This study provides useful insight into differences in intensity of prescribing policy for all antidiabetic medicines and market uptake of new antidiabetic medicines in 11 selected European countries. An increase in the intensity of prescribing policy of antidiabetic medicines was observed in all the countries, suggesting growth in the pharmacological care of diabetic patients and reflects diabetes management as a healthcare priority. It is also in line with the increased number of antidiabetic medicines per patient reported in other recently published literature . However, considering other outcomes of this study, it may also derive from other factors, e.g. changes in country-specific clinical guidelines, national antidiabetic medicines policy, and reimbursement restrictions [12, 14].
At least one new active substance from the group of DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors, as well as insulin degludec was in continuous use in all countries included in the study. The only exception was France, where SGLT-2 inhibitors and insulin degludec as sole agent were not available between 2006 and 2016. After our study period, insulin degludec and SGLT-2 inhibitor dapagliflozine were introduced in 2018 and 2020, respectively .
Spain, was the only country where all new active substances have been available. In contrast, median times to first continuous use of new antidiabetic medicines differ significantly between countries. As expected, Germany was the fastest in launching new agents, most likely due to the current reimbursement policy of free launch followed by the early benefit assessment [20, 21]. Croatia, Poland, and Slovenia were shown to be the slowest in the introduction and continuous use of new antidiabetic agents. It should be mentioned that all available antidiabetic medicines were considered in this time analysis, which could mean that the first representative of the new antidiabetic group was available soon after marketing authorisation, whereas price negotiations for the subsequent medicines last longer due to payer requirements for the same or even lower price. Additionally, prescribing restrictions could affect the intensity of prescribing policy. For instance, Slovenia introduced SGLT-2 inhibitors with several prescribing restrictions , which have been removed in February 2020 and would most probably result in the increase of prescribing.
Although Germany was the fastest in introduction of new antidiabetic agents, it did not have the greatest consumption. It could be linked to the finding, that out of seven evaluated new antidiabetics, only one received an added benefit (non-quantifiable benefit) during the early benefit assessment of the reimbursement procedure by the Federal Joint Committee (G-BA) .
The highest volume market shares (around 27 %) of new antidiabetic medicines were observed in Spain and Austria. On the other hand, Poland had the lowest volume market shares, probably due to high patient co-payments for all new antidiabetic medicines [24, 25]. Reserved use of new antidiabetic medicines in almost all of the selected countries could be related to inadequate evidence of benefits according to the price (cost) of new antidiabetic medicines at the investigated time period. The evidence have been usually attributed to surrogate outcomes such as short-term glycaemic control and treatment of adverse effects . Decisions on reimbursement of new antidiabetic agents at that time were therefore based on a lack of evidence, which is less affordable for lower-income countries [26, 27].
Based on the results of correlation analysis (Fig. 4) related to incretin-based medicines (DPP-4 inhibitors and GLP-1 receptor agonists), two groups of countries can be defined. The first group (Spain, Austria, France, and Germany), representing countries with a high volume market share of new antidiabetic medicines (Table 1 and Appendix Table S2) and a slight increase in intensity of prescribing policy from 2007 to 2011 (Fig. 3). The second group consists of all other countries. Therefore, most of the countries evaluated in this study tried to optimize diabetes care through more intense use of old antidiabetic medicines and insulins, and were probably forced to be more conservative in the use of new antidiabetic medicines.
Countries were also shown to differ in the extent of insulin use. Germany, Sweden, and Slovenia, with a volume market share of at least 30 %, are predominant (Table 1 and Table S2 in the Appendix). The literature has already shown that Sweden has a relatively high use of insulin for the treatment of type 2 diabetes compared to other European countries . Up to 38.6 % of the market share of insulins prescribed in primary care practices was also reported in Germany . Insulin treatment is usually started after the oral therapy is already optimized (in double or triple combination and at the maximum tolerated doses) yet fails to achieve optimal glycaemic control. Nonetheless, the insulin initiation is often inappropriately delayed, putting patients to unnecessarily increased risk of complications and potentially reduced quality of life or and life expectancy. This is termed “clinical inertia,” and it can occur due to a number of factors, including clinical concerns (i.e., risk of weight gain, hypoglycaemia, or patient distress), professional concerns (e.g., lack of clinical experience, skills, or confidence in insulin titration), or health system concerns (e.g., competing priorities, regulatory or financial constraints, or a lack of impartial continued medical education) [30, 31].
Furthermore, a great difference in the annual therapy cost of old antidiabetic medicines compared to the annual therapy cost of insulins and new antidiabetic medicines was observed in all the selected countries. The highest annual therapy cost of old antidiabetic medicines was observed in Slovenia, €58. The highest annual therapy cost of new antidiabetic agents was observed in Sweden, €769; however, the annual cost of insulin therapy was significantly lower in Sweden, €373. In contrast, the annual therapy cost of insulins and new antidiabetic agents in Germany were shown to be almost the same, around €500. Nevertheless, the enormous cost gap between the old and new antidiabetic medicines and their financial burden could affect market uptake and consequently patient access to the new agents .
Strengths and limitations
The study included 11 European countries, and address an important therapeutic area with evaluation of all relevant antidiabetic classes in a 10-year study period. It provides useful insight and strengthens the evidence regarding European countries’ variability in introduction and adoption practices of new antidiabetic medicines at the time when limited evidence to assess risk/benefit of new agents were available. Indeed, inclusion of additional countries would contribute to the overall assessment, however the IQVIA data exhibits limitations in terms of the quality and type of data. The database combines two levels of data (retail and hospital consumption), however not in the same manner for all countries. Hence, certain countries were not eligible for inclusion and the study provides estimates of intensity of prescribing policy, and market uptake of new antidiabetic medicines. Furthermore, we were not able to divide the combinations in two different entities, therefore, aiming to detect any new antidiabetic agent available in the selected countries, fixed combinations for which one of the active substances was a new active substance were assigned to the corresponding group of new medicines. Taking a different approach might yield some difference with our current results. Secondly, the study period ended with 2016, when two major clinical trials [32, 33] changed the perspective on GLP-1 receptor agonists and SGLT-2 inhibitors, which resulted in an updated guidelines on diabetes management in 2018 . Extension of the study period would provide additional insights and comparisons into how the new evidence influenced trends in intensity of prescribing policy, volume market shares and annual therapy cost of all antidiabetics classes. However, the availability of data limited the scope of our study.