This economic analysis applied real-world and population-specific data as model inputs to reflect the cost-effectiveness of SGLT2is versus DPP4is for T2D in usual clinical practice settings in Taiwan. The present study findings, together with the systematic review results, provide supportive evidence that promotes the use of SGLT2is as an economically reasonable alternative to DPP4is for T2D patients in real-world clinical practice regardless of baseline patient status of CVDs.
Comparison with current evidence on the cost-effectiveness of SGLT2is versus DPP4is
The conclusions for this cohort-based modeling CEA are generally consistent with existing studies that primarily utilized individual-based modeling approaches to evaluate the long-term health and economic outcomes of SGLT2is versus DPP4is (Additional file 10). Specifically, the cost-effectiveness results of SGLT2is versus DPP4is observed in our study are comparable with those in the literature, showing that the use of SGLT2is is a cost-effective (11-13, 15-17) or even cost-saving (10, 14, 18) treatment option compared with DPP4is for T2D. Our study further extends current evidence by demonstrating SGLT2is as an economically rational alternative to DPP4is for T2D treatment in routine care. In addition, the probabilities of being cost-effective for using SGLT2is versus DPP4is obtained from the PSAs (i.e., 100% for patients with and without CVD history) in this study are similar to the probability estimates reported in the literature (i.e., near (10, 15, 17) or equal to 100% (14, 16)). However, direct comparisons of cost-effectiveness estimate between our study and previous studies should be done with caution given the differences in the study populations and settings, follow-up periods, analytical design, approaches, and assumptions.
Additionally, several influential drivers for ICER values found in this study (Figure 2) have been identified in previous studies (16, 17), including drug costs of DPP4is and SGLT2is (16, 17), treatment effects of SGLT2is versus DPP4is on cardiovascular and mortality outcomes (16), and health utilities of health states (16, 17). DPP4i drug cost was the most prominent driver of ICERs in our study regardless of patients’ status of CVD history. This may be explained by a wide range of drug costs of DPP4is (i.e., USD 87 to USD 319 per year in Taiwan) used as model inputs under Taiwan’s health insurance system. DPP4is have been reimbursed by Taiwan’s NHI program since 2006. The drug reimbursement fees of DPP4is have changed considerably owing to the launch of generic DPP4i drugs, adjustments of drug pricing, and changes in relevant reimbursement policies under the Taiwan NHI Administration’s regulations (28). Although variations in DPP4i drug costs had a great impact on ICER values, the cost-effective result of using SGLT2is versus DPP4is remained robust in our sensitivity analyses (Figure 2). Regarding other drivers of ICERs, some heterogeneity between the study patients with and without established CVD, described below, should be acknowledged.
Comparison of dominant variables for base-case ICERs between T2D patients with and without established CVD
For the base-case ICER, the treatment effects (i.e., hazard ratios) of SGLT2is versus DPP4is on HF, stroke, and all-cause death were the dominant drivers, other than DPP4i drug costs, for T2D patients with established CVDs, followed by utility penalties of CVDs, drug costs of SGLT2is, and discount rate. However, for T2D patients without established CVDs, only the treatment effects of SGLT2is versus DPP4is on stroke and all-cause death and drug costs of SGLT2is affected the base-case ICER by more than 15%.
As shown in Figure 1, there are some discrepancies in the composition of the estimated event rates of CVDs and all-cause death between the two simulated cohorts (T2D patients with and without CVD history). HF and all-cause death were the two most common events among T2D patients with CVD history in our analyses. Given the apparent benefits of SGLT2i use on HF and all-cause death (9), it is expected that CEA results would be affected by the hazard ratios of SGLT2is versus DPP4is on these two outcomes for T2D patients with CVD history. In contrast, the risk of developing HF was relatively low among T2D patients without CVD history, while stroke and all-cause death accounted for most clinical events for this population. As a result, the hazard ratios of SGLT2is versus DPP4is on stroke and all-cause death, instead of HF, were identified as the leading drivers for the ICER in T2D patients without CVD history. This means that the treatment benefits of SGLT2is versus DPP4is on CVDs and death would be more evident when the patients’ baseline risks of these clinical events were higher, which would further affect the CEA results. In addition, the utility penalties associated with MI, HF, and stroke had considerable impacts on the ICER for patients with CVD history but not those without CVD history. This may also be explained by the relatively low CVD risks in patients without CVD history, and thus the QALYs gained contributed by SGLT2i-associated cardiovascular benefits were trivial in this population.
The DSA findings suggest that among T2D patients with established CVDs whose cardiovascular risks are considerably higher than those without established CVDs, the economic benefit of SGLT2is versus DPP4is would mainly come from the effectiveness of SGLT2is in lowering risks of CVD events (including HF, MI, and stroke) and all-cause death that subsequently lead to improved QALYs and reduced healthcare costs of patients. Conversely, the less beneficial effects of SGLT2is versus DPP4is on CVD events, particularly HF and MI risks, in T2D patients without CVD history might not meaningfully dominate the CEA results, and in this case, the drug costs of SGLT2is are one of the leading drivers of the ICER.
Clinical and health policy implications
Based on our study findings, the use of SGLT2is in real-world practice should be encouraged owing to its lower risks of major clinical events and economic benefits compared with DPP4is. Moreover, from the perspective of the healthcare sector, this study provides supporting evidence for using SGLT2is to facilitate the cost-effective allocation of healthcare resources. Specifically, Additional file 9, which shows the ICERs of SGLT2is versus DPP4is against various SGLT2i drug costs, could assist health policy-makers in pricing SGLT2i reimbursement fees. For example, SGLT2is become a cost-saving treatment option compared with DPP4is when the SGLT2i drug costs are lower than USD 304 and USD 257 per year for patients with established CVD and those without CVD history, respectively. These break-even points may serve as a reference for the reimbursement pricing adjustment of SGLT2is. In addition, it is expected that the economic benefit of SGLT2is would be more amplified when the cost of SGLT2is is significantly reduced owing to the launch of their generic drugs.
Differences in the cost-effectiveness of SGLT2is versus DPP4is contributed by patients’ CVD history were revealed in this study, suggesting the importance for prioritizing the treatment for subgroup populations who can benefit more from using SGLT2is clinically and economically. For example, we found that the use of SGLT2is yielded a more favorable cost-effectiveness profile among patients with established CVDs than those without CVD history; i.e., the ICER estimates were consistently lower in patients with CVD versus those without CVD history in base-case analyses and most scenario analyses (Table 1). Therefore, given limited healthcare resources, the reimbursement or incentive health policies could be tailored to prioritize the use of SGLT2is in T2D populations with CVD history. Further research is warranted to identify the subgroup patient populations with specific characteristics (e.g., comorbid chronic kidney disease, elderly patients) who can benefit more from SGLT2i use to optimize healthcare resource allocation.
Strengths and limitations
Our economic evaluation attentively applied several study designs that can reflect real-life scenarios, including 1) derivation of effectiveness parameters (i.e., transition probabilities regarding CVD events) from a large-scale, real-world T2D cohort population, 2) incorporation of time-varying transition probabilities (i.e., annual risks of CVDs, increased mortalities with aging) in modeling analyses, and 3) stratification of the analyses for patients with established CVD and those without established CVD; such a stratification analysis was less often considered in previous CEAs. In addition, to ensure the applicability of the study results in Taiwan’s healthcare setting, we used data from population-based studies that analyzed Taiwanese T2D populations for the effectiveness, health utility, and cost parameter inputs in the model (i.e., Chen et al.’s study (2), Kuo et al.’s study (21), and the T2D cohort identified from the NHIRD for costs, utility, and effectiveness parameters (19), respectively). The model inputs derived from the same target population (i.e., the T2D cohort from NHIRD) in our study minimize the uncertainties of CEA results that arise from the heterogeneity of multiple data sources.
Several limitations of our study should be acknowledged. First, our Markov decision model included only health states of CVDs and death without considering other clinical outcomes such as kidney diseases and adverse effects of treatments. Given growing evidence about SGLT2i-associated renal benefits (29, 30), the cost-effectiveness of SGLT2is versus DPP4is revealed in the present study could be underestimated. In addition, the impact of adverse drug effects on the CEA results might be negligible given the low incidence of adverse effects (e.g., severe hypoglycemia, diabetic ketoacidosis). Second, the analyses were not performed from the societal perspective because costs from informal healthcare and non-healthcare sectors were not included due to data unavailability. Lastly, the improved health-related quality of life associated with the use of SGLT2is other than those contributed by reduced CVD and mortality events were not considered, e.g., the SGLT2i-associated benefit of body weight loss on patients’ health-related quality of life (31). We might thus have underestimated the economic value of SGLT2is.