Abstract
Aims
Head‐to‐head comparisons among SGLT2 inhibitors treatments in established heart failure remain absent. We conducted a systematic review of dedicated heart failure trials to assess indirectly the composite outcomes and individual clinical endpoints among SGLT2 inhibitor treatments.
Methods and results
We systematically reviewed randomized controlled trials comparing SGLT2 inhibitors versus placebo in patients with established heart failure. A Bayesian approach to network meta‐analysis was applied. Five trials including four treatment strategies were included in this study. The composite of cardiovascular death or hospitalization for heart failure showed no significant difference in the comparison between dapagliflozin and empagliflozin (OR 1.00, 95% CI 0.66–1.55), dapagliflozin and sotagliflozin (OR 1.54, 95% CI 0.91–2.65), and empagliflozin and sotagliflozin (OR 1.53, 95% CI 0.90–2.69). All‐cause mortality showed no significant difference in the comparison between dapagliflozin and empagliflozin (OR 0.92, 95% CI 0.711–1.18), dapagliflozin and sotagliflozin (OR 1.05, 95% CI 0.68–1.59), and empagliflozin and sotagliflozin (OR 1.14, 95% CI 0.74–1.73). Cardiovascular death showed no significant difference in the comparison between dapagliflozin and empagliflozin (OR 0.94, 95% CI 0.71–1.23), dapagliflozin and sotagliflozin (OR 0.96, 95% CI 0.61–1.55), and empagliflozin and sotagliflozin (OR 1.03, 95% CI 0.64–1.66). Hospitalization for heart failure showed no significant difference in the comparison between dapagliflozin and empagliflozin (OR 1.13, 95% CI 0.64–1.97), dapagliflozin and sotagliflozin (OR 1.56, 95% CI 0.74–3.15), and empagliflozin and sotagliflozin (OR 1.39, 95% CI 0.68–2.78).
Conclusions
In patients with established heart failure, there was no significant difference of the major efficacy outcomes among SGLT2 inhibitor treatments; however, sotagliflozin may be associated with the lowest risk of the composite of cardiovascular death or hospitalization for heart failure, and dapagliflozin may be associated with the lowest risk of all‐cause and cardiovascular mortality.
Keywords: SGLT2 inhibitors, Heart failure, Hospitalization for heart failure, Cardiovascular death, Indirect comparison
Introduction
The overall global prevalence of heart failure is estimated at 2.6%, 1 which is becoming more prevalent among adults and remains a leading cause of death, hospitalization, and poor quality of life. 2 , 3 , 4 In patients with type 2 diabetes mellitus (T2DM), sodium glucose cotransporter 2 (SGLT2) inhibitors reduce blood glucose by decreasing renal glucose reabsorption and increasing urinary glucose excretion. 5 To date, SGLT2 inhibitors have shown the significant benefits reducing the risk of cardiovascular death, heart failure hospitalization, and serious adverse renal events in patients with T2DM. 6 , 7 , 8 , 9 , 10 Previous large cardiovascular outcomes trial, which investigated empagliflozin in 7020 patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD), reported a significant 38% reduction in cardiovascular death and a 32% reduction in hospitalization for heart failure. 10 In the DECLARE‐TIMI 58 trial, 9 treatment with dapagliflozin did result in a lower rate of cardiovascular death or hospitalization for heart failure in patients with T2DM who were at risk for atherosclerotic cardiovascular disease. CANVAS Program 8 also reported that patients with T2DM and an elevated risk of cardiovascular disease were associated with a lower risk of cardiovascular events on canagliflozin treatments.
In recent years, lots of dedicated heart failure trials have attempted to evaluate the efficacy of SGLT2 inhibitors in patients with heart failure. DAPA‐HF trial was the first published outcome trial specifically designed to evaluate the effect of SGLT2 inhibitors in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. 11 EMPEROR‐Reduced 12 and EMPEROR‐Preserved 13 reported the benefits of empagliflozin on the composite of cardiovascular death or hospitalization for heart failure in patients with HFrEF and heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). Meanwhile, DELIVER trial 14 has added new evidence to the comparison for patients with HFmrEF/HFpEF. The latest meta‐analysis of five placebo‐controlled trials 15 demonstrated that SGLT2 inhibitors reduced the risk of cardiovascular death and hospitalization for heart failure in a broad range of patients with heart failure. To our knowledge, we are uncertain as to which SGLT2 inhibitor is optimal for patients with heart failure, due to the lack of head‐to‐head comparisons among SGLT2 inhibitor treatments in patients with established heart failure.
We therefore conducted a systematic review of dedicated heart failure trials to assess indirectly the composite outcomes and individual clinical endpoints among SGLT2 inhibitors treatments by Bayesian network meta‐analysis.
Methods
Search strategy and selection criteria
We followed the Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) guidelines for our study. 16 , 17 According to the newest recommendation of AHA/ACC/HFSA guideline for the management of heart failure, HFrEF is defined as left ventricular ejection fraction ≤40%; the threshold for HFpEF is a left ventricular ejection fraction ≥50%; patients with heart failure and left ventricular ejection fraction between HFrEF and HFpEF range are termed as HFmrEF. Because previous clinical trials defined HFrEF as a left ventricular ejection fraction ≤40%, whereas HFpEF was defined as a left ventricular ejection fraction >40%, we included all relevant randomized controlled trials (RCTs), comparing SGLT2 inhibitors vs. placebo in patients with established heart failure regardless of left ventricular ejection fraction. In addition, we performed subgroup analysis by patients with HFrEF and HFmrEF/HFpEF. The primary exclusion criteria were non‐randomized, post hoc analysis of heart failure strata within trials that were not focusing on heart failure, observational or registry studies. We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to 20 August 2022. The literature was updated on 4 September 2022 during the final revision process. Web of Science and clinicaltrial.gov were also searched for more trials. In addition to searching databases, reference lists of all identified trials were also manually searched. The search strategy was presented in detail in Table S1 .
Two researchers (HBC and YLY) independently selected study and assessed the eligibility of studies identified through search of relevant databases, with conflicts resolved by consensus. Studies were considered for inclusion based on the following criteria: (i) RCTs, (ii) patients with heart failure were randomly assigned to SGLT2 inhibitors and placebo, and (iii) published in the English language.
Data analysis
We extracted and presented data according to the PRISMA. 18 Two researchers (HBC and RSM) independently performed data extraction for aggregated study‐level data, with conflicts resolved by consensus. The major efficacy outcomes of interest were the composite of cardiovascular death or hospitalization for heart failure. The second efficacy outcomes of interest included all‐cause mortality, cardiovascular death, and hospitalization for heart failure. We used the Cochrane Collaboration's recommended tool 19 to assess the risk of bias in the included trials. We did not assess publication bias as there were small numbers of studies included in this meta‐analysis.
Statistical analysis
Results are presented as odds ratio (OR) with corresponding 95% confidence intervals (CI). We evaluated heterogeneity between studies by the Q test and I 2 statistic. Indirect comparison of SGLT2 inhibitors was performed by Bayesian network meta‐analysis, which enables the calculation of the probability, of which the competing intervention is best. 20 , 21 , 22 A network geometry graph was used to represent the correlation between the comparisons and the pooled sample sizes for each group of available studies. The size of the nodes represented the participants in particular intervention, whereas the thickness of the line represented the number of studies for which there were direct comparisons. 23 Markov chain Monte Carlo methods and sampling for four chains using the GeMTC package (version 1.0‐1) in R4.1.3 (R Language and Environment for Statistical Computing) were used in our study. An initial burn‐in period of 30 000 iterations was set to allow convergence, and then a posterior summary was generated based on a further 100 000 iterations, and a random effects model was used. In the light of non‐direct comparisons between SGLT2 inhibitor treatments, we could not assess the consistency by inconsistency factor. When the results of comparisons were non‐significant, ranking probability would be used for reference and represented the likelihood, which meant the probability of a treatment regimen was ranked to be the best (i.e. to be associated with the lowest risk of events) by estimating the median (95% CI) of the posterior distribution for the rank of each treatment regimen. Every treatment regimen was ranked according to the estimated OR in each Markov chain Monte Carlo cycle. The probability of a certain treatment ranking as the best among all treatment regimens was estimated from the proportion of the cycles in which a given regimen was rated as first of the total Markov cycles. To test the robustness of results, we performed a sensitivity analysis by HFrEF and HFmrEF/HFpEF subgroups.
Results
A total of 798 potentially relevant articles were screened, and five RCTs that met the inclusion criteria were included in the final analysis (Figure S1 ), involving two trials for empagliflozin, two trials for dapagliflozin, and one trial for sotagliflozin. Five trials including four treatment strategies (dapagliflozin, empagliflozin, sotagliflozin, and placebo) were included in this network meta‐analysis. They included patients with HFrEF (two trials, n = 8474), HFmrEF/HFpEF (two trials, n = 12 251), and recent worsening heart failure (one trial, n = 1222). The baseline characteristics of the patients enrolled in the five trials included in this study are shown in Table 1 . The median duration of follow‐up was 9.2 months in SOLOIST‐WHF trial, 16 months in EMPEROR‐Reduced trial, 24 months in DAPA‐HF trial, 26.2 months in EMPEROR‐Preserved trial, and 27.6 months in DELIVER trial, respectively. All the trials were judged to be at low risk of bias via the Cochrane's Collaboration tool for risk assessment (Table S2 ).
Table 1.
Baseline characteristics of patients enrolled in the five trials
| DAPA‐HF | EMPEROR‐Reduced | SOLOIST‐WHF | EMPEROR‐Preserved | DELIVER | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Dapagliflozin | Placebo | Empagliflozin | Placebo | Sotagliflozin | Placebo | Empagliflozin | Placebo | Dapagliflozin | Placebo | |
| Trial type | RCT | RCT | RCT | RCT | RCT | |||||
| Publication year | 2019 | 2020 | 2020 | 2021 | 2022 | |||||
| Follow‐up, months (median) | 24 months | 16 months | 9.2 months | 26.2 months | 27.6 months | |||||
| Numbers, no. | 2373 | 2371 | 1863 | 1867 | 608 | 614 | 2997 | 2991 | 3131 | 3132 |
| Mean age (years) | 66.2 | 66.5 | 67.2 | 66.5 | 69.0 | 70.0 | 71.8 | 71.9 | 71.8 | 71.5 |
| Female, no. (%) | 564(23.8) | 545(23.0) | 437(23.5) | 456(24.4) | 198(32.6) | 214(34.9) | 1338(44.6) | 1338(44.7) | 1364(43.6) | 1383(44.2) |
| Race, no. (%) | ||||||||||
| White | 1662(70.0) | 1671(70.0) | 1325(71.1) | 1304(69.8) | 567(93.3) | 572(93.2) | 2286(76.3) | 2256(75.4) | 2214(70.7) | 2225(71.0) |
| Black | 122(5.1) | 104(4.4) | 123(6.6) | 134(7.2) | 25(4.1) | 25(4.1) | 133(4.4) | 125(4.2) | 81(2.6) | 78(2.5) |
| Asian | 552(23.3) | 564(23.8) | 337(18.1) | 335(17.9) | 8(1.3) | 7(1.1) | 413(13.8) | 411(13.7) | 630(20.1) | 644(20.6) |
| Other | 37(1.6) | 32(1.3) | 78(4.2) | 94(5.0) | 2(0.3) | 4(0.7) | 165(5.5) | 199(6.7) | 206(6.6) | 185(5.9) |
| Region, no. (%) | ||||||||||
| North America, no. (%) | 335(14.1) | 342(14.4) | 212(11.4) | 213(11.4) | 39(6.4) | 41(6.7) | 360(12.0) | 259(12.0) | 428(13.7) | 423(13.5) |
| South America, no. (%) | 401(16.9) | 416(17.5) | 641(34.4) | 645(34.5) | 132(21.7) | 134(21.8) | 758(25.3) | 757(25.3) | 602(19.2) | 579(18.5) |
| Europe, no. (%) | 1094(46.1) | 1060(44.7) | 676(36.3) | 677(36.3) | 399(65.6) | 401(65.3) | 1346(44.9) | 1343(44.9) | 1494(47.7) | 1511(48.2) |
| Asia or other, no. (%) | 543(22.9) | 553 (23.3) | 334 (17.9) | 332(17.8) | 38(6.2) | 383(6.2) | 533(17.7) | 532(17.8) | 607(19.4) | 619(19.8) |
| NYHA class | ||||||||||
| II | 1606(67.7) | 1597(67.4) | 1399(75.1) | 1401(75.0) | NA | NA | 3(0.1) | 1(<0.1) | 2314(73.9) | 2399(76.6) |
| III | 747(31.5) | 751(31.7) | 455(24.4) | 455(24.4) | NA | NA | 2432(81.1) | 2451(81.9) | 807 (25.8) | 724 (23.1) |
| IV | 20(0.8) | 23(1.0) | 9(0.5) | 11(0.6) | NA | NA | 10(0.3) | 8(0.3) | 10(0.3) | 8(0.3) |
| Mean LVEF | 31.2 | 30.9 | 27.7 | 27.2 | 35 | 35 | 54.3 | 54.3 | 54.0 | 54.3 |
| NT‐proBNP, pg/mL | 1428 | 1446 | 1887 | 1926 | 1817 | 1741 | 994 | 946 | NA | NA |
| Systolic blood pressure, mmHg | 122.0 | 121.6 | 122.6 | 121.4 | 122.0 | 122.0 | 131.8 | 131.9 | NA | NA |
| Estimated GFR, mL/min/1.73 m2 | 66.0 | 65.5 | 61.8 | 62.2 | 49.2 | 50.5 | 60.6 | 60.6 | 61 | 61 |
| Heart failure medication, no. (%) | ||||||||||
| ARB | 675(28.4) | 632(26.7) | 451(24.2) | 457(24.5) | 245(40.3) | 270(44.0) | NA | NA | NA | NA |
| ACE inhibitor | 1332(56.1) | 1329(56.1) | 867(46.5) | 836(44.8) | 254(41.8) | 241(39.3) | NA | NA | NA | NA |
| ARNI | 250(10.5) | 258(10.9) | 340(18.3) | 387(20.7) | 93(15.3) | 112(18.2) | NA | NA | NA | NA |
| Beta blocker | 2278(96.0) | 2280(96.2) | 1765(94.7) | 1768(94.7) | 564(92.8) | 561(91.4) | NA | NA | NA | NA |
| MRA | 1696(71.5) | 1674(70.6) | 1306(70.1) | 1355(72.6) | 403(66.3) | 385(62.7) | NA | NA | NA | NA |
ACE, angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; GFR, glomerular filtration rate; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NA, not available; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA, New York Heart Association; RCT, randomized controlled trial.
Indirect treatment comparison: The composite of cardiovascular death or hospitalization for heart failure
Five trials and 21 927 patients were included for the composite of cardiovascular death or hospitalization for heart failure assessment. In both the consistency and inconsistency models, the composite of cardiovascular death or hospitalization for heart failure showed no significant difference in the comparison among three treatments: dapagliflozin and empagliflozin (OR 1.00, 95% CI 0.66–1.55, consistency model, and OR 1.00, 95% CI 0.64–1.56, inconsistency model, respectively), dapagliflozin and sotagliflozin (OR 1.54, 95% CI 0.91–2.65, consistency model, and OR 1.54, 95% CI 0.89–2.64, inconsistency model, respectively), empagliflozin and sotagliflozin (OR 1.53, 95% CI 0.90–2.69, consistency model, and OR 1.53, 95% CI 0.88–2.67, inconsistency model, respectively) (Figure 1 A and Figure S2A ). We ranked the risk of the composite of cardiovascular death or hospitalization for heart failure in patients with heart failure taking SGLT2 inhibitors. As a result, sotagliflozin was identified as having the lowest risk of the composite of cardiovascular death or hospitalization for heart failure (Figure 2 A ). In patients with HFrEF and HFmrEF/HFpEF subgroup analysis, the composite of cardiovascular death or hospitalization for heart failure showed no significant difference in the comparison between dapagliflozin and empagliflozin (OR 0.99, 95% CI 0.55–1.81, OR 1.02, 95% CI 0.63–1.63, consistency model, and OR 0.99, 95% CI 0.55–1.81, OR 1.02, 95% CI 0.63–1.63, inconsistency model, respectively) (Figure 3 and Figure S3 ). Dapagliflozin and empagliflozin were both identified as having similar risk of the composite of cardiovascular death or hospitalization for heart failure by rank probability (Figure 4 A and Figure 4 B ).
Figure 1.
Forest plot of indirect comparison among SGLT2 inhibitors treatments. (A) The composite of cardiovascular death or hospitalization for heart failure. (B) All‐cause mortality. (C) Cardiovascular death. (D) Hospitalization for heart failure.
Figure 2.
Plot of rank probability. The lowest probability of SGLT2 inhibitor treatment regimen, which was associated with the lowest risk of events, was ranked to be the best. (A) The composite of cardiovascular death or hospitalization for heart failure. (B) All‐cause mortality. (C) Cardiovascular death. (D) Hospitalization for heart failure.
Figure 3.
Subgroup analysis in patients with HFrEF and HFmrEF/HFpEF.
Figure 4.
Plot of rank probability for the composite of cardiovascular death or hospitalization for heart failure and all‐cause mortality by subgroup analysis in patients with HFrEF and HFmrEF/HFpEF. The lowest probability of SGLT2 inhibitor treatment regimen, which was associated with the lowest risk of events, was ranked to be the best. (A) The composite of cardiovascular death or hospitalization for heart failure in patients with HFrEF. (B) The composite of cardiovascular death or hospitalization for heart failure in patients with HFmrEF/HFpEF. (C) All‐cause mortality in patients with HFrEF. (D) All‐cause mortality in patients with HFmrEF/HFpEF.
Indirect treatment comparison: All‐cause mortality
Five trials and 21 927 patients were included for all‐cause mortality assessment. In both the consistency and inconsistency models, all‐cause mortality showed no significant difference in the comparison among three treatments: dapagliflozin and empagliflozin (OR 0.92, 95% CI 0.711–1.18, consistency model, and OR 0.92, 95% CI 0.71–1.18, inconsistency model, respectively), dapagliflozin and sotagliflozin (OR 1.05, 95% CI 0.68–1.59, consistency model, and OR 1.04, 95% CI 0.67–1.62, inconsistency model, respectively), empagliflozin and sotagliflozin (OR 1.14, 95% CI 0.74–1.73, consistency model, and OR 1.03, 95% CI 0.74–1.76, inconsistency model, respectively) (Figure 1 B and Figure S2B ). Results were corroborated in subgroup analyses by patients with HFrEF [dapagliflozin vs. empagliflozin (OR 0.88, 95% CI 0.57–1.34, consistency model, and OR 0.88, 95% CI 0.57–1.34, inconsistency model, respectively)] and patients with HFmrEF/HFpEF [dapagliflozin vs. empagliflozin (OR 0.95, 95% CI 0.76–1.19, consistency model, and OR 0.95, 95% CI 0.76–1.19, inconsistency model, respectively)] (Figure 3 and Figure S3 ). We ranked the risk of all‐cause mortality in patients with heart failure taking SGLT2 inhibitors. As a result, dapagliflozin was identified as having the lowest risk of all‐cause mortality (Figure 2 B , Figure 4 C , Figure 4 D ).
Indirect treatment comparison: Cardiovascular death
Five trials and 21 927 patients were included for cardiovascular death assessment. In both the consistency and inconsistency models, cardiovascular death showed no significant difference in the comparison among three treatments: dapagliflozin and empagliflozin (OR 0.94, 95% CI 0.71–1.23, consistency model, and OR 0.93, 95% CI 0.71–1.23, inconsistency model, respectively), dapagliflozin and sotagliflozin (OR 0.96, 95% CI 0.61–1.55, consistency model, and OR 0.98, 95% CI 0.58–1.55, inconsistency model, respectively), and empagliflozin and sotagliflozin (OR 1.03, 95% CI 0.64–1.66, consistency model, and OR 1.05, 95% CI 0.64–1.68, inconsistency model, respectively) (Figure 1 C and Figure S2C ). Results were corroborated in subgroup analyses by patients with HFrEF [dapagliflozin vs. empagliflozin (OR 0.89, 95% CI 0.58–1.39, consistency model, and OR 0.89, 95% CI 0.58–1.39, inconsistency model, respectively)] and patients with HFmrEF/HFpEF [dapagliflozin vs. empagliflozin (OR 0.95, 95% CI 0.67–1.35, consistency model, and OR 0.95, 95% CI 0.67–1.35, inconsistency model, respectively)] (Figure 3 and Figure S3 ). We ranked the risk of cardiovascular death in patients with heart failure taking SGLT2 inhibitors. As a result, dapagliflozin was identified as having the lowest risk of cardiovascular death (Figure 2 C , Figure 5 A , Figure 5 B ).
Figure 5.
Plot of rank probability for cardiovascular death and hospitalization for heart failure by subgroup analysis in patients with HFrEF and HFmrEF/HFpEF. The lowest probability of SGLT2 inhibitor treatment regimen, which was associated with the lowest risk of events, was ranked to be the best. (A) Cardiovascular death in patients with HFrEF. (B) Cardiovascular death in patients with HFmrEF/HFpEF. (C) Hospitalization for heart failure in patients with HFrEF. (D) Hospitalization for heart failure in patients with HFmrEF/HFpEF.
Indirect treatment comparison: Hospitalization for heart failure
Five trials and 21 927 patients were included for hospitalization for heart failure assessment. In both the consistency and inconsistency models, hospitalization for heart failure showed no significant difference in the comparison among three treatments: dapagliflozin and empagliflozin (OR 1.13, 95% CI 0.64–1.97, consistency model, and OR 1.12, 95% CI 0.63–2.01, inconsistency model, respectively), dapagliflozin and sotagliflozin (OR 1.56, 95% CI 0.74–3.15, consistency model, and OR 1.56, 95% CI 0.78–3.18, inconsistency model, respectively), empagliflozin and sotagliflozin (OR 1.39, 95% CI 0.68–2.78, consistency model, and OR 1.39, 95% CI 0.68–2.79, inconsistency model, respectively) (Figure 3 and Figure S3 ). We ranked the risk of hospitalization for heart failure in patients with heart failure taking SGLT2 inhibitors. As a result, sotagliflozin was identified as having the lowest risk of hospitalization for heart failure (Figure 2 D ). In patients with HFrEF and HFmrEF/HFpEF subgroup analysis, hospitalization for heart failure showed no significant difference in the comparison between dapagliflozin and empagliflozin (OR 1.03, 95% CI 0.50–2.09, OR 1.07, 95% CI 0.56–2.04, consistency model, and OR 1.03, 95% CI 0.50–2.09, OR 1.07, 95% CI 0.56–2.04, inconsistency model, respectively) (Figure 3 and Figure S3 ). Empagliflozin was identified as having the lowest risk of hospitalization for heart failure by rank probability (Figure 5 C and Figure 5 D ).
Qualitative assessment and sensitivity analysis
We assessed the risk of bias of the included trials using the Cochrane Collaboration's recommended tool. A summary of the quality assessment of each trial is shown in Table S2 . Heterogeneity test show no evidence of heterogeneity for all‐cause mortality (I 2 = 0%, P = 0.57), hospitalization for heart failure (I 2 = 0%, P = 0.49). Heterogeneity test show evidence of heterogeneity for the composite of cardiovascular death or hospitalization for heart failure (I 2 = 71%, P = 0.007) and cardiovascular death (I 2 = 63%, P = 0.03). The funnel plot for outcomes showed mild asymmetry (limited by the small number of trials) (Figures S4 – S7 ).
Discussion
Previous studies have shown significant benefits of SGLT2 inhibitors on cardiovascular and renal outcomes in patients with T2DM. 6 , 7 , 8 , 9 , 10 Our study sought to assess indirectly the composite outcomes and individual clinical endpoints among SGLT2 inhibitors treatments in patients with heart failure by Bayesian network meta‐analysis, which demonstrated several findings. Firstly, in patients with heart failure, there was no significant difference among SGLT2 inhibitor treatments for the composite outcomes and individual clinical endpoints. Secondly, sotagliflozin was identified as having the lowest risk of the composite of cardiovascular death or hospitalization for heart failure by ranking probability. Thirdly, dapagliflozin was identified as having the lowest risk of all‐cause mortality and cardiovascular death by ranking probability. Finally, dapagliflozin was identified as having the lowest risk of mortality by ranking probability regardless of the patients with HFrEF or HFmrEF/HFpEF.
Sodium glucose cotransporter 2 (SGLT2) inhibitors reduce blood glucose by decreasing renal glucose reabsorption and increasing urinary glucose excretion, which were developed to lower blood glucose in patients with T2DM. 5 , 24 DAPA‐HF trial, the first SGLT2 inhibitors dedicated heart failure trial, which studied 4744 patients with established HFrEF, regardless of the presence or absence of T2DM, showed a significant 23.1% reduction in the composite of cardiovascular death or hospitalization for heart failure and a 16.5% reduction in cardiovascular death and a 16.6% reduction of all‐cause death. 11 A pooled analysis of EMPEROR‐Reduced and EMEROR‐Preserved trials showed that the magnitude of the effect of empagliflozin on heart failure outcomes was clinically significant and similar in patients with an ejection of ≤25% to ≤65%, but in patients with an ejection fraction of ≥65% the effect of empagliflozin on heart failure was attenuated. 25 Another pooled analysis of DAPA‐HF and DELIVER trials demonstrated that dapagliflozin significantly reduced the risk of cardiovascular death and all‐cause death in patients with heart failure, irrespective of left ventricular ejection fraction. 26 The latest meta‐analysis of five dedicated heart failure trials, 15 which was a prespecified meta‐analysis of DELIVER and EMPEROR‐Preserved, and subsequently included trials that enrolled patients with HFrEF (DAPA‐HF and EMPEROR‐Reduced) and those admitted to hospital with worsening heart failure (SOLOIST‐WHF), reported that SGLT2 inhibitors reduced the risk of cardiovascular death and hospitalization for heart failure in a broad range of patients with heart failure. That meta‐analysis focused on examining the effect s of SGLT2 inhibitors on fata and non‐fatal events overall and in subgroups of interest using data from DELIVER and EMPEROR‐Preserved. In addition, it aligned data from adjacent population of DAPA‐HF, EMPEROR‐Reduced, and SOLOIST‐WHF, which supported the role of the SGLT2 inhibitors as a foundational therapy in the management of heart failure, irrespective of left ventricular ejection fraction or care setting. Our study also included these five RCTs; however, our aim is to systematically review all dedicated heart failure trials to assess indirectly the composite outcomes and individual clinical endpoints among SGLT2 inhibitors treatments. It is clear that SGLT2 inhibitors have robust benefits in patients with heart failure, irrespective of left ventricular ejection fraction. However, we are uncertain as to which SGLT2 inhibitor is optimal for patients with heart failure, due to the lack of head‐to‐head comparisons among SGLT2 inhibitor treatments in patients with established heart failure. In our pooled analysis, we found that there was no significant difference for the interest outcomes among SGLT2 inhibitors treatments; however, sotagliflozin may be prescribed as the choice for patients with heart failure due to the advantage of reducing hospitalization for heart failure. To the mortality, including cardiovascular death and all‐cause mortality, dapagliflozin may be prescribed as the best choice for patients with heart failure.
Because SOLOIST‐WHF trial 27 enrolled patients with any ejection fraction, therefore, to test the robustness of results, we performed a sensitivity analysis by HFrEF and HFmrEF/HFpEF subgroups. Previous meta‐analysis 28 of EMPEROR‐Reduced and DAPA‐HF trials suggested that SGLT2 inhibitors could improve renal outcomes and reduce all‐cause and cardiovascular death in patients with HFrEF. According to the EMPEROR‐Preserved and DELIVER trials' results, empagliflozin and dapagliflozin did reduce the combined risk of cardiovascular death or hospitalization in patients with HFmrEF/HFpEF; however, we are uncertain as to which SGLT2 inhibitor is optimal for these populations. We are the first study that compared the effect of empagliflozin vs. dapagliflozin based on existing evidence in dedicated heart failure trials, which demonstrated that the composite outcomes showed no significant difference in the comparison between dapagliflozin and empagliflozin in patients with HFmrEF/HFpEF subgroup analysis. In addition, these two SGLT2 inhibitors were both identified as having similar risk of the composite of cardiovascular death or hospitalization for heart failure by rank probability. But dapagliflozin seemed to be the best choice regardless of the patients with HFrEF or HFmrEF/HFpEF, due to the advantage of reducing all‐cause mortality and cardiovascular mortality. The exact mechanisms of SGLT2 inhibitors in cardioprotective and nephroprotective effects may be related to sodium balance, energy homoeostasis, and relief of cellular stress. 29 , 30
Strengths of our study include the inclusion of only RCTs and indirect comparison by Bayesian network meta‐analysis based on existing evidence in dedicated heart failure trials. Limitations of our study included the relatively small number of trials included in our study. We evaluated outcomes using trial‐level data rather than individual participant data. Furthermore, the subtle potential biases included in the trials, for example, sampling bias, selection bias, and within‐study bias, remain a possible limitation of this and any systematic review. In addition, the trials included in our study were clinically heterogeneous, as is often the case in systematic reviews, and we used sensitivity analysis to accounted for this. Finally, head‐to‐head comparisons between SGLT2 inhibitor treatments in patients with heart failure remain absent; further trials about SGLT2 inhibitors in heart failure and head‐to‐head comparisons are needed in the future.
In conclusion, in patients with established heart failure, there was no significant difference of the major efficacy outcomes among SGLT2 inhibitors treatments; however, sotagliflozin may be associated with the lowest risk of the composite of cardiovascular death or hospitalization for heart failure, and dapagliflozin may be associated with the lowest risk of mortality.
Conflict of interest
The authors have no competing interests to disclose.
Funding
Not applicable.
Supporting information
Table S1. Search strategy in Pubmed.
Table S2. Risk of bias of individual studies by Cochrane risk assessment tool.
Table S3. Original data extracted from available trials included in this meta‐analysis.
Figure S1. Flow diagram of the trial selection process meta‐analysis.
Figure S2. Indirect comparison among SGLT2 inhibitors treatments by inconsistency model (A: the composite of cardiovascular dearth or hospitalization for heart failure; B: all‐cause mortality; C: cardiovascular dearth; D: hospitalization for heart failure).
Figure S3. Subgroup analysis in patients with HFrEF and HFmrEF/HFpEF by inconsistency model.
Figure S4. Funnel plot of cardiovascular death or hospitalization for heart failure.
Figure S5. Funnel plot of all‐cause mortality.
Figure S6. Funnel plot of cardiovascular death mortality.
Figure S7. Funnel plot of hospitalization for heart failure.
Chen, H.‐B. , Yang, Y.‐L. , Meng, R.‐S. , and Liu, X.‐W. (2023) Indirect comparison of SGLT2 inhibitors in patients with established heart failure: evidence based on Bayesian methods. ESC Heart Failure, 10: 1231–1241. 10.1002/ehf2.14297.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Search strategy in Pubmed.
Table S2. Risk of bias of individual studies by Cochrane risk assessment tool.
Table S3. Original data extracted from available trials included in this meta‐analysis.
Figure S1. Flow diagram of the trial selection process meta‐analysis.
Figure S2. Indirect comparison among SGLT2 inhibitors treatments by inconsistency model (A: the composite of cardiovascular dearth or hospitalization for heart failure; B: all‐cause mortality; C: cardiovascular dearth; D: hospitalization for heart failure).
Figure S3. Subgroup analysis in patients with HFrEF and HFmrEF/HFpEF by inconsistency model.
Figure S4. Funnel plot of cardiovascular death or hospitalization for heart failure.
Figure S5. Funnel plot of all‐cause mortality.
Figure S6. Funnel plot of cardiovascular death mortality.
Figure S7. Funnel plot of hospitalization for heart failure.