Using South Korea’s comprehensive and nationwide real-world data, we found significantly longer persistence, higher adherence, and lower risk of clinical outcomes associated with patients on FDC therapy versus TPC therapy among patients with type 2 diabetes. Based on the observed higher rates of treatment adherence and persistence associated with FDC and given that adherence to treatment leads to improved glycemic control among patients with type 2 diabetes [7, 20], our findings provide additional reasons for health care providers to consider FDC therapy over TPC therapy as an optimal treatment strategy for patients with type 2 diabetes with increased baseline cardiovascular risks, especially hospitalization for stroke.
Our findings are generally consistent with those of previous studies that showed a positive association between FDC therapy and adherence and persistence [11, 12, 21–24]. A meta-analysis conducted by Bangalore revealed that FDC therapy improved medication non-compliance by 26% (pooled relative risk, 0.74; 95% CI 0.69–0.80; P < 0.0001) when compared with a free-drug combination . Another study by Barner et al. found 9% improvement in medication adherence, but did not compare it to an active comparator, making it difficult to directly compare with to our results . Although we were able to provide a more accurate estimate of adherence by comparing the FDC to the TPC group, Nishimura et al. reported a much stronger finding than that of our study (> 90% versus 47.5% for the adherent patient rate with PDC ≥ 0.8 in the FDC group at 12 months) . However, this finding may have resulted from a different definition of the grace period, which was not used in our study. In our sensitivity analysis that varied the grace period, we found an enhanced adherence rate with PDC ≥ 0.8 at 12 and 24 months under less stringent conditions (Supplemental Table S5). Although further investigations are warranted on the adherence and persistence of FDC therapy, our findings support the previously reported positive association between FDC therapy and increased adherence and persistence compared with TPC therapy among patients with type 2 diabetes.
Several studies have examined the association between clinical outcomes and FDC and TPC groups, focusing on the improvement of glycemic control through regime simplification [25–28]. Although one study showed an association between non-adherence and increased mortality rates, it was likely caused by poor glycemic control . Another study that compared drug compliance and morbidities over a 3-year period failed to detect a statistically significant difference in morbidities between TPC and FDC . Our findings for the composite clinical outcome and hospitalization for stroke associated with FDC versus TPC revealed statistically significant differences in favor of the FDC group. The FDC group had 6.50 and 5.02 fewer events per 1,000 person-years, respectively than the TPC group (Table 3). However, there was no significant difference in mortality rates between the FDC and TPC groups (Supplemental Fig. S3), which is consistent with the findings of a previous study. Hence, because FDC therapy was associated with reduced risk of adverse clinical outcomes and improved medication adherence, patients with type 2 diabetes could experience greater clinical benefits with FDC therapy than with TPC therapy.
Our study has several strengths. First, our findings are likely generalizable to the patient population in South Korea and are representative of real-world clinical practice, because we identified our study cohort using a nationwide NHIS-NSC database. Second, we identified our study cohort as patients who initiated FDC or TPC therapy within 120 days after their incident diagnosis of type 2 diabetes to restrict the study cohort to patients at similar stages of disease progression [30–32]. Third, in contrast to previous studies that had a relatively short follow-up of < 12 months [12, 22–24, 33–35], we examined the long-term outcomes with a maximum follow-up of 12 years. This is particularly important when investigating treatment patterns in patients with chronic diseases (e.g., type 2 diabetes), because it allows for a better understanding of the long-term benefits versus risks associated with FDC versus TPC therapy. Lastly, our findings suggest that FDC therapy may be a more optimal strategy for patients with type 2 diabetes and could further reduce the cost burden, as such treatments, resulting in lower reimbursement cost than that for TPC.
Our study has several limitations. First, we were unable to identify the cause of the prominent improvement in hospitalization for stroke associated with FDC versus TPC therapy. Several randomized trials and observational studies have shown that tight glycemic control does not offer any benefit in the prevention of stroke [36, 37]. However, there were significant differences in patient characteristics between the aforementioned studies, which included those prevalent in diabetes and cardiovascular disease, and our study, which included only incident patients with diabetes and cardiovascular diseases. In support of this, our subgroup findings showed a significant reduction instroke -and heart failure-naïve patients receiving FDC medication (Supplemental Table S10). Considering this, we suggest that FDC medications could contribute to the prevention of hospitalization for stroke among incident patients with diabetes with no prior history of cardiovascular diseases. Second, laboratory or lifestyle variables, such as HbA1c levels, stress, and family history of chronic diseases, were unavailable for assessment from the NHIS-NSC database. However, we adopted a new user design, performed several sensitivity analyses, and had consistent results, which are suggestive of minimal residual confounding from such unmeasured covariates. Third, of the nine DPP4i molecules currently marketed and reimbursed in South Korea as of November 2021, we were able to include mainly vildagliptin and sitagliptin at the time of study cohort entry, because the other DPP4i drugs were either yet to be approved or recently launched and introduced into the South Korean market in December 2013. Hence, future studies with more recent real-world data, including sodium glucose cotransporter-2 inhibitors, are needed. Fourth, we measured adherence using the PDC based on the medication dispensed and assumed that medications were taken exactly as prescribed. Although this is not a direct measure of medication adherence, it is considered appropriate when using secondary databases . Lastly, despite the use of multiple methodological approaches to mitigate confounding variables, residual confounding is possible owing to the nature of observational studies. Therefore, we calculated the E-value , which indicated that our effect estimates were likely to be directed toward the null only when there was a very strong unmeasured confounder (Supplemental Table S15).