Consumption of single products versus fixed-dose combination medicines for hypertension and hyperlipidemia during 2015–2019 in South Korea

Background Fixed-dose combinations can simplify prescribing, and numerous combination products exist for hypertension and dyslipidemia in South Korea. This study’s aim was to compare trends in the consumption of single products versus fixed-dose combinations for hypertension and hyperlipidemia. Methods and findings We analyzed the Korean national health insurance claims database from January 2015 through December 2019. Consumption of medicines was calculated using the defined daily dose per 1,000 inhabitants per day (DIDs) and expenditures over time. During 2015–2019, the use of antihypertensive drugs increased with an annual growth rate (AGR) of 0.9% for single products and with an AGR of 35.6% for fixed-dose combinations. A notable increase was observed for antihyperlipidemic combination drugs with an AGR of 268.1% compared to single products with 35.7%. For older adults (65+ years), the consumption of drugs for hypertension and hyperlipidemia was 3–4.5 and about 3 times higher, respectively, than in adults aged 20–64 years, and a sharp increase was found in antihyperlipidemic fixed-dose combinations among older adults. A large increase was seen for C09 (agents acting on the renin-angiotensin system) with an AGR of 36.5%, especially C09DB (angiotensin II receptor blockers + calcium channel blockers) was widely used and steeply increased with 114.2%. For antihyperlipidemic drugs, C10AA (HMG CoA reductase inhibitors) accounted for a large share and sharply increased, with 52.1 DIDs in 2019 and with an AGR of 78.4%, whereas C10BA (combinations of various lipid modifying agents) increased 9.6 times from 2.9 DIDs (96 million USD) in 2015 to 27.7 DIDs (912 million USD) in 2019. Conclusion The findings of increased consumption and drug spending among older adults underscores the need for real-world evidence about health outcomes of fixed-dose combinations in this population.


Introduction
Hypertension and dyslipidemia are known to be major risk factors for cardiovascular disease (CVD) [1]. In 36 Organization for Economic Co-operation and Development (OECD) countries, cardiovascular disease is the top cause of death as of 2017, accounting for 31% of deaths [2]. Therefore, to control blood pressure or cholesterol, the International Society has published treatment recommendations such as JNC 8. In South Korea (hereafter, Korea) in 2018, the prevalence of hypertension was 28.3%, that of hypercholesterolemia was 21.4%, and that of hypertriglyceridemia was 17.1% [3].
Fixed-dose combinations (FDCs) for antihypertensive or antihyperlipidemic drugs can make it easier for patients to take those drugs, thereby improving medication compliance. According to the National Committee (JNC 8) guideline in 2014, American College of Cardiology (ACC) and American Heart Association (AHA) guideline in 2017, and European Society of Cardiology/European Society of Hypertension guideline in 2018, FDCs can improve adherence and help to achieve treatment outcomes [1,[4][5][6]. Furthermore, the ACC/AHA guideline on the prevention of cardiovascular disease and the Clinical Practice Guidelines of the Korean Society of Lipid and Atherosclerosis recommended that combination therapy could lower low-density lipoprotein cholesterol levels [7,8].
In Korea, 996 and 300 combination drugs for hypertension and dyslipidemia, respectively, were reimbursed in 2019, and the use of combination drugs is high [9], whereas most other countries generally use single-ingredient products. The OECD has published Health Statistics and Pharmaceutical Market Statistics, and requires each member country to submit pharmaceutical consumption data for drugs that have defined daily dose (DDD) values according to the World Health Organization (WHO) ATC-DDD classification [10]. The consumption of cardiovascular drugs such as antihypertensive and antihyperlipidemic drugs in Korea has been reported to be lower than that of other countries, while their expenditures are relatively high [11].
Several studies have analyzed the overall consumption of antihypertensive drugs [12][13][14][15]. However, few studies have examined single pill versus FDC therapy, because there are limited real-world data for comparisons of FDC use [16,17]. Moreover, few studies analyzed use of antihyperlipidemic drugs [18]. Nationwide trends in the use of antihypertensive and antihyperlipidemic FDCs can provide insight into the need for further studies. Therefore, we aimed to examine patterns of use of combination drugs for hypertension and hyperlipidemia in Korea by patient age and therapeutic group using a nationwide database.

Data source
We conducted a retrospective population-based study using the Korean national health insurance claims database from January 2015 through December 2019. This database contains information on both in-hospital and outpatient visits from a population of 51.8 million as of 2020. The database includes demographic characteristics, diagnosis, health care utilization, and medicine use (product name, ingredient name, dose, days of therapy, and spending). The analytical unit of this study was the medications listed in the health care claims data from the entire population.

Study medicines and therapeutic class
Based on the WHO Anatomical Therapeutic Chemical (ATC) classification, drugs were selected if their ATC-2 classification indicated that they were antihypertensive drugs (C02, C03, C07, C08, C09) or antihyperlipidemic drugs (C10) [19]. For combination drugs, each drug was calculated by summing the DDDs for the main active ingredients. We classified the medicines into the ATC-4 level. The ATC-3 level refers to the pharmacological subgroup, and the ATC-4 level refers to the chemical subgroup. For example, level 3 C10A contains plain lipid-modifying agents, and level 4 C10AA refers to HMG CoA reductase inhibitors, and level 5 C10AA01 is simvastatin.
The number of combination drugs for hypertension increased from 767 in 2015 to 996 in 2019, and the number of combination drugs for hyperlipidemia steadily increased from 111 in 2015 to 300 in 2019. However, it temporarily decreased due to the valsartan carcinogen incident in 2019 [20].

Measures and calculations
We analyzed changes in consumption and pharmaceutical spending according to each dimension using the health insurance database. The measure indicators were consumption and sales. Drug consumption figures were presented as numbers of DDDs/1000 inhabitants/day (DIDs), which is calculated as number of DDDs × 1000 / total population / 365, and pharmaceutical sales are given in units of millions of dollars [10,11]. Using the ATC/DDD system allows standardization of drug groupings and stable drug utilization metrics to enable comparisons of drug use between countries, regions, and other health care settings, as well as making it possible to examine trends in drug use over time and in different settings. DIDs may provide a rough estimate of the proportion of the population within a defined area treated daily with certain drugs. DDDs provide a fixed unit of measurement independent of price, currency, package size, and strength, enabling researchers to assess trends in drug consumption and to perform comparisons between population groups. Pharmaceutical spending referred to total spending including value-added tax (VAT). We analyzed the consumption and spending according to each dimension.
The analytical dimensions were patients' age and drug classification based on (ATC) system. We used the number of population by year and age of the Statistic Korea. Sales were calculated in millions of dollars. The age of the patients was divided into those under 65 and over 65 years of age.  Table 2 shows trends in consumption and pharmaceutical expenditures by age groups. In older adults, the consumption of drugs for hypertension was 3-4.5 times higher than among adults 20-64 years of age, and the consumption of antihyperlipidemic drugs was about 3 times higher. Table 3 shows trends in antihypertensive drug use by ATC level 2 and level 3 classification. The consumption of C03 (diuretics) showed no change, that of C07 (beta-blocking agents) increased slightly, and that of C08 (calcium channel blockers) decreased slightly. The only obvious increase was found for C09 (agents acting on the renin-angiotensin system) with an AGR of 36.5%. C09D (ARBs, combination) increased greatly from 112.3 DIDs in 2015 to 153.3 DIDs in 2019 and C09C (ARBs, plain) increased from 40.1 DIDs to 45.8 DIDs, while C01A (ACE inhibitors plain) decreased from 5.6 DIDs to 4.1 DIDs.

Discussion
This study investigated national trends in antihypertensive and antihyperlipidemic drugs in terms of single products versus FDCs during 2015-2019 using national health insurance claims data. Of note, the patterns that we found are meaningfully different from those observed in other countries. During the past 5 years, ARBs and CCBs were the most commonly used drugs in Korea. In contrast, a study in Denmark found that ACE inhibitors were the most frequently used drugs. According to Sundbøll et al., the overall consumption of antihypertensive drugs was 379 DIDs, and the most commonly used therapeutic classes were ACE inhibitors with 105 DIDs, CCBs with 82 DIDs, diuretics with 81 DIDs, and ARBs with 72 DIDs [15]. Another study from Croatia stated that the most common ATC level 2 subgroup was C09 (agents acting on the renin-angiotensin system (RAS)), with 202 DIDs; followed by C08 (CCB), with 70.7 DIDs; and C03 (diuretics), with 48.2 DIDs in 2016 [13]. However, that study did not analyze more specific therapeutic groups. According to Huang et al., the highest utilization of antihypertensive drugs in Taiwan was found for CCBs (35.1 DIDs), followed by ACE inhibitors (19.6 DIDs) and beta-blockers (19.9 DIDs) [12]. A study from the Russian Federation analyzed the use of combination drugs and reported that the leading therapeutic class was the combination of ARBs + diuretics [17]. Similarly, a study in Campania (Italy) and Aragon (Spain) showed that ACE inhibitors were most frequently used, followed by ARBs and CCB or ARB + diuretics (40.2 DIDs, 13% in Campania and 33.9 DIDs, 13.2% in Aragon, respectively) [16]. However, notably, the combination of ARBs + CCBs was the most frequently used drug in Korea. We also found an increasing trend in this combination among older adults. The JNC8 guideline and Korean Society of Hypertension recommend combination therapy of ARB or ACE inhibitor + CCB, ARB or ACE inhibitor + diuretics, and CCB + diuretics [1,21]. The Korean Society of Lipid and Atherosclerosis also recommended combination therapy of statin and other lipid-modifying agents in their guideline for the management of dyslipidemia. This result is consistent with the recommendation of FDC use to reach the target.  According to several meta-analysis studies, the FDC treatment is associated with a significant improvement in adherence and persistence in comparison with single therapy or free-equivalent combined therapies (FECs), thereby increase of BP control effect [22,23], so these strategies have been preferred compared with conventional therapies [24]. To our knowledge, this is first study that conducted an analysis of the pharmaceutical market including single pills and FDCs because there are limited real-world data on the amount of FDCs. Second, considering recall and withdrawal of valsartan due to the carcinogen nitrosodimethylamine (NDMA) in August 2018, this result showed the corresponding change in therapeutic classes. Lastly, most existing studies were limited to a single region, whereas we used a nationwide population dataset to obtain representative results. However, the patterns of clinical practice are different from those reported in other studies; in particular, the use of CCBs was found to be somewhat high in the Korean antihypertensive drug market. Thus, future research investigating physicians' and patients' preferences for antihypertensive drugs might clarify this finding.
Our study has several limitations. First, our analysis used an administrative dataset; thus, information was lacking on the clinical factors associated with therapy selection. For example, the combination of beta-blockers and diuretics might increase the risk of incidence of diabetes mellitus. Because we could not distinguish patients' conditions, we only analyzed the amount of drug consumption and spending. Like other administrative databases, the Korean health insurance claims data are the basis for payment, resulting in inherent limitations, including incompleteness and inaccuracy in complicated diagnoses. Second, when calculating drug spending, preparation fees by pharmacists were not included in this study.
Despite these limitations, this is the first study to investigate trends in single pill versus fixed-dose combinations in antihypertensive and antihyperlipidemic drugs using real-world data at the national level. In conclusion, consistent with the increased prevalence of hypertension and dyslipidemia due to population aging, the consumption and drug spending of antihypertensive and antihyperlipidemic fixed-dose drugs was higher in older adults, and a marked increase in FDCs was found among older adults, driven by ARBs + CCBs as antihypertensive drugs. Special attention should be paid to real-world evidence on the health outcome of FDCs in terms of improved medication adherence and control of blood pressure or lipid levels in older adults.