What this is
- This study evaluates the cardiovascular and limb event risks associated with sodium-glucose co-transporter-2 inhibitors (SGLT2i) vs. dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with type-2 diabetes mellitus (T2DM) and ().
- Using a nationwide cohort from Taiwan, the researchers analyzed data from over 100,000 patients to compare outcomes related to heart failure, limb ischemia, and mortality.
- The study aims to clarify whether SGLT2i offer advantages over DPP4i in reducing adverse events in a high-risk diabetic population.
Essence
- SGLT2i are associated with lower risks of congestive heart failure, lower limb ischemia requiring revascularization or amputation, and cardiovascular death compared to DPP4i in patients with T2DM and .
Key takeaways
- SGLT2i treatment resulted in a hazard ratio (HR) of 0.66 for congestive heart failure, indicating a lower risk compared to DPP4i. This finding suggests that SGLT2i may be a safer option for managing heart failure in these patients.
- Patients on SGLT2i had a lower risk of lower limb ischemia requiring revascularization (HR: 0.73) and lower limb amputation (HR: 0.43) compared to those on DPP4i. This indicates a potential benefit of SGLT2i in preventing serious limb complications.
- Cardiovascular mortality was also lower in the SGLT2i group (HR: 0.67), suggesting that SGLT2i may contribute to improved survival rates in patients with T2DM and .
Caveats
- Residual confounding may exist due to unmeasured variables and prescribing behaviors, which could affect the results. The retrospective nature of the study limits causal inferences.
- The study did not include laboratory data such as body weight and HbA1c levels, which are important for assessing cardiovascular risk, potentially affecting the accuracy of the findings.
- Findings may not be generalizable beyond the Taiwanese population, as the study focused solely on Asian patients with T2DM and .
Definitions
- SGLT2 inhibitors: Medications that lower blood glucose by preventing glucose reabsorption in the kidneys, used in diabetes management.
- DPP4 inhibitors: Drugs that enhance insulin secretion and decrease glucagon levels, improving glycemic control in patients with diabetes.
- Peripheral artery disease (PAD): A condition characterized by narrowed arteries reducing blood flow to the limbs, often leading to pain and increased risk of amputation.
AI simplified
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 [1–4]. 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) [1–3]. Nevertheless, the CANVAS 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 et al. reported no increased risk of amputations (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.68–1.41); Adimadhyam et al. reported increased risk (HR 1.38, 95% CI 0.83–2.31); and Udell et al. reported an increased risk (HR 1.99, 95% CI 1.12–3.51) for SGLT2i treatment compared with nonSGLT2i agents [5–7].
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% [8–10]. 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.
Methods
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.
Study cohort
Enrollment of patients with concomitant type-2 diabetes mellitus (T2DM) and peripheral artery disease (PAD). From May 1, 2016 to December 31, 2017, a total of 11,431 patients with T2DM and comorbid PAD treated with sodium-glucose co-transporter-2 inhibitors (SGLT2i) and 11,431 1:1 propensity score matched patients treated with dipeptidyl peptidase-4 inhibitors (DPP4i) were enrolled in the present study. Abbreviations:dipeptidyl peptidase-4 inhibitor,peripheral artery disease;sodium-glucose co-transporter-2 inhibitor,type 2 diabetes mellitus DPP4i PAD SGLT2i T2DM
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: Tables S1 and S2. 1
Statistical analysis
| Before PSM | After PSM | |||||
|---|---|---|---|---|---|---|
| SGLT2i | DPP4i | ASMD | SGLT2i | DPP4i | ASMD | |
| (n = 12,355) | (n = 93,972) | (n = 11,431) | (n = 11,431) | |||
| Baseline characteristics | ||||||
| Age (years) | ||||||
| Mean | 64.3 ± 10.6 | 70.5 ± 11.3 | 0.5639 | 64.7 ± 10.7 | 65.1 ± 14.5 | 0.0331 |
| < 65 | 6188 (50.08%) | 27900 (29.69%) | 0.5385 | 5487 (48.00%) | 5662 (49.53%) | 0.0716 |
| 65–74 | 3990 (32.29%) | 29360 (31.24%) | 3789 (33.15%) | 3677 (32.17%) | ||
| 75–84 | 1861 (15.06%) | 26506 (28.21%) | 1839 (16.09%) | 1791 (15.67%) | ||
| ≧ 85 | 316 (2.56%) | 10206 (10.86%) | 316 (2.76%) | 301 (2.63%) | ||
| Male | 6167 (49.92%) | 44738 (47.61%) | 0.0462 | 5603 (49.02%) | 5660 (49.51%) | 0.01 |
| Chronic lung disease | 376 (3.04%) | 3852 (4.10%) | 0.0569 | 339 (2.97%) | 344 (3.01%) | 0.0026 |
| Chronic kidney disease | 3276 (26.52%) | 37701 (40.12%) | 0.2917 | 3117 (27.27%) | 2997 (26.22%) | 0.0237 |
| Congestive heart failure | 407 (3.29%) | 5279 (5.62%) | 0.1128 | 354 (3.10%) | 351 (3.07%) | 0.0015 |
| Hypertension | 10530 (85.23%) | 84307 (89.72%) | 0.1358 | 9779 (85.55%) | 9730 (85.12%) | 0.0121 |
| Dyslipidemia | 11062 (89.53%) | 80720 (85.90%) | 0.111 | 10208 (89.30%) | 10199 (89.22%) | 0.0025 |
| Previous stroke | 1159 (9.38%) | 14043 (14.94%) | 0.1708 | 1102 (9.64%) | 1.036 (9.06%) | 0.0198 |
| Ischemic heart disease | 2595 (21.00%) | 18827 (20.03%) | 0.024 | 2176 (19.04%) | 2172 (19.00%) | 0.0009 |
| Gout | 3823 (30.94%) | 32206 (34.27%) | 0.0711 | 3562 (31.16%) | 3532 (30.90%) | 0.0057 |
| Malignancy | 826 (6.69%) | 8644 (9.20%) | 0.093 | 776 (6.79%) | 782 (6.84%) | 0.0021 |
| History of bleeding | 96 (0.78%) | 1639 (1.74%) | 0.0868 | 95 (0.83%) | 86 (0.75%) | 0.0089 |
| PCI | 1570 (12.71%) | 11113 (11.83%) | 0.0269 | 1277 (11.17%) | 1256 (10.99%) | 0.0059 |
| CABG | 296 (2.40%) | 2547 (2.71%) | 0.0199 | 253 (2.21%) | 267 (2.34%) | 0.0082 |
| History of diabetic ulcer | 161 (1.30%) | 2117 (2.25%) | 0.0719 | 148 (1.29%) | 183 (1.60%) | 0.0256 |
| Baseline medications | ||||||
| Use of APT | 5506 (44.56%) | 41766 (44.45%) | 0.0024 | 4969 (43.47%) | 4903 (42.89%) | 0.0117 |
| Use of NSAIDs | 3516 (28.46%) | 25954 (27.62%) | 0.0187 | 3299 (28.86%) | 3260 (28.52%) | 0.0075 |
| Use of PPI | 859 (6.95%) | 8454 (9.00%) | 0.0755 | 820 (7.17%) | 781 (6.83%) | 0.0134 |
| Use of ACEI/ARB | 7970 (64.51%) | 57265 (60.94%) | 0.0739 | 7299 (63.85%) | 7305 (63.91%) | 0.0011 |
| Use of amiodarone | 202 (1.63%) | 2564 (2.73%) | 0.0749 | 197 (1.72%) | 205 (1.79%) | 0.0053 |
| Use of dronedarone | 14 (0.11%) | 145 (0.15%) | 0.0112 | 9 (0.08%) | 13 (0.11%) | 0.0113 |
| Use of beta-blocker | 4703 (38.07%) | 34399 (36.61%) | 0.0302 | 4222 (36.93%) | 4166 (36.44%) | 0.0102 |
| Use of verapamil/diltiazem | 688 (5.57%) | 5454 (5.80%) | 0.0102 | 615 (5.38%) | 601 (5.26%) | 0.0055 |
| Use of digoxin | 247 (2.00%) | 2125 (2.26%) | 0.0182 | 220 (1.92%) | 220 (1.92%) | 0 |
| Use of statin | 8469 (68.55%) | 51472 (54.77%) | 0.2862 | 7609 (66.56%) | 7651 (66.93%) | 0.0078 |
| Use of metformin | 6910 (55.93%) | 33242 (35.37%) | 0.4217 | 6403 (56.01%) | 6484 (56.72%) | 0.0143 |
| Use of sulfonylurea | 8282 (67.03%) | 50171 (53.39%) | 0.2815 | 7630 (66.75%) | 7751 (67.81%) | 0.0226 |
| Use of glinide | 811 (6.56%) | 11886 (12.65%) | 0.2076 | 785 (6.87%) | 753 (6.59%) | 0.0112 |
| Use of acarbose | 2194 (17.76%) | 12488 (13.29%) | 0.1236 | 1889 (16.53%) | 1870 (16.36%) | 0.0045 |
| Use of glitazone | 2617 (21.18%) | 9538 (10.15%) | 0.3071 | 2244 (19.63%) | 2305 (20.16%) | 0.0134 |
| Use of insulin | 3841 (31.09%) | 26103 (27.78%) | 0.0727 | 3433 (30.03%) | 3326 (29.10%) | 0.0205 |
| Use of loop diuretics | 1286 (10.41%) | 14791 (15.74%) | 0.1586 | 1191 (10.42%) | 1170 (10.24%) | 0.006 |
| Use of MRA | 663 (5.37%) | 5025 (5.35%) | 0.0008 | 592 (5.18%) | 617 (5.40%) | 0.0098 |
| Use of ARNI | 16 (0.13%) | 28 (0.03%) | 0.0353 | 7 (0.06%) | 10 (0.09%) | 0.0096 |
Results
Baseline characteristics of SGLT2i and DDP4i groups
Among the 452,149 patients with T2DM and concomitant PAD, a total of 12,355 and 93,972 were treated with SGLT2i and DDP4i, respectively, from May 1, 2016 to December 31, 2017 (Fig. 1). The mean follow-up periods were 0.96 ± 0.57 and 0.66 ± 0.45 years for SGLT2i and DDP4i, respectively. In the SGLT2i group, 6,915 (56.0%) and 5,440 (44.0%) patients were treated with dapagliflozin and empagliflozin, respectively. In the DDP4i group, 29,782 (31.7%), 24,833 (26.4%), 28,534 (30.4%), 10,636 (11.3%), and 187 (0.2%) patients were treated with sitagliptin, vildagliptin, linagliptin, saxagliptin, and alogliptin, respectively. Before PSM, the SGLT2i group was younger and had a lower prevalence of chronic kidney disease (CKD), hypertension, CHF, hypertension, and stroke history compared with the DDP4i group. The SGLT2i group had a higher rate of dyslipidemia, higher rate of prescriptions for statins, metformin, sulfonylurea, acarbose, and glitazones and a lower rate of prescriptions for glinides. Both study groups were well balanced in all characteristics after PSM (all ASMD < 0.1) (Table 1).
Main analysis of SGLT2i versus DDP4i
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) (), acute myocardial infarction (AMI) (), congestive heart failure (CHF) (), lower extremity revascularization () or amputation (), all-cause mortality (), and cardiovascular mortality () 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:acute myocardial infarction,congestive heart failure,ischemic stroke,propensity score matching. Other abbreviations are the same as those in Fig. a b c d e f g AMI CHF IS PSM 1
Forest plot of the hazard ratios of clinical outcomes for SGLT2i versus DPP4i among patients with type-2 diabetes mellitus (T2DM) comorbid with peripheral artery disease (PAD) after propensity score matching (PSM). SGLT2i were associated with a comparable risk of thromboembolic events and with lower risks of CHF, lower limb revascularization or amputation, and all-cause or cardiovascular mortality compared with DPP4i among patients with T2DM and concomitant PAD after PSM. Abbreviation:confidence interval,hazard ratio. Other abbreviations are the same as those in Figs., CI HR 1 2
| SGLT2i | DPP4i | Cox model | ||||
|---|---|---|---|---|---|---|
| (n = 11,431) | (n = 11,431) | |||||
| Clinical outcome | Number | Incidence rate (per 100 PYs) | Number | Incidence rate (per 100 PYs) | HR (95% CI) | p value |
| Ischemic stroke (IS) | 96 | 1.26 | 120 | 1.54 | 0.81 (0.62–1.06) | 0.1213 |
| Acute myocardial infarction (AMI) | 50 | 0.66 | 60 | 0.77 | 0.84 (0.58–1.23) | 0.3702 |
| Congestive heart failure (CHF) | 73 | 0.96 | 111 | 1.43 | 0.66 (0.49–0.89) | 0.0062 |
| Lower limb ischemia requiring revascularization | 74 | 0.97 | 103 | 1.32 | 0.73 (0.54–0.98) | 0.0367 |
| Lower limb amputation | 41 | 0.54 | 96 | 1.23 | 0.43 (0.30–0.62) | < 0.0001 |
| All-cause mortality | 243 | 3.19 | 425 | 5.44 | 0.58 (0.49–0.67) | < 0.0001 |
| Cardiovascular mortality | 69 | 0.91 | 104 | 1.33 | 0.67 (0.49–0.90) | 0.0089 |
| Safety outcome | ||||||
| Urinary tract infection | 331 | 4.42 | 297 | 3.87 | 1.13 (0.96–1.32) | 0.1367 |
| Bone fracture | 76 | 1 | 71 | 0.91 | 1.08 (0.78–1.50) | 0.6284 |
Subgroup analysis of high-risk patients
![Subgroup analysis of the hazard ratios for the risks of ischemic stroke (IS) () acute myocardial infarction (AMI) (), and congestive heart failure (CHF) () for SGLT2i versus DPP4i among T2DM patients with concomitant peripheral artery disease after propensity score matching. In general, the subgroup analysis revealed consistent results for the risks of IS () AMI (), and CHF () for SGLT2i versus DPP4i among patients aged75 years, the presence of chronic kidney disease (CKD) and established CV disease, consistent with the main analysis. The subgroup analysis indicated that SGLT2i reduced the risk of IS and AMI in patients with concomitant CKD but not in patients without CKD (interactions = 0.02). Abbreviations:chronic kidney disease,cardiovascular disease. Other abbreviations as in Figs.,,. a b c a b c \documentclass[12pt]{minimal}
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Subgroup analysis of the hazard ratios for the risks of ischemic stroke (IS) () acute myocardial infarction (AMI) (), and congestive heart failure (CHF) () for SGLT2i versus DPP4i among T2DM patients with concomitant peripheral artery disease after propensity score matching. In general, the subgroup analysis revealed consistent results for the risks of IS () AMI (), and CHF () for SGLT2i versus DPP4i among patients aged75 years, the presence of chronic kidney disease (CKD) and established CV disease, consistent with the main analysis. The subgroup analysis indicated that SGLT2i reduced the risk of IS and AMI in patients with concomitant CKD but not in patients without CKD (interactions = 0.02). Abbreviations:chronic kidney disease,cardiovascular disease. Other abbreviations as in Figs.,,. a b c a b c \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\ge $$\end{document} ≥ p CKD CV 1 2 3
Subgroup analysis of hazard ratios for the risk of major adverse lower limb events including lower limb revascularization procedureand amputation () for SGLT2i versus DPP4i among T2DM patients with concomitant with peripheral artery disease after propensity score matching. The subgroup analysis revealed consistent results for lower limb revascularization () or amputation () for SGLT2i versus DPP4i among patients aged ≥ 75 years, the presence of CKD and established CV disease, consistent with the main analysis (allinteractions > 0.05). The abbreviations are the same as those in Figs.,,, (a) b a b p 1 2 3 4
Subgroup analysis of hazard ratios for the risk of all-cause mortality () and cardiovascular mortality () for SGLT2i versus DPP4i among T2DM patients with peripheral artery disease after propensity score matching. The subgroup analysis revealed consistent results for all-cause mortality () and cardiovascular mortality () for SGLT2i versus DPP4i among patients aged ≥ 75 years, the presence of chronic kidney disease and established CV disease, consistent with the main analysis (allinteractions > 0.05). The abbreviations are the same as those in Figs.,,, a b a b p 1 2 3 4
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, 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 [20–22]. 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 nonSGLT2i antidiabetic agents have consistently reported that SGLT2i reduces the risk of CHF [25–27]. 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 person-years, p = 0.53) [1–3]. 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 distal peripheral vasculature [1, 31]. Although a meta-analysis 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 person-years, 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 [1–3]. 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 [34–36]. 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 [8–10], 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 second-line 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.
Supplementary information
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 co-transporter-2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP4i) before propensity score matching.