Comparison of heart failure risk and medical costs between patients with type 2 diabetes mellitus treated with dapagliflozin and dipeptidyl peptidase-4 inhibitors: a nationwide population-based cohort study

Type 2 diabetes mellitus (T2DM), a classic metabolic disorder, is consistently on the rise globally and is highly prevalent in Korea, with a prevalence of 14.4% among adults aged ≥ 30 years and 29.8% among adults aged ≥ 65 years as of 2016 [1]. Diabetes mellitus (DM) is known to exacerbate the clinical state of patients with heart failure (HF) and is associated with all-cause and cardiovascular mortality [2]. Further, HF with reduced ejection fraction (HFrEF) is used as an independent predictor of the treatment outcomes in T2DM [3, 4]. The percentage of patients with HF among the T2DM participants recruited in recent clinical trials ranged from 10 to 28% [5‐12]. T2DM is known as an independent risk factor for HF incidence [13], and the incidence of HF was 2.5 times higher in the T2DM group than the non-T2DM group in a retrospective cohort study that followed-up with the patients for 72 months [14]. Therefore, HF management in patients with T2DM is a clinically important issue.

In general, current guidelines for T2DM treatment recommend metformin as the first-line therapy, and if appropriate blood glucose regulation is not achieved with monotherapy, a combination therapy with additional drugs is recommended [15‐17]. Recently updated guidelines recommend sodium glucose co-transporter 2 inhibitors (SGLT-2i) or glucagon-like peptide 1 (GLP-1) receptor agonist treatment as first-line in patients with established cardiovascular disease (CVD) and newly diagnosed T2DM [18]. In Korea, more than 70% of the patients with DM were prescribed combination therapy consisting of more than two drugs in 2016, among which, 56% of the combinations involved metformin and dipeptidyl peptidase-4 inhibitors (DPP-4i) [1]. This suggests that DPP-4i is the second most common drug used after metformin. On the other hand, the use of SGLT-2i, a recently introduced DM medication beginning with dapagliflozin, is consistently on the rise since their inclusion in the health insurance coverage in Korea. Though only 3% of the patients prescribed two-drug therapy were prescribed with metformin and SGLT-2i in 2016 [1], the use of SGLT-2i, owing to the drug’s cost, in the following 3 years increased fourfold than that in 2016 [19].

However, a controversy regarding the potential association between DPP-4i, which is the most widely used drug as a second-line therapy, and HF exists. While alogliptin, vildagliptin, sitagliptin, and linagliptin were not found to significantly increase the risk for HF [6‐9], saxagliptin has been reported to significantly increase the risk of HF [5]. On the contrary, SGLT-2i, another second-line drug for DM, has been reported to lower the risk of HF [10‐12]. In addition to randomized controlled trials, several studies using real-world evidence in actual clinical environments have reported such trends [20‐26].

The risk of HF among patients with DM is an important determining factor for choosing drugs in clinical practice. Reduced HF risk, as a clinical outcome of drug therapy, is associated not only with improved quality of life but also with lower medical costs. As the soaring medical cost is affecting governments’ and hospitals’ decision-making process, cost must be taken into consideration while making choices in a clinical setting. Both clinical and economic outcomes have become an important factor for choosing medications for the highly prevalent DM in today’s aging society.

Economical evaluation of DPP-4i and SGLT-2i, including dapagliflozin, as a second-line therapy for DM in the UK and US has shown that SGLT-2i is cost-effective and reduces the medical costs [27‐29]. However, the results of pharmaco-economical evaluations vary according to the health insurance or healthcare service systems across countries, so it is difficult to directly cite the results reported in other countries. Therefore, country-specific assessment of the economic outcomes of the new class of DM drug, dapagliflozin, is necessary.

Consequently, the present study aimed to compare the differences in the risk of hospitalization due to HF between the dapagliflozin group, which is the first in a new class of SGLT-2i licensed in Korea, and the DPP-4i group, which are the most widely used second-line drugs for T2DM, using the latest real-world nationwide population data in Korea. Additionally, we aimed to examine the impact of clinical outcomes on medical costs in the two groups from an economic perspective.

The present study showed that dapagliflozin lowered the risk for hHF and subsequently lowered direct medical costs as compared to DPP-4i in patients with T2DM.

Two large cardiovascular outcomes trials (CVOTs) of SGLT-2i—Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and Canagliflozin Cardiovascular Assessment Study (CANVAS)—demonstrated consistent reduction in the incidence of hHF among patients with T2DM, although hHF was not a primary endpoint in these trials [10, 11]. In the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) study, treatment with dapagliflozin resulted in a lower rate of cardiovascular death or hHF (one of the primary outcomes) in patients with T2DM [12]. Moreover, a recent meta-analysis of these 3 CVOTs showed that SGLT-2i reduced the risk of hHF in patients with T2DM regardless of the presence of CVD or history of HF [36]. Previous CVOTs of SGLT-2i included T2DM patients with established CVD or at the high risk for CVD. However, the present study covered a wider range of nationwide population cohort including patients with and without CVD. Our results showed that dapagliflozin reduced the risk for hHF in patients with and without CVD, and the HF protective effect of dapagliflozin was more evident among patients with underlying CVD.

In the present study, we compared dapagliflozin, a first-in-class SGLT-2i, with DPP-4i, one of the most widely used second-line oral anti-hyperglycemic agents in a real-world observational cohort. The findings of our study showed that the use of dapagliflozin reduced hHF as compared to DPP-4i. Our results are consistent with the results of previous observational studies, wherein, SGLT-2i was compared with other non-SGLT-2i oral anti-hyperglycemic agents [20‐23], sulfonylureas and DPP-4i [24], or DPP-4i in a similar cohort [25]. A large Scandinavian cohort study also reported that SGLT-2i use compared with DPP-4i use was associated with a reduced risk of HF, with similar HR to that in our study both in on-treatment analysis and intention-to-treat analysis. Moreover, the magnitude of the protective association between SGLT-2i and HF was larger in on-treatment analysis, suggesting that the HF protective effect of SGLT-2i could be stronger during the time that patients stay on the drug [26]. A network meta-analysis to compare the effect on CV outcomes among SGLT-2i, GLP-1 receptor agonist, and DPP-4i also reported that SGLT-2i show clear superiority in reducing hHF among the three new drug classes [37].

Our data provide information on the risk of hHF of dapagliflozin, not of all SGLT2i. The effects on hHF may differ between individual SGLT-2i, because not all SGLT-2i share the same pharmacokinetic properties [38]. A retrospective cohort study reported that dapagliflozin users had a significantly lower risk of HF as compared to empagliflozin users, and further studies are required to confirm the findings [39].

A recent placebo-controlled trial (DAPA-HF trial) showed that the risk of worsening HF or death from cardiovascular causes was lower among the HF patients with reduced ejection fraction who received dapagliflozin than those who received placebo, regardless of the presence or absence of diabetes [40]. Moreover, dapagliflozin reduced hHF both in patients with and without HFrEF in the stratified analysis by baseline ejection fraction of DECLARE-TIMI 58 patients. [41]. Thus, the growing evidence is suggestive of HF protective effects of SGLT-2i. Several underlying mechanisms have been proposed to explain the HF protective effect of SGLT-2i, such as improvement in ventricular loading conditions through a reduction in preload and afterload, improvement in cardiac metabolism and bioenergetics, myocardial Na⁺/H⁺ exchange inhibition, reduction of necrosis and cardiac fibrosis and an alteration in adipokine production [42].

The recent consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) addresses the approaches to management of glycemia in patients with T2DM, with the goal of reducing complications and maintaining quality of life in the context of comprehensive cardiovascular risk management changed from the prior consensus statements, wherein, efficacy in reducing hyperglycemia, along with tolerability and safety were primary factors in glucose-lowering medication selection [16]. The recently updated consensus report by the ADA and the EASD suggested that SGLT-2i are recommended in patients with T2DM and HF, particularly those with HF with HFrEF, to reduce hHF, major adverse cardiovascular event, and CVD death [43]. Our study showed the superiority of dapagliflozin to DPP-4i, one of the most widely used oral hypoglycemic agents, in terms of HF protection in a real-world clinical setting and broad T2DM population, and in accordance with the current guideline, prior CVOTs, meta-analyses, and observation studies.

Our economical evaluation, based on a simulation on 1000 patients for each group, showed that the dapagliflozin group saved about $12,000 of medical costs in the first year, with a two-fold greater cost reduction in the second year as compared to the DPP-4i group. With the use of dapagliflozin, approximately $58,000 of medical cost was saved over 3 years, with a threefold greater cost reduction among patients with underlying CVD. Similar results were found in the sensitivity analysis on intend-to-treat patients, thereby confirming that dapagliflozin is highly effective in lowering hHF risk and cutting medical costs in patients with underlying CVD.

An analysis for cost-effectiveness of dapagliflozin, conducted in the UK, showed that dapagliflozin had an incremental cost-effectiveness ratio (ICER) of ₤6761 per quality adjusted life years (QALY) gained as compared to DPP-4i; based on which, dapagliflozin was found to be a cost-effective agent as an addition to the regimen for patients with DM whose blood glucose was not appropriately controlled with only metformin as compared to DPP-4i, which was the most widely used agent for the purpose [27]. The changes in HbA1c level and body weight for 1 year were used as the parameters for comparing clinical outcomes between the dapagliflozin and DPP-4i groups, and the authors claimed that the superior weight-loss effects of dapagliflozin were the underlying reasons for increased QALY. In a simulation of 30,000 patients for 40 years using a model, including the probability of DM complications in relation to weight loss and related QALY and cost, dapagliflozin was associated with ₤216 more cost and 0.032 increase of QALYs compared to DPP-4i. These findings were obtained on the basis of long-term simulation with weight loss as the major outcome amid a lack of long-term clinical outcome data and data on major DM complications associated with dapagliflozin and DPP-4i, which may lead to a difference from the results that reflect the real-world reports of CVD and renal complications. In contrast, we analyzed a simplified model for a relatively short time period (3 years), reflecting the clinical outcomes and cost values measured through real-world data analysis to minimize the influence of the limitations of economic analysis, such as excessive extrapolation and assumption.

In another economic evaluation conducted in Australia, decision analysis was applied to assess the cost-effectiveness of first-line combination dapagliflozin and metformin (first-line use) versus first-line metformin monotherapy followed by gradual addition of dapagliflozin over time (delayed use) [28]. Clinical outcomes were derived from a published observational study, CVD-REAL Nordic, and a Markov model was used to simulate the progress for 20 years. The Australia study showed that first-line use had an ICER of AUD $12,477 per QALY gained as compared to delayed use, even though first-line use of the combination is not recommended in the current guidelines [28]. Both UK and Australian studies have shown that dapagliflozin is not only effective compared to DPP-4i or delayed use, but also increases costs. This study did not analyze the ratio of the cost to the effectiveness, but showed the reduced the medical cost due to the improved clinical outcomes. Therefore, care should be taken to quantitatively compare and interpret the results of this study with other CE analysis.

Further, Garry et al. analyzed the medical costs between patients who used SGLT-2i and patients who used DPP-4i as second-line therapy using insurance claims data in the US and reported that the annual total cost of care was $3419 (95% CI − $11,264 to − $4426) lower among patients in the CVD high risk group who used SGLT-2i [29]. The patients were classified according to the first drug used in the second-line therapy, and a pairwise comparison was performed between the SGLT-2i and DPP-4i groups using adjusted deciles of propensity score and Cox proportional hazards regression model, with treatment costs compared without any simulation. Studies that compare costs related to the use of specific drugs produce markedly different outcomes depending on the structure of the model, variables used, and the method of computing parameters. In our study, we focused only on hHF, the primary clinical outcome related to dapagliflozin using real-world data and the total cost was estimated using a simple model simulation by analyzing the cost incurred according to the incidence of hHF as opposed to the actual cost per drug group. Currently, five SGLT-2is—dapagliflozin, ipragliflozin, empagliflozin, canagliflozin, and ertugliflozin—are available in Korea; however, dapagliflozin was the only drug included in the national health insurance formulary during the patient enrollment period of this study, from September 01, 2015 to August 31, 2016. In the early days following the introduction of a novel class of drugs in clinical practice, treatment decisions are made on the basis of clinical trials of the drugs, so patients make prudent selections. Inevitably, there are differences between patients who use DPP-4i, which has significantly accumulated usage data, and those who choose dapagliflozin, which is a novel drug. Even if these differences are adjusted for statistically, the influence of unmeasured confounders cannot be completely eliminated. Moreover, as using insurance claims data is bound by limitations such as lack of detailed clinical documentation, misdiagnosis, and miscoding; it may be challenging to identify unmeasured confounders. Therefore, we used direct measurements of cost according to the incidence of hHF as the model parameter to minimize such influence, and for this reason, our model simulation computed cost incurred according to the risk for hHF by drug group.

A CVD event is a major cause of elevated medical cost for patients with DM. Garry et al. reported that among patients with high CVD risk, the total cost of care was higher for DPP-4i users than for dapagliflozin users [29], and our study also found that the difference in cost was higher among patients with underlying CVD. Thus, dapagliflozin may have maximal economic value when administered in patients with a high risk of a CVD event.

It is common for a typical economic evaluation to help decision making by presenting an increased amount of cost as a ratio as well as an increased effect (ICER) between alternatives. However, in this study, the analysis based on real-world data showed that dapagliflozin has an effect of reducing risk of hHF compared to DPP-4i, and even economical results of reducing medical costs, even though only by 2%. Ultimately, it supports that dapagliflozin is a dominant treatment strategy compared to DPP-4i. In countries with different health care systems, there may be quantitative differences in the economic performance of the same comparative alternative. This study is meaningful in that it estimated the amount of direct medical cost reduction due to a reduction in hHF risk in certain health care systems in Korea.

Our study had a few limitations. First, because it was a retrospective observational study, residual confounding factors could not be completely excluded, although we used propensity score weighting to adjust effects of confounders. In addition, our national claims data do not contain information concerning demographics such as diabetes duration, body mass index, or laboratory test results. Second, we relied on diagnostic codes for outcome ascertainment. However, a validation study reported that the overall positive predictive value of the ICD-10 codes was approximately 70%, compared with medical records reviews [44]. Moreover, mortality data were analyzed on the basis of diagnosis codes for the meddling, so it may differ from the actual mortality data. Third, this study used only hHF as the major clinical outcome and only compared direct medical costs incurred over 3 years. However, there are several other complications that contribute to the treatment cost of patients with DM, such as myocardial infarction, stroke, kidney complication, and premature death; and the duration of DM spans several decades. A long-term analysis including these major clinical outcomes need to be performed to more comprehensively compute the economic outcomes of a specific drug in order for the findings to serve as useful evidence for determining treatment strategies in clinical practice and devise health insurance financial policies.

In conclusion, this study showed that dapagliflozin lowers the risk for hHF and subsequently, reduces direct medical costs as compared to DPP-4i. The protective effect against hHF was more evident among patients with underlying CVD.