New recommendations for simvastatin use in Asians based on findings from the HPS2-THRIVE study

HSA is recommending for the local package inserts of simvastatin-containing products to be updated to provide new recommendations for the use of simvastatin in Asians. These recommendations are based mainly on findings from the Heart Protection Study 2 – Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE),¹ which showed a higher rate of myopathy in the Chinese population.

Simvastatin is a HMG-CoA reductase inhibitor indicated as an adjunct to diet for dyslipidemia. In patients at high risk of coronary heart disease (CHD) or with existing CHD, it is indicated to reduce the risk of CHD death, non-fatal myocardial infarction and stroke, as well as to reduce the need for coronary and non-coronary revascularisation procedures.

Background

The HPS2-THRIVE study recruited over 25,000 patients with pre-existing cardiovascular disease from the UK, Scandinavia and China. It was designed to assess cardiovascular outcomes following addition of extended-release niacin/laropiprant 2g/40mg or placebo to simvastatin (with or without ezetimibe). No other statins were investigated in this study. Failure to achieve the study’s primary endpoint of reducing cardiovascular events, coupled with a statistically significant increased risk of non-fatal serious adverse events, led to the worldwide withdrawal of niacin/laropiprant in January 2013.

A subsequent review of the study data revealed important observations about the use of simvastatin in Chinese patients, who formed 40% of the study population. This led to new precautions advising caution when prescribing simvastatin to Asian patients and that the lowest dose necessary should be employed. Although Chinese patients were the only Asians assessed in HPS2-THRIVE and data in other Asian populations is limited, MSD Pharma (Singapore) Pte Ltd, the local product licence holder for Zocor® (the innovator brand of simvastatin), had proposed for these new precautions for simvastatin use to be extended to all Asians, including Japanese, Malays and Asian-Indians, due to the potential seriousness of myopathy.²

Asian data from HPS2-THRIVE^2,3

Overall, the risk of myopathy observed in HPS2-THRIVE was four times greater with niacin/laropiprant and simvastatin compared to simvastatin alone (0.58% vs 0.13%, p<0.0001). This difference was primarily driven by a higher occurrence of myopathy in Chinese patients, where the incidence with dual therapy was 1.24% compared to 0.24% in the simvastatin control group (p<0.0001). In Europe, the incidence was 0.05% and 0.03%, respectively. However, the results did not show statistical significance (p=0.37).

To date, the specific cause of the increased susceptibility of Chinese patients to myopathy has not been identified. Other studies have shown a trend of marginally higher exposure of simvastatin and its active metabolite, simvastatin acid, in Asians compared to non-Asian subjects taking simvastatin.² However, the higher myopathy rates in Chinese patients taking both simvastatin and niacin/laropiprant did not correspond with higher exposure of simvastatin compared to non-Asians taking this drug combination. This suggests there may be other factors apart from pharmacokinetics that could cause an increase in myopathy among Chinese patients. Previous studies have shown that polymorphisms in the SLCO1B1 gene are associated with an increase in myopathy due to their effect on the metabolism of simvastatin. However, the prevalence of variants appears to be similar in Asian and European population. Thus, this genetic factor currently does not explain the differential risk observed.

HSA’s advisory and actions

The benefit-risk profile of simvastatin remains positive when used for its licensed indications. Healthcare professionals are advised to prescribe simvastatin with caution to Asian patients and to use the lowest dose necessary. In addition, co-administration of simvastatin with lipid modifying doses (>1g/day) of niacin is not recommended in Asian patients. As the data supporting these new recommendations arose from the HPS2-THRIVE study that did not investigate other statins, it is not known at this point if these findings can be extrapolated to other statins. In the meantime, HSA is working with the companies to update the new recommendations in the local package inserts of all simvastatin-containing products.

References

1. Eur Heart J 2013; 34: 1279-91
2. Clinical overview provided by MSD Pharma (Singapore) Pte Ltd to HSA
3. Singapore package insert for Zocor®. Approved 26 Mar 2014

Published: 29 Aug 2014

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