Add-on and substitution effects of novel antidiabetic drugs

There has been a clear volume dynamic on the German pharmaceutical market for several years [1]. In addition, factors such as demographic change, medical-technical progress and the increase in outpatient therapy options lead to increasing pharmaceutical expenditure [2]. The legislature took up this progressive development by introducing the Medicines Market Reorganization Act (AMNOG) in 2011. Since then, new medications have been evaluated for their additional benefits. It turns out that a large number of new pharmaceutical products continue to come onto the German market, the additional benefit of which often cannot be proven or for which only a small additional benefit has been identified [3]. In addition, in the period from 2013 to the beginning of 2014, drugs that had already been approved were assessed as part of the AMNOG with regard to their additional benefit (so-called existing market call).1 The only group of active ingredients whose process was completed include the DPP-4 inhibitors (also gliptins).

>> Using the example of these oral antidiabetics for the treatment of type 2 diabetes, the present analysis sheds light on the market diffusion of novel drugs. The selected active ingredients sitagliptin, vildagliptin and saxagliptin are patent-protected preparations that were approved either as a monopreparation or as a fixed combination preparation between 2007 and 2009 for the treatment of type 2 diabetes. In 2013, the antidiabetics under consideration were examined by the G-BA (Federal Joint Committee) as part of an existing market assessment with regard to their additional benefits. A minor added benefit was found for two of the three active ingredients - sitagliptin and saxagliptin - while vildalgiptin had no added benefit [5]. Due to the time limitation of these decisions, a new benefit assessment for sitagliptin and saxagliptin and the corresponding combination preparations with metformin was carried out three years later (December 2016) [5, 6]. Only a hint of a minor added benefit could be found for sitagliptin, while there was no longer any added benefit for saxagliptin. With a view to this assessment by the G-BA and with a focus on guideline therapy, the market dynamics of the active ingredients under consideration will be examined below. One focus is on the question of whether the selected antidiabetic drugs could be add-on preparations.
methodology
To examine market penetration, routine data from the Techniker Krankenkasse (TK) from 2010 to 2015 was used. The selected active ingredients are used continuously to treat diabetes mellitus and thus enable an observation over time. The gliptins and fixed combination preparations with metformin were identified using the ATC code and assigned to a calendar year by the dispensing date. All prescriptions for antidiabetic drugs (excluding insulins and analogues) were used to differentiate. Insured persons under the age of 18 were excluded because the active ingredients considered are only approved for use in adult type 2 diabetics. In addition, insured persons with residence abroad, without regional information or missing socio-demographic information were excluded. With regard to the prescription costs, the GKV perspective was adopted, ie costs minus statutory deductions and additional payments. A total of 1,172,788 prescriptions were analyzed, which could be attributed to 122,488 insured persons. In the same period, there were 6,320,224 prescriptions for 421,759 insured people in the overall market for antidiabetic drugs (see Table 1).
In the treatment of type 2 diabetes, in addition to the monopreparations sitagliptin, vildagliptin and saxagliptin, there are fixed combination preparations as treatment alternatives [7]. It is also possible to prescribe other active ingredients such as metformin, sulfonylureas or thiazolidinediones separately [7]. In this case, (individual) combination therapy also takes place. The national care guideline for the treatment of type 2 diabetes recommends monotherapy with metformin as the first-line antidiabetic drug. Only if there is intolerance should you switch to gliptins or other antidiabetic drugs. However, combination therapy is only recommended in cases in which the individual HbA1c target has not been achieved after 3 to 6 months with monotherapy [8].
In order to capture the entire combination spectrum of gliptins, different variants were determined based on the ATC code, the delivery date, the billing number and a 30-day interval around the time of gliptin delivery. On this basis, it was examined to what extent substitution or add-on effects exist for the selected antidiabetic drugs. The entire combination spectrum of gliptins is made up of different levels (see Table 2). First, the ready-made combination preparations with metformin were identified and compared with the entire gliptin prescriptions (stage 1). Additional combination therapies were identified by analyzing prescriptions containing metformin, a sulfonylurea, or a thiazolidinedione at the same time as a gliptin (level 2). In the last step, prescriptions that were independent of gliptin were also taken into account, although this could also be a combination therapy, as a separate prescription for metformin, a sulfonyurea or thiazolidinedione was made within a 30-day interval before or after gliptin administration took place (level 3) (see Table 2).
The market penetration of medicines is measured based on the regulations or the prescribed daily doses. There is a deviation from the DDD concept [9], as market penetration is measured based on actual prescribed daily doses and prescription numbers. In order to measure the market penetration of gliptins on the antidiabetic market, the substitution concept according to Hajen et al. was used to define the market. (2010), in which a single indication group is examined in more detail [10].2 Here, the share of gliptin prescriptions was compared to the entire antidiabetic drug market.
Results
During the entire study period, the number of insured people rose continuously both on the entire antidiabetic market and on the gliptin market. Taking into account the growth in TK's insured population, the proportion of gliptin recipients on the overall market has almost doubled from 16.5% to 33%. This development can be attributed to the generally growing prescription volume of DPP-4 inhibitors on the entire German antidiabetic market [11, 7] and indicates increasing market penetration of gliptins. From Figure 1
shows that the number of prescriptions on the gliptin market for both mono- and combination preparations increased continuously throughout the entire investigation period. Only for vildagliptin (A10BH02) and the corresponding combination preparation with metformin (A10BD08) were declining rates observed in 2014 and 2015, which can be attributed to the withdrawal of vildagliptin from the market on July 1, 2014 [7]. Furthermore, it can be observed that prescription figures for the combination preparation of saxagliptin and metformin (A10BD10), which was approved in November 2011, are only available from the 4th quarter of 2012. The remaining active ingredients, both mono and combination preparations, are subject to a continuously increasing trend throughout the entire study period (Fig. 1).
The daily doses and expenditure (in euros) for the gliptins have increased continuously since 2010. While the daily doses increased from 946 to 2,624 units in the study period, the expenditure was subject to a cost increase from 1,607 to 3,916 euros by 2015 (in contrast to Figure 1, the reference value used here is: per 1,000 insured persons). While the proportion of prescriptions with a large pack size (N3) on the gliptin market was 78.5% in 2010, this rose to 93.2% by 2015, so that there is a trend towards prescribing and dispensing large packs. This trend can be seen across the entire pharmaceutical market [12]. Compared to the overall market, where there was an increase in expenditure and daily doses per prescription, the costs per prescription with increasing daily doses on the gliptin market have been declining since 2010 (see Figures 2 and 3).
With regard to the market penetration of DPP-4 inhibitors, sitagliptin (A10BH01) can claim the highest share among the monopreparations with a market share of 31.9%. Among the fixed combination preparations, the combination of sitagliptin and metformin (A10BD07) also has the highest market share with 41%. The market division can be attributed to the time of market access, as sitagliptin is the first representative of the gliptin drug class [13]. With regard to the combination spectrum of gliptins, a prescription rate of 57.1% was determined for ready-made combination preparations with metformin, which means that more combination preparations than mono preparations were prescribed (level 1).
If one takes into account prescriptions in which metformin, a sulfonylurea or a thiazolidinedione were present at the same time as a gliptin, the proportion of combination therapies in the total gliptin prescriptions increases to 66.7% (level 2). If separate prescriptions of metformin, a sulfonyurea or thiazolidinedione are also taken into account in a 30-day interval, the proportion of prescriptions increases by a further 10% to 76.5% (level 3).
The proportion of combination therapies in total gliptin prescriptions has been declining over time (see Fig. 4). While in 2010 82.3% of the prescriptions could be traced back to combination therapy, this proportion had fallen to 72.4% by 2015. Even though the proportion of combination therapies with the same prescription and different prescriptions was 24.7% in 2010, this fell to 18.2% in 2015. For the fixed combination preparations there was a slight decrease from 57.7% to 54.2%. At the same time, the proportion of pure monotherapies increased from 17.7% in 2010 to 27.6% in 2015.
Discussion and limitations
discussion
With regard to the opposite development of increasing daily doses and decreasing costs per prescription, the result of the reimbursement negotiations between the National Association of Statutory Health Insurance Funds and the pharmaceutical manufacturers, which were concluded in 2014, can be used [14]. The resulting reduced reimbursement amount from the health insurance companies may have contributed to the decline in expenditure per prescription. However, the increase in costs per prescription on the entire antidiabetic drug market is probably due to the change in the structural component. Prescribing different dosages or pack sizes could have resulted in an increase in expenditure per prescription over time [15]. In the future, it is to be expected that if the trend of increasing gliptin prescriptions continues, this will result in further rising drug costs, since the DPP-4 inhibitors with annual therapy costs of over 500 euros significantly exceed the annual costs of the appropriate comparative therapy (metformin) at around 70 euros exceed [7].
Since the majority of gliptin prescriptions are given as part of a combination therapy, it can be assumed that the majority of gliptins are add-on preparations. It follows from this that the market launch of gliptins can ultimately be interpreted as primarily economic innovations with the aim of making profits in a promising indication area. In only 23.5% of the prescriptions, a monopreparation was prescribed or the prescription of other possible combination active ingredients was outside the 30-day interval considered. However, particularly with regard to the possible change in drug therapy, it cannot be determined with certainty whether a combination therapy was already present or a change has just taken place. From this point of view, combination therapy could represent a transitional solution for switching from an old to a new active ingredient, which could explain the decreasing proportion of combination therapies over time. In the long term, add-on therapies that deviate from the guideline-based care lead to additional financial burdens for the payers and the insured community. In this context, the GKV-SV [16] and the Techniker Krankenkasse [3] point out the burdens associated with a pseudo-innovation, which can lead to additional costs and risks in patient care.

limitations
The deletion periods underlying the routine data only allow a look at the analysis years 2010 to 2015, so that it was not possible to use a longer examination period, which in particular includes the years of market launch. Furthermore, routine data does not contain information about the patient's health status or the severity of the disease, which could have an impact on his medication consumption. The fact that the number of TK insured persons rose continuously during the investigation period was taken into account by referencing the overall market. In addition, it should be taken into account that so far only clinical studies have been carried out for the active ingredients under consideration, but there is no information regarding effectiveness (effect under everyday conditions).
Conclusion
The present analysis shows that gliptins were increasingly prescribed during the study period, although the costs per prescription fell. With regard to the consumption of antidiabetic drugs, it was shown that gliptins are mainly used as add-on preparations and thus cause additional costs on the pharmaceutical market. Since add-on therapies can contribute to further cost increases without significantly improving the quality of care for patients, the use of these add-on medications should be critically examined against the background of efficient use of resources and limited financial resources. Considerations must be made as to the extent to which new drugs are necessary from a cost and benefit perspective or whether oversupply can be avoided. The results make it clear that, in addition to the additional benefit assessment, other influencing factors, such as stakeholder-specific interests and legal requirements, are crucial for the market penetration of novel drugs. Overall, the analysis shows a tension between the recommendations of the national supply guidelines regarding the prescription of gliptins, the benefit assessment of the G-BA and the existing market dynamics. It remains to be noted that the reality of care does not correspond to the guideline recommendations. Given that the costs of novel drugs exceed those of the appropriate comparative therapy, future research should focus more on reconciling benefit assessments and guideline-based care. <<