My CPK is always high, so my cardiologist put me on Repatha to decrease my LDL of 130 (statins are contraindicated for people with high CPK). I just ran a Cardio IQ profile before starting the drug tomorrow. I will get results in 2-3 weeks and run another Cardio IQ in 6 weeks to see changes in all my lipid particles.
I was researching Repatha's effect on calcium score (mine is 100).
Repatha (Evolocumab) and Coronary Artery Calcium (CAC) Scores
Introduction
Coronary artery calcium (CAC) scoring is a non-invasive imaging measure of calcified plaque in the coronary arteries. Higher CAC scores are strongly correlated with an elevated risk of future cardiovascular events and complications during interventions 1 . CAC scoring is widely used to improve risk stratification in patients; for example, individuals with higher CAC are more likely to benefit from preventive therapies. An important clinical question is whether aggressive lipid-lowering therapies can slow or alter CAC progression. Repatha (evolocumab) is a PCSK9 inhibitor that dramatically lowers low-density lipoprotein (LDL) cholesterol (typically by ~60%) and has proven clinical benefits in reducing cardiovascular events when added to statin therapy 2. This report examines what is known about Repatha’s effect on CAC scores, in terms of slowing CAC progression or potentially stabilizing atherosclerotic plaques.
Repatha (Evolocumab) and Lipid-Lowering Therapy
Evolocumab (Repatha) is a monoclonal antibody that inhibits the protein PCSK9, thereby increasing hepatic LDL receptors and dramatically lowering circulating LDL cholesterol. In the FOURIER outcomes trial involving over 27,000 high-risk patients, adding evolocumab to statin therapy reduced LDL to a median of 30 mg/dL and led to a significant reduction in major cardiovascular events compared to statins alone 2. This established PCSK9 inhibitors as an effective adjunct to statins for cardiovascular risk reduction. Importantly, evolocumab also modestly lowers lipoprotein(a) [Lp(a)] levels, a genetically determined lipid that is associated with both atherosclerosis and calcific processes in arteries.³. By driving LDL to very low levels (and reducing other atherogenic particles like Lp(a)), Repatha offers a novel opportunity to impact plaque biology beyond what standard statins can achieve.
Effects on Atherosclerotic Plaque Volume and Composition
Prior to examining CAC specifically, it is useful to consider how evolocumab affects atherosclerotic plaque in general. The GLAGOV trial (Global Assessment of Plaque Regression with a PCSK9 Antibody) used intravascular ultrasound (IVUS) imaging to measure coronary plaque volume in patients on statin vs. statin plus evolocumab. GLAGOV demonstrated that adding evolocumab resulted in regression of coronary plaque volume: after 18 months, the statin-only group had essentially no change in plaque (+0.05% in percent atheroma volume), whereas the evolocumab combination group showed a
–0.95% change (net plaque regression) 3. Moreover, 64% of patients on statin+evolocumab had any plaque regression, significantly more than the 47% on statins alone 3. These findings indicate that driving LDL to very low levels with a PCSK9 inhibitor can
regress atherosclerotic plaque and potentially stabilize it. Notably, intensive LDL lowering often increases the calcification density within plaques (a phenomenon observed with statin therapy as well), which is generally interpreted as a plaque-stabilizing effect. However, IVUS imaging (as in GLAGOV) assesses total plaque volume rather than calcification specifically, so it did not directly measure changes in CAC scores. To understand CAC, we turn to studies that employed cardiac CT calcium scans.
Impact of Repatha on CAC Progression
Until recently, no pharmacotherapy had been proven to halt or slow the progression of CAC — statin therapy, while reducing cardiac events, typically
does not decrease CAC progression and may even be associated with continued calcium accumulation in plaques 4. The advent of PCSK9 inhibitors raised the question of whether more intensive LDL (and Lp(a)) reduction could modulate calcification. Emerging evidence now suggests that adding a PCSK9 inhibitor like evolocumab can significantly
slow the progression of CAC scores compared to standard therapy.
A pivotal study by Ikegami et al. (2018) examined CAC changes in patients on statins with or without a PCSK9 inhibitor. They reported that the annual increase in CAC score was
significantly lower with combined statin+PCSK9 inhibitor therapy than with statins alone. In this study, patients on high-intensity statin monotherapy had an average CAC progression of about
29.7% per year, whereas those who received add-on PCSK9 inhibitor (evolocumab or alirocumab) showed only about
14.3% per year CAC progression – roughly half the rate observed with statin alone 5. In fact, the authors concluded that “CAC may be prevented” with the addition of a PCSK9 inhibitor, as some patients had little to no calcium score increase over the observation period 5.
More recently, a randomized controlled trial by Gao et al. (2022) specifically investigated CAC outcomes with a PCSK9 inhibitor (alirocumab, which is mechanistically similar to evolocumab) versus statin therapy. In 61 patients with coronary artery disease, one group received standard statin therapy alone and the other received statin plus alirocumab 75 mg every 2 weeks. All patients underwent coronary CT calcium scanning at baseline and after a follow-up period. The results were striking:
CAC scores rose much more slowly in the PCSK9 inhibitor group. The statin-only group had a median CAC score increase of
+10.6% (over ~1 year), whereas the alirocumab-added group had a median change of only
+2.9%, with many patients in the PCSK9 group actually showing negligible progression or even slight decreases in CAC 6. By another metric, the
annualized CAC progression rate was
2.7% per year with statins versus only
0.6% per year with statin+alirocumab (a significant difference) 6. These findings align with the 2018 study and reinforce that PCSK9 inhibition on top of statins can substantially
attenuate the increase in calcified plaque over time.
It is important to clarify that neither of these studies showed outright
reduction of existing CAC – rather, they demonstrate
slowing of CAC growth. In the PCSK9-treated groups, calcium scores tended to remain relatively stable (or increase only very modestly), whereas in statin-only groups CAC continued to climb more steeply. Slowing CAC progression is considered beneficial given that rapid CAC increases are associated with higher risk. However, even if CAC doesn’t regress, a slower progression suggests less ongoing plaque build-up and possibly a healthier plaque phenotype.
Potential Mechanisms and Interpretation
The mechanism by which evolocumab (and other PCSK9 inhibitors) slows CAC progression is an area of active investigation. Several factors have been proposed:
- Intensive LDL Lowering: By driving LDL-C to very low levels, PCSK9 inhibitors dramatically reduce the influx of cholesterol into arterial walls. This likely reduces the formation of new atherosclerotic plaques and the growth of existing ones. With less new plaque formation, there is less new calcification. The slowed CAC increase observed with PCSK9 therapy may simply reflect overall reduced plaque burden accumulation. In contrast, statin therapy (which lowers LDL moderately) still allows some plaque progression; calcification may continue as part of the plaque aging process.
- Plaque Stabilization and Calcification Pattern: There is evidence that statins promote a transformation of plaque composition — turning softer, lipid-rich plaques into more calcified, stable plaques over time 4. This can lead to increases in CAC score despite overall risk reduction. PCSK9 inhibitors, when added, may further alter plaque biology. Some data suggest that PCSK9 inhibitor therapy increases calcified plaque volume to a lesser extent than statins alone, possibly because plaques undergo regression (shrinking) rather than simply calcifying in place. In the 2018 Ikegami study, for example, the combination therapy group had much smaller calcium score increases despite aggressive LDL lowering, hinting that plaque regression with PCSK9 inhibitors does not trigger as much compensatory calcification as statins do alone 5. The net effect is a slower rise in CAC.
- Lipoprotein(a) Reduction: PCSK9 inhibitors like evolocumab also reduce Lp(a) levels by ~20–30% on average. Lp(a) is a known independent promoter of calcification; elevated Lp(a) is correlated with higher CAC scores and aortic valve calcification 3,7. Statins do not lower (and can even raise) Lp(a), whereas evolocumab provides a meaningful reduction in this pro-calcific particle. In the Gao et al. trial, patients on alirocumab saw a significant drop in Lp(a) which did not occur in the statin-only group, and this could be one reason the PCSK9 group showed minimal CAC progression<sup>6</sup>. Lower Lp(a) might translate to less inflammatory and calcific activity in plaques.
- PCSK9 and Vascular Calcification Pathways: PCSK9 itself may have direct effects on vascular cells. Some research has found that higher circulating PCSK9 levels are associated with more extensive coronary calcification in patients (even after accounting for LDL levels)<sup>7</sup>. Moreover, genetic loss-of-function variants in PCSK9 (which mimic the action of PCSK9 inhibitors) are linked to lower incidence of calcific aortic valve disease 6. These observations raise the possibility that PCSK9 activity could influence calcification pathways in the vessel wall. By inhibiting PCSK9, evolocumab might indirectly reduce signaling that leads to calcium deposition in plaques, though this mechanism is not fully elucidated.
In interpreting these findings, it’s crucial to recognize that
CAC score is only one aspect of atherosclerosis assessment. An increasing CAC score in a patient on therapy does not necessarily mean the treatment is failing – for instance, statins often increase CAC while markedly
reducing heart attack risk (by stabilizing plaques). Likewise, the lower CAC progression seen with PCSK9 inhibitors complements the known plaque regression and risk reduction benefits of these drugs, but it doesn’t imply that calcium deposits are being removed. Instead, it suggests that
new calcific plaque formation is being suppressed, and perhaps existing plaques are becoming more stable without an excessive calcium buildup response.
From a clinical perspective, these findings are encouraging. They indicate that Repatha (evolocumab) not only lowers cholesterol and cardiovascular events, but also has a favorable impact on the
trajectory of coronary calcification. Slowing CAC progression could translate into a lower long-term burden of calcified plaque, which in turn might reflect a lower burden of total atherosclerosis (since calcified plaque is a subset of total plaque). That said, CAC score changes should be interpreted with caution. A patient on Repatha might see little change in CAC over a few years, but this should be taken as a positive sign in context (given the evidence), whereas a patient with rapidly rising CAC despite therapy might warrant further risk assessment and management.
Conclusion
In summary,
Repatha (evolocumab) appears to decelerate the progression of coronary artery calcium scores when added to statin therapy. Studies have shown roughly a 50% reduction in the annual CAC increase with PCSK9 inhibitors, and in some cases near-zero progression of calcium scores over one to two years of therapy 5,6. This effect is likely driven by intensive LDL lowering, reduction in pro-calcific factors like Lp(a), and overall plaque stabilization/regression. While evolocumab does not “erase” existing calcified plaque, its ability to slow CAC growth is a unique and beneficial property not observed with conventional therapies alone. Patients on Repatha can be reassured that, in addition to lowering LDL and event risk, their therapy might also be mitigating the advancement of calcified plaque in their arteries. Further research is ongoing to confirm the long-term clinical significance of slowed CAC progression – including whether it correlates with fewer events over time – but current evidence positions PCSK9 inhibition as an important tool in not only risk reduction but also favorably influencing coronary plaque characteristics.
References
- Nakahara, T., Dweck, M. R., Narula, N., Pisapia, D., Narula, J., & Strauss, H. W. (2017). Coronary artery calcification: from mechanism to molecular imaging. JACC: Cardiovascular Imaging, 10(5), 582–593. Redirecting
- Sabatine, M. S., Giugliano, R. P., Keech, A. C., Honarpour, N., Wiviott, S. D., Murphy, S. A., et al. (2017). Evolocumab and clinical outcomes in patients with cardiovascular disease. New England Journal of Medicine, 376(18), 1713–1722. https://doi.org/10.1056/NEJMoa1615664
- Alonso, R., Mata, P., Muñiz, O., Fuentes-Jiménez, F., Díaz, J. L., Zambón, D., et al. (2016). PCSK9 and lipoprotein(a) levels are two predictors of coronary artery calcification in asymptomatic patients with familial hypercholesterolemia. Atherosclerosis, 254, 249–253. Redirecting
- Puri, R., Nicholls, S. J., Shao, M., Kataoka, Y., Uno, K., Kapadia, S. R., et al. (2015). Impact of statins on serial coronary calcification during atheroma progression and regression. Journal of the American College of Cardiology, 65(13), 1273–1282. Redirecting
- Ikegami, Y., Inoue, I., Inoue, K., Shinoda, Y., Iida, S., Goto, S., Nakano, T., Shimada, A., & Noda, M. (2018). The annual rate of coronary artery calcification with combination therapy with a PCSK9 inhibitor and a statin is lower than that with statin monotherapy. NPJ Aging and Mechanisms of Disease, 4(1), Article 7. The annual rate of coronary artery calcification with combination therapy with a PCSK9 inhibitor and a statin is lower than that with statin monotherapy - npj Aging
- Gao, F., Li, Y. P., Ma, X. T., Wang, Z. J., Shi, D. M., & Zhou, Y. J. (2022). Effect of alirocumab on coronary calcification in patients with coronary artery disease. Frontiers in Cardiovascular Medicine, 9, 907662. Frontiers | Effect of Alirocumab on Coronary Calcification in Patients With Coronary Artery Disease
- Zhao, X., Zhang, H. W., Li, S., Zhang, Y., Xu, R. X., Zhu, C. G., et al. (2018). Association between plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration and coronary artery calcification. Annals of Clinical Biochemistry, 55(1), 158–164. https://doi.org/10.1177/0004563217695351