Introduction

Diabetes Mellitus (DM) is a significant global public health burden, reported to have caused 1.5 million global deaths in 2019 [1]. The global prevalence of DM was estimated at 9.5% in 2019 and is expected to rise up to 10.2% in 2030 and 10.9% in 2045 [2]. Subsequently, the prevalence of diabetes and pre-diabetes was reported as8.5% and 9.2% in 2020 in Nepal, respectively [3, 4]. Notably, DM incidence is rising quickly in low-and middle-income countries (LMICs), including Nepal [1, 5–7]. This has significantly affected the clinical outcomes and economic conditions of patients and the nation [8]. Yang et al. (2019) reported that individuals with diabetes have a 1.89-fold greater risk of death than non-diabetes in Asia [9]. Similarly, hypertension, a prevalent issue in Nepal, has double the risk of developing diabetes in Nepal [4, 10]. As per Shrestha et al. (2013), patients with DM for 16 to 20 years have 161% higher direct health expenses compared to those with DM for 1 to 5 years [11]. Overall, type 2 DM (T2DM) complications cost up to nine times higher than non-T2DM patients [12].

Therefore, good adherence to medication can prevent further complications, mortality and associated economic burden which might occur in time to come [13–15]. A study found DM patients spend up to 80% of their total expenses on medications during out-patient clinic visits in Nepal, primarily through out-of-pocket (OOP) payments [11]. In Nepal, a substantial portion of health expenditure is dedicated to medicine and medicinal products, accounting for 63.4% of out-of-pocket (OOP) expenses. Non-communicable diseases (NCDs) make up two-thirds of these total OOP expenses on diseases [16]. Similarly, past studies have reported finances (participants’ income and medicine costs) as a significant challenge to medication adherence for DM patients in Nepal [17, 18]. Furthermore, the high price variation of NCD medications, including oral hypoglycaemic medicines (OHMs), reported earlier, has further added barriers to medication adherence in DM patients in Nepal [19–21].

Most medicines available in Nepal are brand-named generics, meaning they have the same active ingredient but different trade names. According to the Department of Drug Administration (DDA), there are 128 pharmaceutical manufacturers in Nepal as of 29^th September 2022, with118 producing allopathic medicines, and 123 registered importers according to online data as of 19th October 2023 [22, 23]. However, Nepal lacks specific regulations in medicine pricing and controlling price variation between brand-named medicines of the same generic medicine items [24, 25]. Despite this, the government attempted to ensure access by fixing the price of some essential medicines, providing some essential medicines for free in limited centres, and including a broader range of medicines (not all OHMs) in the national health insurance scheme [26–28]. However, these freely available medicines, including OHMs, are inadequate and are reported to be of substandard quality [29, 30]. Moreover, health insurance services are also available in limited facilities, and patients have been reported to withdraw from this scheme due to inadequate medicine availability [31, 32]. These factors force patients to depend on OOP expenditure and private pharmacy outlets, facing high and inconsistent medicine costs.

All the above-mentioned medicine-related characteristics, including formulation, composition, manufacturer competition, dosage form types, and coverage in the national medicine program list, can influence price of the medicine and its price variation among different manufacturers [33–36]. However, none of the previously published studies have examined the detailed analysis of the availability and variation in the prices of available OHMs in the country [20, 21, 37–39]. Thus, this study aimed to investigate the price variation of OHMs based on different medicine-related characteristics to provide a comprehensive overview and suggest better ways to manage medicine costs in the future.

Materials and methods

Results

Characteristics of oral hypoglycaemic medicines available in Nepal

Fourteen oral hypoglycaemic medicines and 57 generic medicines with different doses and dosage formulations are available in Nepal. Among 57 generic medicine items, 17 medicines are available in fixed-dose combinations under two types in terms of pharmacological categories (second generation sulfonylureas + biguanides and dipeptidyl peptidase-IV (DPP-4) inhibitors + biguanides) and 40 medicines are available as single molecules in their respective dosage forms. Among 57 generic medicine items, 48 medicines were “Immediate Release (IR)”, and 9 were “Modified Release (MR)” dosage formulations.

Similarly, those 57 different OHMs were available in 348 trade/brand names in Nepal. There was a maximum of 29 brand-named medicines and a minimum of one brand-named medicine available for each generic hypoglycaemic medicine item in Nepal. A maximum of up to four countries were found to be involved in manufacturing one generic medicine item. Around 90% of medicines available in the Nepalese market were not on the WHO and Nepal’s essential medicines lists. Similarly, among 57 generic medicines items, the government has fixed the rate for only seven items and provided only one medicine free of cost to designated government healthcare institutions (Table 1). All the details of medicines are given in the S1 File.

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Table 1. Characteristics of OHMs available in Nepal and their relationship with price variation [N = 57].

https://doi.org/10.1371/journal.pone.0310706.t001

Manufacturer details of OHMs available in Nepal

Nepal is the prominent manufacturer (64.7%) of OHMs in the Nepalese market, followed by its neighbouring country, India (31.9%). Bangladesh occupied 1.4% of OHMs available in the Nepalese market, while Denmark, Germany and Italy occupied less than 1% of OHMs in the Nepalese market (Fig 1).

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Fig 1. Manufacturer details of OHMs available in Nepal.

https://doi.org/10.1371/journal.pone.0310706.g001

Price variation of oral hypoglycaemic medicines

An average of 62.28% price variation was determined among all OHMs in Nepal. There were three medicines with price variations >200% and eleven with price variations between 100 to 200%. Altogether, fifteen medicines have price differences above 10 NPR with a maximum of 50 NPR. Gliclazide 60 mg MR had the lowest price difference (0.03), while empagliflozin 10 mg IR and 25 mg IR had the highest price difference (50 and 39.52, respectively) (Table 2). However, 18 generic medicine items showed no price variation. None of the government-fixed rate medicines were priced higher than their set rates. Detailed information on the price variations of all the over-the-counter medicines (OHMs) can be found in S1 File.

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Table 2. Top 20 oral hypoglycaemic medicines with the highest price variation available in Nepal.

https://doi.org/10.1371/journal.pone.0310706.t002

Pharmacological category-wise presentation of price variation and medicine summary

Altogether, a total of 7 pharmacological categories of oral hypoglycaemic medicines are found in a total of 14 types of medicines in Nepal. The most common pharmacological class of OHMs was second-generation sulfonylureas (4, 28.57%), followed by DPP-4 inhibitors (3, 21.43%) based on the types of medicines. However, based on the number of brand medicines in the market, biguanides (86, 24.71%) and second-generation sulfonylureas (78, 22.41%) were the most common medicines used in the Nepalese market. Except for dipeptidyl peptidase-IV (DPP-4) inhibitors and thiazolidinediones (TZDs), all other pharmacological categories have more than 100% price variation medicines. Biguanides, 2nd generation sulfonylureas, and meglitinides categories of medicines have an item with more than 200% of price variation. Except for alpha-glucosidase inhibitors and meglitinide categories of medicines, all other categories have medicines with a minimum of zero price variation (Table 3).

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Table 3. Pharmacological category-wise presentation of price variation and medicine summary.

https://doi.org/10.1371/journal.pone.0310706.t003

Discussion

The study found seven pharmacological categories of oral hypoglycaemic medicines available in Nepal. The most commonly available categories of medicines in the market were second-generation sulfonylureas (4, 28.57%), followed by dipeptidyl peptidase-IV (DPP-4) inhibitors (3, 21.43%). Based on the number of available brand-named medicines, the most frequently used medicines in the market were biguanides (86, 24.71%) and second-generation sulfonylureas (78, 22.41%). These categories of medicines, particularly glimepiride and metformin, are recommended in diabetes management guidelines and are commonly used in Nepal and its neighbouring countries such as India [48–54]. Therefore, the quality and cost of these OHMs must be monitored stringently with priority. The government of Nepal has fixed the price of metformin 500 mg IR and 1000 mg IR, glimepiride 1 mg IR, 2 mg IR, and 3 mg IR and pioglitazone 15 mg IR and 30 mg IR so far [26]. Metformin 500 mg IR is made freely accessible in designated government healthcare centres [47]. Previously, limited studies reported higher price variation on one of the fixed-rate medicines (metformin 500 mg IR, 330.769% in 2015 and 254.6% in 2017) [21, 39]. However, the current study showed lower price variation of government fixed-rate medicines (glimepiride 1 mg IR, 6%, glimepiride 2 mg IR, 7.5%, glimepiride 3, 0%, and metformin 500 mg IR, 92.31%) without crossing the government ceiling price. The possible cause of less price differences despite having fixed retail prices could be the higher market competition (metformin 500 mg IR, 29 brands; glimepiride 1 mg IR, 17 brands, 2 mg IR, 16 brands, and 3mg IR, 11 brands), frequent prescription of metformin and glimepiride in Nepal and involvement of foreign manufacturer [48–50].

Except for dipeptidyl peptidase-IV (DPP-4) inhibitors and Thiazolidinediones (TZDs), all other pharmacological categories of medicines have more than 100% price variation. Biguanides, second-generation sulfonylureas, and meglitinide are medicines with more than 200% price variation. Fourteen generic-medicine items have a price variation greater than 100%, fifteen have a price variation of more than 10 rupees, and eighteen medicines don’t have any price variation. Specifically, repaglinide 2mg IR (484.82%, 7 brands), glipizide 5mg IR (273.13%, 3 brands), and metformin 850mg IR (222.22%, 22 brands) were the highest price variation items found in our study. However, a recent study in India showed glimepiride 1 mg (3503.22%, 108 brands), and metformin 500 mg SR (3668.51%, 73 brands) were the medicines with the highest price variation, which are the most commonly used medicines in Nepal [55]. The price variation of these items in Nepal was much lower compared to India.

Moreover, FDCs are commonly used in the Nepalese pharmaceutical market to reduce drug non-adherence and overall cost reduction [56]. However, the cost comparison showed no reduction in cost by most FDCs; instead, the cost of FDCs was higher compared to the cost of its component medicines. Nine FDCs were found to have higher mean cost than the sum of their components’ mean price, where glimepiride 1 mg + metformin 500 mg IR (45.8%) and glimepiride 2 mg + metformin 500 mg IR (37.1%) were found to have the highest price difference. In our context, the higher prices of FDCs could have occurred using the mean price of all available brand-named medicines. Nevertheless, it is determined that most FDCs’ component generic medicine items can be found at lower prices in the Nepalese market if the patient wants to buy them separately. Still, a question arises among consumers about the higher price of FDCs compared to the sum of their individual components even though the cost of labour, packaging, transportation, and other items born by the manufacturer has already been reduced by almost half.

The study revealed a significant difference in price variation among different number of brand-named medicines available for each generic medicine item. However, the p-value did not provide a conclusive remark adequately due to the limited data (less than 5 brand-named medicines in some generic medicine items). Alternatively, more brand-named medication options for generic medicine items were found to increase. A 2017 Nepalese study reported 1 and 18 brand-named medicines for glibenclamide 5mg and metformin 500 mg [21], which was found to increase in our study, 2 and 29, respectively. This possibly reflects the growth in the availability of the brand alternatives. However, the price differences among the brand-named medicines may direct patients into buying expensive items despite providing the opportunity to choose cost-effective ones. This can be suspected due to the prevalent practice of prescribing in brand names, brand promotion, and patients’ deficient medicinal knowledge and practice of choosing prescriber-prescribed brand-named medicines in Nepal [57–59]. Therefore, the generic prescribing practice should be encouraged, which allows and eases patients to choose the available cost-effective brand-named medicine; however, the quality of medicines needs to be ensured by concerned regulatory authorities [57].

Interestingly, the average price variation was observed more among the generic medicine items listed in the national and WHO EML and the government-free medicine list. However, none of these characteristics were significantly associated with price variation. This could possibly be due to the small sample size in our study. Also, these categories typically consist of a minimal number of medicines. Generally, the medicines listed in national and WHO EML are mostly old molecules with low or affordable market prices [60]. Government-funded medication programs should incorporate anti-diabetic drugs that are widely used, evidence-based, and recommended by guidelines as safe and effective to ensure access to quality medicines. This measure can help mitigate the potential economic burden that diabetic patients may face in the country. For instance, glimepiride medicine which was recently incorporated into the government’s free medicine list [47, 61]. This is most preferred, practiced, and recommended in relevant guidelines and lists for diabetes treatment in LMICs, including Nepal [50, 54].

Most of the OHMs in the Nepalese market were manufactured within the country (64.7%), which is a good indicator of making the country self-reliant in producing required OHMs. The remaining OHMs were imported from five foreign countries, most from India (31.9%). While the availability of multiple manufacturers’ products provides patients with a wide range of options to make choices, it may also increase medication costs due to increased transportation and marketing costs. This may ultimately cause patients to buy expensive medications as the patients rely solely on doctors’’ suggestions and only take the prescribed brand-named medicines [57, 58]. Therefore, fixing the maximum price in collaboration with the expertise of the pharmaceutical market, prioritising quality over price, could be the appropriate way for patients to reduce the negative impact of price variation. Also, mandating the service of drug and therapeutic committees in hospitals and healthcare facilities may help to manage patients’ medicine access issues with medicine cost, if encountered.

Overall, the wide variation in the price of OHMs observed in the study highlights the possibility of unfair financial burden to diabetic patients who need to take the medications regularly, usually for a lifetime. There may be many contributing factors for such variations, including market influence and infiltration by the pharmaceutical companies, and lack of stringent policies and guidelines from the authorities focusing on the regulations of the market price of medications [24, 57, 62]. Nepal has no clear and transparent medicine pricing policy; even where policies exists, they are not implemented strictly [24, 63]. Shrestha et al. have also revealed that the formulated policies are not effective enough to control the price variation of anticancer medicines in Nepal [63]. The current study presented a picture of the price scenario of OHMs to develop effective drug policies for implementation.

Conclusion

Most of the OHMs available in the Nepalese market are self-manufactured. However, the available OHMs, single and fixed-dose combinations, significantly vary in price in Nepal. At the same time, several brand-name medicines and manufacturers provide a possible linkage with price variation but not a definitive relationship. This study presented and discussed the price variation scenario of OHMs in various medicine-related characteristics to develop and implement effective drug policies and programs that can address medication price-related issues to ensure access to OHMs without placing an economic burden on patients. Furthermore, the study recommended exploring the potential impact of price variation on patients’ capacity to afford and adhere to diabetic medicines in the future.

Supporting information