Anyone taking PCSK9 inhibitors (i.e. Repatha)?

I have a scrip for Repatha but haven't yet started. Covered by insurance so cost not an issue. Was concerned that LDL would go too low and cause issues. Also, side effects. Read that it can cause hyperglycemia (diabetes). Any input would be greatly appreciated.

 

PCSK9 inibitors are the best option for reducing lipids. Highly effective and pretty much side effect free. It has not been my experience that they cause hyperglycemia and a I'm not aware of any evidence that they do. Since PCSK9 inhibitors were developed to mimic a genetic mutation that results in low levels of PCSK9, we know from studies of those with the mutation that there does not appear to be any long term adverse affect from lifelong reduced PCSK9. Too low of LDL is unlikely and generally would require multiple lipid reducing agents before that becomes a concern. Infants have LDL levels of ~20 mg/dl, so it takes really low levels of LDL before you're likely to have any adverse effects.

 

PCSK9 inibitors are the best option for reducing lipids. Highly effective and pretty much side effect free. It has not been my experience that they cause hyperglycemia and a I'm not aware of any evidence that they do. Since PCSK9 inhibitors were developed to mimic a genetic mutation that results in low levels of PCSK9, we know from studies of those with the mutation that there does not appear to be any long term adverse affect from lifelong reduced PCSK9. Too low of LDL is unlikely and generally would require multiple lipid reducing agents before that becomes a concern. Infants have LDL levels of ~20 mg/dl, so it takes really low levels of LDL before you're likely to have any adverse effects.

Thanks. Here are some links of concern:

Doubling of Hemoglobin A1c on PCSK9 Inhibitor Therapy​

Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data​

The latter study casts further doubt and the usefulness of PCSK9 inhibitors. Yes, they can push numbers around but do they REALLY provide any benefit?

 

This first link is of no concern. A single case report of a diabetic whose diabetes got worse with no effort to eliminate other confounding variables. This sort of thing happens frequently with diabetics. Something a simple as an infection could cause the hyperglycemia in an insulin dependent diabetic like this.

The second link I hadn't seen before. This is obviously concerning. Fraud is a major problem in medical research and this has all the hallmarks of fraud. It's hard to draw any conclusions when the data is faked. The only other things I can point to that may alleviate your concern is there is the Odyssey trial which had a little bit longer follow-up period (2.8 years) and showed improvement in mortality (of course there's always the possibility that this data was faked too). Then there's post-marketing experience which hasn't identified any major issues. PCSK9 inhibitors have been used for 7 years now, which is enough time for an issue to be exposed. Vioxx being a good example, it became well known that it was causing cardiovascular issues after about 5 years of use.

 

This first link is of no concern. A single case report of a diabetic whose diabetes got worse with no effort to eliminate other confounding variables. This sort of thing happens frequently with diabetics. Something a simple as an infection could cause the hyperglycemia in an insulin dependent diabetic like this.

The second link I hadn't seen before. This is obviously concerning. Fraud is a major problem in medical research and this has all the hallmarks of fraud. It's hard to draw any conclusions when the data is faked. The only other things I can point to that may alleviate your concern is there is the Odyssey trial which had a little bit longer follow-up period (2.8 years) and showed improvement in mortality (of course there's always the possibility that this data was faked too). Then there's post-marketing experience which hasn't identified any major issues. PCSK9 inhibitors have been used for 7 years now, which is enough time for an issue to be exposed. Vioxx being a good example, it became well known that it was causing cardiovascular issues after about 5 years of use.

A followup to the Fourier Trial: Study Alleges Mortality Miscount in FOURIER Trial; TIMI Group Disagrees

Recount of FOURIER Data Finds Higher Mortality With Evolocumab

A readjudication of mortality data from the FOURIER trial by outside researchers concludes CV death was higher with evolocumab than originally reported. But FOURIER trialists stand by their conclusions.

www.medscape.com

Doesn't give me much confidence.

 

I have been on Rapatha and just had 6 month labs:
LDL Calculated: 39 from 129 and higher
HDL: 28 from 33, higher a couple years ago
Total Cholesterol: 91 from 193, but has been as high as 245

No obvious side effects.
Injection every 2 weeks.

Over the years I was off and on Statins, had joint and muscle pain so I would stop taking them for months or years, then the Dr kept trying to scare me into taking them. My high LPa is what convinced me to push to get the Rapatha.

 

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 progression⁶. 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)⁷. 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​

1. 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
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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

 

Does Repatha affect hormones like statins do?

Short answer: Large safety datasets show no clinically meaningful change in sex- or adrenal-steroid hormones when evolocumab (Repatha) is added to statin therapy. Small pilot studies have noted modest laboratory effects on stimulated aldosterone and early cortisol responses, but baseline hormone levels, adrenal reserve, and clinical endocrine function have remained normal. Overall, Repatha is not currently associated with clinically important endocrine disturbances.

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Why hormones were a theoretical concern​

PCSK9 directs LDL-receptor recycling in many tissues, including adrenal and gonadal cells that rely on LDL-cholesterol as substrate for steroidogenesis. When LDL is driven to very low concentrations, investigators therefore looked closely for signs of impaired steroid production. So far, those concerns have not translated into clinically significant effects. pmc.ncbi.nlm.nih.gov

Large trials and pooled safety laboratories​

• Phase II–III pooled analyses and the 52-week BERSON study: Evolocumab lowered LDL to ~30 mg/dL yet produced no changes in cortisol, testosterone, estradiol, progesterone, LH, FSH, or ACTH, and no biochemical signs of hypoadrenalism or hypogonadism. pmc.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.govahajournals.org
• Long-term extension and real-world cohorts: Periodic chemistry panels likewise show stable thyroid‐stimulating hormone, fasting insulin, and glucose; incident diabetes appears comparable to statin-treated controls. pmc.ncbi.nlm.nih.gov

Small mechanistic or pilot studies​

Pilot observation	Key finding	Clinical relevance
ACTH–aldosterone test (15 pts, 3 mo)	40 % fall in baseline and ACTH-stimulated aldosterone after adding evolocumab; cortisol unchanged. mdpi.com	Isolated lab change; blood pressure, potassium, and renin remained normal.
ACTH–cortisol response (24 pts, 6 mo)	Modestly lower peak cortisol after ACTH in first months of PCSK9-i therapy; baseline cortisol normal and no symptoms. pubmed.ncbi.nlm.nih.gov	Authors interpreted as adaptive, not adrenal insufficiency.

Genetic and extreme LDL data​

A report of a person with complete PCSK9 deficiency (lifelong LDL ~ 15 mg/dL) documented normal adrenal and gonadal steroid output, supporting the clinical trial experience. internationaljournalofcardiology.com

Consensus from recent safety reviews​

Multiple 2023-2024 pharmacovigilance reviews conclude that PCSK9-targeted therapy is “unlikely to exert clinically significant impacts on steroid hormone synthesis” and requires no routine endocrine monitoring beyond standard care. pmc.ncbi.nlm.nih.gov

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Practical take-aways for clinicians and patients​

Point	What the evidence says
Sex hormones	Testosterone, estradiol, LH/FSH unchanged in both men and women across short- and long-term studies.
Adrenal glucocorticoids	Baseline cortisol normal; no cases of overt adrenal insufficiency reported. Blunted stimulated cortisol in one small study has not shown clinical sequelae.
Mineralocorticoids	One pilot noted lower aldosterone after 3 months; blood pressure/electrolytes unaffected.
Thyroid & metabolic hormones	TSH, free T<sub>4</sub>, insulin, and HbA1c stable; hyperglycemia incidence comparable to background risk.
Clinical monitoring	Routine endocrine labs are not recommended solely because a patient starts Repatha. Consider testing only if symptoms suggest hormonal dysfunction or if the patient has pre-existing adrenal disorders.

Bottom line​

Across thousands of patient-years, Repatha has not demonstrated clinically significant hormone disruption. Isolated biochemical changes (e.g., attenuated aldosterone or cortisol responses) have been small, transient, and without symptomatic consequences. Endocrine safety surveillance continues, but current data support Repatha’s use without additional hormonal precautions in the general population.