Understanding Cholesterol and Its Impact on Health

What is Cholesterol?

Cholesterol is a waxy, fat-like substance found in your blood that your body needs to build healthy cells. However, having high levels of certain types of cholesterol can lead to serious health issues, including heart disease. Cholesterol is transported through the blood in lipoproteins, and there are two primary types: low-density lipoprotein (LDL) and high-density lipoprotein (HDL).

• LDL ("Bad" Cholesterol): LDL is often referred to as "bad" cholesterol because it can build up on the walls of your arteries, leading to narrowing and hardening, which increases the risk of heart attacks and strokes.
• HDL ("Good" Cholesterol): HDL helps remove LDL cholesterol from the bloodstream, transporting it to the liver where it can be processed and removed from the body.

Why Canadians Need to Care

In Canada, cardiovascular disease remains one of the leading causes of death. According to Statistics Canada, high cholesterol is a major contributing factor to these conditions, with nearly 40% of Canadian adults aged 20 to 79 reporting unhealthy cholesterol levels. Unchecked, high LDL cholesterol can lead to the formation of plaques in the arteries, which restricts blood flow and increases the risk of serious cardiovascular events, including heart attacks and strokes.

Overview of Statins

How Statins Work

Statins are one of the most commonly prescribed medications for lowering cholesterol and reducing the risk of cardiovascular disease. These drugs work by inhibiting an enzyme in the liver called HMG-CoA reductase, which plays a crucial role in the production of cholesterol. By blocking this enzyme, statins reduce the liver's cholesterol production, leading to a decrease in the amount of cholesterol circulating in the blood.

In addition to lowering LDL cholesterol levels, statins may have anti-inflammatory effects on the walls of the arteries, which can help stabilize plaques and further reduce the risk of heart attacks and strokes.

Common Statins Available in Canada

Statins are widely available in both brand-name and generic forms across Canada. Some of the most common statins prescribed by Canadian healthcare providers include:

• Atorvastatin (Lipitor): Known for its potent ability to lower LDL cholesterol, it's often prescribed for individuals with high cardiovascular risk.
• Rosuvastatin (Crestor): Another powerful statin, particularly effective in reducing cholesterol in individuals with genetic predispositions.
• Simvastatin (Zocor): Generally used for moderate cholesterol reduction and well-tolerated by many patients.

Effectiveness

Statins are highly effective at reducing LDL cholesterol levels. Studies have shown that these medications can lower LDL cholesterol by 30% to 50%, depending on the dosage and the specific statin prescribed. In addition to lowering LDL, statins also contribute to reducing the risk of cardiovascular events such as heart attacks and strokes. Their widespread use and proven efficacy make them a cornerstone in cholesterol management.

• Research Data: A large body of evidence supports the use of statins for primary and secondary prevention of cardiovascular disease, with benefits extending to various patient populations, including those with diabetes, high blood pressure, and a history of heart disease.

Side Effects

While statins are generally well-tolerated, some patients may experience side effects. The most common side effect is muscle pain, ranging from mild discomfort to more severe cases that affect daily activities. In rare instances, statins can lead to liver enzyme abnormalities, which may require regular monitoring by healthcare providers. Additionally, there is a small risk of developing type 2 diabetes, especially in those who are already at risk for the condition.

• Muscle Pain: Statins are known to cause myopathy, a condition characterized by muscle aches and weakness.
• Liver Effects: Though rare, elevated liver enzymes can occur in some patients, necessitating blood tests to monitor liver function.
• Diabetes Risk: Statins may slightly increase the risk of developing diabetes, particularly in individuals with other risk factors for the disease.

Overview of PCSK9 Inhibitors

How PCSK9 Inhibitors Work

PCSK9 inhibitors are a newer class of cholesterol-lowering drugs that target a specific protein in the body known as proprotein convertase subtilisin/kexin type 9 (PCSK9). This protein plays a role in regulating the number of LDL receptors on the liver. By blocking PCSK9, these drugs prevent the degradation of LDL receptors, allowing the liver to remove more LDL cholesterol from the blood. As a result, PCSK9 inhibitors significantly reduce LDL cholesterol levels, often achieving greater reductions than statins.

These drugs are particularly beneficial for individuals who cannot reach their cholesterol goals with statins alone or for those who are unable to tolerate statins due to side effects. PCSK9 inhibitors are administered via injection, typically every two to four weeks.

Common PCSK9 Inhibitors in Canada

PCSK9 inhibitors are a relatively new addition to the cholesterol-lowering arsenal and are typically prescribed for high-risk patients. The two most common PCSK9 inhibitors available in Canada are:

• Alirocumab (Praluent): This drug is often prescribed for individuals with familial hypercholesterolemia or those who need additional LDL reduction despite being on maximum statin therapy.
• Evolocumab (Repatha): Another highly effective PCSK9 inhibitor, Evolocumab is used to lower LDL cholesterol in patients who are at high risk of cardiovascular events or who have not achieved sufficient cholesterol reduction with statins.

Both drugs have shown significant LDL-lowering effects and are used to reduce the risk of heart attack, stroke, and other cardiovascular events in certain populations.

Effectiveness

PCSK9 inhibitors are known for their powerful LDL-lowering abilities. Clinical trials have demonstrated that these drugs can reduce LDL cholesterol by an additional 50% to 60% when added to statin therapy. In some cases, patients experience reductions of over 70%. Beyond just lowering cholesterol, PCSK9 inhibitors have been shown to reduce the risk of major cardiovascular events, including heart attacks and strokes, making them a promising option for patients at high risk.

• Research Data: A study published in The New England Journal of Medicine found that PCSK9 inhibitors significantly reduced the occurrence of cardiovascular events in patients with established heart disease. These results reinforce their role in high-risk populations, particularly for those who need more aggressive cholesterol management.

Side Effects

Unlike statins, which work throughout the body, PCSK9 inhibitors have a more targeted approach, leading to less side effects. The most common side effects include injection site reactions, such as redness, swelling, or itching. Some patients may also experience flu-like symptoms, including fatigue and muscle pain. There have been reports of possible cognitive side effects, such as memory impairment, though these are rare and still being studied.

• Injection Site Reactions: Many patients experience mild discomfort at the injection site, though this typically resolves on its own.
• Flu-like Symptoms: Some patients report general fatigue, muscle aches, and other flu-like symptoms after injections.
• Cognitive Effects: Rare reports of memory loss or confusion have been noted, though further research is needed to confirm any significant connection.

Key Differences Between Statins and PCSK9 Inhibitors

Cost and Accessibility

One of the most significant differences between statins and PCSK9 inhibitors is their cost and accessibility. Statins have been on the market for decades and are available as affordable generics, making them accessible to most Canadians. The monthly cost for a statin prescription can range from $10 to $50, depending on the specific drug and whether a generic version is available.

In contrast, PCSK9 inhibitors are much more expensive, primarily because they are newer, branded medications. The cost for PCSK9 inhibitors can exceed $600 to $800 per month, placing them out of reach for many patients unless covered by insurance. In Canada, some provincial drug plans and private insurance may cover PCSK9 inhibitors for high-risk patients who meet specific criteria, such as those with familial hypercholesterolemia or individuals who have not responded well to statins. However, coverage is not universal, and access may be limited based on the province or insurance plan.

Method of Administration

Another key difference lies in the method of administration. Statins are taken orally in the form of a daily pill, which makes them convenient and easy to incorporate into a daily routine. They require minimal patient effort beyond adherence to the prescribed dosage.

PCSK9 inhibitors, on the other hand, are administered via injection. Patients typically inject the medication every two to four weeks. While some may prefer the less frequent dosing schedule, the requirement for self-injection can be a barrier for individuals who are uncomfortable with needles or who prefer the convenience of an oral medication.

Target Patient Populations

Statins are generally considered the first-line treatment for most patients with high cholesterol, particularly those at risk for cardiovascular disease. They are effective for a broad range of patients and are often prescribed for individuals who need to lower their cholesterol levels as part of their overall heart health strategy.

PCSK9 inhibitors, on the other hand, are typically reserved for more specific, high-risk populations. These include:

• Patients with Familial Hypercholesterolemia (FH): A genetic disorder that causes very high LDL cholesterol levels, often from a young age. PCSK9 inhibitors are especially effective in reducing LDL levels in this population.
• Statin-Intolerant Patients: For those who cannot tolerate statins due to muscle pain or other side effects, PCSK9 inhibitors offer an alternative route to cholesterol reduction.
• High-Risk Cardiovascular Patients: Individuals who have already suffered from heart attacks or strokes, or who have not achieved sufficient cholesterol reduction on statins alone, may benefit from the additional cholesterol-lowering effect of PCSK9 inhibitors.

Efficacy in LDL Reduction and Cardiovascular Outcomes

Both statins and PCSK9 inhibitors are effective in reducing LDL cholesterol, but PCSK9 inhibitors tend to produce more dramatic reductions. While statins typically lower LDL cholesterol by 30% to 50%, PCSK9 inhibitors can reduce LDL by an additional 50% to 60% on top of statin therapy, and in some cases even more.

In terms of cardiovascular outcomes, both statins and PCSK9 inhibitors have been shown to reduce the risk of heart attacks, strokes, and other cardiovascular events. Statins have a long track record of success in this area, with decades of research backing their efficacy. PCSK9 inhibitors, while newer, have also demonstrated significant reductions in cardiovascular events in clinical trials, particularly for patients at higher risk or those with pre-existing heart disease.

Long-Term Safety and Side Effects

Statins have been studied extensively for over 30 years, and their long-term safety profile is well-documented. While side effects such as muscle pain and liver enzyme changes can occur, they are generally well-tolerated by most patients. The long-term benefits of statins, particularly in reducing the risk of heart disease and stroke, far outweigh the risks for the majority of patients.

PCSK9 inhibitors, being relatively new, have less data on long-term safety. Short- to medium-term studies have shown them to be safe and well-tolerated, with few serious side effects. However there is data from people with natural genetic mutations that mimic the effects of PCSK9 inhibitors which provides insight into the long-term safety and efficacy of these drugs.

Ongoing research will continue to monitor their safety over longer periods, especially as their use expands to more patient populations.

When to Consider PCSK9 Inhibitors Over Statins

Statin Intolerance or Ineffectiveness

For most patients, statins are the go-to treatment for lowering LDL cholesterol and reducing the risk of cardiovascular disease. However, not everyone can tolerate statins. Statin intolerance, particularly due to muscle pain (myalgia), is a significant issue for some patients. This condition can range from mild discomfort to more severe pain that interferes with daily activities, leading some patients to discontinue their statin therapy.

In cases where statins cause intolerable side effects or do not reduce cholesterol levels sufficiently, PCSK9 inhibitors provide an alternative. These drugs can deliver substantial reductions in LDL cholesterol without the muscle-related side effects commonly associated with statins. Patients who have experienced significant side effects from statins often find PCSK9 inhibitors to be a more tolerable and effective option.

Familial Hypercholesterolemia (FH)

PCSK9 inhibitors are particularly effective for individuals with familial hypercholesterolemia (FH), a genetic condition that leads to extremely high LDL cholesterol levels from an early age. For patients with FH, standard statin therapy may not be enough to achieve the necessary cholesterol reductions, and many may remain at high risk for cardiovascular events despite treatment. In these cases, adding a PCSK9 inhibitor can result in significant additional LDL lowering, helping these patients achieve safer cholesterol levels and reducing their risk of heart attacks, strokes, and other cardiovascular issues.

• Example: A patient with FH may be on maximum doses of statins but still have LDL cholesterol levels that are much higher than desired. Adding a PCSK9 inhibitor can help them achieve an additional 50% or more reduction in LDL cholesterol, potentially bringing their levels into a safer range.

High-Risk Cardiovascular Patients

Patients who have already experienced cardiovascular events, such as a heart attack or stroke, are often considered high-risk and may require more aggressive cholesterol-lowering strategies. Even if these patients are on high doses of statins, their LDL cholesterol levels may remain elevated, putting them at continued risk for further cardiovascular problems. In such cases, PCSK9 inhibitors can be added to statin therapy to achieve even lower LDL levels, further reducing the risk of recurrent cardiovascular events.

PCSK9 inhibitors have been shown in clinical trials to provide significant cardiovascular benefits in high-risk populations, including those with established heart disease and those who have not responded adequately to statins alone. For these patients, the added benefit of PCSK9 inhibitors in preventing future heart attacks and strokes may justify the higher cost and the injectable route of administration.

Patients with Diabetes or Multiple Comorbidities

Patients with diabetes or multiple other risk factors for cardiovascular disease may also benefit from PCSK9 inhibitors, especially if their cholesterol levels remain high despite optimal statin therapy. In patients with diabetes, aggressive cholesterol management is crucial to reducing the risk of heart attacks, strokes, and other complications. In such cases, PCSK9 inhibitors can be used as part of a comprehensive strategy to manage cholesterol and lower cardiovascular risk.

• Key Consideration: For patients with diabetes who experience side effects from statins, such as worsening blood sugar control, PCSK9 inhibitors offer an alternative that does not have the same impact on glucose metabolism.

Personalization of Treatment

Ultimately, the decision to use PCSK9 inhibitors over statins—or in combination with them—depends on the individual patient's risk profile, treatment goals, and tolerance to therapy. For most patients, statins remain the first-line treatment due to their proven efficacy, affordability, and ease of use. However, for those who need more intensive cholesterol-lowering therapy or cannot tolerate statins, PCSK9 inhibitors represent a powerful tool in managing cardiovascular risk.

Clinical Guidelines in Canada

Canadian Cardiovascular Society Guidelines

In Canada, the management of cholesterol and cardiovascular risk is guided by recommendations from the Canadian Cardiovascular Society (CCS). According to the CCS, statins are considered the first-line treatment for most patients with high cholesterol, particularly those with an elevated risk of heart disease. The guidelines emphasize the importance of reducing LDL cholesterol levels as a primary goal in preventing cardiovascular events.

However, for patients who are either intolerant to statins or who do not achieve sufficient LDL reductions with statins alone, the CCS recommends considering the addition of PCSK9 inhibitors. These guidelines are based on a growing body of evidence showing that PCSK9 inhibitors can provide significant additional cholesterol lowering and reduce the risk of heart attacks and strokes in high-risk populations.

Treatment Protocols

The CCS guidelines suggest a stepwise approach to cholesterol management:

1. Initial Treatment with Statins: Most patients, especially those at moderate to high cardiovascular risk, will start with statin therapy. Statins are usually prescribed at a dose that can achieve a 30% to 50% reduction in LDL cholesterol. For patients with atherosclerotic cardiovascular disease (ASCVD) or other high-risk factors, higher doses or more potent statins (e.g., atorvastatin or rosuvastatin) may be used.
2. Escalation to PCSK9 Inhibitors: If a patient’s LDL cholesterol remains above the target level despite being on maximum tolerated doses of statins, or if they cannot tolerate statins due to side effects, PCSK9 inhibitors may be introduced. This approach is particularly recommended for patients with familial hypercholesterolemia or those who have already suffered from cardiovascular events and remain at high risk for future events.
3. Combination Therapy: In some cases, the guidelines recommend a combination of statins and PCSK9 inhibitors to achieve maximum LDL reduction, particularly in very high-risk patients. This dual therapy can provide a more aggressive reduction in cholesterol levels and a further decrease in cardiovascular risk.
4. Regular Monitoring and Adjustment: The CCS recommends regular monitoring of cholesterol levels and cardiovascular risk factors. Patients who are on statin or PCSK9 inhibitor therapy should have their LDL cholesterol levels checked periodically to ensure that treatment goals are being met. If necessary, treatment plans should be adjusted based on response and tolerance to the medication.

Cost Considerations in Canadian Healthcare

While the clinical efficacy of PCSK9 inhibitors is well-established, the high cost of these drugs remains a barrier for widespread use. In the Canadian healthcare system, public and private insurance plans may cover PCSK9 inhibitors for patients who meet specific criteria, such as those with familial hypercholesterolemia or individuals with high cardiovascular risk who have not achieved sufficient LDL reduction with statins.

The CCS guidelines acknowledge the importance of cost-effectiveness in treatment decisions and recommend that PCSK9 inhibitors be reserved for patients who truly need them. For most patients, statins remain the more affordable and accessible option, especially since many statins are available in generic forms.

Ongoing Research and Future Updates

As new data emerges from ongoing clinical trials, the CCS periodically updates its guidelines to reflect the latest evidence on the efficacy and safety of cholesterol-lowering therapies. For example, the long-term safety of PCSK9 inhibitors is still being studied, and future updates may provide more insights into the optimal use of these drugs in different patient populations.

Conclusion

The choice between statins and PCSK9 inhibitors ultimately depends on individual patient circumstances, including tolerance to medication, cholesterol levels, and overall cardiovascular risk. For most people, statins will remain the foundation of cholesterol management due to their proven benefits and affordability. However, for those who need additional LDL lowering or who cannot tolerate statins, PCSK9 inhibitors represent a new frontier in cholesterol-lowering therapies.

As always, consulting with a healthcare provider is essential for developing a personalized treatment plan. Your doctor can help assess your cardiovascular risk and determine whether statins, PCSK9 inhibitors, or a combination of therapies is the best approach for your long-term heart health.

FAQ

Can PCSK9 inhibitors cause fatty liver?

There is no strong evidence that PCSK9 inhibitors, like Repatha, directly cause fatty liver disease. In fact, these drugs lower LDL cholesterol without significantly affecting liver fat in most cases. However, monitoring liver function during treatment is standard, particularly in patients with existing liver conditions.

Can Repatha replace a statin?

Repatha (a PCSK9 inhibitor) is typically used when statins alone are insufficient or not tolerated. It can replace a statin for people who can’t use statins due to side effects, but for most, it is prescribed alongside statins to further lower cholesterol levels.

Does Repatha remove plaque from arteries?

Repatha does not directly remove plaque from arteries. It significantly lowers LDL cholesterol, which can slow the progression of plaque buildup and may slightly reduce the amount of existing plaque over time, but it does not physically clear it out.

Who should not use Repatha?

People who should not use Repatha include those with a known hypersensitivity or allergic reaction to any component of the drug. Additionally, individuals with active liver disease or certain liver conditions should use it with caution. Pregnant or breastfeeding women should consult with their healthcare provider to weigh risks and benefits.

Do you stay on Repatha forever?

Repatha is typically used as a long-term therapy for managing cholesterol, meaning patients may stay on it indefinitely. However, this depends on individual health factors, cholesterol levels, and cardiovascular risk. Patients may be advised to continue using Repatha as long as it remains effective and no significant side effects occur.

Does Repatha raise A1c?

Repatha has not been shown to raise A1c levels. Unlike some other cholesterol-lowering drugs, such as statins, which may have a small impact on blood sugar levels, PCSK9 inhibitors like Repatha generally do not have a significant effect on A1c or the development of diabetes.

Is Repatha hard on the kidneys?

Repatha is not typically associated with kidney damage or being hard on the kidneys. Clinical studies have not shown a significant negative impact on kidney function, and it is generally considered safe for individuals with kidney disease. However, as with any medication, kidney function should be monitored in patients with pre-existing kidney conditions.

Disclaimer: This blog post is intended for educational purposes only and should not be taken as medical advice. Always consult your healthcare provider for personal health concerns.