Abstract
Background
Inhibitors for sodium‐glucose transport protein 2 (SGLT2) are being used widely in recent years to treat patients with type 2 diabetes (T2D). Studies demonstrated that SGLT2 inhibitors exhibit protective effect for certain cardiovascular diseases. However, no study has explored the effect of SGLT2 inhibitors on risk of aortic dissection in patients with T2D.
Methods
We extracted and retrospectively analyzed the data of all patients with T2D from Taiwan National Health Institution databases between May 1, 2016, and December 31, 2021. Patients with T2D taking DPP4 (dipeptidyl peptidase 4) inhibitors were included for comparison to exclude glucose lowering effect on aortic dissection. In this cohort, 242 563 patients received SGLT2 inhibitors (T2D‐SGLT2i), and 376 062 patients received DPP4 inhibitors (T2D‐DPP4i). The inverse probability of treatment weighting statistical method was performed, which avoids sample loss due to matching. The hazard ratios (HRs) and 95% CIs for these patients with T2D were calculated using multivariate Cox models to approximate the associations.
Results
The overall aortic dissection incidence per 100 000 patient‐years was 14.83 for patients with T2D‐SGLT2i and 29.56 for patients with T2D‐DPP4i. Patients with T2D‐SGLT2i were associated with a lower risk of aortic dissection as compared with patients with T2D‐DPP4i after the adjustment of potential risk factors and comorbidity. Subgroup analysis indicated that use of SGLT2 inhibitor lowers the risk of aortic dissection in some subgroups of patients with T2D.
Conclusions
Our study suggested that use of SGLT2 inhibitors correlated with lower risk of aortic dissection.
Keywords: aortic dissection, DPP4 inhibitors, inverse probability of treatment weighting, SGLT2 inhibitors, type 2 diabetes
Subject Categories: Aortic Dissection
Nonstandard Abbreviations and Acronyms
- DPP4
dipeptidyl peptidase‐4
- DPP4i
dipeptidyl peptidase‐4 inhibitor
- IPTW
inverse probability of treatment weighting
- NHIRD
Taiwanese National Health Insurance Research Database
- SGLT2i
sodium‐dependent glucose cotransporter inhibitor
- T2D
type 2 diabetes
Clinical Perspective.
What Is New?
This nationwide, retrospective cohort study using the Taiwanese National Health Insurance Research Database is the first to demonstrate an association between the use of sodium‐dependent glucose cotransporter (SGLT2) inhibitors and a significantly reduced risk of aortic dissection in patients with type 2 diabetes.
Compared with dipeptidyl peptidase‐4 inhibitors, SGLT2 inhibitors were associated with nearly a 50% reduction in the incidence of aortic dissection, based on >600 000 patients analyzed using inverse probability of treatment weighting‐adjusted Cox models.
The vascular benefit of SGLT2 inhibitors appears to extend beyond glycemic control, suggesting a novel protective role against major aortic pathology.
What Are the Clinical Implications?
These findings suggested that SGLT2 inhibitors may offer additional protective effects for the aortic wall in patients with diabetes, potentially altering future cardiovascular risk stratification and treatment strategies.
In patients with type 2 diabetes at high risk for vascular complications, SGLT2 inhibitors may be preferentially considered not only for glycemic control but also for prevention of aortic dissection.
Aortic dissection is a potentially fatal condition characterized by the separation between the tunica media of the aorta and tunica intima. Dissection occurring in the ascending aorta are classified as Stanford type A (or DeBakey type I and II), and aortic dissections happening in the descending aorta are classified as Stanford type B (or DeBakey IIIa and IIIb). 1 , 2 Most aortic dissection cases are Type A and are acute. Type B aortic dissections are generally chronic but may occasionally progress to the formation of aneurysm. 2 , 3 Recently, a distinct category of aortic dissection, termed non‐A‐non‐B, has also been identified. This form of dissection is isolated to the aortic arch, lying between the ascending and descending aorta, and involves unique risks due to its location near critical branches supplying the brain and upper body. Several risk factors contribute to the onset of aortic dissection, including hypertension, dyslipidemia, atherosclerosis, vasculitis, connective tissue diseases, and trauma. 2 , 3 Complications associated with encompass stroke, renal failure, lower extremity ischemia, myocardial infarction, intestinal ischemia, and paralysis. 3 Despite these serious risks, no medications currently exist to prevent or mitigate the risk of aortic dissection.
The risk of cardiovascular disease in patients with type 2 diabetes (T2D) was 2‐ to 4‐fold higher as compared with patients without T2D. 4 T2D was reported to associate with reduced long‐term risk of aortic aneurysm and aortic dissection in some previous studies. Analysis of the Nationwide Inpatient Sample database showed that diabetes is associated with a reduced rate of hospitalization due to aortic aneurysm and aortic dissection in proportion to the severity of diabetic complications. 5 A study using the Swedish National Diabetes Register from 1998 to 2015 revealed that patients with diabetes had a 28% reduction and 47% reduction, respectively, for the relative risk for aortic aneurysm and aortic dissection compared with the control population. 6 Analysis of 11 studies demonstrated that diabetes was negatively associated with the incidence of thoracic aortic dissection and thoracic aortic aneurysm. 7 Diabetes reduced clinical complications and mortality in patients with Stanford type B aortic dissection after thoracic endovascular aortic repair. 8 Diabetes was also found to be associated with lower aortic dissection risk in a Chinese hospital‐based case–control study. 9 These reduced incidence of aortic dissection in patients with T2D may be due to certain T2D medicines that may exhibit protective effects for aortic dissection. In patients with T2D, elevated renal glucose reabsorption contributes to hyperglycemia. Sodium‐dependent glucose cotransporters (SGLT) mediate the glucose reabsorption. 10 There are 2 members of SGLT, SGLT1 and SGLT2. Compared with SGLT1, SGLT2 has a lower affinity but a higher capacity for glucose transport. 10 , 11 SGLT1 is primarily expressed in intestine, kidney, heart, and skeletal muscle, whereas SGLT2 is mainly expressed in the kidney, with additional presence in vascular cells, adipose tissue, aorta, and endothelial cells. 10 , 11 , 12 , 13 , 14 Three selective SGLT2 inhibitors (SGLT2is), dapagliflozin, canagliflozin, and empagliflozin, were approved between 2012 and 2014 for the treatment of T2D in the United States and Europe. SGLT2 inhibitors promote glucosuria via suppression of renal glucose reabsorption, thereby lowering plasma glucose concentrations. 10 We explored if SGLT2 inhibitor treatment contributes to the reduction of aortic dissection in patients with T2D. Metformin is commonly used as a first‐line treatment for diabetes, and SGLT2is or DPP4 (dipeptidyl peptidase‐4) inhibitors (DPP4i) are often used as second‐line medications. As having aortic aneurysm increases the risk of aortic dissection and patients with T2D being treated with DPP4 inhibitor are not associated with lower risk of aortic aneurysm according to study using the Taiwanese National Health Insurance Research Database (NHIRD), 15 we therefore used patients being treated with DPP4i for comparison with patients receiving SGLT2i in this study. We used the NHIRD to investigate whether the use of SGLT2 inhibitor exhibits protective effects against aortic dissection in patients with T2D.
METHODS
Database Information
The NHIRD contains data recording medical history of clinics, drug prescription history, hospital visit, laboratory test results, and surgery records for 23 000 000 Taiwanese citizens and residents since 1995. All data extracted from NHIRD were delinked from patients’ personal identity, thereby waiving the requirement for patient consent. This cohort study was reviewed and approved by the Institutional Review Board of China Medical University Hospital. We adhered to the guidelines and requirements of both China Medical University and the Strengthening the Reporting of Observational Studies in Epidemiology.
Data Availability Statement
Anonymized data are available from the corresponding author on reasonable requests and with approval of NHIRD from the date of publication for 3 years.
Study Design and Participants
International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification (ICD‐9‐CM and ICD‐10‐CM) codes were used to identify patients with T2D (Table S1). 16 We selected patients with T2D who had at least 1 hospitalization or 3 outpatient visits within 1 year. This is according to the validated disease definition standard previously established for Taiwan's National Health Insurance database, 17 resulting in a cohort of 618 625 patients with T2D who received either SGLT2is or DPP4is between May 1, 2016, and December 31, 2021. The National Health Insurance Plan in Taiwan approved and included SGLT2i for treatment of T2D on May 1, 2016, hence the selection of this as the starting date for this analysis. The index date was defined as the date of the patient's first prescription for an SGLT2i or DPP4i, which occurred after the initial T2D diagnosis. Detailed methods are provided in Figure 1 illustrates the design and flow chart of our cohort analysis.
Figure 1. A flow chart demonstrating the study design and patient criteria.
Data from 621 845 patients with type 2 diabetes who were prescribed either a single type of SGLT2 inhibitor or DPP4 inhibitor between May 2016 and December 2021, and with at least 12 months of prescription history before cohort entry, was extracted from the Taiwanese National Health Insurance Research Database. A propensity score‐matched cohort of 53 325 pairs of SGLT2 inhibitor users and DPP4 inhibitor users (1:1 matching) was then constructed for further analysis. DPP4 indicates dipeptidyl peptidase‐4; and SGLT2, sodium‐dependent glucose cotransporter.
Administration of SGLT2 Inhibitors or DPP4 Inhibitors
The SGLT2is analyzed in this study included dapagliflozin, empagliflozin, and canagliflozin, and the DPP4is included alogliptin, linagliptin, sitagliptin, saxagliptin, and vildagliptin. Data on the drug type, quantity, dosage, dispensing date, and duration of use were extracted from the NHIRD database. Similar to SGLT2is, treatment with DPP4is was used as second‐line therapy for T2D. As having aortic aneurysm increases the risk of aortic dissection and patients with T2D being treated with DPP4is are not associated with lower risk of aortic aneurysm according to a study using the NHIRD, 15 we therefore used patients being treated with DPP4is for comparison with patients receiving SGLT2is in this study. We adopted an intention‐to‐treat approach in this study, whereby all participants were evaluated according to their initially designated treatment groups, irrespective of subsequent therapy modifications or cessation during the follow‐up duration.
Definition of Aortic Dissection Consequences and Covariates
The primary outcome of this study was defined as the incidence of aortic dissection with at least 1 inpatient visit or 3 outpatient visits, identified using ICD‐9‐CM and ICD‐10‐CM codes (Table S1). Diagnoses included dissections of the abdominal, thoracic, and thoracoabdominal aorta, covering type A, type B, and non‐A‐non‐B aortic dissections. A validation study conducted in Taiwan found that the ICD‐9‐CM code 441.0 for aortic dissection diagnosis demonstrated a high positive predictive value of 97.06%, confirming the reliability of this diagnostic coding in the Taiwanese health care database. 18 Age, sex, income, baseline comorbidities, and medication use between patients prescribed SGLT2is and those taking DPP4is were compared. The comorbidities analyzed within 1 year of the index date included hypertension, hyperglycemia, hyperlipidemia, hyperuricemia, chronic kidney disease, chronic obstructive pulmonary disease, aortitis, and systemic lupus erythematosus. Diabetes‐related medication (GLP‐1 [glucagonlike peptide‐1] agonists, insulin, metformin, sulfonylureas, glinides, α‐glucosidase inhibitors, and thiazolidinedione), hypertension‐related medication angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, β‐blockers, calcium‐channel blockers, statins, hyperuricemia‐related medication (allopurinol, febuxostat, and benzbromarone), other medication included diuretics, aspirin, nonsteroidal anti‐inflammatory drugs as well as proton pump inhibitors were all collected in the analysis.
Statistical Analysis
Mean±SD was calculated for continuous variables, and numbers and frequencies were calculated for categorical variables. For patients with T2D‐SGLT2i, multiple logistic regression analysis was conducted to evaluate the propensity scores, using maximum likelihood estimations conditional on baseline covariates. To minimize confounding effects, we implemented inverse probability of treatment weighting in our analysis. This methodology helped us achieve balance in baseline characteristics, comorbidities, and concurrent medication use between the study groups. We calculated the risk of aortic dissection of patients with T2D‐SGLT2i or patients with T2D‐DPP4i using a comprehensive set of covariates, which formed the foundation for each patient's propensity score calculation. 19 Weights were derived as 1/propensity score for patients being prescribed for SGLT2is, whereas those receiving DPP4is were weighted as 1/(1‐propensity score). This approach assigned greater analytical weight to patients with a lower likelihood of receiving their actual treatment, enhancing the representativeness of our comparison. To improve statistical efficiency, we stabilized the weights by incorporating the marginal treatment probability in the numerator. The effectiveness of our balancing procedure was evaluated using standardized mean differences, with values <0.10 considered indicative of adequate covariate balance between the SGLT2i and DPP4i groups. 20 Cohort follow‐up began from the index date and continued until aortic dissection diagnosis, death, or the end of the study period (December 31, 2021). The cause‐specific hazard function was implemented in all Cox models to incorporate death as a competing risk when assessing the associated hazards. Weighted Kaplan–Meier method was used to plot survival curves for aortic dissection incidence in patients with T2D‐SGLT2i and T2D‐DPP4i. Log‐rank test was performed to compare distinctions between survival curves. Schoenfeld residuals were used to test the proportional hazards assumption. Following identification of assumption violations, we implemented time‐dependent weighted Cox proportional hazards regression models to derive crude and adjusted hazard ratios (HRs) and their 95% CIs for evaluating aortic dissection risks. Multiple weighted Cox proportional hazards regression models were used in post hoc subgroup analyses of baseline comorbidities and other prescribed medication. SAS, version 9.4 statistical software (SAS Institute Inc., Cary, NC, USA) was used for the statistical analysis in this study. A P value <0.05 was considered as a statistically significant difference.
RESULTS
Characteristics of Propensity Score‐Matched Study Participants
A total of 242 563 patients with T2D‐SGLT2i and 376 062 patients with T2D‐DPP4i were compared for age, sex, comorbidities, and medications in Table 1. The mean±SD age for this population was 63.14 (13.47) years old. There were 284 171 female patients (45.94%). The balances of comorbidities and medicine use between patients with T2D‐SGLT2i and T2D‐DPP4i were measured by standardized mean differences values. The difference between the 2 groups was regarded insignificant if the standardized mean differences value was <0.10.
Table 1.
Comparisons of Baseline Information in the Inverse Probability of Treatment Weighting Population With Type 2 Diabetes Using Dipeptidyl Peptidase 4 Inhibitors and Sodium‐Glucose Cotransporter 2 Inhibitors
| Overall | DPP4 inhibitor | SGLT2 inhibitor | SMD | ||
|---|---|---|---|---|---|
| (N=618 625) | (N=376 062) | (N=242 563) | Unweighted | Weighted | |
| Index y, N (%) | |||||
| 2016 | 62 834 (10.16%) | 49 180 (13.08%) | 13 654 (5.63%) | 0.26 | 0.02 |
| 2017 | 94 754 (15.32%) | 69 187 (18.40%) | 25 567 (10.54%) | 0.22 | 0.01 |
| 2018 | 95 141 (15.38%) | 64 067 (17.04%) | 31 074 (12.81%) | 0.12 | 0.00 |
| 2019 | 108 724 (17.58%) | 63 331 (16.84%) | 45 393 (18.71%) | −0.05 | −0.01 |
| 2020 | 132 442 (21.41%) | 70 429 (18.73%) | 62 013 (25.57%) | −0.17 | −0.01 |
| 2021 | 124 730 (20.16%) | 59 868 (15.92%) | 64 862 (26.74%) | −0.27 | −0.01 |
| Age, y, mean±SD | 63.14±13.47 | 65.92±13.29 | 58.83±12.59 | −0.55 | −0.03 |
| Stratified by age, y | |||||
| 18–24 | 2085 (0.34%) | 802 (0.21%) | 1283 (0.53%) | ||
| 25–34 | 10 936 (1.77%) | 4175 (1.11%) | 6761 (2.79%) | ||
| 35–44 | 44 916 (7.26%) | 19 056 (5.07%) | 25 860 (10.66%) | ||
| 45–54 | 97 395 (15.74%) | 47 645 (12.67%) | 49 750 (20.51%) | ||
| 55–64 | 170 774 (27.61%) | 95 239 (25.33%) | 75 535 (31.14%) | ||
| 65–74 | 164 162 (26.54%) | 104 815 (27.87%) | 59 347 (24.47%) | ||
| 75–84 | 95 993 (15.52%) | 75 334 (20.03%) | 20 659 (8.52%) | ||
| 85+ | 32 364 (5.23%) | 28 996 (7.71%) | 3368 (1.39%) | ||
| Sex (female) | 284 171 (45.94%) | 183 450 (48.78%) | 100 721 (41.52%) | 0.15 | 0.00 |
| Monthly income | 28728.00±24929.00 | 27313.30±24248.00 | 30921.30±25796.00 | ||
| Stratify by monthly income | |||||
| NTD 0–14 999 | 142 236 (22.99%) | 94 381 (25.10%) | 47 855 (19.73%) | 0.13 | 0.00 |
| NTD 15 000–24 999 | 229 967 (37.17%) | 143 881 (38.26%) | 86 086 (35.49%) | 0.06 | 0.00 |
| NTD 25 000+ | 246 422 (39.83%) | 137 800 (36.64%) | 108 622 (44.78%) | −0.17 | −0.01 |
| Comorbidity | |||||
| Hypertension | 336 479 (54.39%) | 212 095 (56.40%) | 124 384 (51.28%) | 0.10 | 0.01 |
| Hyperglycemia | 7066 (1.14%) | 4636 (1.23%) | 2430 (1.00%) | 0.02 | 0.00 |
| Hyperlipidemia | 388 129 (62.74%) | 224 558 (59.71%) | 163 571 (67.43%) | −0.16 | −0.01 |
| Hyperuricemia | 6823 (1.10%) | 4443 (1.18%) | 2380 (0.98%) | 0.02 | 0.00 |
| Chronic kidney disease | 116 404 (18.82%) | 84 179 (22.38%) | 32 225 (13.29%) | 0.24 | 0.02 |
| Chronic obstructive pulmonary disease | 35 723 (5.77%) | 25 615 (6.81%) | 10 108 (4.17%) | 0.12 | 0.01 |
| Aortitis | 385 (0.06%) | 257 (0.07%) | 128 (0.05%) | 0.01 | 0.00 |
| Aortic valve disease | 856 (0.14%) | 677 (0.18%) | 179 (0.07%) | 0.03 | 0.00 |
| Mitral valve disease | 9834 (1.59%) | 6310 (1.68%) | 3524 (1.45%) | 0.02 | 0.00 |
| Connective tissue diseases | 785 (0.13%) | 542 (0.14%) | 243 (0.10%) | 0.01 | 0.00 |
| Medication (diabetes) | |||||
| Glucagon‐like peptide‐1 agonists | 3939 (0.64%) | 1066 (0.28%) | 2873 (1.18%) | −0.11 | 0.01 |
| Insulin | 51 230 (8.28%) | 25 746 (6.85%) | 25 484 (10.51%) | −0.13 | 0.00 |
| Metformin | 204 764 (33.10%) | 122 484 (32.57%) | 82 280 (33.92%) | −0.03 | −0.02 |
| Sulfonylureas | 136 594 (22.08%) | 81 655 (21.71%) | 54 939 (22.65%) | −0.02 | −0.01 |
| Glinides | 21 215 (3.43%) | 15 086 (4.01%) | 6129 (2.53%) | 0.08 | 0.00 |
| α‐glucosidase inhibitors | 43 984 (7.11%) | 25 624 (6.81%) | 18 360 (7.57%) | −0.03 | −0.01 |
| Thiazolidinedione | 46 749 (7.56%) | 23 778 (6.32%) | 22 971 (9.47%) | −0.12 | −0.01 |
| Medication (hypertension) | |||||
| Angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers | 233 663 (37.77%) | 134 721 (35.82%) | 98 942 (40.79%) | −0.10 | −0.01 |
| β‐blockers | 125 488 (20.28%) | 73 371 (19.51%) | 52 117 (21.49%) | −0.05 | −0.01 |
| Calcium channel blockers | 110 805 (17.91%) | 73 225 (19.47%) | 37 580 (15.49%) | 0.10 | −0.01 |
| Medication (hyperlipidemia) | |||||
| Statins | 227 051 (36.70%) | 125 103 (33.27%) | 101 948 (42.03%) | −0.18 | −0.01 |
| Medication (hyperuricemia) | |||||
| Allopurinol | 5031 (0.81%) | 3273 (0.87%) | 1758 (0.72%) | 0.02 | 0.00 |
| Febuxostat | 13 591 (2.20%) | 10 051 (2.67%) | 3540 (1.46%) | 0.09 | 0.01 |
| Benzbromarone | 19 968 (3.23%) | 12 068 (3.21%) | 7900 (3.26%) | 0.00 | 0.00 |
| Medication (other) | |||||
| Diuretics | 51 890 (8.39%) | 35 214 (9.36%) | 16 676 (6.87%) | 0.09 | 0.00 |
| Aspirin | 96 465 (15.59%) | 56 463 (15.01%) | 40 002 (16.49%) | −0.04 | −0.01 |
| Nonsteroidal anti‐inflammatory drugs | 228 747 (36.98%) | 135 189 (35.95%) | 93 558 (38.57%) | −0.05 | −0.01 |
| Proton pump inhibitors | 28 052 (4.53%) | 17 471 (4.65%) | 10 581 (4.36%) | 0.01 | 0.00 |
DPP4 indicates dipeptidyl peptidase‐4; SGLT2, sodium‐dependent glucose cotransporter; and SMD, standardized mean difference.
Use of SGLT2 Inhibitors Reduces Risk of Aortic Dissection
During the study period, 78 patients of the group with T2D‐SGLT2i and 300 patients of the group with T2D‐DPP4i were diagnosed with aortic dissection (Table 2). The incidence rate was 14.83 versus 29.56 cases per 100 000 patient‐years in the groups with T2D‐SGLT2i and T2D‐DPP4i, respectively. Figure 2 illustrated the weighted Kaplan–Meier survival curves, which demonstrated that patients using SGLT2i exhibited significantly reduced cumulative incidence of aortic dissection when compared with those on DPP4i therapy. In the group with T2D‐SGLT2i, the adjusted HRs after controlling for baseline factors (age, sex, diabetes duration, comorbidities, and medication use) were 0.75 for aortic dissection (95% CI, 0.57–1.00; P=0.0475) as shown in Table 2. Furthermore, the distribution of SGLT2i prescriptions was 51.5% for dapagliflozin, 41.3% for empagliflozin, and 7.2% for canagliflozin. Overall, SGLT2is had a significantly protective effect against aortic dissection compared with DPP4is. However, when individual SGLT2is (ie, dapagliflozin, empagliflozin, and canagliflozin), were separately compared with DPP4is, none of them showed a statistically significant protective effect against aortic dissection.
Table 2.
Risk of Aortic Dissection Between Patients With Dipeptidyl Peptidase 4 Inhibitor and Sodium‐Glucose Cotransporter 2 Inhibitor Use in the Inverse Probability of Treatment Weighting Patients With Type 2 Diabetes
| Event | Patient | Incidence | Rate | Crude | P value | Adjusted | P value | |
|---|---|---|---|---|---|---|---|---|
| Year | Rate† | Difference | HR (95% CI) | HR (95% CI)* | ||||
| DPP4 inhibitor (N=376 062) | 300 | 1 014 958 | 29.56 | REF | REF | REF | ||
| SGLT2 inhibitor (N=242 563) | 78 | 525 939 | 14.83 | −4.76×10−4 (−5.91×10−4 to −3.61×10−4) | 0.70 (0.53–0.93) | 0.0126 | 0.75 (0.57–1.00) | 0.0475 |
| Canagliflozin (N=17 673) | 3 | 26 412 | 11.36 | −6.28×10−4 (−8.40×10−4 to −4.16×10−4) | 0.44 (0.13–1.46) | 0.1774 | 0.40 (0.12–1.35) | 0.1412 |
| Dapagliflozin (N=124 804) | 43 | 276 928 | 15.53 | −4.53×10−4 (−5.90×10−4 to −3.16×10−4) | 0.71 (0.50–1.02) | 0.0609 | 0.80 (0.56–1.15) | 0.2371 |
| Empagliflozin (N=100 086) | 32 | 222 599 | 14.38 | −4.78×10−4 (−6.21×10−4 to −3.35×10−4) | 0.71 (0.47–1.09) | 0.1142 | 0.73 (0.48–1.12) | 0.1457 |
DPP4 indicates dipeptidyl peptidase‐4; HR, hazard ratio; and SGLT2, sodium‐dependent glucose cotransporter.
All variables included age, sex, comorbidities (hypertension, hyperglycemia, hyperlipidemia, hyperuricemia, chronic kidney disease, chronic obstruction pulmonary disease, aortitis, aortic valve disease, mitral valve disease, and connective tissue diseases) and medications (glucagon‐like peptide‐1 agonists, insulin, metformin, sulfonylureas, glinides, α‐glucosidase inhibitors, thiazolidinedione, angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers, β‐blockers, calcium channel blockers, statins, allopurinol, febuxostat, benzbromarone, diuretics, aspirin, nonsteroidal anti‐inflammatory drugs, and proton pump inhibitors) were considered in the adjusted Cox's hazard proportional models.
Incidence rates were calculated as events of aortic dissection per 100 000 person‐years.
Figure 2. Incidence of aortic dissection in patients with type 2 diabetes receiving either dipeptidyl peptidase 4 inhibitors or sodium‐dependent glucose cotransporters inhibitors.
Cumulative incident probability of aortic dissection in patients with T2D receiving DPP4 inhibitors or SGLT2 inhibitors was shown in overall cohort population. DPP4 indicates dipeptidyl peptidase‐4; SGLT2, sodium‐dependent glucose cotransporter; and T2D, type 2 diabetes.
Subgroup Analyses
The relationship between SGLT2i usage and aortic dissection was further investigated through subgroup analyses based on patient comorbidity profiles and concomitant medications, which were described in Figure 3. SGLT2i treatment in patients with T2D was associated with reduced aortic dissection risk in specific subgroups: monthly income 0 to 14 999 new Taiwan dollars (HR, 0.56 [95% CI, 0.32–0.96]; P=0.0364), patients with hypertension (HR, 0.63 [95% CI, 0.45–0.89]; P=0.0089), and those without hyperlipidemia (HR, 0.73 [95% CI, 0.55–0.97]; P=0.0286), aortitis (HR, 0.75 [95% CI, 0.57–1.00; P=0.0475), aortic valve disease (HR, 0.74 [95% CI, 0.56–0.98]; P=0.0381), and mitral valve disease (HR, 0.73 [95% CI, 0.55–0.97]; P=0.031).
Figure 3. Interaction analysis of aortic dissection incidence in patients with type 2 diabetes receiving dipeptidyl peptidase 4 inhibitors and sodium‐glucose cotransporter 2 inhibitors.
Stratified analysis of aortic dissection incidence in patients with type 2 diabetes receiving dipeptidyl peptidase 4 inhibitors and sodium‐glucose cotransporter 2 inhibitors using baseline comorbidities and other medications in the propensity score‐matched population. DPP4 indicates dipeptidyl peptidase‐4; HR, hazard ratio; NTD, new Taiwan dollar; and SGLT2, sodium‐dependent glucose cotransporter.
Additionally, patients with T2D receiving SGLT2i therapy showed reduced aortic dissection risk when not concurrently using other antidiabetic medications (insulin, glinides, α‐glucosidase inhibitors), antihypertensive medications (angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers, β‐blockers, calcium channel blockers), benzbromarone, diuretics, and nonsteroidal anti‐inflammatory drugs (HRs ranged from 0.59 to 0.74; all P<0.05) (Figure 3 and Table S2).
DISCUSSION
Diabetes is widely recognized as a prominent cardiovascular risk factor. However, paradoxical inverse relationship has been observed between diabetes and the risk of aortic dissection. 7 , 9 Our analysis demonstrated that, after adjusting for potential confounders, treatment with SGLT2is reduced the HR of aortic dissection in patients with T2D to 0.75 (95% CI, 0.57–1.00) as compared with those treated with DPP4is. Our study suggested that SGLT2i treatment contributed to 25% reduction of incidence of aortic dissection.
Oxidative stress and inflammation are critical risk factors for aortic dissection. 21 Patients with acute myocardial infarction receiving SGLT2i treatment for diabetes showed significantly lower inflammatory response and smaller infarct size as compared with patients receiving other oral antidiabetic agents. 22 SGLT2is canagliflozin and empagliflozin have been shown to activate AMPK (AMP‐activated protein kinase), which is a crucial regulator of metabolism and suppressor of inflammation. 14 , 23 , 24 Activation of AMPK by SGLT2is reduced levels of inflammatory cytokines as well as decreased oxidative. 25 SGLT2is have also been shown to repress inflammation and oxidative stress via stabilization of superoxide‐generating enzyme NOX1 (NADPH oxidase 1) and inhibition of NLRP3 (NLR family pyrin domain‐containing 3) inflammasome activation. 26 , 27 , 28 These antioxidative and anti‐inflammatory properties of SGLT2is may contribute to the protection of patients with T2D from aortic dissection.
Additionally, canagliflozin treatment has been observed to improve arterial stiffness, 29 a condition marked by the transformation of elastic fibers in the lamina media of the aorta into collagen fibers, which increases aortic impedance and contributes to the progression towards dissection. 30 Empagliflozin has been shown to mitigate extracellular matrix remodeling and to reduce the expression of profibrotic markers, including ACTA2, COL1A1, CCN2, and MMP2. 31 These facts implied that SGLT2is can preserve vessel wall integrity, which may in turn reduces the risk of aortic dissection.
Serum uric acid levels positively correlate to the risk of aortic aneurysm 32 and are elevated in patients with aortic dissection. 33 Hyperuricemia is a risk factor for aortic dissection‐related mortality. 34 SGLT2is effectively reduce serum uric acid levels in patients with T2D by modulating uric acid transport activity in the renal tubules. 35 , 36 , 37 , 38 The reduction in serum uric acid contributes partially to the observed decrease in cardiovascular mortality associated with SGLT2is. 39 The decline in serum uric acid may as well decrease the incidence of aortic dissection in patients with T2D. SGLT2is are able to modulate lipid metabolism, affecting both lipogenesis and lipolysis. 40 , 41 In a diabetic murine model, 3 weeks of empagliflozin treatment inhibited fatty liver development by downregulating fatty acid synthase and acetyl‐CoA carboxylase. 42 A meta‐analysis encompassing 48 randomized controlled trials revealed that SGLT2i treatment was associated with reduction of triglyceride levels. 43 Because dyslipidemia is linked to an increased risk of aortic dissection, 2 the triglyceride‐lowering effects of SGLT2is may contribute to a reduced incidence of aortic dissection in patients with T2D.
Sympathetic hyperactivity is recognized as a contributing factor in the pathological progression of type B aortic dissection. 44 , 45 SGLT2is have been shown to reduce sympathetic nerve activity deriving from brown adipose tissue. 46 Dapagliflozin treatment suppresses norepinephrine turnover in brown adipose tissue. 46 In diabetic rats, SGLT2is improved baroreflex sensitivity by lowering sympathetic nerve activity, consequently stabilizing arterial pressure. 47 In addition, dapagliflozin reduced levels of inflammatory cytokines TNF‐α (tumor necrosis factor alpha) and IL‐1β (interleukin‐1beta), which subsequently decreased noradrenaline production in the kidneys and hearts of high‐fat diet‐fed mice. 48 These findings collectively suggest that the sympathoinhibitory effects of SGLT2is may reduce the risk of aortic dissection.
Hypertension is a significant risk factor for aortic dissection and is notably prevalent in patients with T2D. 49 , 50 Compared with placebo, DPP‐4is reduced 3.04 mm Hg and 1.47 mm Hg for systolic and diastolic blood pressure, respectively. 51 In contrast, SGLT2is demonstrated greater antihypertensive effects, lowering systolic blood pressure and diastolic blood pressure by 4.44 mm Hg and 2.15 mm Hg. 51 Canagliflozin, 50 , 52 dapagliflozin, 53 and empagliflozin 54 all demonstrated notable antihypertensive effects. Other antidiabetic agents such as metformin, exenatide, 55 and liraglutide 56 do not reduce blood pressure. The discrepancy in blood pressure‐lowering effects may elucidate the superior protective effect of SGLT2is against aortic dissection.
Limitations
This study is subject to several limitations. First, due to deidentification of data from patients with T2D, comprehensive biochemical parameters (such as weight, blood sugar, blood pressure, renal‐related values, and uric acid level), laboratory values, dietary and exercise habits, and genomic profiles were unavailable. In addition, this is an analysis based on the National Health Insurance database, which does not contain personal lifestyle habits such as smoking status. We therefore used chronic obstructive pulmonary disease as a surrogate marker for smoking and included it in our adjustment model. The absence of this information could have influenced our findings to some extent. Additionally, the Taiwan Food and Drug Administration did not approve the use of SGLT2is for T2D treatment until 2016. This constraint limited the sample size, event rate, observation periods, and duration of outcome assessment, potentially reducing our study's power to detect differences between SGLT2is and DPP‐4is. The lack of a statistically significant difference in the protective effect against aortic dissection between different SGLT2is and DPP4is was likely due to the strict exclusion of various comorbidities and medication usage, which resulted in a reduced number of cases, making it difficult to achieve statistical significance. Despite these constraints, we still identified a significant association between SGLT2i use and a reduced risk of aortic dissection. We anticipate that future studies with extended follow‐up for patients on SGLT2is may reveal even greater reductions in aortic dissection incidence, as improvements in blood pressure, inflammation, and triglyceride levels may gradually translate to lower risk over time.
CONCLUSIONS
Our results demonstrated that treatment with SGLT2is reduced the HR of aortic dissection in patients with T2D to 0.75 (95% CI, 0.57–1.00) as compared with those treated with DPP4is. This represented a 25% reduction of incidence of aortic dissection associated with use of SGLT2is. This protective effect may be attributed to the SGLT2i‐induced reduction of reactive oxygen species and inflammation, blood pressure, lipid levels, and uric acid, as well as improvement of arterial stiffness.
Patient Consent
The NHIRD contains data recording medical history of clinics, drug prescription history, hospital visit, laboratory test results and surgery records for 23 000 000 Taiwanese citizens and residents since 1995. All data extracted from NHIRD were delinked from patient's personal identity, thereby waiving the requirement for patient consent.
Sources of Funding
This study was supported by grant CMU112‐MF‐56 (China Medical University); CS‐113‐PP‐03; CS‐112‐PP‐03; CS‐110‐PP‐03; CS‐111‐PP‐03 (National Health Research Institutes); NSTC 111‐2811‐B‐400‐029; NSTC 112‐2314‐B‐400‐031, NSTC 113‐2314‐B‐400‐004, NSTC 113‐2320‐B‐400‐024‐MY3, NSTC 112‐2314‐B‐038‐122‐MY3 (National Science and Technology Council (Taiwan)). Role of the Funder/Sponsor: China Medical University Hospital, National Health Research Institutes, and National Science and Technology Council (Taiwan) had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; and decision to submit the article for publication.
Disclosures
All authors met the International Committee of Medical Journal Editors authorship criteria. All authors made substantial contributions to the article submitted for publication, read and approved the article, and have no commercial financial incentive with publishing the article. The corresponding author Prof. Chuu certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the article (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending) for all authors, are the following: None.
Supporting information
Tables S1–S2
Acknowledgments
Author contributions: Prof. C.‐P. Chuu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: C.‐P. Chuu, C.‐J. Chung. Acquisition, analysis, or interpretation of data: L.‐Y. Wu, H.‐Y. Lu, C. Huo, L.‐K. Kuo, C.‐C.‐Liu, C.‐J. Chung, C.‐P. Chuu. Drafting of the article: C.‐J. Chung, H.‐Y. Lu, C. Huo, L.‐Y. Wu, L.‐K. Kuo, C.‐C.‐Liu, C.‐P. Chuu. Critical revision of the article for important intellectual content: C.‐J. Chung, H.‐Y. Lu, C.‐P. Chuu, J. Chung. Statistical analysis: L.‐Y. Wu, C.‐J. Chung. Obtained funding: C.‐J. Chung, H.‐Y. Lu, C.‐P. Chuu. Administrative, technical, or material support: C.‐J. Chung, C.‐P. Chuu. Supervision: C.‐P. Chuu.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.124.040260
For Sources of Funding and Disclosures, see page 10.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Tables S1–S2
Data Availability Statement
Anonymized data are available from the corresponding author on reasonable requests and with approval of NHIRD from the date of publication for 3 years.