Pharmacological Therapy

Recommendations for Treatment Strategy:

  • Initially, treatment with a high-intensity statin at the highest tolerated dose is recommended. The statins simvastatin, lovastatin, pravastatin, and fluvastatin are still widely used. However, due to their limited efficacy, they should no longer be used; treatment with a high-intensity statin is recommended
  • In patients at very high risk, LDL-C should be lowered in apparently healthy individuals under 70 years of age to < 1.4 mmol/L (55 mg/dL) and by at least more than 50% from baseline.
  • In patients at high risk, LDL-C should be lowered in apparently healthy individuals under 70 years of age to < 1.8 mmol/L (70 mg/dL) or by at least more than 50% from baseline.
  • In patients with known ASCVD (atherosclerotic cardiovascular disease), LDL-C should be reduced to < 1.4 mmol/L (55 mg/dL) and by at least more than 50% from baseline.
  • If this target is not achieved with the maximum tolerated statin dose, combination therapy with ezetimibe is recommended.
  • If patients in secondary prevention do not reach target levels with a combination of statin and ezetimibe, additional treatment with a PCSK9 inhibitor is recommended.
  • Patients at very high risk (patients with ASCVD or another major risk factor) who do not reach their LDL-C target with the maximum tolerated doses of statins and ezetimibe should receive combination therapy with a PCSK9 inhibitor.
  • In cases of statin intolerance, treatment with bempedoic acid or ezetimibe can be considered.
  • If patients in secondary prevention with statin intolerance do not reach target levels with a combination of bempedoic acid and ezetimibe, additional treatment with a PCSK9 inhibitor is recommended.
  • Patients at very high risk (with ASCVD or another major risk factor) who do not reach their LDL-C target with a combination of bempedoic acid and ezetimibe due to statin intolerance, should be treated with combination therapy including a PCSK9 inhibitor.
  • Statins
  • Statins inhibit cholesterol synthesis by competitively inhibiting the activity of HMG-CoA reductase. The decrease in intracellular cholesterol concentration leads to an increased expression of LDL receptors on the surface of liver cells.
  • As a result, there is an increased uptake of LDL-C and triglycerides by the liver cells and hepatocytes, leading to a reduction in the blood concentrations of lipoproteins.
    The extent of this reduction is dose-dependent and varies depending on the specific statin used.
  • With statins, LDL cholesterol levels can be reduced by 30 to 40%.
    This reduction is dose-dependent. Doubling the statin dose does not cut cholesterol in half, but only reduces it by approximately 6% (known as the “Rule of Six”).
  • Statins reduce the risk of combined major coronary events, both fatal and non-fatal strokes, and the need for revascularization. The greater the reduction in LDL-C, the lower the rate of combined serious cardiovascular events.
  • A reduction of LDL-C by 40 mg/dL decreases the risk of coronary events by 21% and the risk of stroke by 17%.
  • The benefits of statin therapy were consistent across all analyzed subgroups.
    Even in the first year of treatment, a significant benefit was observed, which increased in subsequent years.
  • The studies found no evidence that statin therapy increases the risk of other causes of death, particularly cancer.
  •  
  • The risk reduction in primary prevention is roughly equal to that in secondary prevention. Of course, the absolute risk of cardiovascular events is lower in primary prevention.
    The reduction in cardiovascular events is independent of which statin is used; it depends solely on the extent of LDL-C lowering.
  • Due to the higher incidence of coronary events, statin therapy in diabetic coronary patients is, on average, more effective in reducing cardiovascular events than in coronary patients without diabetes.
  • Statins also reduce cardiovascular events in diabetic individuals without manifest coronary heart disease.
  • In the meta-analysis, no difference was found between diabetics and non-diabetics.

Treatment of unstable plaque with statins

Aspirin was long recommended as a prophylactic therapy, based on the idea that its antithrombotic properties could reduce the risk of vascular occlusion in the event of plaque rupture.

However, three large studies on aspirin showed only minimal benefits in patients with unstable plaques, while the risk of bleeding remained elevated.
Therefore, effectively managing the lipid profile through medication is more beneficial than the prophylactic use of aspirin.

 

Statin therapy has been shown in numerous studies to reduce plaque volume by approximately 3.6%, decrease non-calcified plaque volume, and increase calcified plaque volume.
In contrast, the control groups showed a significant increase in both calcified and non-calcified plaque volume. A significant reduction in vulnerable plaques can be achieved with treatment durations of less than six months

Side Effects of Statins

Statins have been thoroughly studied regarding potential increased risks for dementia, liver failure, cancer, thrombosis, polycystic ovary syndrome (PCOS), and Alzheimer’s disease.
So far, no clinically relevant effect has been found for any of these conditions.
A Cochrane analysis specifically found no evidence that statins increase the risk of Alzheimer’s disease.

The most clinically significant side effect of statins is statin-associated muscle symptoms (SAMS), which often lead to discontinuation of treatment.
The incidence of SAMS is difficult to estimate. In randomized clinical trials, the frequency of muscle complaints was similar in both placebo and treatment groups.
In registry studies, incidence rates range from 10 to 30% of treated individuals.

Statins can cause pre-existing mild myopathies to become symptomatic.
A delayed remission of symptoms after discontinuing the statin may be a clue.
In most cases, creatine kinase (CK) levels are elevated, and these patients often already had elevated CK values before treatment.

Rhabdomyolysis is a particularly feared complication. Patients experience muscle pain, and in advanced stages, muscle breakdown occurs, CK levels rise to more than ten times the normal value, and life-threatening kidney failure can result.
Rhabdomyolysis is rare, occurring in approximately 1 to 3 cases per 100,000 patient-years.
Much more common are myalgias without elevated CK—about 10 to 15% of patients report muscle pain.

Simvastatin and atorvastatin are metabolized via the cytochrome P450 isoenzyme 3A4.
If myalgia occurs, switching to rosuvastatin should be considered.

In 0.5 to 2% of patients, statins cause an increase in glutamate-pyruvate transaminase (GPT).
This mild elevation does not affect liver function, and liver failure is extremely rare, so routine GPT monitoring is not necessary.

Statins slightly increase the risk of developing type 2 diabetes.
To cause one case of diabetes, 255 patients would need to be treated with statins for four years.

Nearly all patients with type 2 diabetes mellitus have metabolic syndrome, which includes overweight or obesity, high blood pressure, lipid metabolism disorders, and impaired glucose tolerance.
These patients are at significantly increased risk for heart attack and stroke.
This risk rises years before a diabetes diagnosis.

One of the most effective ways to reduce this risk is treatment with statins.
Especially in patients who have already had a heart attack, reducing LDL-C with statins is absolutely essential to prevent another potentially fatal heart attack.

Therefore, the decision to take a statin should be based on the individual’s risk profile.
In this context, the small increased risk of developing diabetes earlier is negligible.

Drug Interactions with Statins

Except for pravastatin and rosuvastatin, the other statins are metabolized in the liver via the cytochrome P450 system.

  • About 10% of rosuvastatin is metabolized by the enzyme CYP2C9, while other CYP enzymes play only a minor role. This reduces the risk of interactions with other medications that affect the cytochrome P450 system.
  • The majority of rosuvastatin (around 90%) is excreted unchanged via the bile and stool, distinguishing it from other statins that are more extensively metabolized. This means that rosuvastatin largely remains in its active form in the body and acts directly before being excreted.
  • Other drugs that are metabolized via the same pathway can cause a significant increase in plasma concentrations of statins, potentially leading to myalgias and rhabdomyolysis.

These interacting drugs include antimicrobials such as:

  • Itraconazole
  • Ketoconazole
  • Erythromycin
  • Clarithromycin
  • HIV protease inhibitors

The same metabolic pathway is also used by calcium channel blockers:

  • Verapamil
  • Diltiazem
  • Amlodipine

Especially in patients with metabolic syndrome and hypertension, statin therapy should be started with an agent that does not interact with calcium channel blockers.
When treating with amlodipine, doses of simvastatin higher than 20 mg should not be used.

Other substances that also interact with statins include:

  • Ciclosporin
  • Danazol
  • Amiodarone
  • Grapefruit juice
  •  

Practical Approach

Treatment should be started with highly effective statins such as atorvastatin or rosuvastatin.
Both can be taken in the morning, which improves compliance, as the medication is less likely to be forgotten.

  • Pravastatin and simvastatin should be taken in the evening, which unfortunately often leads to missed doses.
    Pravastatin and simvastatin are not more cost-effective than atorvastatin and rosuvastatin, and the latter are significantly more effective.