In dementia, a clinical syndrome caused by more than 70 diseases, multiple cognitive impairments caused by acquired brain diseases result in daily life problems.¹⁾ As its prevalence increases with age, dementia has become a major health problem facing modern society, which is aging rapidly.^2,3) In particular, Korea is one of the fastest aging countries, with 15.7% of the population aged 65 years or older in 2020.⁴⁾ The large proportion of older people in Korea means that Alzheimer’sdisease (AD) affect the older people and their families. Prevalence of dementia in Korea is estimated to 10.3% of the population aged 65+ in 2020.⁵⁾ Alzheimer’s disease is the most common dementia with a prevalence of 7.8%, whereas that of vascular dementia and other dementias is 0.89% and 1.63%, respectively.

Alzheimer’s disease dementia is known to be caused by the accumulation of beta-amyloid protein in the brain during aging, including vascular dementia, Lewy body dementia, alcohol-related dementia, and Parkinson’s dementia.⁶⁾ In the absence of a fundamental treatment for dementia, pharmacological therapy is known to slow the progression of disease and improve cognitive function, which is important in the initial management of dementia.⁷⁾ To date, anti-dementia drugs approved by the FDA and South Korea have two main mechanisms.^8-11) Cholinesterase inhibitors inhibit the degradation of acetylcholine, a neurotransmitter that reduces Alzheimer’s dementia, and N-methyl-Daspartate (NMDA) receptor antagonists cause intraneural excitotoxicity and inhibit brain plasticity. Cholinesterase inhibitors include donepezil, rivastigmine, and galantamine, whereas NMDA receptor antagonists include memantine. In particular, donepezil is the most commonly used dementia drug in the world, and its use in Korea is increasing substantially.¹²⁾

Previous studies on the efficacy and safety of drugs in patients with dementia have been conducted,^13-16) but none of them have focused on the trend of drug use at the national level. As a nationwide phenomenon, the use of drugs not found in previous studies can be understood by investigating the trends in the use of anti-dementia drugs by region, medical institutions, and dementia type. In particular, Korea has a 100% computerized claim rate for national health insurance; therefore, the National Health Insurance Claims Data can be used to secure data on drug use throughout the country. The purpose of this study was to investigate the cost and dosage of donepezil, galantamine, rivastigmine, and memantine in 2016-2020, and to provide the latest data on the current use of anti-dementia drugs by region, medical institution, and dementia type.

Data Source

In this study, we used the “Healthcare Big Data Open System,” which includes the statistics of medicines using the data for the National Health Insurance claims in Korea.¹⁷⁾ The electronic claim rate of the National Health Insurance (NHI) is over 99.9% for all people; therefore, the data can be considered as a library capturing all drug utilization reimbursed by the NHI.¹⁸⁾ From which the utilization statistics for medicines can be extracted by region and institution type, and in particular, the main diagnostic code on which the medicine is prescribed can be obtained. These statistics were re-organized as time-series data for the relevant time frame included in this analysis: January 2016 to December 2020. Treatments included in the study

Donepezil, galantamine, rivastigmine, and memantine, which are currently used as anti-dementia drugs, were reviewed in the summary of anti-dementia drugs which included the date of market entry, patent status, formulation, and reimbursement criteria. In the analysis by region, provider type, and diagnostic code, only donepezil was included because donepezil accounts for the majority utilization (more than 80%) of anti-dementia drugs usage.

Variables

In this study, we investigated the current utilization pattern by month, focusing on cost and usage volume. The cost is the total expenditure of the drug and includes out-of-pocket payments and health insurance costs (NHI subsidy). The usage volume was measured as a natural unit (e.g., tablets, capsules, and patches), which differed for each product. Therefore, it was converted to the defined daily dose (DDD) presented by the World Health Organization (WHO). DDD signifies the average daily maintenance dose for an adult when administered to treat the main indications of a drug.^12,19)

Analysis

First, we compared the monthly cost from 2016 to 2020 by considering the DDD of a given dementia drug. Second, by introducing 17 administrative districts, we compared the cost and DDD of donepezil from 2016 to 2020 by region. Third, we divided the types of medical providers into general hospitals, clinics, long-term care hospitals, and pharmacies, and compared the cost and DDD of donepezil. Finally, donepezil-prescribed diagnostic codes were divided into the following categories: Alzheimer’s disease, vascular dementia, Parkinson’s disease, and other dementias. The cost was converted by applying an exchange rate of 1150:1 in USD to KRW.²⁰⁾ To quantify the change in claims for 2016-2020, the growth rate period was calculated as the compound annual growth rate (CAGR), which can be interpreted as the average annual growth rate of the value (V) over a period of time (t years).

CAGR=(V_final/V_begin)^(1/t)–1

Utilization trends of anti-dementia drugs

The first anti-dementia drug to be introduced was donepezil in April 2000, followed by rivastigmine, memantine, and galantamine (Table 1). Since then, donepezil was the first generic product introduced in December 2008, followed by galantamine, memantine, and rivastigmine. The formulations of anti-dementia drugs are mainly tablets and capsules. Donepezil and memantine are administered as an orally disintegrated tablet, and rivastigmine as patches and endothelial fluid, respectively. The DDD used to calculate usage was donepezil (7.5 mg), galantamine (16 mg), rivastigmine (9 mg), and memantine (20 mg). The prescription criteria for donepezil state that it can be used in all stages of mild, moderate, and severe dementia, whereas galantamine and rivastigmine are recommended for use in mild or moderate dementia, and memantine is used in cases of severe dementia. Among these four anti-dementia drugs, donepezil was the most used throughout the analysis period (80.3% in 2018) (Table 1). Donepezil accounted for the largest share of DDD (75.8% in 2018) (Table 1).

Table 1

Alzheimer’s Disease treatments included in the analysis

	Donepezil	Galantamine	Rivastigmine	Memantine
Marketed date	2000/04	2004/09	2000/10	2003/09
Entry date of generics	2008/12	2009/11	2014/09	2012/04
Formulation	Tablet, ODF	Sustained Release tablet, Sustained Release capsule	Capsule, Patch, ,Liquid	Tablet, ODT
DDD	7.5 mg	16 mg	9 mg	20 mg
Criteria for NHI funding	Mild, moderate, severe AD	Mild-moderate AD	Mild-moderate AD	Moderate-severe AD
MMSE score	MMSE≤26	10≤MMSE≤26	10≤MMSE≤26	MMSE≤20
Cost ratio (2018yr)	80.3%	3.5%	5.1%	11.1%
DDD ratio (2018yr)	75.8%	2.7%	5.4%	16.1%

Note: ODF: Oral Dissolving Film, ODT: Oral Dissolving Tablet, NHI: National Health Insurance, AD: Alzheimer’s Dementia, MMSE: Mini-Mental State Examination

Utilization trends of donepezil by region

The cost of donepezil continued to increase from 2016 to 2020, with an average annual growth rate of 9.3% (Table 2). Sejong, a newly established city specializing in government organizations, had the highest annual growth rate of 28.3%, and Incheon had the second highest annual growth rate of 14.7%. The regions with high costs are Gyeonggi, Seoul, Gyeongnam, and Busan. The DDD of donepezil increased continuously from 2016 to 2020 in the same manner as the cost of the drug, with an average annual growth rate of 11.1%, which is faster than the cost (Table 2). The trend of DDD by region was similar to that of cost, with Sejong presenting the highest annual growth rate of 29.3% and Incheon with the second highest at 14.1%. The regions with high DDD were Gyeonggi, Seoul, Busan, and Gyeongnam.

Table 2

Cost and utilization trends of donepezil by region

	Proportion of cost (1,000 USD)						Proportion of utilization (1,000 DDD)
	2016	2017	2018	2019	2020	CAGR1)	2016	2017	2018	2019	2020	CAGR
Nationwide cost	177,097	199,455	225,259	248,159	257,788	9.3%	121,375	138,505	156,833	172,781	184,925	11.1%
Seoul	16.5%	16.2%	16.0%	15.7%	15.6%	7.8%	15.5%	15.3%	15.1%	14.8%	14.2%	8.8%
Busan	8.6%	8.2%	7.9%	7.6%	7.2%	4.8%	8.3%	8.0%	7.7%	7.5%	7.4%	8.0%
Incheon	3.6%	3.9%	4.2%	4.3%	4.4%	14.7%	4.0%	4.1%	4.3%	4.4%	4.4%	14.1%
Daegu	6.1%	5.9%	5.9%	5.8%	5.8%	7.6%	5.6%	5.4%	5.4%	5.4%	5.3%	9.9%
Gwangju	3.5%	3.4%	3.3%	3.2%	3.1%	6.0%	3.7%	3.5%	3.5%	3.4%	3.4%	8.9%
Daejeon	3.4%	3.4%	3.4%	3.3%	3.1%	6.7%	3.4%	3.3%	3.3%	3.2%	3.1%	9.0%
Ulsan	1.5%	1.5%	1.4%	1.4%	1.3%	5.4%	1.5%	1.5%	1.4%	1.4%	1.4%	9.3%
Gyeonggi	18.7%	18.8%	19.1%	19.3%	19.8%	10.9%	18.8%	18.9%	19.3%	19.5%	19.7%	12.4%
Gangwon	2.8%	2.9%	2.9%	3.0%	3.1%	13.1%	2.9%	3.1%	3.1%	3.1%	3.2%	13.7%
Chungbuk	3.1%	3.1%	3.2%	3.2%	3.3%	11.5%	3.1%	3.2%	3.2%	3.3%	3.3%	13.0%
Chungnam	4.2%	4.4%	4.4%	4.4%	4.5%	11.1%	4.3%	4.5%	4.6%	4.7%	4.7%	13.5%
Jeonbuk	5.8%	5.8%	5.7%	5.7%	5.7%	9.0%	6.1%	6.1%	6.0%	6.0%	6.2%	11.6%
Jeonnam	5.2%	5.4%	5.4%	5.7%	5.8%	12.1%	5.4%	5.4%	5.4%	5.6%	5.8%	12.9%
Gyeongbuk	6.6%	6.8%	6.9%	7.0%	7.0%	11.2%	7.7%	8.0%	8.1%	8.3%	8.3%	12.9%
Gyeongnam	8.6%	8.6%	8.6%	8.7%	8.5%	8.9%	7.9%	7.8%	7.8%	7.8%	7.9%	11.0%
Jeju	1.8%	1.7%	1.6%	1.5%	1.5%	4.9%	1.8%	1.7%	1.6%	1.6%	1.5%	6.4%
Sejong	0.1%	0.1%	0.2%	0.2%	0.2%	28.3%	0.1%	0.1%	0.2%	0.2%	0.2%	29.3%

¹⁾CAGR (Compound Annual Growth Rate) formula which means average growth rate of value (V) during time in years (t) calculated by a formula; (Vfinal/Vbegin)^(1/t)–1.

Utilization trends of donepezil by healthcare provider type

The cost of donepezil by the type of healthcare provider was the highest in pharmacies, implying that the proportion of outpatients prescription is high. Next were followed by the in-patient utilization of long-term care hospitals, general hospitals, and hospitals (Table 3). The cost of donepezil in long-term care hospitals has decreased sharply since May 2019 (Fig. 1b). The average annual increase in cost was high in clinics (15.6%), whereas that in hospitals and long-term care hospitals decreased. The DDD of donepezil was higher in the order of pharmacies, long-term care hospitals, and general hospitals, but since 2019, the values for clinics have increased compared with those for hospitals (Table 3). The average annual increase in DDD was 15.4% in clinics.

Table 3

Cost and utilization trends of donepezil by provider type

	Proportion of cost (1,000 USD)						Proportion of utilization (1,000 DDD)
	2016	2017	2018	2019	2020	CAGR1)	2016	2017	2018	2019	2020	CAGR
Nationwide cost	177,075	199,446	225,269	248,178	253,104	9.3%	120,180	136,791	154,665	170,472	182,904	11.1%
Teritiary hospital	1.4%	1.3%	1.2%	1.3%	1.3%	7.1%	2.1%	1.7%	1.4%	1.5%	1.4%	1.0%
General hospital	4.1%	3.8%	3.6%	3.3%	3.2%	3.1%	5.1%	4.9%	4.8%	4.3%	4.0%	4.2%
Hospital	4.0%	3.3%	3.1%	2.8%	2.6%	-2.3%	5.0%	4.1%	4.0%	3.7%	3.3%	0.3%
Long-term care hospital	18.8%	18.5%	17.3%	14.7%	10.0%	-6.7%	21.1%	21.3%	20.5%	18.5%	17.4%	5.9%
Clinic	1.8%	1.8%	1.8%	2.1%	2.2%	15.6%	3.4%	3.5%	3.6%	3.8%	3.9%	15.4%
Pharmacy	70.0%	71.4%	72.9%	75.8%	80.7%	13.3%	63.3%	64.3%	65.7%	68.2%	69.8%	13.8%
etc.	0.1%	0.1%	0.1%	0.1%	0.1%	20.3%	0.1%	0.1%	0.1%	0.1	0.1	14.6%

¹⁾CAGR (Compound Annual Growth Rate) formula which means average growth rate of value (V) during time in years (t) calculated by a formula; (Vfinal/Vbegin)^(1/t) – 1.

Fig. 1. Cost and utilization trends of donepezil by provider type

Utilization trends of donepezil by diagnostic code

The cost of donepezil used to treat Alzheimer’s disease was the highest among diagnostic codes, and the proportion of costs for treating Alzheimer’s disease increased from 2016 to 2020 (Fig. 2a). In contrast, the cost of treating vascular dementia has been decreasing since 2019. The treatment cost for AD has increased by 19.0% annually (CAGR 19.0%) and 15.4% (CAGR 15.4%) for other dementias (Table 4). The treatment cost for vascular dementia has decreased annually (CAGR −9.6%). For the DDD of donepezil, patterns similar to the cost were observed. The DDD for Alzheimer’s disease was the highest, followed by that for other dementias; the DDD for vascular dementia has been decreasing (Table 4).

Table 4

Cost and utilization trends of diagnostic code treated with donepezil

	Proportion of cost (1,000 USD)						Proportion of utilization (1,000 DDD)
	2016	2017	2018	2019	2020	CAGR1)	2016	2017	2018	2019	2020	CAGR
Nationwide cost	79,007	90,451	107,163	124,613	139,246	15.2%	56,802	66,112	78,118	90,585	106,906	17.1%
Alzheimer’s D	64.6%	64.8%	65.5%	69.4%	73.7%	19.0%	66.1%	66.0%	66.7%	70.3%	74.3%	20.6%
Vascular D	6.7%	6.3%	6.3%	4.6%	2.5%	-9.6%	5.7%	5.4%	5.4%	3.8%	2.0%	-9.3%
Parkinson’s D	7.2%	6.9%	6.5%	5.8%	5.0%	5.5%	6.7%	6.5%	6.0%	5.5%	4.9%	8.2%
Other D	9.6%	9.7%	9.7%	9.8%	9.7%	15.4%	8.5%	8.4%	8.4%	8.5%	8.2%	16.1%
Others (non-Dementia)	11.9%	12.3%	11.9%	10.4%	9.1%	7.8%	13.0%	13.6%	13.4%	11.9%	10.5%	11.2%

Note: D: Dementia

¹⁾CAGR (Compound Annual Growth Rate) formula which means average growth rate of value (V) during time in years (t) calculated by a formula; (Vfinal/Vbegin)^(1/t) – 1.

Fig. 2. Cost and utilization trends of donepezil by diagnostic code

The rate of aging in Korea is rapid. Since 2000, the proportion of elderly individuals (aged 65 years or older) in Korea has reached over 7% of the total population. This indicates that the Korean population is turning into an “aging society,” and the proportion has been increasing rapidly. In 2017, over 14% of the South Korean population comprised elderly individuals; hence, it was stratified as an “aged society.” It took 17 years for the Korean population to transition from being an “aging society” to an “aged society,”⁴⁾ indicating that the aging population is progressing very quickly compared with that in other countries such as Japan, the United States, and France, which required 24, 72, and 115 years, respectively, to undergo this transition.²¹⁾ As a result, Korea’s expenditure on medical care has increased substantially, raising controversies regarding the size of the health care budget for elderly individuals,²²⁾ and various policies have been changed in this milieu. Aging is the biggest risk factor for dementia, and the rise in the aging population is likely to increase the prevalence of dementia.²³⁾ A study using Korean NHI claims data showed that donepezil accounted for the second highest expenditure among elderly population, despite being off-patent since 2008.²⁴⁾ Cost burden of the anti-dementia drugs to both individuals and public payers, therefore, has increased in Korea.

While the studies using patient-level data can suggest the optimal pharmacological therapies, the studies using populationlevel data provide a wide discussion about policy intervention such as drug price and reimbursement policy and disease management program. Anti-dementia drugs account for a relatively high proportion of national pharmaceutical cost in Korea. This is also evident when comparing with foreign countries after adjusting for the proportion of the elderly population of each country. Previous study has reported that the utilization of antidementia drugs in Korea is higher and increases faster than Australia, Sweden, and Norway.¹²⁾ This can be explained by Korea’s (1) generous reimbursement criteria for anti-dementia drugs, (2) dementia-friendly policy by government such as National Dementia Management Plan (including anti-dementia drugs subsidy program), and (3) cultural aspects of drug prescription. The policy intervention can be designed and implemented regarding these points.

The main findings of this study are as follows. First, the overall DDD of anti-dementia drugs increased rapidly from 143,464,515 in 2016 to 229,659,149 in 2020. This is a high figure compared with the 5% annual increase in the elderly population from 2016 to 2020. National-level studies on the use of donepezil have also been conducted abroad. In New Zealand, donepezil utilization increased from 5.2 to 8.2 DDD per thousand older people between 2011 and 2013.²⁵⁾ In Australia, the utilization of antidementia drugs increased 58% in terms of DDD per thousand people per day between 2002 and 2007.²⁶⁾ The anti-dementia drugs use also has been increased in Korea, although the timing of the analysis is different, implying that cost-effective use is important as suggested in previous studies. The rate of early diagnosis of dementia has increased because of the strengthening of the government’s dementia-prevention policy. Hence, the utilization of donepezil, the most commonly used treatment for dementia, accounts for 70% of the total use of dementia drugs,^7,27) has increased by 11% every year from 2016 to 2020. The overwhelming use of donepezil is mainly because it has a wider range of reimbursement criteria than other drugs, covering mild to severe symptoms.

Second, in terms of provider type, pharmacies account for the largest proportion of use among various types of institutions. This shows that there are more dementia out-patients than in-patients. In addition to pharmacies, long-term care hospitals accounted for the highest cost, but the cost sharply declined since 2019 (Fig. 1a). Contrary to the decrease in the cost of donepezil used in long-term care hospitals, there was no decrease in the utilization volume in terms of DDD (Fig. 1b), which implies that the use of cheaper donepezil generics increased after 2019. On May 31, 2019, the NHI payment system of long-term care hospitals was revised to ensure that the drug cost for dementia treatments was incorporated into the fixed fee per day. As a result, cheaper donepezil products were preferred in long-term care hospitals in situations where the price difference of donepezil was large. According to the NHI Pharmaceutical Reimbursement Price Table on April 2021, the cheapest donepezil is KRW 690, which is approximately one-third the price of the original drug (Aricept), KRW 2,283.²⁸⁾

Third, although the prevalence of Alzheimer’s dementia in Korea remained unchanged from 7.28% to 7.8% from 2016 to 2020, and that of vascular dementia increased from 0.84% to 0.89%,⁵⁾ the cost and utilization volume (DDD) of donepezil treatment for vascular dementia decreased in the same period, especially since 2019. The sudden decrease in the volume of donepezil utilization in vascular dementia can be interpreted as a result of the recent revision of the NHI reimbursement criteria. The NHI decided not to reimburse for donepezil when used to improve the symptoms of vascular dementia (dementia with cerebrovascular disease) from 2019 after the clinical re-evaluation process.²⁹⁾

Finally, there were different trends in cost and DDD by region. For example, Gyeongbuk Province ranked higher in DDD than in cost. When calculating cost per DDD, which can be interpreted as the average price, it varied in Gyeongbuk Province from KRW 200 to KRW 400, whereas the variations were smaller in other regions. This implies that cheaper donepezil products were used more frequently in Gyeongbuk Province than in other regions. Previous studies in different countries explored the similar question on regional variations in the prescribing patterns of anti-dementia drugs. In the United States, a study on the anti-dementia drugs prescribed by a primary care physician has reported that the geographic variations are evident in medication prescription patterns.³⁰⁾ Based on the assumption that a young physician is more likely to adopt a new medical technology, the variations of the age of prescribers may induce different prescribing patterns. Additionally, the regions that have more specialist-prescribers may show the pattern of more anti-dementia drugs use, as a German study reported that neurologists and psychiatrists prescribes more anti-dementia drugs.³¹⁾

This study had some limitations. First, we used aggregated time-series data, and it was difficult to capture patient characteristics. However, as discussed in previous drug utilization studies,^32,33) we could analyze the total consumption of medicines at the national level and provide useful information on the utilization of donepezil based on the type of medical institution and disease. Second, the data included were only for five years (2016-2020), and the long-term trends were not analyzed in this study. However, certain changes in utilization patterns due to major changes in pharmaceutical policies were confirmed in this study. Finally, the utilization pattern by diagnostic codes for different Alzheimer’s diseases may have been underestimated because the data only captured the first diagnostic code when the patient had multiple morbidities. However, the changing trends over time could be interpreted meaningfully when compared to the actual prevalence of these types of dementia.

Considering the fact that the proportion of elderly individuals is increasing, with a concomitant demand for pharmacological treatment for Alzheimer’s disease, this study demonstrated the utilization trends of anti-dementia drugs using data from 2016 to 2020 at the national level. This study provides evidence of the increasing use of low-cost drugs in long-term care hospitals and lays a foundation for further research on the prescription trends and treatment outcomes of these drugs. After the revision of the National Health Insurance Pharmaceutical Reimbursement Scheme for anti-dementia drugs, some changes in the utilization of donepezil have been observed. This study provides recent statistical evidence on the utilization trends of anti-dementia drugs in South Korea.

This study was supported by a research grant of Basic Science Research Program from the National Research Foundation of Korea (grant No. 2021R1F1A1062230).

All authors declare that they have no competing interests.