Updated October 2025
Secondary Prevention | Lipids
Lipid Management in Secondary Prevention: Beyond Statins
In secondary prevention, aggressive LDL-C lowering reduces recurrent ASCVD events. When maximally tolerated statins are insufficient or not tolerated, adding ezetimibe, PCSK9 inhibitors, or bempedoic acid achieves further LDL-C reduction and event lowering. Evidence supports a log-linear relationship between absolute LDL-C lowering and risk reduction, with similar per–mmol/L benefits across statin and non‑statin agents that upregulate the LDL receptor. Uptake remains low despite clear indications; cost-effectiveness varies by agent and risk.
Clinical question
Which non-statin therapies should be prioritized in secondary prevention to reduce cardiovascular events when LDL-C goals are not met or statins are not tolerated?
Secondary PreventionLDL-CEzetimibePCSK9 inhibitorsBempedoic acidCost-effectivenessGuidelines
Key points
Principle of risk reduction
Across statins and non-statins that upregulate LDL receptors, risk reduction tracks with absolute LDL-C lowering—similar relative benefits per mmol/L decrease in LDL-C [1].
Therapeutic hierarchy
In very-high-risk ASCVD with LDL-C above threshold on maximal statin, add ezetimibe first; escalate to PCSK9 mAb if still above goal per ACC ECDP [2].
Real-world gap
Despite proven event reduction, utilization of non-statin therapy is low in secondary prevention, leaving preventable residual risk [3], [4].
Economic lens
Cost-effectiveness is agent- and price-dependent; PCSK9 value improves at very high risk or lower prices, while ezetimibe is generally favorable; bempedoic acid varies by context [5].
Emerging options
New oral and injectable agents (e.g., bempedoic acid, PCSK9 inhibitors) expand options when statins alone fall short or are not tolerated [6], [7], [8].
Evidence highlights
Each ~1 mmol/L (≈39 mg/dL) LDL-C drop → ~20–25% MACE reduction [1]
LDL-C reduction principle
Ezetimibe per ACC when LDL-C above goal on maximal statin [2]
First add-on
Non-statin uptake remains low in eligible secondary prevention patients [3], [4]
Residual risk gap
Stepwise Intensification Beyond Statins
Anchor therapy is the maximally tolerated high-intensity statin. Add agents sequentially to achieve LDL-C thresholds while balancing efficacy, safety, access, and cost.
1
Confirm risk, goals, and adherence
Verify clinical ASCVD and very-high-risk features; confirm adherence and high-intensity statin dosing. Recheck fasting lipid panel 4–12 weeks after changes. Target LDL-C <70 mg/dL, often <55 mg/dL in very-high-risk patients depending on local standards, acknowledging log-linear benefit with further reductions [1], [2].
2
Add ezetimibe (first-line non-statin)
Ezetimibe offers ~15–25% additional LDL-C lowering and has outcome data as add-on to statins, with favorable tolerability and cost. ACC ECDP recommends ezetimibe as the initial add-on when LDL-C remains above goal on maximally tolerated statin [2], [8].
3
Escalate to a PCSK9 inhibitor when needed
If LDL-C remains above threshold, add a PCSK9 monoclonal antibody. These agents provide ~50–60% additional LDL-C reduction and robust event reduction; per‑mmol/L benefit parallels statins due to LDL receptor upregulation [1], [2], [6], [7].
4
Consider bempedoic acid in statin-intolerant or as add-on
An oral ATP‑citrate lyase inhibitor that reduces LDL-C ~17–23% on background therapy; can be combined with ezetimibe. Useful in statin-intolerance or when PCSK9 access is limited; outcome benefits beyond LDL-C lowering are supported by emerging evidence summarized in contemporary reviews [6], [7].
5
Reassess, personalize, and address access
Reassess LDL-C and adherence every 4–12 weeks after intensification. Optimize combinations tailored to LDL-C gap, comorbidities, route preference, and cost-effectiveness considerations; address prior authorization and patient assistance to overcome underuse [3], [5], [4].
Non‑Statin Options: Efficacy, Outcomes, and Practicalities
Select agents based on expected LDL-C reduction, outcomes evidence, tolerability, route, and value.
Ezetimibe
Mechanism: inhibits NPC1L1; upregulates LDL receptors.
LDL-C reduction: ~15–25% add-on; larger when baseline LDL-C high [8].
Outcomes: Add-on to statins reduces ASCVD events; benefit aligns with per‑mmol/L LDL-C reduction seen across therapies [1], [8].
Safety: Generally well tolerated; minimal drug interactions [8].
Role: First add-on in secondary prevention per ACC [2].
Access/Cost: Generic; typically cost-effective [5], [2].
PCSK9 monoclonal antibodies
Mechanism: increases LDL receptor recycling; potent LDL-C lowering.
LDL-C reduction: ~50–60% on top of statins; rapid onset [6], [7].
Outcomes: Significant MACE reduction proportional to LDL-C lowering; risk reduction per 1 mmol/L similar to statins [1].
Safety: Injection-site reactions; very low myopathy rates; no significant glycemia signal in meta-analyses [6], [7].
Role: Add after ezetimibe if LDL-C above threshold, or earlier in very-high-risk with large LDL-C gap [2].
Value: Cost-effectiveness improves in very-high-risk populations and at lower net prices [5].
Bempedoic acid
Mechanism: ATP-citrate lyase inhibitor; prodrug activated in liver, minimizing muscle exposure.
LDL-C reduction: ~17–23% alone; synergistic with ezetimibe [6], [7].
Outcomes: Reduces LDL-C and ASCVD risk in contemporary evidence syntheses; favorable for statin-intolerant patients [6], [7].
Safety: Can raise uric acid; rare tendon rupture; generally well tolerated [6].
Role: Consider in statin intolerance or when PCSK9 not available; as add-on to reach goals [2], [6].
Value: Variable; may be cost-effective in selected scenarios [5].
Implementation and Systems
Underuse persists: low uptake of non-statins in eligible secondary prevention patients [3], [4].
Close follow-up: check LDL-C 4–12 weeks after each intensification [2].
Documentation: record statin intensity, intolerance rationale, and prior LDL-C responses to support coverage [2].
Equity: address prior authorization and affordability to narrow treatment gaps [5], [4].
References
Source material
Primary literature that informs this article.
Association Between Lowering LDL-C and Cardiovascular ...
jamanetwork.com
2022 ACC ECDP on Role of Nonstatin Therapies for LDL- ...
www.acc.org
Uptake of non-statin lipid-lowering therapies for secondary ...
www.sciencedirect.com
Uptake of non-statin lipid-lowering therapies for secondary ...
pubmed.ncbi.nlm.nih.gov
A Systematic Review of Cost-Effectiveness of Non-Statin ...
www.sciencedirect.com
Cutting-edge lipid-lowering pharmacological therapies
pubmed.ncbi.nlm.nih.gov
New, Novel Lipid-Lowering Agents for Reducing ...
pubmed.ncbi.nlm.nih.gov
Oral Lipid-Lowering Treatments Beyond Statins
pmc.ncbi.nlm.nih.gov
A systematic review of randomised controlled trials
www.sciencedirect.com