Trends and regional differences in antidiabetic medication use: a nationwide retrospective observational study

This is the first study to analyze antidiabetic drug utilization in Hungary, including not only reimbursed but also non-reimbursed antidiabetics. It is also the first study to analyze antidiabetic medication use and its determinants at the regional level in Hungary. In recent years, substantial novelties in diabetes therapy and therapeutic protocols impacted antidiabetic medication utilization patterns [11]. This retrospective drug utilization study confirmed that antidiabetic medication use has changed remarkably between 2015 and 2021 in Hungary.

In all Hungarian counties, total antidiabetic use emerged, but with an interesting peak in 2020. This utilization peak coincided with the coronavirus disease-19 outbreak when the Hungarian population tended to stock their chronic medications. This stockpiling effect was also observed in the medication utilization data of other nations [18].

Regarding antidiabetic subgroups, metformin was the most commonly used antidiabetic alone or in fixed-combination with other antidiabetic drugs (DPP4Is and SGLT2Is) during the entire study period. This was explained by the Hungarian guidelines where metformin is the first drugs of choice alone or in combination if the patients are newly diagnosed with type 2 diabetes and do not have HbA1c above 9% with catabolic symptoms [5]. The high rate of metformin use is similarly observed in Denmark, where metformin use was 39% of the total antidiabetic use in 2021 [19]. Sulfonylureas are still included in Hungarian and international therapeutic guidelines but not as preferred agents due to their side effects, such as hypoglycemia and weight gain, and furthermore, this drug group does not decrease the risk of major cardiovascular events [4, 5, 7]. Although sulfonylurea use has decreased continuously, its share of total antidiabetic medication use was still remarkable in Hungary. The utilization of sulfonylureas has shown high differences among some European countries. In Hungary the share of sulfonylurea use at the national level was 19.2% in 2021; in Denmark, it was only 3.6% in 2021, while in Romania, the sulfonylurea use was estimated to be 27.9% of the total antidiabetic medication use in 2019 [19, 20]. Despite the growing prevalence of diabetes, insulin use remained relatively stable, while the utilization of newer antidiabetics, mainly SGLT2Is and GLP1As, has emerged dynamically. The use of newer antidiabetic groups may delay the initiation of insulin therapy in type 2 diabetes, because the availability of these drug groups provides a wider choice for clinicians before considering insulin therapy [21]. Additionally, while SGLT2Is and GLP1As have positive cardiovascular and renal effects, insulin has a neutral effect in this respect, but has a high risk of hypoglycemia and weight gain [4, 5, 7]. The emerging tendency of SGLT2I and GLP1A use and the change in the use of DPP4I in 2021 is partly due to the different place of these drug groups in therapeutic guidelines. Currently, GLP1As and SGLT2Is are preferred agents in cases of established/high risk of atherosclerotic cardiovascular disease or chronic kidney disease [4, 22]. In addition, SGLT2Is are preferred in cases of established/high risk of heart failure and GLP1As are preferred if the main goal is weight management above glycemic targets [4, 22]. DPP4Is have neutral effects on weight and cardiovascular and renal problems with moderate effect on blood glucose control, and their use is preferred if the main goal is to improve glucose control without hypoglycemia in the case of elder, frail people [3, 4]. The emerging use of DPP4Is, SGLT2Is and GLP1As use has also been observed in other countries’ utilization data, such as Denmark or Portugal [9, 19].

Regarding interregional differences, we found stable and considerable variability in the use of antidiabetics which has not been previously studied. Regional differences in total antidiabetic use remained stable and low, in contrast with some antidiabetic subgroups. Insulin use and its regional differences were relatively stable in all counties, and we did not find a geographical gradient in the utilization pattern or association with regional diabetes prevalence. Although insulin use did not correlate with the unemployment rate, an association was found between insulin use and the number of public medical card holders per ten thousand inhabitants. The initiation of insulin therapy is not a financial issue, because human insulin preparations are available with 100% reimbursement (with only minimal patient co-payment of approx. 0.8 EUR/box), so the patient’s financial situation has no influence on receiving insulin therapy [17]. However, if patients with type 2 diabetes need to receive insulin analogues that are more expensive, these preparations are available with 50% or 100% reimbursement coverage depending on the patients’ HbA1c levels [17, 23]. Therefore, patients with a poorer financial situation are more likely to receive human insulin therapy than the more expensive insulin analogues. This is supported by the positive association between human insulin use and the number of public medical card holders. The positive correlation between insulin use and the number of attendances in diabetologic outpatient service per thousand inhabitants may be explained by the fact that insulin can be prescribed with reimbursement only under regular diabetologist supervision [17]. The positive correlation between insulin use and percentage of people with age 60 years or older can be explained by the fact that older people are more likely to have diabetes for a longer period of time, therefore, their diabetes is more likely to have progressed to the stage where insulin therapy is necessary to be initiated.

In the case of metformin, the relatively low difference in use among counties and the lack of associations with socioeconomic factors may be explained by the high use of metformin in all counties because of therapeutic recommendations, and its affordability and availability. Metformin alone is relatively inexpensive and therefore does not impose a high financial burden on patients, and GPs can prescribe these agents without regular supervision by diabetologists [17]. Other fixed-dose preparations, mainly with DPP4Is and SGLT2Is are available with 70% reimbursement, but only under regular diabetologist supervision [17].

In addition to the considerable utilization of sulphonylureas, we found high differences among counties. The high use of sulfonylureas in Hungary can be explained by some factors. Sulfonylureas are inexpensive agents, especially in contrast to newer drug groups, such as GLP1As, which are the most expensive antidiabetic drug group. In Hungary, the full price of sulfonylurea is approximately 0.06–0.14 EUR/DDD and available with 55% reimbursement. Although GLP1As are available with 70% reimbursement coverage, their full price is much higher, approximately 2.12–4.72 EUR/DDD. Additionally, sulfonylureas, similar to metformin, are easily accessible because GPs can prescribe these drugs, while other drug groups (e.g. novel antidiabetic drug groups) can be prescribed with reimbursement only under regular diabetologists’ supervision [17]. This seemed to be confirmed by the positive associations with some socioeconomic factors such as unemployment rate, the number of public medical card holders per ten thousand inhabitants and percentage of the 60 years and older among the total population.

Regarding DPP4I use, although the max/min difference between regions was 1.70 in 2021, a notable regional pattern and association with socioeconomic factors could not be detected. Higher interregional differences were found in the case of SGLT2Is, and higher use was observed in the southern counties; however, we did not find any relevant socioeconomic factors that explains these differences. The utilization of GLP1As showed the largest interregional differences among antidiabetics (max/min ratio 3.00 in 2021). We did not find any socioeconomic factors that explained the detected southwest-northeast gradient. Although we did not detect an association with socioeconomic factors, many issues may influence the use of these drug groups. First, their price (mainly GLP1As and SGLT2Is) was significantly higher than that of metformin or SU. Second, these drugs can only be prescribed with reimbursement by GPs under the recommendations of diabetologists [17], which may complicate access to these medications for some patients. Additionally, most GLP1As are subcutaneous injections, which may be difficult for some patients to accept, although one orally administered GLP1A has been available since 2020.

Our data clearly show that drug choice depends not only on socioeconomic factors, but also on numerous other factors, which may be difficult to detect at the population level, as the choice of drug is highly individualized. We did not find any other studies that investigated the possible determinants of regional antidiabetic medication use. However, in one study that investigated geographical variation in antibiotic use and its possible determinants in Hungary, large interregional differences and associations with some socioeconomic factors were found [24].

Comparing the results of our study, which included both reimbursed and non-reimbursed medication use, to the results of a previously published study based on only reimbursed medication use, it was revealed that there were considerable differences in the results [11]. The overall use of antidiabetic medications was 24% higher in our study in 2015 compared to the use of only reimbursed medication. In the cases of most antidiabetic subgroups, the differences were very small (the lowest was for insulins being only 1.2%) but was enormous in the case of metformin. The overall use of metformin in our study was more than double that of the reimbursed only metformin use. This can be explained by the fact that while most antidiabetic medications are reimbursed, some widely used metformin products are not.

The present study has some strengths and limitations that must be considered. As far the strengths, first, to the best of our knowledge this is the first study to investigate both total national and interregional antidiabetic medication utilization trends and differences in Hungary. Second, the database covers total antidiabetic drug sales in Hungary, including both reimbursed and non-reimbursed medications, and our study has total population coverage (nearly 10 million people), which enables us to detect a complete and detailed picture of the national and interregional trends and differences in antidiabetic medication use.

Regarding the limitations of this retrospective study, a wholesale database containing antidiabetic medication sales for pharmacies was used. Due to the nature of the data source, it provides a slight overestimation of antidiabetic use, as not all the medications acquired by pharmacies reach the patients for various reasons (e.g. medication expires before selling, damaged medications). In addition, the data were aggregated and it was not possible to distinguish between the drug claims of patients with type 1 and type 2 diabetes. Some antidiabetics, such as metformin, may be used for indications other than diabetes, but our data did not contain information about indications of use. The database contains sales data of reimbursed and non-reimbursed medicines, however, the differentiation among these drug categories was not possible in the present study. In some cases, data on regional level were not available for potentially relevant determining factors. It should be noted that this study aimed to analyze antidiabetic medication use at the population level and explore the changes over time, but did not aim to evaluate the appropriateness of the choice of treatment, as it could only be performed on individual patient-level medication use and clinical data.