Search results and eligible studies
The preferred reporting items for systematic reviews and meta-analyses are presented in the (PRISMA) flowchart in Figure 1. The initial search strategy yielded 2,152 studies. After removing duplicates, the title and abstract of the 1,503 identified studies were screened. We excluded 1,264 articles which were not RCTs or did not match the search strategy. Subsequently, 34 articles were excluded due to the unavailability of full-text and published data, or withdrawal from ClinicalTrials.gov. Then, we retrieved 205 studies, of which 195 were excluded after the full-texts assessed. (Figure 1) Finally, 10 RCTs with qualitative synthesis of complete data were included for the current meta‐analyses.6-11,25-28
Characteristics of the studies and populations included
The 10 included RCTs evaluated the effects of five SGLT2 inhibitors, canagliflozin (the CANVAS PROGRAM trial),6 dapagliflozin (the DEFINE-HF trial, the DECLARE-TIMI 58 trial, and the DAPA-HF trial),8,9,25 empagliflozin (the EMPA-RESPONSE-AHF trial, the EMPA-REG OUTCOME trial, and the EMPEROR-Reduced trial),7,10,26 sotagliflozin (the SOLOIST-WHF trial and SCORED trial),11,28 and ertugliflozin (the VERTIS-CV trial).27
A total of 52,607 patients were included in the meta-analysis. The mean age of the patients with EMPA-RESPONSE-AHF was the highest (79 years old in the empagliflozin group; 73 years old in the placebo group), while the DEFINE-HF patients were the youngest (on average 62 years old in the dapagliflozin group; 60 years old in the placebo group). The DECLARE-TIMI 58 trial had the longest follow-up period at 4.2 years,8 and the EMPA-RESPONSE-AHF had the shortest follow-up period at only 12 weeks.26 (Table 1 and Supplementary Table 1).
The CANVAS PROGRAM, DECLARE-TIMI 58, SCORED, VERTIS-CV, and EMPA-REG OUTCOME trials included patients irrespective of the presence or absence of HF, while the DEFINE-HF, EMPA-RESPONSE-AHF, EMPEROR-Reduced, SOLOIST-WHF, and DAPA-HF trials only focused on patients with HF. In the meta-analysis, data from the above eight studies were pooled to compare the total number of cardiovascular deaths or hospitalizations for HF of SGLT2 inhibitors versus placebo in patients with and without HF.
Risk of bias assessment
Supplementary Figure 1 and Figure 2 show the results of quality assessment.
In addition to the DECLARE-TIMI 58 and DEFINE-HF trial, eight of the included studies had a low risk of bias with adequate randomization, sequence descriptions, and allocation concealment. Blinding for the participants was carried out in all studies but six studies did not explicitly describe the blinding for assessors. All studies had low rates of lost to follow-up, and they all used intention-to-treat analysis and had available protocols.
Meta-analyses of primary outcomes
Figure 2 shows the primary endpoint, i.e., the composite of cardiovascular deaths and hospitalizations for HF. The risk of a primary endpoint event was 7.23% (2,510/34,699) in the SGLT2 inhibitors group and 9.35% (2,633/28,149) in the placebo group, respectively. SGLT2 inhibitors significantly reduced the risk of total cardiovascular death or hospitalization for HF by 21% (RR 0.79, [95% CI: 0.74 to 0.84]; p < 0.001, I2 = 31%). In addition, the individual risk reduction for patients with HF was 24% (RR 0.76, [95% CI: 0.72 to 0.81]; p < 0.001, I2 = 0%), and that for patients with non-HF was 17% (RR 0.83, [95% CI: 0.72 to 0.95]; p = 0.006, I2 = 49%).
Meta-analyses of secondary outcomes
Figure 3 and 4 show the results of the secondary endpoints, MACE, all-cause death, cardiovascular death, hospitalization for HF, myocardial infarction and stroke from the eligible trials.
In the SGLT2 inhibitors group, 9.77% of the patients (1,952/19,960) had MACE and 10.21% (1,601/15,670) in the placebo group. SGLT2 inhibitors reduced the risk of MACE by 7% (RR 0.93, [95% CI: 0.88 to 0.99]; p = 0.03, I2 = 0%). However, SGLT2 inhibitors did not significantly reduce the risk of MACE in patients with HF (RR 0.98, [95% CI: 0.85 to 1.14]; p = 0.81, I2 = 24%), while it resulted in a significant reduction for patients without HF (RR 0.92, [95% CI: 0.85 to 0.99]; p = 0.02, I2 = 0%). (Figure 3A)
The all-cause mortality risk for patients using SGLT2 inhibitors was 7.05% (1,200/17,019) and 7.80% (1,216/15,578) for the placebo group. SGLT2 inhibitors significantly reduced the overall mortality by 8% (RR 0.92, [95% CI: 0.85 to 0.99]; p = 0.03, I2 = 0%). In HF patients, SGLT2 inhibitors caused a significant risk reduction for all-cause mortality (RR 0.89, [95% CI: 0.80 to 0.99]; p = 0.04, I2 = 0%), while the effect was absent for non-HF patients (RR 0.94, [95% CI: 0.85 to 1.05]; p = 0.26, I2 = 0%). (Figure 3B)
The number of cardiovascular deaths was 953, comprised of 4.92% (953/19,352) in the SGLT2 inhibitors group, and 5.51% (985/17,889) in the placebo group. In comparison, SGLT2 inhibitors significantly decreased the risk of cardiovascular death (RR 0.91, [95% CI: 0.83 to 0.99]; p = 0.03, I2 = 0%). The risk of cardiovascular death in HF patients was significantly reduced by SGLT2 inhibitors (RR 0.88, [95% CI: 0.79 to 0.97]; p = 0.01, I2 = 0%), but the reduction was insignificant in non-HF patients (RR 0.98, [95% CI: 0.84 to 1.14]; p = 0.77, I2 = 0%). (Figure 4A)
The risk of hospitalization for HF was 4.36% (819/18,784) for patients using SGLT2 inhibitors and 6.34% (1,099/17,334) for those not using SGLT2 inhibitors. SGLT2 inhibitors significantly reduced the risk of hospitalization for HF (RR 0.72, [95% CI: 0.66 to 0.79]; p < 0.001, I2 = 0%). The risk reduction due to SGLT2 inhibitors was significant in both HF (RR 0.72, [95% CI: 0.64 to 0.80]; p < 0.001, I2 = 8%) and non-HF patients (RR 0.74, [95% CI: 0.61 to 0.89]; p = 0.001, I2 = 0%). (Figure 4B)
The risk of myocardial infarction in patients using SGLT2 inhibitors was 4.30% (624/14,508), and 4.89% in the placebo group (639/13,057). The risk of myocardial infarction was significantly reduced by 11% (RR 0.89, [95% CI: 0.80 to 0.99]; p = 0.03, I2 = 0%). For patients with HF, SGLT2 inhibitors did not contribute to a significant risk reduction in myocardial infarction (RR 0.95, [95% CI: 0.65 to 1.39]; p = 0.79, I2 = 30%), but there was a significant reduction for patients without HF (RR 0.88, [95% CI: 0.78 to 0.99]; p = 0.03, I2 = 0%). (Figure 4C)
The risk of stroke was 2.76% (401/14,508) for the SGLT2 inhibitors group and 2.93% (382/13,057) for placebo group. SGLT2 inhibitors did not significantly lower the risk of stroke (RR 0.94, [95% CI: 0.82 to 1.08]; p = 0.37, I2 = 0%). Likewise, SGLT2 inhibitors did not cause a significant risk reduction in stroke irrespective of the presence or absence of HF. (for HF patients, RR 0.95, [95% CI: 0.67 to 1.36]; p = 0.80, I2 = 12%; for non-HF patients, RR 0.93, [95% CI: 0.80 to 1.09]; p = 0.39, I2 = 0% ). (Figure 4D)
Subgroup analysis
In the subgroup analysis, dapagliflozin, empagliflozin, canagliflozin and sotagliflozin significantly reduced the risk of cardiovascular death or hospitalization for HF in patients with HF. In patients without HF, only dapagliflozin and empagliflozin resulted in a significant risk reduction. (Table 2)
In terms of cardiovascular death, no individual SGLT2 inhibitor showed a significant risk reduction for both HF and non-HF patients. Regarding hospitalization for HF, dapagliflozin, empagliflozin and canagliflozin showed a significant risk reduction for patients with HF, while only dapagliflozin and canagliflozin showed evidence to support the risk reduction for patients without HF.
Both high and low SGLT2/SGLT1 selectivity inhibitors significantly reduced the risk of cardiovascular death or hospitalization for HF in HF patients (RR 0.79, [95% CI: 0.74 to 0.85]; p < 0.05, I2 = 0 % for high SGLT2/SGLT1 selectivity; RR 0.69, [95% CI: 0.62 to 0.77]; p < 0.05, I2 = 0 % for low SGLT2/SGLT1 selectivity); particularly, they resulted in a significant risk reduction in hospitalization for HF. (Table 2) Notably, for non-HF patients, only high SGLT2/SGLT1 selectivity inhibitors contributed to a significantly reduced risk of hospitalization for HF ( RR 0.81 [0.66-0.99], p < 0.05, I2 = 71%). (Table 2)