Major adverse cardiovascular and limb events in patients with diabetes and concomitant peripheral artery disease treated with sodium glucose cotransporter 2 inhibitor versus dipeptidyl peptidase-4 inhibitor

Background Whether sodium glucose co-transporter 2 inhibitors (SGLT2i) are associated with a lower risk of cardiovascular as well as adverse lower limb events in patients with type-2 diabetes mellitus (T2DM) and concomitant peripheral artery disease (PAD) is unclear. We aimed to evaluate the risk of cardiovascular and limb events, and death associated with the use of SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i) among a longitudinal and national cohort of patients with T2DM. Methods In this nationwide retrospective cohort study based on the Taiwan National Health Insurance Research Database, we identified a total of 11,431 and 93,972 consecutive T2DM patients with PAD taking SGLT2i and DPP4i, respectively, from May 1, 2016, to December 31, 2017. We used 1:1 propensity score matching (PSM) to balance covariates across study groups. Patients were followed from the drug index date until the occurrence of clinical outcomes, death, discontinuation of the index drug, or the end of the study period, whichever occurred first. Results Overall, 56% and 44% of the patients were treated with dapagliflozin and empagliflozin, respectively. The use of SGLT2i had comparable risks of ischemic stroke and acute myocardial infarction, and was associated with lower risks of congestive heart failure (CHF) [hazard ratio (HR): 0.66; 95% confidence interval (CI) 0.49–0.89; p = 0.0062], lower limb ischemia requiring revascularization (HR: 0.73; 95% CI 0.54–0.98; p = 0.0367) or amputation (HR: 0.43; 95% CI 0.30–0.62; p < 0.0001), and cardiovascular death (HR: 0.67; 95% CI 0.49–0.90; p = 0.0089) when compared with the DDP4i group after PSM. The subgroup analysis revealed consistent results for CHF and major adverse limb outcomes for SGLT2i versus DPP4i among patients aged ≥ 75 years, the presence of chronic kidney disease and established cardiovascular disease was consistent with the main analysis. Conclusions SGLT2i were associated with lower risks of CHF and adverse lower limb events compared with DPP4i among patients with T2DM and PAD in real-world practice.


Background
Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have shown benefits for different endpoints, such as renal outcomes, heart failure, and major cardiovascular (CV) events among patients with type-2 diabetes mellitus (T2DM) treated with antihyperglycemic agents [1][2][3][4]. Although the two available trials with dapagliflozin and empagliflozin did not report a significant increase in amputations, the Canagliflozin Cardiovascular Assessment Study (CANVAS) program indicated a higher rate of amputations in the canagliflozin group compared with the placebo group (6.3 vs. 3.4 patients per 1000 patient-years) [1][2][3]. Nevertheless, the CAN-VAS results raised concerns regarding the suitability of SGLT2i for patients with T2DM with a high risk of amputation, such as those with concomitant peripheral artery disease (PAD). A few observational studies have investigated the association of SGLT2i with the risk of lower limb amputation; however, these studies have reported inconsistent and conflicting findings. For example, Yuan [5][6][7].
T2DM is a major risk factor for CV disease and PAD, and the prevalence of PAD in patients with T2DM has been estimated to reach 20% [8][9][10]. Patients with T2DM and concomitant PAD have an increased risk of CV events and amputation compared with those without PAD [11]. Subgroup analyses of the landmark studies on empagliflozin revealed consistent CV benefits in patients with T2DM and concomitant PAD without an increased risk of amputation [12]. However, real-world data on the effectiveness, safety, and limb outcomes for such a specific population treated with SGLT2i are scarce. Dipeptidyl peptidase-4 inhibitors (DPP4i) improve glycemic control by increasing the serum levels of glucagon-like peptide 1 (GLP-1) and exhibit a neural effect in CV composite outcomes, that are clinically widely prescribed as second-line agents in the management of hyperglycemia for patients with T2DM [13,14]. Our study investigated the outcomes of patients with T2DM and concomitant PAD treated with SGLT2i compared with those treated with DPP4i in a large, real-world setting.

Study population
This retrospective nationwide cohort study analyzed data from the Taiwan National Health Insurance (NHI) Research Database (NHIRD), which contains detailed health-care information for more than 23 million enrollees with a > 99% coverage rate of residents of Taiwan [15]. This study was approved by the Institutional Review Board of Chang Gung Medical Foundation, Taiwan (104-8079B and 201801427B0). Informed consent was waived because the original identification number of each patient in the NHIRD had been encrypted and de-identified to protect their privacy.

Conclusions:
SGLT2i were associated with lower risks of CHF and adverse lower limb events compared with DPP4i among patients with T2DM and PAD in real-world practice.

Covariates and study outcomes
Baseline covariates were obtained from all claim records with diagnoses, procedures, or medication codes prior to the index date. A history of all prescription medications was confined to medications used at least once within 3 months before the index date. We reported the following outcomes in the present study: (i) ischemic stroke (IS), (ii) acute myocardial infarction (AMI), (iii) congestive heart failure (CHF), (iv) lower limb ischemia requiring revascularization, (v) lower limb amputation, (vi) all-cause mortality, and (vii) cardiovascular mortality. All study outcomes should be the primary discharge diagnosis to avoid misclassification. The diagnostic codes of the NHIRD were shifted from the ICD-9-CM to ICD-10-CM after January 1, 2016. The ICD-9-CM and ICD-10-CM codes used to identify study outcomes along with the baseline covariates are summarized in Additional file 1: Tables S1 and S2.

Statistical analysis
The propensity score matching (PSM) method, which simulates the design of a randomized clinical trial for observational cohort data by forming matched sets of treated and untreated subjects who share a similar value of the propensity score [16], was used to compare the study outcomes between the SGLT2i and DPP4i group. We calculated propensity score, the predicted probability of treatment conditional on all the covariates in Table 1, by using the generalized boosted model (GBM). The GBM involves an iterative process with multiple regression trees to capture complex and nonlinear relationships between treatment assignment and the pretreatment covariates without over-fitting the data and leading the best balance across study groups [17]. The PSM ratio between the SGLT2i users and DPP4i users was 1:1 without replacement and nearest neighbor matching within a caliper width (8-to-1 digit matching) [18]. The balance of potential confounders at the baseline (index date) between study groups was assessed using the absolute standardized mean difference (ASMD) rather than statistical testing because balance is a property of the sample and not of the underlying population. An ASMD value of ≤ 0.1 would indicate a nonsignificant difference in potential confounders between the two study groups [19]. Incidence rates were estimated using the total number of study outcomes during the follow-up period divided by person-years at risk. The risk of study outcomes occurring over the follow-up duration for SGLT2i versus DPP4i (reference) was obtained using survival analysis (Kaplan-Meier method and log-rank test for univariate analysis and Cox proportional hazards model for multivariate analysis), and they were presented as HRs with 95% CIs. Statistical significance was defined as a p value of < 0.05. All statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).

Main analysis of SGLT2i versus DDP4i
The SGLT2i group had comparable cumulative risks of IS and AMI compared with the DPP4i group after PSM. The SGLT2i group was associated with a lower cumulative risk of CHF (log-rank p = 0.0059), all-cause (logrank p < 0.0001) and cardiovascular mortality (log-rank p = 0.0085) compared with the DPP4i group after PSM. Regarding major adverse limb events, the use of SGLT2i was associated with a lower cumulative risk of lower limb revascularization (log-rank p = 0.0359) and amputation (log-rank p < 0.0001) compared with the use of DPP4i (Fig. 2 Fig. 3). The use of SGLT2i was not associated with an increased risk of bone fracture or urinary tract infection compared with DDP4i use after PSM (Table 2 and Additional file 1: Table S1).

Subgroup analysis of high-risk patients
The subgroup analysis indicated that SGLT2i reduced the risk of AMI in patients with concomitant CKD but not in those without CKD (p interaction = 0.02; Fig. 4). In general, the subgroup analysis revealed consistent results for CHF, major adverse limb outcomes, and mortality for SGLT2i versus DPP4i among patients aged ≥ 75 years, the presence of CKD and established CV disease, consistent with the main analysis (Figs. 4, 5 6 ).

Discussion
To the best of our knowledge, the present study is the first and largest population-based cohort study to investigate the outcomes of patients with T2DM and concomitant PAD treated with SGLT2i compared with those treated with DPP4i. Our findings indicate that SGLT2i was associated with comparable risks of IS and AMI,

Table 1 Clinical characteristics of patients with concomitant type-2 diabetes mellitus (T2DM) and peripheral artery disease (PAD) treated with sodium-glucose co-transporter-2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP4i) before and after propensity score matching (PSM)
ACEI angiotensin-converting-enzyme inhibitor, APT antiplatelet agent, ARB angiotensin II receptor antagonists, ARNI angiotensin receptor neprilysin inhibitor, ASMD absolute standardized mean difference, CABG coronary artery bypass graft, DDP4i dipeptidyl peptidase-4 inhibitors, DM diabetes mellitus, MRA mineralocorticoid receptor antagonist, NSAIDs nonsteroid anti-inflammatory drugs, PAD peripheral artery disease, PCI percutaneous coronary intervention, PPI proton pump inhibitor, PSM propensity score matching, SGLT2i sodium-glucose co-transporter-2 inhibitors, T2DM type-2 diabetes mellitus and significantly lower risks of CHF, lower limb ischemia requiring revascularization or amputation, and all-cause or cardiovascular mortality when compared with DPP4i. This study suggests that SGLT2i is an effective and safe alternative to DPP4i for patients with T2DM and concomitant PAD. DPP4i improves glycemic control by increasing the serum levels of glucagon-like peptide 1 (GLP-1) through the inhibition of GLP-1 degradation, which indirectly stimulates insulin secretion and enhances beta-cell function. Previous large-scale clinical trials, including EXAMINE, SAVOR-TIMI53, and TECOS, have indicated that the use of DPP4i has a neutral effect in CV composite outcomes for patients with T2DM, except for a higher risk of CHF for those treated with saxagliptin [20][21][22]. Those clinical studies did not explore the risk of lower limb outcomes for patients with T2DM treated with DPP4i. A previous meta-analysis of the three clinical trials confirmed the benefit of SGLT2i on CHF (HR 0.69; 95% CI 0.61-0.79), all-cause death (HR 0.85; 95% CI 0.78-0.93), and reduced risk of major adverse CV events (composite of myocardial infarction, stroke, and cardiovascular death; HR 0.89, CI 0.83-0.96]) [23]. One large retrospective cohort study also indicated that SGLT2i were associated with lower risks of CHF and death compared with DPP4i in patients with diabetes [24]. Other cohort studies investigating SGLT2i versus other non-SGLT2i antidiabetic agents have consistently reported Fig. 2 Cumulative incidence curves of outcomes for patients with concomitant type-2 diabetes mellitus (T2DM) and peripheral artery disease (PAD) treated with SGLT2i versus DPP4i after propensity score matching (PSM). Cumulative incidence curves of effectiveness outcomes including ischemic stroke (IS) (a), acute myocardial infarction (AMI) (b), congestive heart failure (CHF) (c), lower extremity revascularization (d) or amputation (e), all-cause mortality (f), and cardiovascular mortality (g) for patients with T2DM and concomiant PAD taking SGLT2i versus DPP4i after PSM are presented. SGLT2i were associated with lower cumulative risks of CHF, all-cause and cardiovascular mortality, and lower extremity revascularization or amputation compared with DPP4i among patients with T2DM and concomitant PAD. Abbreviations: AMI acute myocardial infarction, CHF congestive heart failure, IS ischemic stroke, PSM propensity score matching. Other abbreviations are the same as those in Fig. 1 that SGLT2i reduces the risk of CHF [25][26][27]. A recent clinical trial also showed the beneficial role of SGLT2i on reducing the risk of HF hospitalization [28,29].
Patients with T2DM have a higher prevalence of PAD compared with those without T2DM, and patients with T2DM and concomitant PAD have a higher risk of mortality and amputation [11,30]. However, evidence supporting the benefits of SGLT2i in patients with diabetes and concomitant PAD is limited. The CANVAS program reported a higher rate of amputations in the canagliflozin group compared with the placebo group (0.63 vs. 0.34 per 100 person-years, p < 0.001), but not in the pivot studies of empagliflozin (0.65 vs. 0.65 per 100 person-years, p = 1.000) and dapagliflozin (1.4 vs. 1.3 per 100 personyears, p = 0.53) [1][2][3]. A clear mechanism explaining why canagliflozin contributes to amputation is lacking; this adverse event may be related to volume depletion, which might accordingly cause circulatory failure in the

Table 2 Number of events, event rates, and hazard ratio (HR) among patients with type-2 diabetes mellitus and concomitant peripheral artery disease (PAD) using sodium-glucose co-transporter-2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP4i) after propensity score matching
AMI acute myocardial infarction, CHF congestive heart failure, CI confidence interval, DDP4i dipeptidyl peptidase-4 inhibitors, HR hazard ratio, IS ischemic stroke, PAD peripheral artery disease, PSM propensity score matching, PYs person-years, SGLT2i sodium-glucose co-transporter-2 inhibitors, T2DM type-2 diabetes mellitus  distal peripheral vasculature [1,31]. Although a metaanalysis showing patients treated with SGLT2i without a significant association with increased risk of amputation, a large-scale cohort study revealed that SGLT2is were associated with an increased risk of amputation compared with other antihyperglycemic agents for type 2 diabetes [32,33]. Subgroup analyses from the pivot study of empagliflozin for patients with T2DM and concomitant PAD also revealed benefits of reduced risks of death and CHF without an increased risk of amputation [12]. Consistent with the data, our results indicated that SGLT2i can reduce the risks of CHF and mortality in such a high-risk population. Notably, SGLT2i (dapagliflozin and empagliflozin) were associated with a lower risk of adverse limb events (lower limb ischemia requiring revascularization and lower limb amputation) compared with DDP4i in our study (0.97 vs. 1.32 per 100 personyears, p = 0.0367 and 0.54 vs. 1.23 per 100 person-years, p < 0.0001). In the assessment of patients with T2DM and concomitant PAD with a relatively high risk of amputation, the absolute risk of amputation in patients treated with SGLT-2i was similar or lower than those seen in the pivot studies, and there is no increase in the probability of amputation [1][2][3]. In animal or human studies, SGLT2i have been reported to have many benefits for vasculature, such as improved endothelial function, vasodilatation, and attenuated oxidative stress, suggesting that SGLT2i may be able to halt the progression of atherosclerosis and  improve vascular outcomes [34][35][36]. In addition, SGLT2i had been reported to improve cardiometabolic risk factors than DDP4i [37]. PAD is a manifestation of systemic atherosclerosis, and because SGLT2i could reduce the risk of adverse atherosclerotic events, it may also be beneficial in reducing the risk of adverse limb events for patients with PAD [23,38,39]. However, studies investigating SGLT2i in patients with T2DM and concomitant PAD are scarce. A subgroup analysis revealed a trend of a lower risk of lower limb amputation (HR: 0.84, 95% CI 0.54-1.32) in the empagliflozin group among patients with T2DM and concomitant PAD [12]. Because patients with T2DM have a high prevalence of PAD [8][9][10], further randomized or prospective studies should investigate the effect of SGLT2i on lower limb outcomes in such a high-risk population.

Limitations
To avoid time-lag bias from the prescriptions of study drugs, which may lead to false positive or negative associations depending on the treatments for patients with early or advanced disease, we selected the same secondline hypoglycemic agents of DDP4i as the comparator in our study [7,40]. To avoid immortal time bias, our study only included new descriptions of study drugs of SGLT2i or DDP4i without baseline use [40,41]. Nevertheless, the present study had several limitations. First, although PSM with several variables allowed the matching of baseline comorbidities among the study groups, residual confounding by unmeasured variables and prescribing behavior could not be excluded in this retrospective cohort study. Second, the NHIRD does not contain several crucial types of laboratory data such as body weight, glycohemoglobin (HbA1c), and serum creatinine, all of which are associated with the risk of CV events and death among patients with T2DM [42]. In addition, even with adjustment for CKD, the diagnosis of CKD by coding could not reflect the severity of renal disease, which may interfere with SGLT2i or DDP4i selection for each patient. Third, although we utilized some criteria for the selection of the PAD population, our PAD study patients included only part of the PAD population. Thoroughly screening patients with PAD is difficult because PAD populations are typically underrecognized or undertreated in clinical practice, and the incidence of asymptomatic PAD is higher than that of symptomatic PAD [43,44]. Fourth, miscoding and misclassification of underlying comorbidities and outcomes registered by each physician were another limitation. Therefore, we only considered primary discharge diagnoses to improve the outcome accuracy. However, minor cardiovascular or limb events without admission may have been missed in the present study. Fifth, we did not analyze canagliflozin because of its approval date after March 1, 2018 in Taiwan. Finally, we only investigated Asian patients, and whether our results can be extrapolated to other races remains unclear.

Conclusions
Our data indicated that SGLT2i, compared with DDP4i, were associated with lower risks of CHF, lower limb ischemia requiring revascularization or amputation, and all-cause death for patients with T2DM and concomitant PAD. Further prospective studies are necessary to evaluate the effects of SGLT2i on lower limb outcomes among such patients in the future.
Additional file 1: Table S1. International Classification of Diseases (9th and 10th edition) Clinical Modification (ICD 9-CM and ICD 10-CM) codes used to define comorbidities and clinical outcomes in this study. Table S2.
International Classification of Diseases (9th and 10th edition) Clinical Modification (ICD 9-CM and ICD 10-CM) codes used to define major adverse limb outcomes in this study. Table S3. Number of events, event rates, and hazard ratio (HR) among patients with type-2 diabetes mellitus concomitant with peripheral artery disease using sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP4i) before propensity score matching.