Secondary Targets in Dyslipidemia Management
After achieving LDL-C goals, non-HDL-C is the primary secondary target, set 30 mg/dL higher than the corresponding LDL-C goal, particularly when triglycerides are ≥200 mg/dL. 1, 2
Non-HDL-C as the Key Secondary Target
Non-HDL-C represents the most important secondary target because it captures all atherogenic lipoproteins including VLDL, IDL, LDL, and remnant particles that contribute to residual cardiovascular risk even after LDL-C optimization. 1, 3
Specific Non-HDL-C Goals by Risk Category:
- Very high-risk patients (established CVD, diabetes with target organ damage): Non-HDL-C <100 mg/dL (2.6 mmol/L) 1, 2
- High-risk patients: Non-HDL-C <130 mg/dL (3.4 mmol/L) 1, 2
- Moderate-risk patients: Non-HDL-C goal is 30 mg/dL above their LDL-C target 1, 2
The rationale for the 30 mg/dL differential is that it corresponds to the cholesterol content in triglyceride-rich lipoproteins when TG levels are at the upper limit of normal (150 mg/dL). 1
Alternative Secondary Targets
Apolipoprotein B (Apo B)
Apo B serves as an equally valid alternative secondary target with specific thresholds:
Apo B may actually be superior to LDL-C as a risk marker and treatment target, particularly in patients with elevated triglycerides, because it counts each atherogenic particle (one Apo B molecule per particle) regardless of cholesterol content. 1 The measurement has less laboratory error than calculated LDL-C, especially when triglycerides are elevated. 1
HDL-C and Triglyceride Targets
While not formal "targets" in the same sense as LDL-C and non-HDL-C, optimal levels for residual risk reduction include:
These parameters identify patients with atherogenic dyslipidemia who may benefit from additional interventions beyond statin therapy. 5, 6
When to Focus on Secondary Targets
Secondary targets become clinically relevant in two specific scenarios:
When triglycerides are ≥200 mg/dL: Non-HDL-C automatically becomes a co-primary target alongside LDL-C because it better captures the atherogenic burden from triglyceride-rich remnant particles. 1, 2
After achieving LDL-C goals in very high-risk patients: If non-HDL-C remains elevated or HDL-C remains low despite optimal LDL-C, this signals residual risk that warrants discussion of additional therapy. 1, 2
Treatment Approach for Elevated Secondary Targets
First Priority: Maximize Statin Therapy
Before adding non-statin agents, ensure the patient is on maximally tolerated statin therapy, as statins lower both LDL-C and non-HDL-C proportionally. 1 This avoids premature polypharmacy and minimizes adverse effects.
Adding Non-Statin Agents
If non-HDL-C remains elevated after statin optimization:
- Consider ezetimibe first: Provides an additional 18-25% LDL-C reduction with strong safety data and proven cardiovascular benefit when added to statins in acute coronary syndrome patients. 1
For persistent low HDL-C (<40 mg/dL) and elevated triglycerides (>200 mg/dL):
Fenofibrate is preferred over gemfibrozil when combining with statins to minimize myopathy risk. 4, 2, 7 Fenofibrate increases HDL-C by 15-25% and reduces triglycerides. 2, 7
Niacin can be considered but recent trials show no incremental cardiovascular benefit when added to well-treated statin patients, despite raising HDL-C. 1, 6
Critical Caveats
The evidence for treating secondary targets to reduce hard outcomes is substantially weaker than for LDL-C lowering. 1, 8 While non-HDL-C and Apo B are validated risk markers, large randomized trials have not definitively proven that targeting these parameters with combination therapy reduces cardiovascular mortality beyond statin monotherapy. 1, 8
Combination therapy increases adverse event risk, particularly myopathy when combining statins with fibrates, and liver enzyme elevations with high-dose statins. 1, 8 The incremental benefit must justify these risks, which is clearest in very high-risk secondary prevention patients with established residual dyslipidemia. 1, 8
In primary prevention patients with lower absolute risk, aggressive pursuit of secondary targets with combination therapy is not supported by mortality data and may cause more harm than benefit. 8