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, 4–6]. 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 [12-15]. 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.

Materials and methods

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.

Results

Consumption and sale by single pill versus fixed-dose combinations

Table 1 examines the consumption and total pharmaceutical expenditures by categories of medicines. In 2019, the number of patients prescribed combination drugs for hypertension and hyperlipidemia was about 6 million and 2.3 million, respectively. During 2015–2019, the use of antihypertensive drugs increased from 123.4 DIDs to 124.9 DIDs with an annual growth rate (AGR) of 0.9% in single products and from 113.7 DIDs to 154.2 DIDs with 35.6% in FDCs. The antihypertensive FDC market share based on consumption increased from 48% in 2015 to 55.3% in 2019. Pharmaceutical expenditures for single products and FDC drugs increased from 0.7 billion USD in 2015 to 0.78 billion USD in 2019 and from 0.59 billion USD to 0.78 billion USD, respectively.

Table 1

Use and pharmaceutical expenditures on antihypertensive and antihyperlipidemic drugs.

	2015		2016	2017	2018	2019		Annual growth rate(%)
Antihypertensive drugs
Total use (DID)	237.1		247.2	256.6	268.2	278.7		(17.5)
Use of plain products (DID)	123.4	(52.0%)	123.1	121.9	122.3	124.5	(44.7%)	(0.9)
Use of FDC (DID)	113.7	(48.0%)	124.1	134.7	145.9	154.2	(55.3%)	(35.6)
Total expenditures (million USD)	1,326		1,381	1,431	1,506	1,569		(18.4)
Expenditures for plain products (million USD)	736	(55.5%)	740	744	760	784	(49.9%)	(6.5)
Expenditures for FDCs (million USD)	590	(44.5%)	641	688	746	786	(50.1%)	(33.2)
Antihyperlipidemic drugs
Total use (DID)	71.3		86.4	100.9	114.3	129.5		(81.6)
Use of plain products (DID)	57.2	(80.2%)	63.4	67.6	72.7	77.6	(59.9%)	(35.7)
Use of FDCs (DID)	14.1	(19.8%)	23.0	33.3	41.6	51.9	(40.1%)	(268.1)
Total expenditures (million USD)	819		943	1,075	1,200	1,347		(64.4)
Expenditures for plain products (million USD)	688	(83.9%)	743	785	836	888	(65.9%)	(29.2)
Expenditures for FDCs (million USD)	132	(16.1%)	201	291	364	459	(34.1%)	(248.4)

DID: DDD/1,000 inhabitants/day

FDC: fixed-dose combinations.

A notable increase was observed for antihyperlipidemic FDCs (from 14.1 DIDs and 0.1 billion USD in 2015 to 51.9 DIDs and 0.46 billion USD in 2019) with an AGR of 268.1% compared to single products (from 57.2 DIDs to 77.6 DIDs, and from 0.69 billion USD to 0.89 billion USD).

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 2

Use and spending on antihypertensive and antihyperlipidemic drugs by age.

	2015	2016	2017	2018	2019
Antihypertensive drug use (DIDs)
Plain products in 20–64 years	83.5	82.8	80.3	80.2	103.9
Plain products in ≥65 years	518.2	503.8	490.4	476.2	463.4
FDCs in 20–64 years	94.2	102.8	110.7	119.4	161.5
FDCs in ≥65 years	389.1	411.3	437.3	457.5	464.2
Antihypertensive drug spending (USD per capita)
Plain products in 20–64 years	10.1	10.1	10.0	10.1	13.3
Plain products in ≥65 years	58.5	56.9	56.0	55.2	54.3
FDCs in 20–64 years	9.6	10.4	11.0	11.8	15.9
FDCs in ≥65 years	39.3	41.3	43.4	45.3	45.7
Antihyperlipidemic drug use (DIDs)
Plain products in 20–64 years	46.2	50.8	53.1	56.2	76.1
Plain products in ≥65 years	201.4	218.6	231.6	243.6	251.5
FDCs in 20–64 years	11.1	19.1	28.2	35.0	55.8
FDCs in ≥65 years	51.0	75.4	104.4	125.7	151.0
Antihyperlipidemic drug spending (USD per capita)
Plain products in 20–64 years	10.7	11.4	11.7	12.2	16.4
Plain products in ≥65 years	48.5	51.1	53.7	55.7	57.0
FDCs in 20–64 years	2.1	3.3	4.8	6.0	9.6
FDCs in ≥65 years	9.2	12.7	17.5	21.1	25.4

DID: DDD/1,000 inhabitants/day

FDC: fixed-dose combinations

Pharmaceutical expenditures per capita were calculated by dividing expenditures by the total population.

Use by drug classification

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.

Table 3

Use and pharmaceutical expenditures for antihypertensive drugs by therapeutic class.

	2015	2016	2017	2018	2019	Annual growth rate (%)
Antihypertensive drug use (DIDs)
C02 (Antihypertensive)	2.0	1.9	1.8	1.8	1.7	(-11.1)
C03 (Diuretics)	14.7	14.6	14.5	14.5	14.6	(-0.5)
C07 (Beta-blocking agents)	13.6	13.7	13.6	13.8	14.0	(3.3)
C08 (Calcium channel blockers)	48.6	47.7	46.4	45.4	44.7	(-8.0)
C09 (Agents acting on the renin-angiotensin system)	158.3	169.4	180.3	192.8	203.4	(28.5)
• C09A (ACE inhibitors, plain)	5.6	5.2	4.8	4.4	4.1	(-26.6)
• C09B (ACE inhibitors, combination)	0.3	0.3	0.3	0.2	0.2	(-36.8)
• C09C (ARBs, plain)	40.1	41.1	41.6	43.2	45.8	(14.2)
• C09D (ARBs, combination)	112.3	122.9	133.6	144.9	153.3	(36.5)
Antihypertensive drug spending (million USD)
C02 (Antihypertensive)	23	25	27	29	31	(36.9)
C03 (Diuretics)	16	16	16	17	19	(19.3)
C07 (Beta-blocking agents)	100	100	102	106	111	(10.5)
C08 (Calcium channel blockers)	284	279	274	271	270	(-4.9)
C09 (Agents acting on the renin-angiotensin system)	903	961	1,011	1,082	1,139	(26.1)
• C09A (ACE inhibitors, plain)	32	29	27	26	24	(-25.9)
• C09B (ACE inhibitors, combination)	2	2	2	1	1	(-36.2)
• C09C (ARBs, plain)	284	293	299	312	331	(16.5)
• C09D (ARBs, combination)	585	637	684	743	783	(33.8)

DID: DDD/1,000 inhabitants/day.

Most drug spending increased except for C09A (ACE inhibitors, plain) and C09B (ACE inhibitors, combination). The greatest increase was noted in C09D (ARBs, combination), followed by C09C (ARBs, plain).

Table 4 shows trends by ATC level 4 drug classification. Among antihypertensive drugs, a large share of the market and increased consumption were found for C09DB (ARBs + CCBs), from 42.4 DIDs (0.6 billion USD) in 2015 to 90.8 DIDs (1.2 billion USD) in 2019 with an AGR of 114.2%, followed by C09DA (ARBs + diuretics), C08CA (CCBs, dihydropyridine derivatives), and C09CA (ARBs, plain) which were single products. The highest pharmaceutical expenditures were found for C09DB (ARBs + CCBs), followed by C09DA (ARBs + diuretics), C09CA (ARBs, plain), and C08CA (CCBs, dihydropyridine derivatives).

Table 4

Use and spending on antihypertensive and antihyperlipidemic drugs by ATC class and single versus combination.

ATC class		Drug use (DIDs)					Drugs spending (million USD)
		2015	2016	2017	2018	2019	2015	2016	2017	2018	2019
Antihypertensive drugs, plain
C02AC	Imidazoline receptor agonists	0.0	0.0	0.0	0.0	0.0	0	0	0	0	0
C02CA	Alpha-adrenoreceptor antagonists	2.0	2.2	2.2	2.3	2.5	7	6	6	6	6
C02DB	Hydrazinophthalazine derivatives	0.0	0.0	0.0	0.0	0.0	0	0	0	0	0
C02DC	Pyrimidine derivatives	0.0	0.0	0.0	0.0	0.0	0	0	0	0	0
C02DD	Nitroferricyanide derivatives	0.0	0.0	0.0	0.0	0.0	0	0	0	0	0
C02KX	Antihypertensives for pulmonary arterial hypertension	0.0	0.0	0.0	0.0	0.0	35	43	55	62	67
C03AA	Thiazides, plain	2.7	2.6	2.5	2.6	2.5	0	0	0	0	0
C03BA	Sulfonamides, plain	1.1	1.0	1.1	1.2	1.6	8	6	7	7	8
C03CA	Sulfonamides, plain	4.7	4.9	5.4	5.8	7.1	19	19	20	22	23
C03DA	Aldosterone antagonists	0.7	0.7	0.8	0.9	1.0	2	2	2	2	2
C03DB	Other potassium-sparing agents	0.1	0.1	0.1	0.1	0.1	0	0	0	0	0
C03XA	Vasopressin antagonists	0.0	0.0	0.0	0.0	0.0	1	1	1	1	4
C07AA	Beta blocking agents, non-selective	0.5	0.5	0.5	0.6	0.6	6	6	7	8	8
C07AB	Beta blocking agents, selective	4.9	5.0	5.2	5.3	5.4	50	48	46	45	44
C07AG	Alpha and beta blocking agents	2.5	2.6	2.7	2.9	3.2	66	64	64	67	68
C08CA	Dihydropyridine derivatives	35.5	37.0	38.9	39.8	43.9	378	371	370	359	362
C08DA	Phenylalkylamine derivatives	0.3	0.3	0.3	0.3	0.3	4	5	5	5	5
C08DB	Benzothiazepine derivatives	1.1	1.2	1.3	1.3	1.2	15	15	15	13	11
C09AA	ACE inhibitors, plain	5.8	5.5	5.3	5.2	5.2	64	57	52	47	44
C09CA	Angiotensin II receptor blockers (ARBs), plain	28.0	30.6	33.3	35.5	40.6	444	455	483	502	539
Antihypertensive drug combinations
C03EA	Low-ceiling diuretics and potassium-sparing agents	-	-	-	-	-	0	0	0	0	0
C07BB	Beta blocking agents, selective, and thiazides	0.3	0.3	0.2	0.2	0.2	4	4	4	3	3
C07CB	Beta blocking agents, selective, and other diuretics	1.1	1.0	0.9	0.8	0.8	7	6	5	5	4
C07FB	Beta blocking agents and calcium channel blockers	0.0	0.0	0.0	0.0	0.0	0	0	0	0	0
C09BA	ACE inhibitors and diuretics	0.1	0.1	0.1	0.1	0.1	1	1	1	1	1
C09BB	ACE inhibitors and calcium channel blockers	0.4	0.4	0.3	0.3	0.3	8	7	6	5	5
C09DA	Angiotensin II receptor blockers (ARBs) and diuretics	48.8	49.3	50.7	51.8	52.7	716	702	702	696	679
C09DB	Angiotensin II receptor blockers (ARBs) and calcium channel blockers	42.4	54.9	70.0	80.0	90.8	632	797	1001	1088	1177
C09DX	Angiotensin II receptor blockers (ARBs), other combinations	3.1	4.0	5.2	8.6	11.4	49	59	74	133	166
Antihyperlipidemic drugs, plain
C10AA	HMG CoA reductase inhibitors	29.2	35.0	39.9	45.8	52.1	1,141	1,259	1,366	1,491	1,593
C10AB	Fibrates	2.0	2.2	2.6	3.1	3.6	53	57	66	76	89
C10AC	Bile acid sequestrants	0.0	0.0	0.0	0.0	0.0	1	1	1	1	1
C10AD	Nicotinic acid and derivatives	0.1	0.0	0.0	0.0	0.0	3	3	1	1	1
C10AX	Other lipid modifying agents	0.1	0.1	0.1	0.2	0.3	5	5	5	8	11
Antihyperlipidemic drug combinations
C10BA	Combinations of various lipid modifying agents	2.9	8.4	14.6	20.4	27.7	96	315	528	703	912
C10BX	Lipid modifying agents in combination with other drugs	7.0	10.4	13.2	15.4	18.8	175	249	300	333	383

For antihyperlipidemic drugs, C10AA (HMG CoA reductase inhibitors) accounted for a large share, with 52.1 DIDs and 1.6 billion USD in 2019, 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 (0.9 billion USD) in 2019, followed by C10BX (lipid-modifying agents in combination with other drugs) with 18.8 DIDs and 0.4 billion USD in 2019 (Table 4).

The ingredients that accounted for large amounts of antihypertensive drug consumption in 2019 were carvedilol (4.8 DIDs, 67 million USD), nebivolol (2.6 DIDs, 9 million USD), and bisoprolol (2.4 DIDs, 18 million USD) among beta-blockers; amlodipine (32.6 DIDs, 0.19 billion USD), nifedipine (4.1 DIDs, 18 million USD), diltiazem (2.6 DIDs, 24 million USD) among CCBs; and telmisartan+amlodipine (34.4 DIDs, 0.18 billion USD), valsartan+amlodipine (34.2 DIDs, 0.19 billion USD), olmesartan medoxomil+amlodipine (16.2 DIDs, 75 million USD), losartan+amlodipine (13.3 DIDs, 75 million USD), losartan+diuretics (12.8 DIDs, 60 million USD), and losartan (11.9 DIDs and 86 million USD). The ingredient with the largest consumption among antihyperlipidemic drugs was atovastatin (29.4 DIDs, 0.47 billion USD), followed by rosuvastatin (29.2 DIDs, 0.25 billion USD), rosuvastatin + ezetimibe (25.9 DIDs, 0.24 billion USD), pitavastatin (9.1 DIDs, 73.5 million USD) (Fig 1).

Fig 1

Drug spending on antihypertensive and antihyperlipidemic drugs by ingredients.

Note. C02CA04: doxazosin, C03AA03: hydrochlorothiazide, C03CA01: furosemide, C03DA01: spironolactone, C07AG02: carvedilol, C07AB12: nebivolol, C07AB07: bisoprolol, C07AB03: atenolol, C07AA05: betaxolol, C08CA01: amlodipine, C08CA05: nifedipine, C08DB01: diltiazem, C08CA13: lercanidipine, C08CA02: felodipine, C08CA14: cilnidipine, C09DB04: telmisartan+amlodipine, C09DB01: valsartan+amlodipine, C09DB02: olmesartan medoxomil+amlodipine, C09DB06: losartan+amlodipine, C09DA01: losartan+diuretics, C09CA01: losartan, C09CA06: candesartan, C09DX03: olmesartan, edoxomil, amlodipine+hydrochlorothiazide, C09CA03: valsartan, C09CA07: telmisartan, C09DA03: valsartan+diuretics, C09DA06: candesartan+diuretics, C09DA07: telmisartan+diuretics, C09CA08: olmesartan medoxomil+diuretics, C09CA10: fimasartan, C09DB07: candesartan+amlodipine, C09DA08: olmesartan medoxomil+diuretics, C09CA04: irbesartan, C10AA05: atorvastatin, C10AA07: rosuvastatin, C10BA06: rosuvastatin+ezetimibe, C10AA08: pitavastatin, C10AB05: fenofibrate, C10BA05:atorvastatin+ezetimibe, C10BX03: atorvastatin+amlodipine, C10BA02: simvastatin+ezetimibe, C10BA03: pravastatin+fenofibrate, C10AB11: choline fenofibrate, C10AA01: simvastatin, C10AA03: pravastatin, C10BX10: rosuvastatin+valsartan.

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.

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12 Aug 2021

PONE-D-21-21296

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

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Please submit your revised manuscript by Sep 26 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Kind regards,

Masaki Mogi

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript is well written and clear to the reader.

Only two remarks:

• In "Use by drug classification" chapter, paragraph 5, line 2, after "...carvedilol (4.8 DIDs, 67 million USD", it needs a parenthesis ")";

• In "Discussion" chapter, paragraph 1, line 9, it is "...followed by C08 (CCB), with 70.7 DIDs".

Reviewer #2: The present study is a retrospective study based on the Korean national health insurance claims database, describing the trends in consumption of fixed-dose combinations of lipid-lowering and antihypertensive drugs. The study is of interest and the following comments should be taken into account to improve its quality.

-The available data regarding triple combinations (e.g. 2 antihypertensive drugs+statin or 1 antihypertensive drug+statin+ezetimibe) should be reported.

-The results of large meta-analyses in the field should be discussed.

-Pharmacokinetic/pharmacodynamic data regarding potential interactions should be elaborated in the Discussion section.

-Figure 1, despite being comprehensive, is complicated. An additional figure is suggested showing the consumption trends of the most common antihypertensive drugs and combinations, presenting the name of the class (e.g. Diuretics) and not the drug codes in order to be easily interpretable by clinicians.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Artur Mendes Moura

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: Revision manuscript PlosOne.docx

Click here for additional data file.

10 Oct 2021

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

Response to reviews’ comments

Dear Masaki Mogi

We appreciate the opportunity to revise our manuscript (manuscript ID PONE-D-21-21296), based on your comments in an e-mail that was dated August 13, 2021. The manuscript has been revised based on the comments that were provided.

We have enclosed the revised manuscript with the changes highlighted as well as a response to the reviewers comment (below). Also, we revised the reference list.

Thank you for your ongoing consideration, and we look forward to hearing from you.

Sincerely,

Dong-Sook Kim

Response to the reviewer #1’s comment

We would like to thank the reviewer for improving the manuscript.

The manuscript is well written and clear to the reader.

Only two remarks:

In "Use by drug classification" chapter, paragraph 5, line 2, after "...carvedilol (4.8 DIDs, 67 million USD", it needs a parenthesis ")";

In "Discussion" chapter, paragraph 1, line 9, it is "...followed by C08 (CCB), with 70.7 DIDs".

Author’s Response: Thank you for the time and effort you invested in thoroughly reviewing this manuscript. According to your comment, we revised.

Response to the reviewer #2’s comment

We would like to thank the reviewer for improving the manuscript.

The present study is a retrospective study based on the Korean national health insurance claims database, describing the trends in consumption of fixed-dose combinations of lipid-lowering and antihypertensive drugs. The study is of interest and the following comments should be taken into account to improve its quality.

-The available data regarding triple combinations (e.g. 2 antihypertensive drugs+statin or 1 antihypertensive drug+statin+ezetimibe) should be reported.

Author’s Response: Thank you for your comment.

The unit of analysis of this study was to medicine. We analyzed the characteristics of patients who use fixed dose combination (FDC). However, multiple use of hypertension and hyperlipidemia combinations in the patient unit was not analyzed.

-The results of large meta-analyses in the field should be discussed.

-Pharmacokinetic/pharmacodynamic data regarding potential interactions should be elaborated in the Discussion section.

Author’s Response: Thank you for these helpful comments. However pharmaceutical company must submit approval data to Food and Drug Administration, so doctors might prefer to prescribe fixed dose combination (FDC) of hypertensive drugs or hyperlipidemia rather than to combine each drug. Therefore, we did not consider regarding potential interactions because this study examined the pattern or trend of combination drugs. Also, we mentioned the large meta-analyses of fixed-dose combination drugs and changed the Discussion section as follows:

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 FECs, thereby increase of BP control effect, so these strategies have been preferred compared with conventional therapies.

-Figure 1, despite being comprehensive, is complicated. An additional figure is suggested showing the consumption trends of the most common antihypertensive drugs and combinations, presenting the name of the class (e.g. Diuretics) and not the drug codes in order to be easily interpretable by clinicians.

Author’s Response: Thank you for your suggestion. According to your comment, we revised.

Submitted filename: Response to reviewer.docx

Click here for additional data file.

20 Oct 2021

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

PONE-D-21-21296R1

Dear Dr. Kim,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Masaki Mogi

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

No further comment.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: The authors have adequately revised their manuscript; therefore, it can be accepted for publication.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Artur Mendes Moura

Reviewer #2: No

6 Dec 2021

PONE-D-21-21296R1

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

Dear Dr. Kim:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Masaki Mogi

Academic Editor

PLOS ONE