The cohort study was consist of 17,588 SGLT2I users and 17,588 SGLT2I non-user. As shown as Table 1, the distributions of gender and age group within two groups were similar. The proportions of each comorbidities had no difference between SGLT2I users and non-users. Beside of diabetes, Hypertension, hyperlipidemia and stroke were the most common comorbidities in this study. The drug prescription pattern in the two group was similar and the common medicines were ARBs, CCBs and statins. The mean of the follow-up time for SGLT2I users was 1.75(± 1.01) years and that for SGLT2I non-users was 1.99(± 0.88) years.
Table 1
Demographic, comorbidities, and medications in HF patients with and without SGLT2is
Variable | Non-SGLT2is users | SGLT2is users | SMD |
n (%) / Mean ± SD | n (%) / Mean ± SD |
All | 17,588 | 17,588 | |
Sex | | | 0.0063 |
Female | 7,390 (42.02) | 7,335 (41.70) | |
Male | 10,198 (57.98) | 10,253 (58.30) | |
Age group (year) | | | |
< 50 | 1,942 (11.04) | 2,010 (11.43) | 0.0122 |
50–59 | 3,392 (19.29) | 3,555 (20.21) | 0.0233 |
> 60 | 12,254 (69.67) | 12,023 (68.36) | 0.0284 |
Age (year) | 65.29 ± 12.35 | 64.96 ± 12.43 | 0.0272 |
Comorbidities | | | |
AF | | | 0.0284 |
No | 14,564 (82.81) | 14,373 (81.72) | |
Yes | 3,024 (17.19) | 3,215 (18.28) | |
Diabetes | | | 0.0115 |
No | 948 (5.39) | 903 (5.13) | |
Yes | 16,640 (94.61) | 16,685 (94.87) | |
Hyperlipidemia | | | 0.0122 |
No | 3,983 (22.65) | 4,073 (23.16) | |
Yes | 13,605 (77.35) | 13,515 (76.84) | |
Hypertension | | | 0.0192 |
No | 1,687 (9.59) | 1,788 (10.17) | |
Yes | 15,901 (90.41) | 15,800 (89.83) | |
Chronic kidney disease | | | 0.0175 |
No | 14,750 (83.86) | 14,636 (83.22) | |
Yes | 2,838 (16.14) | 2,952 (16.78) | |
COPD | | | 0.0094 |
No | 13,556 (77.08) | 13,486 (76.68) | |
Yes | 4,032 (22.92) | 4,102 (23.32) | |
AMI | | | 0.0123 |
No | 14,642 (83.25) | 14,561 (82.79) | |
Yes | 2,946 (16.75) | 3,027 (17.21) | |
Stroke | | | 0.0041 |
No | 13,377 (76.06) | 13,346 (75.88) | |
Yes | 4,211 (23.94) | 4,242 (24.12) | |
Medications | | | |
Aspirin | | | 0.0004 |
No | 3,385 (19.25) | 3,382 (19.23) | |
Yes | 14,203 (80.75) | 14,206 (80.77) | |
Clopidogrel | | | 0.0028 |
No | 10,099 (57.42) | 10,075 (57.28) | |
Yes | 7,489 (42.58) | 7,513 (42.72) | |
Warfarin | | | 0.0359 |
No | 15,588 (88.63) | 15,383 (87.46) | |
Yes | 2,000 (11.37) | 2,205 (12.54) | |
NOACs | | | 0.0178 |
No | 15,428 (87.72) | 15,324 (87.13) | |
Yes | 2,160 (12.28) | 2,264 (12.87) | |
Amiodarone | | | 0.0240 |
No | 14,211 (80.80) | 14,043 (79.84) | |
Yes | 3,377 (19.20) | 3,545 (20.16) | |
Dronedarone | | | 0.0089 |
No | 17,453 (99.23) | 17,439 (99.15) | |
Yes | 135 (0.77) | 149 (0.85) | |
ACEIs | | | 0.0021 |
No | 6,957 (39.56) | 6,939 (39.45) | |
Yes | 10,631 (60.44) | 10,649 (60.55) | |
ARBs | | | 0.0288 |
No | 2,108 (11.99) | 2,275 (12.93) | |
Yes | 15,480 (88.01) | 15,313 (87.07) | |
α-blockers | | | 0.0000 |
No | 10,471 (59.53) | 10,471 (59.53) | |
Yes | 7,117 (40.47) | 7,117 (40.47) | |
β-blockers | | | 0.0090 |
No | 10,822 (61.53) | 10,899 (61.97) | |
Yes | 6,766 (38.47) | 6,689 (38.03) | |
CCBs | | | 0.0230 |
No | 2,911 (16.55) | 3,063 (17.42) | |
Yes | 14,677 (83.45) | 14,525 (82.58) | |
Diuretics | | | 0.0015 |
No | 2,824 (16.06) | 2,814 (16.00) | |
Yes | 14,764 (83.94) | 14,774 (84.00) | |
Entresto | | | 0.0148 |
No | 17,119 (97.33) | 17,076 (97.09) | |
Yes | 469 (2.67) | 512 (2.91) | |
Statins | | | 0.0216 |
No | 2,997 (17.04) | 3,141 (17.86) | |
Yes | 14,591 (82.96) | 14,447 (82.14) | |
Follow-up period (year) | 1.75 ± 1.01 | 1.99 ± 0.88 | 0.2572 |
SMD: standard mead difference; AF: atrial fibrillation; COPD: chronic obstructive pulmonary disease; AMI: acute myocardial infarction; NOACs: novel oral anticoagulant drugs; ACEIs: angiotensin-converting enzyme inhibitors; AEBs: angiotensin II receptor blockers; CCBs: calcium channel blockers; |
Table 2 presents the associated of the covariates and the CV outcome. The adjusted hazard ratio of CV event for SGLT2I users relative to SGLT2I non-users was 0.50 (95% CI = 0.48 0.53). Male patient were more likely to have CV outcome compared to female patients, adjusted HR was 1.18 (95% CI = 1.12, 1.25). with consider patients younger than 50 year old as reference group, 50–59 years old patients and greater than 60 years old patients increase the risk of CV outcome by 1.11 folds (95% CI = 1.00, 1.25) and 1.59 folds (95% CI = 1.45, 1.74), respectively. Patients with diabetes (adjusted HR = 1.25; 95% CI = 1.10, 1.41), chronic kidney disease (adjusted HR = 1.65; 95% CI = 1.56, 1.73), COPD (adjusted HR = 1.08; 95% CI = 1.03, 1.14), AMI (adjusted HR = 1.36; 95% CI = 1.28, 1.42) and stroke (adjusted HR = 1.56; 95% CI = 1.49, 1.64) will increase the risk of CV outcome. Patients with hyperlipidemia (adjusted HR = 0.84; 95% CI = 0.80, 0.89) reduces the risk of CV outcome. For the medications, clopidogrel (adjusted HR = 1.15; 95% CI = 1.09, 1.21), amiodarone (adjusted HR = 1.24; 95% CI = 1.16, 1.31), ACEIs (adjusted HR = 1.09; 95% CI = 1.04, 1.14), CCBs (adjusted HR = 1.08; 95% CI = 1.00, 1.16) and diuretics (adjusted HR = 2.22; 95% CI = 2.02, 2.43) were the risk factors of CV outcome, however, dronedarone (adjusted HR = 0.75; 95% CI = 0.59, 0.96), ARBs (adjusted HR = 0.87; 95% CI = 0.59, 0.96), β-blockers (adjusted HR = 0.90; 95% CI = 0.86, 0.95) and statins (adjusted HR = 0.84; 95% CI = 0.79, 0.89) were the protection factors of the CV outcomes.
Table 2
Risk of CV outcomes associated with SGLT2is, demographics, comorbidities, and medications.
Variable | Event | Person-years | IR | Crude HR (95% CI) | Adjusted HR (95% CI) |
N = 7,892 | 100 person-years |
SGLT2is | | | | | |
No | 4,956 | 30,758 | 16.11 | 1 (Reference) | 1 (Reference) |
Yes | 2,936 | 35,037 | 8.38 | 0.53 (0.51, 0.56)*** | 0.50 (0.48, 0.53)*** |
Sex | | | | | |
Female | 3,137 | 27,914 | 11.24 | 1 (Reference) | 1 (Reference) |
Male | 4,755 | 37,882 | 12.55 | 1.11 (1.06, 1.16)*** | 1.18 (1.12, 1.25)*** |
Age (year) | | | | | |
< 50 | 561 | 7,934 | 7.07 | 1 (Reference) | 1 (Reference) |
50–59 | 1,123 | 13,832 | 8.12 | 1.15 (1.04, 1.27)** | 1.11 (1.00, 1.23)* |
> 60 | 6,208 | 44,030 | 14.10 | 1.95 (1.79, 2.12)*** | 1.59 (1.45, 1.74)*** |
Comorbidities | | | | | |
AF | | | | | |
No | 6,172 | 54,613 | 11.30 | 1 (Reference) | 1 (Reference) |
Yes | 1,720 | 11,182 | 15.38 | 1.34 (1.27, 1.41)*** | 1.01 (0.93, 1.09) |
Diabetes | | | | | |
No | 261 | 3,477 | 7.51 | 1 (Reference) | 1 (Reference) |
Yes | 7,631 | 62,318 | 12.25 | 1.64 (1.45, 1.86)*** | 1.25 (1.10, 1.41)*** |
Hyperlipidemia | | | | | |
No | 2,034 | 14,672 | 13.86 | 1 (Reference) | 1 (Reference) |
Yes | 5,858 | 51,123 | 11.46 | 0.83 (0.79, 0.88)*** | 0.84 (0.80, 0.89)*** |
Hypertension | | | | | |
No | 564 | 6,687 | 8.43 | 1 (Reference) | 1 (Reference) |
Yes | 7,328 | 59,108 | 12.40 | 1.46 (1.34, 1.59)*** | 0.96 (0.87, 1.06) |
Chronic kidney disease | | | | | |
No | 5,839 | 56,427 | 10.35 | 1 (Reference) | 1 (Reference) |
Yes | 2,053 | 9,368 | 21.91 | 2.02 (1.92, 2.13)*** | 1.65 (1.56, 1.73)*** |
COPD | | | | | |
No | 5,559 | 51,282 | 10.84 | 1 (Reference) | 1 (Reference) |
Yes | 2,333 | 14,513 | 16.08 | 1.46 (1.39, 1.53)*** | 1.08 (1.03, 1.14)** |
AMI | | | | | |
No | 6,129 | 55,368 | 11.07 | 1 (Reference) | 1 (Reference) |
Yes | 1,763 | 10,428 | 16.91 | 1.50 (1.42, 1.58)*** | 1.36 (1.28, 1.44)*** |
Stroke | | | | | |
No | 5,023 | 51,578 | 9.74 | 1 (Reference) | 1 (Reference) |
Yes | 2,869 | 14,217 | 20.18 | 2.01 (1.92, 2.10)*** | 1.56 (1.49, 1.64)*** |
Medications | | | | | |
Aspirin | 1,183 | 13,083 | 9.04 | 1 (Reference) | 1 (Reference) |
No | 6,709 | 52,712 | 12.73 | 1.39 (1.31, 1.48)*** | 0.94 (0.88, 1.00) |
Yes | | | | | |
Clopidogrel | | | | | |
No | 3,782 | 38,785 | 9.75 | 1 (Reference) | 1 (Reference) |
Yes | 4,110 | 27,010 | 15.22 | 1.54 (1.47, 1.61)*** | 1.15 (1.09, 1.21)*** |
Warfarin | | | | | |
No | 6,787 | 58,000 | 11.70 | 1 (Reference) | 1 (Reference) |
Yes | 1,105 | 7,795 | 14.18 | 1.21 (1.13, 1.29)*** | 0.98 (0.91, 1.05) |
NOAC | | | | | |
No | 6,724 | 58,098 | 11.57 | 1 (Reference) | 1 (Reference) |
Yes | 1,168 | 7,697 | 15.17 | 1.28 (1.20, 1.36)*** | 0.94 (0.87, 1.02) |
Amiodarone | | | | | |
No | 5,857 | 53,698 | 10.91 | 1 (Reference) | 1 (Reference) |
Yes | 2,035 | 12,097 | 16.82 | 1.52 (1.44, 1.59)*** | 1.24 (1.16, 1.31)*** |
Dronedarone | | | | | |
No | 7,823 | 65,288 | 11.98 | 1 (Reference) | 1 (Reference) |
Yes | 69 | 507 | 13.61 | 1.12 (0.88, 1.42) | 0.75 (0.59, 0.96)* |
ACEIs | | | | | |
No | 2,644 | 26589 | 9.94 | 1 (Reference) | 1 (Reference) |
Yes | 5,248 | 39207 | 13.39 | 1.33 (1.27, 1.40)*** | 1.09 (1.04, 1.14)*** |
ARBs | | | | | |
No | 811 | 8405 | 9.65 | 1 (Reference) | 1 (Reference) |
Yes | 7,081 | 57390 | 12.34 | 1.27 (1.18, 1.36)*** | 0.87 (0.81, 0.94)*** |
α-blockers | | | | | |
No | 3,997 | 40408 | 9.89 | 1 (Reference) | 1 (Reference) |
Yes | 3,895 | 25387 | 15.34 | 1.52 (1.45, 1.59)*** | 1.04 (0.99, 1.10) |
β-blockers | | | | | |
No | 4,944 | 40777 | 12.12 | 1 (Reference) | 1 (Reference) |
Yes | 2,948 | 25019 | 11.78 | 0.97 (0.92, 1.01) | 0.90 (0.86, 0.95)*** |
CCBs | | | | | |
No | 978 | 11767 | 8.31 | 1 (Reference) | 1 (Reference) |
Yes | 6,914 | 54028 | 12.80 | 1.52 (1.42, 1.62)*** | 1.08 (1.00, 1.16)* |
Diuretics | | | | | |
No | 528 | 11622 | 4.54 | 1 (Reference) | 1 (Reference) |
Yes | 7364 | 54173 | 13.59 | 2.92 (2.67, 3.19)*** | 2.22 (2.02, 2.43)*** |
Entresto | | | | | |
No | 7685 | 64467 | 11.92 | 1 (Reference) | 1 (Reference) |
Yes | 207 | 1328 | 15.58 | 1.15 (1.00, 1.33)* | 1.08 (0.94, 1.25) |
Statins | | | | | |
No | 1431 | 11344 | 12.61 | 1 (Reference) | 1 (Reference) |
Yes | 6461 | 54451 | 11.87 | 0.94 (0.89, 1.00)* | 0.84 (0.79, 0.89)*** |
IR: incidence rate; HR: hazard ratio; CI: confidence interval; |
AF: atrial fibrillation; COPD: chronic obstructive pulmonary disease; AMI: acute myocardial infarction; NOACs: novel oral anticoagulant drugs; ACEIs: angiotensin-converting enzyme inhibitors; AEBs: angiotensin II receptor blockers; CCBs: calcium channel blockers; |
*:p-value < 0.05; **:p-value < 0.01;***: p-value < 0.001; |
To look into the risk of the individual CV outcomes, SGLT2I users had a lower risk of acute myocardial infraction (adjusted HR = 0.83; 95% CI = 0.74, 0.92), CV death (adjusted HR = 0.47; 95% CI = 0.42, 0.51) and all-cause death (adjusted HR = 0.39; 95% CI = 0.37, 0.41), see Table 3. Except the outcome of the re-hospitalization of HF, the cumulative incidence curves of CV outcomes in SGLT2I user were lower than that of the SGLT2I non-users, see Fig. 1.
Table 3
Risks of different types of CV outcomes associated with SGLT2is in HF patients.
Variable | Non-SGLT2is users | | SGLT2is users | Crude HR (95% CI) | Adjusted HR (95% CI) |
Event | Person-years | IR (100 person-years) | | Event | Person-years | IR (100 person-years) |
CV outcomes | | | | | | | | | |
Acute myocardial infarction | 543 | 30,758 | 1.77 | | 527 | 35,037 | 1.50 | 0.86 (0.77, 0.97)* | 0.83 (0.74, 0.94)** |
Hemorrhagic stroke | 121 | 30,758 | 0.39 | | 113 | 35,037 | 0.32 | 0.83 (0.64, 1.07) | 0.78 (0.61, 1.02) |
Ischemic stroke | 534 | 30,758 | 1.74 | | 622 | 35,037 | 1.78 | 1.03 (0.92, 1.16) | 0.99 (0.89, 1.12) |
CV death | 1,189 | 30,758 | 3.87 | | 646 | 35,037 | 1.84 | 0.49 (0.45, 0.54)*** | 0.47 (0.42, 0.51)*** |
All-cause death | 3,811 | 30,758 | 12.39 | | 1,727 | 35,037 | 4.93 | 0.41 (0.39, 0.43)*** | 0.39 (0.37, 0.41)*** |
IR: incidence rate; HR: hazard ratio; CI: confidence interval; |
*:p-value < 0.05; **:p-value < 0.01;***: p-value < 0.001; |
According to Table 4, patients who used SGLT2I for 1-447 days reduce the risk of CV outcomes by 0.88 times (95% CI = 0.84, 0.93) and SGLT2I users for more than 448 days had an 85% (95% CI = 0.14, 0.17) lower risk of CV outcomes, compared to SGLT2I non-users.
Table 4
Risk of CV outcomes associated with different days' supply of SGLT2is.
Variable | Event | Person-years | IR | Crude HR (95% CI) | Adjusted HR (95% CI) |
N = 7,892 | 100 person-years |
SGLT2is | | | | | |
No | 4,956 | 30,758 | 16.11 | 1 (Reference) | 1 (Reference) |
1-447 days | 2482 | 14697 | 16.89 | 1.02 (0.97, 1.07) | 0.88 (0.84, 0.93)*** |
> 448 days | 454 | 20340 | 2.23 | 0.15 (0.13, 0.16)*** | 0.15 (0.14, 0.17)*** |
IR: incidence rate; HR: hazard ratio; CI: confidence interval; |
*:p-value < 0.05; **:p-value < 0.01;***: p-value < 0.001; |
Table 5 illustrates the relationship between SGLT2I and CV outcomes stratified by AF and CHA2DS2-VASc score. When considered HF patients without AF and SGLT2I as the reference group, HF patients without AF but used SGLT2I reduce the risk of CV outcomes to 0.48 (95%CI = 0.45, 0.50) and HF patients with AF and SGLT2I had the adjusted HR of 0.55 (95%CI = 0.50, 0.61). The adjusted HR of CV outcomes for HF patients with CHA2DS2-VASc score less than 2 and SGLT2I with and without AF relative to HF patients without AF nor SGLT2I were 0.53 (95% CI = 0.41, 0.67) and 0.24 (95% CI = 0.12, 0.47), respectively. Compared to HF patients with no history of AF and SGLT2I, if patients additionally with SGLT2I and CHA2DS2-VASc score ≥ 2, the risk of the CV outcome reduces to 0.48 (95% CI = 0.45, 0.50); if patients additionally with AF and CHA2DS2-VASc score ≥ 2, the risk of the CV outcome reduces to 0.88 (95% CI = 0.80, 0.97); if patients additionally with AF, SGLT2I and CHA2DS2-VASc score ≥ 2, the risk of the CV outcome reduces to 0.53 (95% CI = 0.47, 0.55).
Table 5
Risk of CV outcomes associated with SGLT2is among HF patients stratified by AF.
Variable | Event | Person-years | IR | Crude HR (95% CI) | Adjusted HR (95% CI) |
N = 7,892 | 100 person-years |
AF/SGLT2is | | | | | |
No/No | 3,989 | 25,653 | 15.55 | 1 (Reference) | 1 (Reference) |
No/Yes | 2,183 | 28,960 | 7.54 | 0.50 (0.47, 0.52)*** | 0.48 (0.45, 0.50)*** |
CHA2DS2-VASc score | | | | | |
79 | 1,661 | 4.75 | 0.31 (0.25, 0.39)*** | 0.53 (0.41, 0.67)*** | |
2+ | 2,104 | 27,298 | 7.71 | 0.51 (0.48, 0.54)*** | 0.48 (0.45, 0.50)*** |
Yes/No | 967 | 5,105 | 18.94 | 1.20 (1.12, 1.29)*** | 0.92 (0.84, 1.00) |
CHA2DS2-VASc score | | | | | |
< 2 | 17 | 268 | 6.33 | 0.42 (0.26, 0.67)*** | 0.62 (0.38, 1.02) |
2+ | 950 | 4,837 | 19.64 | 1.23 (1.15, 1.32)*** | 0.88 (0.80, 0.97)* |
Yes/Yes | 753 | 6,077 | 12.39 | 0.80 (0.74, 0.87)*** | 0.55 (0.50, 0.61)*** |
CHA2DS2-VASc score | | | | | |
< 2 | 9 | 310 | 2.90 | 0.20 (0.10, 0.38)*** | 0.24 (0.12, 0.47)*** |
2+ | 744 | 5,768 | 12.90 | 0.84 (0.77, 0.90)*** | 0.52 (0.47, 0.58)*** |
IR: incidence rate; HR: hazard ratio; CI: confidence interval; AF: atrial fibrillation; |
*:p-value < 0.05; **:p-value < 0.01;***: p-value < 0.001; |