Specialty Corner: Differences in Statin Metabolism in East Asians

Elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) play a significant role in the development of Coronary Artery Disease (CAD).(1) In clinical trials, reducing LDL-C to desired levels determined by the individuals’ cardiovascular risk factors and/or having established Atherosclerotic Cardiovascular Disease (ASCVD) has demonstrated a reduction in ASCVD related morbidity and mortality.(2)  According to the 2015-2018 National Health and Examination Survey, 11.4% of the United States population had elevated total cholesterol.(3) To date, there are limited data evaluating the prevalence of dyslipidemia of different racial/ethnic groups, notably the Asian population. Observational studies have noted an increased prevalence of elevated LDL-C among East Asians (Japanese and Vietnamese) in comparison to Caucasians.(4)    3-hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, otherwise known as statins, are the first-line treatment for LDL-C lowering in both primary and secondary prevention. (5) Landmark trials have demonstrated a significant reduction in the cardiovascular burden with statin administration in the general population, however, these trials did not differentiate ethnicity, particularly in Asians, and the differences in statin response.(2,6,7)  This review will focus on differences in statin metabolism in East Asians (referred to as Asians) which includes but is not limited to Chinese, Japanese, Korean, and Vietnamese.

Efficacy and Safety of Statins in Asians
It has been well reported that Asians achieve similar LDL-C goals compared to Caucasians at lower statin doses.(8-12) The Japanese Lipid Intervention Trial (J-LIT), a large scale, open-label, prospective, clinical trial, evaluated the relationship between the incidence of Coronary Heart Disease (CHD) and serum lipid concentrations with low-dose simvastatin in Japanese patients without CHD. Overall simvastatin 5mg daily lowered LDL-C by 26.8% which was comparable to the efficacy of simvastatin 20mg daily used in western countries.(7,8) Similarly, the the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study evaluated the first occurrence of CHD with low dose pravastatin (10-20mg) daily in Japanese patients without CHD. A significant CHD risk reduction (HR: 0.67; 95% CI: 0.49-0.91; p=0.01) was noted with the low pravastatin dose plus diet which is comparable to the efficacy of much higher doses seen in western studies (Table 1).(9)  Also a significant reduction in the mean LDL-C (-18% vs. 3%; p<0.0001) was noted in the pravastatin plus diet group versus the diet alone group, respectively. Even though the pravastatin dose was half the dose of what is typically administered to western patients, this trial demonstrated significant LDL-C and CHD risk reduction in Japanese patients.(9)

In comparison, the Direct Statin Comparison of LDL-C Values: an Evaluation of Rosuvastatin Therapy (DISCOVERY) trials were a series of multicenter trials in different countries that compared the LDL-C percentage change in response to rosuvastatin or atorvastatin therapy in statin-naïve patients or patients who were directly switched from another statin with a 10-year cardiovascular risk > 20% or with a history of CHD.(9.10) The DISCOVERY-Hong Kong trial found that Chinese patients who were statin-naïve had a greater LDL-C reduction (52.8%) compared to patients in the DISCOVERY studies from western countries (-40.9% to- 49.7%) receiving rosuvastatin 10mg daily.(9,10) Unlike rosuvastatin, the DISCOVERY series demonstrated that the LDL-C response to atorvastatin between Chinese patients and other populations was similar. Li et al.(12) conducted a meta-analysis evaluating patients with CHD. The rosuvastatin 40mg daily patient group resulted in a 49.4+2.6% LDL-C reduction and atorvastatin 80mg daily patient group resulted in a 43+2.1% LDL-C reduction for western patients (Europe, America, and Australia). Additionally, rosuvastatin 14.1+4.9mg daily and atorvastatin 18.9+2.9mg daily lowered LDL-C by 44+4.8% and 40.7+5.5 respectively, in Asian patients.(12)

Statin doses are important considerations not only for efficacy but safety. The
4-S trial included 4,444 patients from Scandinavia and the most frequent adverse events observed were liver enzymes abnormalities and an increase in creatine kinase in the simvastatin group.(6) In comparison, a large-placebo trial of 25,673 Chinese patients demonstrated a higher absolute risk of myopathy compared to Europeans with simvastatin 40mg daily.(13) The usage of higher doses of statins may lead to an additional risk for adverse events in Asian patients. The J-LIT trial demonstrated that low-dose statin therapy had an overall adverse event frequency of 3.2% over 6 years with the most frequent side effects noted as hepatic dysfunction.(8) Additionally, the MEGA study found no difference in the rate of myopathy or other adverse events between the diet alone or diet plus pravastatin 10 to 20mg daily.(9)

Pharmokinetics and Pharmacodynamics of Statins
Asians tend to have a lower body mass index and body weight which led to previous prescribing practices to utilize lower statin doses compared to Caucasians.(10,14) It is now known that age, weight, body surface area, and lean body mass have no significant effect on the pharmacokinetics of statins, rather the plasma concentration (Cmax) and area under the curve (AUC) are proportional to the dose and impacts the pharmacological response.(15-17) Plasma exposure and the active metabolites of rosuvastatin were noted to be two-fold higher in Asians compared to Caucasians living in a similar environment.(15) In comparison, pitavastatin demonstrated a similar Cmax despite differences in body weight, height, and BMI between the Asian and Caucasian groups.(17) Additionally, a pharmacodynamic analysis of rosuvastatin between Asians (5-20mg) and Caucasians (10-40mg) demonstrated no significance in the dose-response relationship for LDL-C reduction.(16) Of the seven available statins, the Food and Drug Administration advises initiating a daily low dose (5mg) of rosuvastatin in the Asian population.(18) In Japan the approved maximum dose for all the statins is much less than the approved maximum doses in the United States, except for pitavastatin which is a maximum dose of 4mg for both populations.(7,17)

Implications of Statin Pharmacogenomics  
The exact mechanism behind the differences in statin response between Asians and Caucasians is not fully understood however genetic determinants have been proposed to explain the interethnic differences in pharmacological response. Drug transporters are expressed throughout various organs and facilitate the uptake and efflux of drugs in the body.(19) In particular, organic anion transporting polypeptides (OATPs) are expressed on the basolateral membrane of hepatocytes and mediate the hepatic uptake of statins except for fluvastatin. (7,15,20) OATPs are responsible for gut absorption, hepatocyte transport, and bile excretion. Genetic polymorphism of SLCO1B1 which encodes OATP1B1 and ATP-binding cassette (ABC) transporters may lead to increased influx activity and thus increased plasma exposure.(14) SLCO1B1 polymorphism includes two single-nucleotide peptides (SNP) 388A>G and T521>C which were noted in Asians and demonstrated a two-fold increase in the median exposure of the Cmax and AUC with rosuvastatin administration. (14,15)  Individuals with the SLCO1B1 genotype c.521CC were noted to have 62-117% greater AUC with rosuvastatin therapy and an overall increased plasma concentration with all statins except for fluvastatin.(14) Additionally, SLCO1B1 polymorphism involves four haplotypes and the allele frequency of these haplotypes was observed to be different between ethnic groups (Japanese, European-American, and African-American) which may explain the various pharmacologic response.(7) Notably, SLCO1B1*1b
had upregulated transport activity on hepatic cells whereas SLCO1B1*5 was associated with downregulated transport activity. The major genetic polymorphism associated with the ATP-binding cassette G2 gene (ABCG2) is ABCG2 c.421C>A. This polymorphism was observed to
be more prevalent in East Asians (35%) compared to Caucasians (14%).(10,19) The plasma concentration of rosuvastatin was twice as high in patients with this genetic variant compared to the wild-type genotype.(7,10) Additionally, this genetic variant is associated with a greater LDL-C reduction with rosuvastatin administration in Asians and may contribute to the interethnic differences in the pharmacological response. Further, 16% of Asians were noted to have CYP2C19 slow metabolizer polymorphism compared to 1% of Caucasians which may result in prolonged drug clearance and subsequently an increase in drug exposure.(13) Physicochemical properties and metabolizing pathways may also account for the differences in statin disposition and response. The solubility profile of statins depends on the ability to dissolve in water or lipid-containing media and may impact statin-related adverse events.(43) Lipophilic statins can enter cell membranes through passive diffusion resulting in rapid absorption and wide distribution throughout tissues. In comparison, hydrophilic statins have greater hepatoselectivity and require less modification by cytochrome P450 enzymes for elimination.(43) Rosuvastatin is a hydrophilic molecule with minimal metabolites and few enzymes and transporters in comparison to other statins.(14) (Table 2) Similarly, pravastatin is a hydrophilic molecule however it is eliminated in the kidneys rather than the bile therefore additional efflux transporters are noted.(14) Genetic polymorphism in transporting activity may lead to impaired activity and thus impacting statin response. More studies are required to further explore the pharmacokinetic and pharmacogenetic statin differences as this may translate into assisting the clinician in optimizing statin pharmacotherapy in Asians.

Conclusion
Differences in the pharmacologic responses of statins between the Asian and Caucasian populations have been observed in various studies.(2,4,6-19,22,23,25-27) These differences are largely thought to be caused by a genetic polymorphism in drug metabolism, metabolizing enzymes, and statin transporters. Therefore, it is vital to consider the ethnic differences when initiating statin therapy to assure optimal statin efficacy and minimize adverse events.

Disclosure statement:
Dr. Chan has no financial disclosures to report.
Dr. Coriolan has no financial disclosures to report.
Dr. Plakogiannis has no financial disclosures to report.
References are listed in the 2021 Fall LipidSpin .pdf on www.lipid.org