Clinical Context
Borderline coronary lesions—stenoses of 40-70% that don’t clearly require revascularization—present a clinical dilemma. These lesions may progress to significant stenosis and acute coronary syndrome, or remain stable for years. The traditional approach has been medical management with statins and risk factor modification, reserving intervention for progression or ischemia. However, the optimal intensity of lipid-lowering therapy for these intermediate lesions has been uncertain.
PCSK9 inhibitors (evolocumab, alirocumab) achieve LDL-C reductions of 50-60% when added to statin therapy, reaching levels below 30 mg/dL in many patients. Imaging studies have demonstrated that more intensive LDL-C lowering produces greater plaque regression. The GLAGOV trial showed that evolocumab added to statin therapy achieved plaque regression measured by intravascular ultrasound (IVUS), particularly in patients achieving very low LDL-C levels.
This study extends this question specifically to borderline lesions, comparing three approaches: statin alone, PCSK9 inhibitor alone, and combination therapy. Using IVUS to directly measure plaque volume and arterial dimensions provides mechanistic insight into how lipid-lowering intensity affects atherosclerotic plaque.
Study Summary (PICO Framework)
Summary:
In patients with borderline coronary lesions, combination alirocumab + atorvastatin significantly achieved greater LDL-C reduction (to 1.48 mmol/L), larger lumen volume increase, and greater plaque volume reduction compared to either agent with placebo, with no significant adverse effects.
| PICO | Description |
|---|---|
| Population | 69 patients with IVUS-detected borderline coronary lesions, 48-week follow-up. |
| Intervention | Alirocumab + atorvastatin combination therapy. |
| Comparison | Group A: Alirocumab + placebo. Group B: Atorvastatin + placebo. |
| Outcome | Combination: LDL-C 3.64 → 1.48 mmol/L (57 mg/dL). Greater lumen volume increase (P=0.038), greater plaque reduction (P=0.041). No major side effects. |
Clinical Pearls
1. Lower LDL-C translates to greater plaque regression—a dose-response relationship. The combination group achieved the lowest LDL-C (1.48 mmol/L = 57 mg/dL) and the greatest plaque regression. This reinforces the “lower is better” principle for LDL-C in patients with coronary disease. There appears to be no threshold below which further LDL-C lowering stops providing plaque benefit—at least for regression endpoints.
2. Plaque regression AND lumen expansion were observed with combination therapy. Atherosclerotic arteries undergo “positive remodeling”—enlarging to accommodate plaque while maintaining lumen size. Advanced disease loses this compensation. The finding of both plaque regression and lumen expansion suggests intensive lipid lowering may reverse the remodeling process, not just stabilize existing disease.
3. IVUS provides direct visualization of therapeutic effects invisible to angiography. Angiography shows the lumen silhouette but misses plaque within the vessel wall. IVUS images the full arterial wall, enabling quantification of plaque volume and composition. Changes in plaque burden can occur without angiographic change. This mechanistic endpoint provides insight into how therapies affect disease, even if clinical endpoint trials remain definitive.
4. Borderline lesions represent a therapeutic opportunity. Rather than waiting for lesions to progress and cause events, intensive treatment of borderline lesions might induce regression and prevent progression. This “stabilization strategy” requires long-term data on clinical outcomes, but the plaque imaging results are encouraging.
Practical Application
Consider PCSK9 inhibitor addition for patients with borderline lesions and elevated LDL-C despite statins: For patients with documented coronary disease (even borderline lesions) who don’t achieve goal LDL-C on maximally tolerated statin therapy, adding a PCSK9 inhibitor provides additional plaque regression benefit. Current guidelines support PCSK9 inhibitors for ASCVD patients with LDL-C ≥70 mg/dL on statin therapy.
Aim for very low LDL-C targets in patients with coronary disease: This study achieved LDL-C of 57 mg/dL with combination therapy. Guidelines recommend LDL-C <55 mg/dL (or <70 mg/dL depending on guideline) for very high-risk patients. The plaque imaging data support aggressive LDL-C lowering in patients with documented coronary lesions, not just those post-MI or with prior events.
Use imaging data to motivate patient adherence: For patients ambivalent about adding expensive PCSK9 inhibitors, explaining that combination therapy actually shrinks coronary plaque (not just “lowers a number”) may improve adherence. The tangible concept of plaque regression is compelling compared to abstract LDL-C targets.
Consider cost-effectiveness in therapy decisions: PCSK9 inhibitors remain expensive despite price reductions. For borderline lesions in otherwise lower-risk patients, the cost-benefit may differ from post-MI patients. Insurance coverage, patient risk level, and available alternatives (ezetimibe, bempedoic acid) should factor into treatment decisions.
How This Study Fits Into the Broader Evidence
The GLAGOV trial demonstrated that adding evolocumab to statin therapy achieved plaque regression measured by IVUS, with regression correlating with achieved LDL-C level. Patients reaching LDL-C <20 mg/dL showed the greatest regression. This smaller study extends GLAGOV's findings specifically to borderline lesion populations and confirms the benefit of combination therapy over either agent alone.
Clinical outcome trials (FOURIER, ODYSSEY Outcomes) have shown that PCSK9 inhibitors reduce cardiovascular events when added to statin therapy in patients with established ASCVD. The plaque regression demonstrated in imaging studies like this provides mechanistic explanation for those clinical benefits—therapies that shrink plaque produce fewer plaque rupture events.
The “lower is better” LDL-C paradigm has been supported by meta-analyses showing linear relationships between LDL-C reduction and cardiovascular risk reduction, without evidence of a J-curve or threshold below which benefits cease. This study adds imaging support for that paradigm.
Limitations to Consider
Sample size is small (n=69 across three groups), limiting statistical power and generalizability. IVUS-measured plaque regression is a surrogate endpoint—clinical events (MI, revascularization) are the outcomes that matter to patients. 48 weeks is relatively short for atherosclerosis assessment; longer follow-up might show different patterns. The comparator groups used PCSK9 inhibitor or statin with placebo, which is unusual—most patients with coronary disease would receive statins regardless. Cost-effectiveness wasn’t addressed.
Bottom Line
Combination alirocumab plus atorvastatin therapy achieved greater LDL-C reduction (to 57 mg/dL), larger coronary lumen volume increase, and greater plaque volume reduction over 48 weeks compared to either therapy alone in patients with borderline coronary lesions. This IVUS imaging study supports intensive lipid-lowering with statin plus PCSK9 inhibitor combination for patients with documented coronary atherosclerosis, demonstrating that “lower is better” for LDL-C translates to measurable plaque regression. For patients with borderline lesions who tolerate statin therapy but don’t achieve goal LDL-C, PCSK9 inhibitor addition offers the potential for disease regression rather than just stabilization.
Source: Zeyu Xu, et al. “Clinical Efficacy of Atorvastatin and PCSK9 Inhibitors in Patients With Borderline Coronary Lesions: An Intravascular Ultrasound Assessment.” Read article here.
