Persistence to Treatment with Novel Antidiabetic Drugs (Dipeptidyl Peptidase-4 Inhibitors, Sodium-Glucose Co-Transporter-2 Inhibitors, and Glucagon-Like Peptide-1 Receptor Agonists) in People with Type 2 Diabetes: A Nationwide Cohort Study

Our study demonstrates that at treatment intensification with novel antidiabetic drugs, DPP-4 inhibitors have the highest persistence rate followed by SGLT-2 inhibitors and GLP-1-RAs. Novel oral antidiabetic drugs in fixed combinations with MET have significantly higher persistence than that of free add-on combinations. The persistence to treatment with novel oral antidiabetic agents (DPP-4 inhibitors, SGLT-2 inhibitors) in initial therapy is much better than that with MET or SUs.

We used a nationwide database to determine persistence to treatment with different antihyperglycemic drug classes. It is widely accepted that pharmacy claims databases are a reliable source of data based on prescription refills. Using such database, one can perform an accurate analysis of persistence to a treatment in chronic diseases such as diabetes [23].

In our analysis we investigated a near 3-year-long period from 2014 to 2017. Although DPP-4 inhibitors became available 8–10 years ago, GLP-1-RAs reached the market later and SGLT-2 inhibitors could be prescribed only in the last couple of years. As our original aim was to perform a comparative analysis in the same period, the timeframe of availability of SGLT-2 inhibitors was taken into account.

In our study we used the term persistence. Although there is no clear distinction in some publications between the terms persistence and adherence, and sometimes they are used interchangeably in the literature, we maintain the term persistence—the duration of medication use—as an important indicator of adherence [24, 25].

We evaluated the rates of persistence to the treatment with particular antihyperglycemic drug classes at prespecified time points but we also assessed the hazard ratios of non-persistence by using persistence curves. Although persistence (or non-persistence) data can easily be followed in our study, we acknowledge that another method (i.e., evaluating proportion of days covered) is still in use in the literature [23].

Although persistence to diabetes medication is of great importance, non-persistence is common and varies according to classes of drugs [26]. Former retrospective database analyses from the USA and Germany documented that DPP-4 inhibitors have better persistence than traditional antidiabetic drugs such as SUs or thiazolidinediones [11, 12]. Similar results were found in another study which used a database from the UK [13]. In 2015, the persistence of oral antidiabetic drugs proved to be suboptimal in a meta-analysis [14]. A study from the USA recently documented a better persistence with the SGLT-2 inhibitor canagliflozin compared to dapagliflozin, GLP-1-RAs, or DPP-4 inhibitors [15]. Another study also from the USA reported on better persistence of initial SGLT-2 inhibitors than newly initiated treatment with SUs [16]. In a recent large comparative study from the UK, persistence to older and newer oral antidiabetic drugs was analyzed and the results suggested that medication class was the major influencing factor in medication persistence [17]. Among the GLP-1-RAs, dulaglutide had better persistence data than that of once-weekly exenatide or liraglutide [18]. To the best of our knowledge, our study is the first report from Central-Eastern Europe demonstrating the persistence rates of all novel antidiabetic drug classes either at treatment intensification or at initial treatment. The data from our region add to the current body of knowledge on persistence of novel antidiabetic drugs.

Regarding our results, two recent real-world studies from the USA are of particular interest. Using the same large database (US Centricity Electronic Medical Records), the authors reported on—among others—the discontinuation rate of DPP-4 inhibitors, GLP-1-RAs, and SGLT-2 inhibitors in patients with type 2 diabetes. When these drugs were used as initial treatment, the discontinuation rates at year 1 were 17%, 20%, and 25% resulting in persistence of 83%, 80%, and 75%, respectively. When these drugs were used as second treatment, the discontinuation rates at year 1 were 18%, 21%, and 25% resulting in persistence of 82%, 79% and 75%, respectively. Although the numbers differ, the ranking order of persistence of these novel antidiabetic drugs is very close to what we found in our study either at treatment intensification or at initial treatment [19]. In another publication the authors reported on the sustainability of desirable glycemic control over 2 years with major second-line antidiabetic therapies. They found that patients with second-line incretin-based drugs (DPP-4 inhibitors, GLP-1-RAs) had higher probability of achieving and sustaining acceptable glycemic control compared with those treated with SUs or insulin [20]. Unfortunately, we could not perform such analysis as no laboratory parameters were recorded in our database. Additionally, our data suggest that age of patients may have some influence on persistence (with DPP-4 inhibitors, persistence was higher in patients aged ≥ 51 vs. ≤ 50 years; with SGLT-2 inhibitors, the worst persistence data was observed in patients aged ≥ 71 years; while with GLP-1-RAs, the best persistence rate was observed in patients aged 51–70 years).

It was earlier documented that management of type 2 diabetes using fixed-dose combinations provides a compliance benefit relative to free add-on combinations [27, 28]. In this regard our study should be considered confirmatory with novel oral antidiabetic drugs with MET combinations.

Our results have to be interpreted within the context of their limitations. In our study no specific data were available about important covariates such as severity of the disease, comorbidities, glycemic control, HbA1c values, BMI, renal function, socioeconomic status, or incidence of side effects (especially hypoglycemic event rates) of ongoing antidiabetic treatment. While we acknowledge the importance of these cofounders, we feel that our results are meaningful for characterizing the persistence of treatment with novel antidiabetic drugs in our region. Nevertheless, the generalizability of our results is limited because the healthcare system and accesses to different treatment options are country-specific. In this regard it is noteworthy that our study was based a nationwide register which should be considered as a strength of the investigation. It is also of note that although the prices of novel drugs in different antidiabetic classes differ, all have the same (70%) reimbursement in our country.