Utilization Patterns of Glucagon-Like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus in Italy: A Retrospective Cohort Study

In Italy, 3.5 million people have been diagnosed with diabetes, over 90% of whom have type 2 diabetes mellitus (T2DM), with an estimated burden for the Italian national health system of approximately €8–10 billion yearly for drugs, hospitalizations and visits [1, 2].

Despite recent advances that have expanded the available therapeutic options, achieving and maintaining glycemic control in patients with T2DM remains a major challenge for doctors who must face complex therapeutic decisions [3]. The 2016 Italian Standard of Care [4], in line with the updated 2015 joint position statement released by the American Diabetes Association and European Association for the Study of Diabetes [5], recommends a patient-centered approach with metformin as the first line of therapy and the addition of one (or two) of the other available treatments as the second (or third) line of therapy, with no indicated preference. Doctors should make their initial decision based on the patient's physical and clinical characteristics and the efficacy and safety profiles of the available treatments and then address the eventual progressive worsening of glycemic control through treatment intensification.

Glucagon like peptide-1 receptor agonists (GLP-1 RAs) are a relatively new class of injectable drugs that have emerged as an attractive second- or third-line therapeutic option because of their association with improved glycemic control, lower hypoglycemia rate and weight loss, although gastrointestinal GLP-1 RAs side effects have also been reported [6, 7]. There are several GLP-1 RAs on the market in Europe, each with specific characteristics [3]; they vary in the magnitude of their effect in reducing HbA1c and enhancing weight loss and also in their adverse event profiles [3, 8]. Additionally, injection frequencies are variable, with some GLP-1 RAs offering more convenient dosing (weekly vs. daily injections) and potential higher adherence [9] compared with others. In Italy, the currently available GLP-1 RAs include exenatide twice daily (from now on referred to as exBID), launched February 2008; liraglutide once daily (LIRA), launched August 2010; exenatide once weekly (exQW) and lixisenatide once daily (LIXI), both launched December 2013 and dulaglutide (DULA) once weekly launched February 2016.

For a drug to be effective, patients must adhere to and persist with therapy. Previous studies have shown an association between better adherence and persistence with glucose-lowering treatments and improved clinical and economic diabetes-related outcomes [10‐13]. Persistence with GLP-1 RAs has also been reported to be associated with positive clinical outcomes and reduced healthcare costs [14, 15]. However, to date, real-world data on persistence, discontinuation or switch dynamics with GLP-1 RA are limited. Only a few studies have compared treatment patterns or variable dosing across the different treatments [9, 15‐20], and none of them were conducted in Italy.

Given the current limited evidence and the important clinical and costs implications, the main objective of this study was to provide real-world evidence on treatment patterns for T2DM GLP-1 RA therapy initiators in Italy, specifically persistence with the GLP-1 RA (i.e., index therapy) and treatment modifications, including discontinuation, switch to another hyperglycemic therapy, dosing changes and augmentation (addition of new therapy to the index treatment). Other objectives included evaluating the average daily/weekly dose (ADD/AWD) of the index therapy and describing the baseline characteristics of the patients initiating the different GLP1-RA treatments. These outcomes were retrospectively evaluated using the Italian Longitudinal Prescription (LRx) database, a large database containing information on retail dispensing.

This study was a retrospective cohort study, including all patients receiving the first prescription of GLP-1 RA as exBID, exQW, DULA, LIRA or LIXI. To allow for comparisons, the overall study design and methodologies were like those used in previous studies conducted in other European countries [16, 17]. Ethics committee approval is not required for secondary use of pseudonymized prescription data in Italy.

The results of this retrospective analysis of Italian prescribing data show that there are differences in the real-world utilization patterns of different GLP-1 RAs. Previous real-world studies in Italy have examined diabetes-related outcomes related to GLP-1 RAs [25‐27]; this is the first published study evaluating the real-world treatment patterns of individual GLP-1 RAs in Italy. The results add to the evidence base coming from other European countries as the number of GLP-1 RAs available on the European market increases.

Based on our findings, patients initiating treatment with DULA are more likely to remain persistent compared with other drugs, while greater proportions of patients initiating on exBID and LIXI tend to discontinue or switch treatment. Across the different treatments, persistence with the index therapy at 6 months was exBID < LIXI < exQW < LIRA < DULA. The KM analysis over the full follow-up period confirmed this trend and showed that patients initiating on DULA are less likely to discontinue or switch therapy than patients on other treatments. There are many possible reasons for low treatment persistence, including high injection frequency (twice daily vs. once daily vs. weekly injections), patient low tolerability of treatment, adverse reactions or lack of effectiveness. On the other hand, a higher persistence with therapy has been reported to result in better glycemic control and economic outcomes, with an estimated reduced healthcare cost of 27–30% [14, 15]. Although not ascertained as part of this study, therapies with improved persistence could be associated with better outcomes and lower costs.

The differences in treatment patterns observed in this study are consistent with those recorded in other European countries and in the US. In a similar analysis conducted in T2DM initiating GLP-1 RA treatment in 2013, Divino and colleagues [16] examined treatment patterns with exBID, exQW, LIRA and LIXI over 1 year from initiation in five European countries. The proportion of persistent patients was lower for exBID compared with LIRA and exQW in Germany (29% vs. 43% and 33%, respectively), The Netherlands (34% vs. 61% and 51%) and Sweden (31% vs. 59% and 43%). The proportion of persistent patients was also lower for exBID in Belgium compared with LIRA and LIXI (18% vs. 29% and 50%) and in France compared with LIRA (44% vs. 52%). Previously, the same authors [17] reported that persistence was lower for patients newly initiating on exBID (47–74% across Germany, Belgium, The Netherlands, UK and Sweden) compared with LIRA (51–80%) and exQW (58–75%) in the first 6 months of treatment. Alatorre and colleagues [9] looked at treatment patterns of patients initiating GLP-1 RA treatment with DULA vs. exQW and LIRA between November 2014 and April 2015 in the US. At 6 months from initiation, the proportion of patients discontinuing treatment was lower for DULA vs. exQW (26% vs. 48%) and for DULA versus LIRA (28% vs. 36%). While these trends are overall in line with the results of this study, different proportions across countries can be explained by the inherent characteristics of the local health systems as well as differences in the study designs, time when the studies were carried out and follow-up durations.

This study also found that the average daily doses prescribed to patients on the different GLP-1 RA treatments were generally within the recommended ranges, but for LIXI this was slightly above the recommended range (21.0 mg recorded in this study, label range 5–10 mg twice daily), suggesting that some patients on this drug may require higher doses to maintain or achieve glycemic control.

Differences in the methods used to calculate ADD may limit comparisons with other studies. The methodology used in this study was similar to that used by Divino and colleagues [16], who recorded an ADD of 1.55 mg for patients on LIRA in Germany, similar to this study. ADD varied in other countries and was lower in Belgium (1.41 mg) and higher in France (1.64 mg), The Netherlands (1.68 mg) and Sweden (1.60 mg). In the same study, the authors also recorded an ADD of 20.1 mg for patients on LIXI in Germany [16], in line with the current study, and confirm that slightly higher doses than expected for this treatment may be prescribed by doctors in the real world.

The authors acknowledge some limitations to the study design. First of all, we were unable to investigate reasons for treatment modifications (lack of effectiveness, adverse events, etc.) as these clinical details are not covered by prescription databases. Second, selection bias toward more severe patients may have occurred because of our continuous enrollment requirements based on prescribing activity. However, this effect should be minor in patients affected by chronic diseases, such as diabetes, who are regularly taking treatments over long period of times. In addition, the continuous enrollment criterion was necessary to ensure adequate visibility into the patients’ clinical history. Third, some of the GLP-1 RAs have been launched in Italy only recently; therefore, the average follow-up duration was short (< 1 year). Additional research is needed to confirm our results over longer time periods and to support clinically relevant findings with statistical testing. Finally, irrespective of the launch date of the different products in Italy, the sample size varied greatly across the different treatment cohorts, with only 92 patients identified who initiated treatment with exBID. This small sample size calls for caution in the interpretation of the exBID results.

Limitations consistent with a pharmacy-based database should also be taken into account when interpreting the results of this study. Patients who purchase prescriptions outside the pharmacies included in the database will not have that prescription utilization recorded in the database, which may result in an underestimation of the drug usage. Doses were calculated according to the dispensed packs over time, which means that stockpiling of prescriptions or filling prior to prescription run-out could lead to overestimations in dose. Furthermore, data are only collected from pharmacies that participate in the database, which may cause some levels of selection bias. However, the impact of this is considered to be very limited in the Italian LRx, as the database coverage is around 90% on average across all regions. Finally, pharmacy data do not record patient mortality. Consequently, patients may be considered discontinued because of no evidence of prescriptions after the minimum 6-month follow-up period rather than dead.

This study adds to the limited literature on type 2 diabetes mellitus and GLP-1 receptor agonists by providing new evidence on the real-world usage of exenatide (twice daily and once weekly), dulaglutide, liraglutide and lixisenatide in Italy. Despite country-specific differences in databases, prescribing and dispensing practices and the analytical methods used, the results of the current analysis are aligned with those from other countries and indicate that patients on exenatide twice daily are less likely to remain persistent with their therapy than those on other GLP-1 RA treatments with either weekly (exenatide QW and dulaglutide) or daily dosing schedules (liraglutide and lixisenatide). Patients with the highest persistence initiated dulaglutide. In addition, for lixisenatide, the average daily dispensed doses as derived from pharmacy data may exceed the recommended doses indicated in the summary of product characteristics.

Given the importance of treatment persistence in maintaining glycemic control over time and reducing healthcare costs, these results suggest that dulaglutide may help improve clinical and economic outcomes for patients with T2DM initiating GLP-1 RA treatment. Further studies would be useful to explore the potential clinical and economic benefits associated within the GLP-1 RA class.