Rosuvastatin for cardiovascular disease prevention

As per the New Zealand Cardiovascular Risk Assessment and Management guidelines, patients with a CVD risk of between 5 and 15% should be offered dietary and lifestyle interventions along with consideration of lipid-lowering or blood pressure-lowering pharmacotherapy, based on an individualised assessment of risks and benefits.²

A discussion of dietary and lifestyle modification is beyond the scope of this MedCase but further information can be found in the Cardiovascular Disease Risk Assessment and Management for Primary Care.^2,3

Statins are the preferred first-line medications for lipid management, for both primary and secondary prevention of CVD events.^2,4,5

Multiple, robust clinical trials have demonstrated that statins reduce the risk for nonfatal myocardial infarction, ischemic stroke, need for revascularization, and cardiovascular and all-cause mortality.⁵ They have also been shown to stabilize and even regress established atherosclerotic plaque. Each 1 mmol/L reduction in LDL-C confers a 25% reduction in relative risk of CVD events over 5 years.³ Reductions in LDL-C of >50% can be achieved in people with baseline LDL-C of >4 mmol/L, and CVD risk continues to decline commensurate with LDL-C with no evidence of waning risk reduction even at very low levels of LDL-C.²

In addition to diet and lifestyle changes, Mrs R could benefit from lipid-lowering therapy. Current guidelines recommend a target reduction in LDL-C of at least 40% i.e. target LDL-C of 2.52 mmol/L.

With the recent funding of rosuvastatin, there are now four fully-funded statins to choose from. Any statin may be started, and if treatment is tolerable and targets are achieved there is no need to change therapy.

All statins work to inhibit hepatic cholesterol synthesis, which involves a 30-step pathway.⁵ The rate-limiting step is the reduction of 3-hydroxy-3-methylglutaryl (HMG) to mevalonate. This step is regulated by the enzyme HMG acetyl coenzyme A (HMG-CoA) reductase, which is inhibited by statins. Additionally, statins up-regulate the expression of LDL-C receptors on hepatocytes, promoting clearance of LDL from circulation.⁵

Approximate equivalence of statins (table adapted from He Ako Hiringa and bpac^nz) 

Rosuvastatin is the most potent statin for the reduction of LDL-C, requiring a lower dose to achieve therapeutic effect as shown in the table above.  Higher doses of rosuvastatin allow LDL-C reductions not achievable with other statins, with comparable tolerability, though caution is advised; the 40mg dose is contraindicated in patients with a history of or risk factors for myopathy or rhabdomyolysis (see below).

Additionally, rosuvastatin produces greater increases in HDL-C and reduces triglycerides to an equal or greater extent than atorvastatin, simvastatin or pravastatin.¹¹

Rosuvastatin is currently available under PHARMAC special authority criteria (Appendix 1) for prescription by any relevant practitioner, for patients meeting the eligibility criteria.¹ A flow chart to determine funding eligibility can be found here. If the patient does not meet the funding criteria, consider prescribing a generic to reduce cost.

Points to note about the funding criteria are:

• Pro-equity criteria mean that all Māori and Pacific peoples with an increased CVD risk are eligible for funded first-line treatment with rosuvastatin;
• Patients on a maximum tolerated dose of atorvastatin and/or simvastatin must also have:
  • a calculated risk of CVD of ≥15% over five years, and LDL-C level remains ≥1.8mmol/L;
  • familial hypercholesterolaemia (Dutch Lipid Clinic Network score ≥6), and LDL-C level remains ≥1.8mmol/L;
  • coronary artery disease, proven peripheral artery disease or ischaemic stroke, and LDL-C level remains ≥1.4mmol/L;
  • a recurrent major cardiovascular event (myocardial infarction, ischaemic stroke, coronary revascularisation, hospitalisation for unstable angina) in the last two years, and LDL-C level remains ≥1.0mmol/L;
• The tolerability of a current statin is based on the prescriber’s clinical judgement;
• There is a waiver process for patients currently self-funding rosuvastatin who would have been eligible at the time of starting self-funding. 

Statins are generally well tolerated as a class. Adverse effects from rosuvastatin are usually mild and transient, with a discontinuation rate of less than 4% in clinical trials (similar to placebo).¹² Serious adverse effects are rare and typically emerge in the first three months of treatment.⁷

The most common adverse effects include headache, dizziness, nausea, abdominal pain. Dose-related increases in liver transaminases and creatine kinase (CK) may occur.¹⁰

Myopathy and Rhabdomyolysis

Skeletal muscle effects of statins may range from myalgia to myopathy (muscle pain or weakness with a rise in CK) and rhabdomyolysis.¹⁰ Though rare, these effects are widely known and statin intolerance is often over-diagnosed. A stepwise approach and measurement of CK is recommended for patients reporting muscle pain (see your local HealthPathways or NZ Formulary for specific guidance).¹⁰

Diabetes

Rosuvastatin is associated with dose-related increases in HbA1c, contributing to a potentially higher risk of diabetes mellitus especially in patients at high risk of this condition.

However, the 2010 Cholesterol Treatment Trialists (CTT) meta-analysis found only one extra case or diabetes mellitus, defined as HbA1c of ≥50 mmol/mol on two occasions, per 1000 patients treated for one year with a statin.¹³ 

Thus, the absolute risk is low and must be considered against the benefits of reduced cardiovascular events which more than offset the diabetes effects.

Interactions

Statins have a range of potential interactions though, unlike simvastatin and atorvastatin, there are no clinically significant cytochrome P450 interactions with rosuvastatin. However, there are a number of important interactions based on rosuvastatin’s action as a substrate for transport proteins in the liver. See NZ Formulary and the Rosuvastatin Viatris Data Sheet for information on specific drug-drug interactions, including with commonly used medications such as clopidogrel, warfarin, colchicine and leflunomide.

Before starting treatment, ensure there are recent liver function tests and a CK level for a baseline reference; these should be monitored periodically and rosuvastatin dose reduced or withdrawn if there are persistent elevations in ALT or AST greater than three times the upper limit of normal.¹⁰

For hypercholesterolaemia, the usual dose range is 5-40mg once daily.¹⁰ No dosage adjustments are required for elderly patients or those with mild-to-moderate renal or hepatic impairment; specific recommendations can be found in the data sheet for patients with severe renal or hepatic impairments or genetic polymorphisms.

A lower starting dose of 5mg may be considered for some Asian patients (Filipino, Chinese, Japanese, Korean, Vietnamese or Asian-Indian origin), who may experience two-fold higher systemic concentrations of rosuvastatin. The 40mg dose is relatively contraindicated in these patients and up-titrations should be done with caution.

A response to treatment – a reduction in LDL-C – occurs within one week of starting treatment and 90% of the maximum response is evident after two weeks of treatment.

Rosuvastatin, like atorvastatin, has a long half-life and can be taken at any time of day, with or without food; pravastatin and simvastatin have shorter half-lives and are recommended for night-time dosing to ensure maximum effect on cholesterol synthesis, which peaks during overnight fasting.¹⁰

This MedCase was written in 2022 by Dr Vicki Mount ( MBChB FRNZGP), with expert review by Dr Chris Ellis (BM, MRCP (UK), FRACP, FACC, FCSANZ)