evolocumab between 2017 and 2024 were matched 1:1 to statin-monotherapy initiators. The 12-month primary analysis assessed MACE (myocardial infarction, heart failure, ischaemic stroke, all-cause death), neurodegenerative disease (dementia, Parkinson's disease) and psychiatric disorders (psychosis, bipolar disorder, depression, anxiety), with Bonferroni correction and negative control outcomes. Secondary analyses examined individual agents, ASCVD subtypes, statin use, an intensified lipid-lowering comparator and extended follow-up.
Main Finding
Among 60,885 matched pairs, PCSK9 inhibitor therapy was associated with lower relative 12-month risks of MACE (HR 0.84, 95% CI 0.80–0.88; ~16% lower relative risk), myocardial infarction (HR 0.82, 0.79–0.86), heart failure (HR 0.87, 0.83–0.92) and all-cause mortality (HR 0.40, 0.37–0.43; ~60% lower relative risk); ischaemic stroke did not differ. No neurodegenerative association remained significant after Bonferroni correction. PCSK9 inhibitor use was associated with higher relative 12-month risks of any psychiatric diagnosis (HR 1.33, 1.25–1.42; ~33% higher relative risk), depression (HR 1.44, 1.28–1.61; ~44% higher relative risk) and anxiety (HR 1.39, 1.28–1.50; ~39% higher relative risk), persisting in secondary analyses; negative control outcomes did not differ. All effects are relative; absolute risk differences (events prevented or added per 1,000 patients) were not reported in the abstract.
Confidence Level
Limited — based on abstract only, full methodology not available. Large propensity-matched cohort with confidence intervals, Bonferroni correction and negative control outcomes strengthens internal validity, but the observational design and authors' own caveats about residual confounding, treatment selection and surveillance bias mean findings are hypothesis-generating, not causal.
Study Flags
Red Flags
- •Full text not available - methodology details cannot be verified
- •Observational retrospective design with potential residual confounding, statin-intolerance-related treatment selection and surveillance bias (as noted by authors)
- •Absolute risk differences not reported; only relative risks (HRs) available, limiting real-world interpretation
No biological mechanisms were identified in this study. This may be an epidemiological, observational, or survey-based study that reports associations rather than proposing causal biological pathways.
Surprising Findings
PCSK9 inhibitors were associated with a 60% lower relative risk of all-cause mortality (HR 0.40, 95% CI 0.37–0.43), which is much larger than the reduction in MACE (HR 0.84).
A mortality benefit that large is unusual and could be partly explained by unmeasured confounding, since this is observational and absolute risks were not reported.
Practical Takeaways
Do not stop or avoid a prescribed PCSK9 inhibitor based on this abstract alone. If you notice new or worsening mood symptoms, discuss them with your clinician.
RCT reviewsReviews of RCTs (Meta-analyses)
Max 100Randomized TrialsRandomized Trials
Max 90Reviews of Cohort StudiesReviews of Cohort Studies
Max 85Cohort StudiesCohort Studies
Max 72Reviews of Case-Control StudiesReviews of Case-Control Studies
Max 63Case-Control StudiesCase-Control Studies
Max 58Cross-Sectional & Case SeriesCross-Sectional & Case Series
Max 50Expert OpinionExpert Opinion
Max 553 / 100
Probability of being correct
Groups of people are followed over time to see who develops an outcome. Strong for identifying risk factors and associations, but cannot prove causation as firmly as RCTs.
Human Cohort Study
Subject
Moderate probability
on the GRADE evidence scale
This study looked back at medical records to see if people who took certain cholesterol-lowering drugs had different health outcomes. It can show links, like 'people on these drugs had more anxiety diagnoses,' but it cannot prove the drug caused the difference because people were not randomly assigned. Other differences between the groups could explain the results.
Strengths
- Large sample of 60,885 propensity score-matched pairs
- Propensity score matching to balance measured confounders
- Bonferroni correction for multiple comparisons
Weaknesses
- Full methodology not available - based on abstract only
- Retrospective observational cohort, not randomized
- Blinding status unknown
Methodology
Evidence Keywords
Statistical Reporting
Scoring
How strong is this study?
The study used a very large number of people and tried to match patients who were similar in important ways, which is a strength. But it was not a randomized experiment, and we only have the summary, so we can't be sure all important differences were accounted for. That means the findings are clues for more research, not final proof.
0 / 100
- COI disclosureconflicts of interest not disclosed
- Data availabilitydata not shared
- Code availabilitycode not shared
56 / 100
- Randomizationnot randomized
- Blindingblinding unclear
- Control group+15/15
- Sample size (n=60885)+20/20
- Follow-up+10/10
100 / 100
54 / 100
- P-valuesno p-values reported
- Effect size+20/20
- Confidence intervals+15/15
- Pre-registrationnot pre-registered
Each component is scored out of 100 and then capped by the study design — a case series cannot reach the ceiling a randomised trial can, however well it is reported.
Where it sits
RCT reviewsReviews of RCTs (Meta-analyses)
Max 100Randomized TrialsRandomized Trials
Max 90Reviews of Cohort StudiesReviews of Cohort Studies
Max 85Cohort StudiesCohort Studies
Max 72Reviews of Case-Control StudiesReviews of Case-Control Studies
Max 63Case-Control StudiesCase-Control Studies
Max 58Cross-Sectional & Case SeriesCross-Sectional & Case Series
Max 50Expert OpinionExpert Opinion
Max 553 / 100
Probability of being correct
Groups of people are followed over time to see who develops an outcome. Strong for identifying risk factors and associations, but cannot prove causation as firmly as RCTs.
This design cannot establish causation — the findings describe an association, not a cause. Retrospective observational cohort with propensity score matching cannot prove causation. Lack of randomization leaves residual confounding, treatment selection, and surveillance bias possible; abstract-only prevents verification of methodology.
COI Unknown
Could not determine conflict of interest status
No conflicts of interest or funding disclosures were present in the provided text; potential conflicts cannot be assessed.
The provided text contains only the abstract (Aims, Methods, Results, Conclusions) and lacks any author affiliations, conflict of interest declarations, or funding information. Therefore, industry funding and author relationships are unknown.
Standing
Who’s using this study?
The videos and claims on this site that lean on this study, and the researchers who wrote it.
1 video from Dr Brad Stanfield cite this study, drawing 1 claim from it.
- Very strong evidence
Randomized or controlled trials support this claim, alongside consistent supporting evidence.
Evidence
Authored by
8 researchersIf this is your work, this is how we attribute it on Fit Body Science. T F Gu is listed as the lead author.