Of 205 articles evaluated for eligibility, 7 CVOTs (EMPA-REG OUTCOME (5), CANVAS Program (6), CREDENCE (7), DECLARE-TIMI 58 (8), VERTIS CV (9), DAPA-HF (10) and EMPEROR-Reduced (11) were eligible and included in the meta-analysis (Figure S1). EMPA-REG OUTCOME (5) and VERTIS CV (9) included only diabetic patients with established ASCVD, whereas CANVAS Program (6), DECLARE-TIMI 58 (8), and CREDENCE (7) included also patients with multiple CV risk factors without established ASCVD. DAPA-HF (10) and EMPEROR-Reduced (11) included only patients with HF and reduced ejection fraction with or without type 2 DM. CREDENCE trial (7) enrolled diabetic patients with chronic kidney disease, defined as an eGFR of 30 to < 90 ml/min/1,73 m2 BSA and albuminuria. Meta-analysis included 50964 patients. Mean age of patients was 63.5 ± 0.63 years, 27% were female; mean baseline HbA1c was 8.22 ± 1.03. The median study duration was 2.8 (IQR 0.79) years. Detailed characteristics of trials and patients included in the trials are reported, respectively, in Table 1 and Table 2 (Supplementary material).
Table 1
Characteristics of trials included in the meta-analysis.
|
EMPA-REG OUTCOME
|
CANVAS
|
DECLARE-
-TIMI 58
|
CREDENCE
|
DAPA-HF
|
VERTIS CV
|
EMPEROR Reduced
|
Publication year
|
2015
|
2017
|
2019
|
2019
|
2019
|
|
2020
|
Study design
|
Multicenter, randomized, double-blind, placebo-controlled trial to assess the effect of empagliflozin on CV events in adults with type 2 DM with established CV disease
|
Multicenter, randomized, double blind, placebo-controlled trial to assess the effect of canagliflozin on CV events in patients with type 2 DM, and established atherosclerotic CV disease or 50 years of age with at least two CV risk factors
|
Multicenter, randomized, double-blind, placebo-controlled trial to assess the effect of dapagliflozin on CV events in patients with type 2 DM and established atherosclerotic CV disease or multiple risk CV risk factors
|
Multicenter, randomized, double-blind, placebo-controlled trial to assess the effect of canagliflozin on renal and CV events in patients with type 2 DM and albuminuric chronic kidney disease
|
Multicenter, randomized, double-blind, placebo-controlled trial to assess efficacy and safety of dapagliflozin in patients with HF and a reduced ejection fraction, regardless of presence of DM
|
Multicenter, randomized, double-blind, placebo-controlled trial to assess the effect of ertugliflozin on CV events in patients with type 2 DM and established atherosclerotic CV disease
|
Multicenter, randomized, double-blind, placebo-controlled trial to assess efficacy and safety of empagliflozin in patients with HF and a reduced EF, regardless of presence of DM
|
Sample size
|
7020
|
10142
|
17160
|
4401
|
4744
|
8246
|
3730
|
Inclusion criteria
|
Type 2 DM; established CV disease. No glucose-lowering agents for at least 12 weeks before randomization and HbA1c of at least 7.0–9.0%, or stable glucose-lowering therapy for at least 12 weeks before randomization and HbA1c level of at least 7.0–10.0%
|
Type 2 DM; history or high risk of CV disease. HbA1c level ≥ 7.0% to ≤ 10.5% (1) not currently on antihyperglycemic agent or (2) on monotherapy or combination therapy with any approved class of agents
|
Type 2 DM; high risk for CV events defined as having either established CV disease and/or multiple risk factors. HbA1c level of at least 6.5% but less than 12.0%
|
Type 2 DM; HbA1c ≥ 6.5% to ≤ 12.0%; eGFR ≥ 30 to < 90 mL/min/1.73 m2 (as determined using the CKD-EPI equation); Urinary albumin:creatinine ratio > 300 mg/g to ≤ 5000 mg/g
|
HF with an EF ≤ 40% and New York Heart Association class II, III, or IV symptoms. A plasma level of NT-proBNP of at least 600 pg/ml
|
Type 2 DM; established CVdisease. HbA1c of at least 7.0–10.5%, stable on antihyperglycemic agents or no background therapy for ≥ 8 weeks prior study participation
|
HF with an EF ≤ 40% and New York Heart Association class II-IV; HF hospitalization within 12 mounths; a plasma level of NT-proBNP ≥ 600 pg/ml if EF ≤ 30%, ≥ 1000 pg/ml if EF 31–35%, ≥ 2500 pg/ml if EF > 35%
|
Follow up period (yrs)
|
3.1
|
2.6
|
4.2
|
2.62
|
1.52
|
3.5
|
1.4
|
Primary outcomes
|
MACE-3 (CV death, non-fatal myocardial infarction [excluding silent myocardial infarction], non-fatal stroke)
|
MACE-3 (CV death, non-fatal myocardial infarction, non-fatal stroke)
|
MACE-3 (CV death, non-fatal myocardial infarction, non-fatal stroke); composite of CV death or hospitalization for HF
|
Composite outcome of end-stage kidney disease, doubling of the serum creatinine level, renal death or CV death
|
Composite of worsening HF or CV death
|
MACE-3 (CV death, non-fatal myocardial infarction, non-fatal stroke)
|
Composite of HF hospitalization (first event) and CV death
|
Secondary outcomes
|
MACE-4 (CV death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina)
|
Death from any cause; CV death; progression of albuminuria; composite of CV death or HF hospitalization
|
Renal composite outcome, defined as a sustained decrease of 40% or more in eGFR, new end-stage renal disease, or death from renal or CV causes; death from any cause
|
Composite of CV death or HF hospitalization; CV death, myocardial infarction or stroke; HF hospitalization; end stage kidney disease, renal death or CV death; dialysis, kidney transplantation or renal death
|
Composite of CV death or HF hospitalization; total number of HF hospitalizations and CV deaths; the change from baseline to 8 months in the total symptom score KCCQ; a composite of worsening renal function, end-stage renal disease, or renal death; any-cause death
|
Composite of CV death or HF hospitalization; CV death; renal composite (renal death, doubling of serum creatinine, dialysis/transplant)
|
All adjudicated hospitalization for HF (first and recurrent events). Rate of the decline in the estimated eGFR during double-blind treatment
|
Trial registry reference
|
NCT01131676
|
NCT01989754
|
NCT01730534
|
NCT02065791
|
NCT03036124
|
NCT01986881
|
NCT03057977
|
CV: cardiovascular; DM diabetes mellitus; HbA1c: glicated haemoglobin; HF heart failure; EF: ejection fraction;eGFR: estimated glomerular filtration rate; NT-proBNP N-terminal pro-brain natriuretic peptide; MACE: major cardiovascular events, KCCQ: Kansas City Cardiomyopathy Questionnaire. |
Table 2
Baseline characteristics of patients of included trials.
|
EMPA-REG
OUTCOME
(n = 7020)
|
CANVAS
(n = 10142)
|
DECLARE-TIMI-58
(n = 17160)
|
CREDENCE
(n = 4401)
|
DAPA-HF*
(n = 2139) *
|
VERTIS CV
(n = 8246)
|
EMPEROR Reduced (n = 1856)**
|
Age (yrs), mean (SD)
|
63.1 (8.7)
|
63.3 (8.3)
|
63.9 (6.8)
|
63 (9.2)
|
66.5 (9.8)
|
64.4 (8.05)
|
NA
|
Sex (female), n (%)
|
2005 (28.5)
|
3631 (35.8)
|
6332 (36.9)
|
1492 (33.9)
|
477 (22)
|
2477 (30)
|
NA
|
BMI (kg/m2)
|
30.6 (5.3)
|
32 (5.9)
|
32.1 (6.0)
|
31.3 (6.2)
|
29.3 (6.0)
|
32 (5.5)
|
NA
|
Diabetes, n (%)
|
7020 (100)
|
10142 (100)
|
17160 (100)
|
4401 (100)
|
2139 (100)
|
8246 (100)
|
1856 (100)
|
Hypertension, n (%)
|
6667 (95)
|
9125 (90)
|
NA
|
4260 (96.8)
|
NA
|
NA
|
NA
|
Dyslipidemia, n(%)
|
5684 (81)
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
Smoke, n (%)
|
NA
|
1806 (17.8)
|
NA
|
639 (14.5)
|
NA
|
NA
|
NA
|
HbA1c, mean (SD)
|
8.075 (0.8)
|
8.2 (0.9)
|
8.3 (1.2)
|
8.3 (1.3)
|
7.4 (1.5)
|
8.2 (0.95)
|
NA
|
eGFR (ml/min/1.73mq), mean (SD)
|
NA
|
76.5 (20.5)
|
85.2 (15.9)
|
56.2 (18.2)
|
63.3 (19.3)
|
75.9 (20,85)
|
NA
|
Established ASCVD, n (%)
|
6964 (99.2)
|
7324 (72.1)
|
6974 (40.6)
|
2220 (50.4)
|
1326 (62)#
|
8246 (100)
|
NA
|
CV risk factors only, n (%)
|
56 (0.8)
|
2818 (27.7)
|
10186 (59.6)
|
2181 (49.6)
|
813 (38)#
|
0
|
NA
|
Previous CCS, n (%)
|
5308 (75.6)
|
5721 (56.4)
|
5658 (32.9)
|
NA
|
NA
|
6279 (76.1)
|
NA
|
Previous MI, n (%)
|
3273 (46.6)
|
NA
|
NA
|
NA
|
NA
|
3962 (48)
|
NA
|
Previous HF, n(%)
|
706 (10.05)
|
1461 (14.4)
|
1724 (10.0)
|
652 (14.8)
|
2139 (100)
|
1979 (24)
|
NA
|
Previous cerebrovascular disease, n (%)
|
1637 (23.3)
|
1958 (19.3)
|
1301 (7)
|
NA
|
NA
|
1875 (22.7)
|
NA
|
Previous peripheral arterial disease, n (%)
|
1461 (20.8)
|
2113 (20.8)
|
1025 (6)
|
NA
|
NA
|
1537 (18.6)
|
NA
|
Insuline use, n (%)
|
3387 (48.2)
|
5095 (50.2)
|
7013 (40.8)
|
NA
|
540 (25.2)
|
3933 (47.7)
|
NA
|
Metformin use, n (%)
|
5193 (73.9)
|
7825 (77.2)
|
14068 (81.9)
|
NA
|
1016 (47.6)
|
6312 (76.5)
|
NA
|
Sulfonylurea use, n (%)
|
3006 (42.8)
|
4361 (43)
|
7322 (42.6)
|
NA
|
440 (20.5)
|
3380 (41)
|
NA
|
TZD use, n (%)
|
299 (4.3)
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
DPP-4 inhibitor use, n (%)
|
796 (11.3)
|
1261(12.4)
|
2888 (16.8)
|
NA
|
310 (14.4)
|
902 (10.9)
|
NA
|
GLP-1 RA use, n (%)
|
196 (2.7)
|
407 (4)
|
750 (4.3)
|
NA
|
21 (0.9)
|
263 (3.2)
|
NA
|
Median duration of follow up (yrs)
|
3.1
|
2.6
|
4.2
|
2.62
|
1.52
|
3.5
|
1.4
|
Participants with a primary outcome
|
772
|
1011
|
1559
|
585
|
486
|
980
|
465
|
Primary outcome
(HR and 95% CI)
|
0.86 (0.74–0.99)
|
0.86 (0.75–0.97)
|
0.93 (0.84–1.03)
|
0.70 (0.59–0.82)
|
0.75 (0.63–0.90)
|
0.97 (0.85–1.11)
|
0.72 (0.60–0.87)
|
NA: not available; BMI: body mass index; HbA1c: glycated haemoglobin; eGFR: estimated glomerular filtration rate; ASCVD atherosclerotic cardiovascular disease; CV: cardiovascular; CCS chronic coronary syndrome; MI myocardial infarction; HF heart failure, TZD: Thiazolidinedione; DPP-4: dipeptidyl peptidase 4; GLP-1 RA: glucagon-like peptide-1 receptor agonist; HR: hazard ratio; CI: confidence interval. |
* Data of diabetic patients enrolled in DAPA-HF. |
** Data of diabetic patients enrolled in EMPEROR-Reduced. |
#These numbers refer to HF of ischemic or non-ischemic/unknown etiology. |
Effects of SGLT2i on CV events in the whole population.
Five CVOTs (5) (6) (7) (8) (9) reported the effects on 3-point MACE. SGLT2i significantly reduced by 10% the risk of 3-point MACE compared to placebo (HR 0.90, 95% Confidence Interval (CI) 0.82–0.98; p = 0.025), with low heterogeneity among trials (I2 = 2%) (Fig. 1A).
The analysis of the effects on the composite of CV death or HF hospitalization, reported in all CVOTs (5) (6) (7) (8) (9) (10) (11), demonstrated a significant 24% risk reduction with SGLT2i (HR 0.76, 95% CI 0.70–0.84; p < 0.001), with a moderate degree of heterogeneity among trials (I2 = 31%) (Fig. 1B).
Among the single components of the 3-point MACE, the risk of non-fatal MI (Fig. 2A) (HR 0.91, 95%CI 0.81–1.03; p = 0.094) and non-fatal stroke (Fig. 2B) (HR 1.01, 95%CI 0.86–1.18; p = 0.899), reported in four CVOTs (5) (6) (8) (9), were not significantly affected by SGLT2i, with no heterogeneity among trials for both outcomes. HF hospitalizations, reported in 6 CVOTs (5) (6) (7) (8) (9) (10), were significantly reduced by 30% by SGLT2i (HR 0.70, 95%CI 0.64–0.76; p < 0.001), with no heterogeneity among trials (I2 = 0%) (Fig. 2C). The risk of CV death (Fig. 2D), reported in 6 CVOTs (5) (6) (7) (8) (9) (10), was significantly reduced by SGLT2i (HR 0.83, 95%CI 0.70–0.98; p = 0.035) but with a high degree of heterogeneity among trials (I2 = 55%). Finally, the risk of all-cause mortality, reported in five CVOTs (5) (6) (7) (8) (10), was significantly reduced by SGLT2i (HR 0.82, 95%CI 0.71–0.96; p = 0.024), although with a high degree of heterogeneity among trials (I2 = 54%) (Fig. 2E).
Effect of SGLT2 inhibitors on efficacy outcomes in selected subgroups.
Effect of SGLT2i on CV outcomes in patients with and without ASCVD.
This analysis was restricted to 5 CVOTs (5) (6) (7) (8) (9), two of them enrolling only patients with established ASCVD (EMPA-REG OUTCOME (5) and VERTIS CV (9)) and three (6) (7) (8) enrolling patients with established ASCVD or with multiple CV risk factors only. In these latter trials, the percentage of patients with ASCVD varied from 40–72%.
The effect of SGLT2i on the 3-point MACE composite outcome was evident in patients with ASCVD (HR 0.88, 95%CI 0.81–0.96; p = 0.016) without a significant reduction of risk in subjects with multiple CV risk factors only (HR 0.91, 95% CI 0.54–1.51; p = 0.489); however, no significant interaction was found between the two groups (p for interaction = 0.84) (Fig. 3A).
Differently, both in patients with ASCVD and in patients with multiple CV risk factors, SGLT2i showed a favourable effect on the composite of CV death or HF hospitalizations (HR 0.77, 95% CI 0.65–0.90, p = 0.009 vs. HR 0.81, 95% CI 0.69–0.96, p = 0.032, respectively; p for interaction = 0.42) (Fig. 3B). Substantial reduction of HF hospitalizations was consistently observed both in patients with ASCVD and in patients with multiple CV risk factors (HR 0.70, 95% CI 0.62–0.78, p = 0.001 and HR 0.63, 95% CI 0.59–0.67, p = 0.001) with a greater effect in patients with multiple CV risk factors (p for interaction = 0.03) (Fig. 3C). No differences were documented for other secondary endpoints (Figure S2).
Effect of SGLT2i on CV outcomes in patients with and without HF.
Of seven CVOTs included in the meta-analysis (5) (6) (7) (8) (9) (10) (11), two enrolled only patients with HF at baseline (10) (11) (19), whereas in other trials the percentage of HF patients varied from 10–24%. Independently from HF presence at enrollment, no effects of SGLTi were found on 3-point MACE (HR 0.95, 95%CI 0.78–1.16, p = 0.504 in patients with HF at baseline vs. HR 0.89, 95%CI 0.78–1.01, p = 0.060 in non-HF patients; p for interaction = 0.33) (Fig. 4A).
In contrast, the effect of SGLTi on CV death or HF hospitalization was significant in patients with HF at baseline (HR 0.75, 95%CI 0.66–0.86, p = 0.004), whereas in non-HF patients the risk reduction almost reached statistical significance (HR 0.81, 95%CI 0.63–1.04; p = 0.077), with no significant interaction among the two groups (p for interaction = 0.42) (Fig. 4B).
A remarkable significant reduction of HF hospitalizations was observed in both groups (HR 0.71, 95%CI 0.57–0.90, p = 0.019 in patients with HF at baseline vs. HR 0.70, 95%CI 0.50–0.98, p = 0.046 in non-HF patients; p per interaction = 0.42) (Fig. 4C). CV death trended to be reduced in both groups, although the effect did not reach statistical significance (HR 0.81, 95%CI 0.64–1.02, p = 0.065 in patients with HF at baseline vs. HR 0.82, 95%CI 0.42–1.61, p = 0.340 in non-HF patients; p for interaction = 0.93) (Figure S3A).
The effect of SGLT2i on all-cause mortality was significant in patients with HF at baseline (HR 0.79, 95%CI 0.69–0.91; p = 0.012) without a significant reduction of risk in non-HF patients (HR 0.86, 95% CI 0.54–1.36; p = 0.284); no significant interaction was found among the two groups (p for interaction = 0.50) (Figure S3B).
Effect of SGLT2i on CV in patients with eGFR < 60 ml/min/1,73 m 2 BSA and ≥60 ml/min/1,73 m2 BSA.
The effect of SGLTi on the 3-point MACE composite outcome, reported in four CVOTs (6) (7) (8) (9) was significant for patients with eGFR ≥ 60ml/min/1,73 m2 (HR 0.93, 95%CI 0.90–0.96; p = 0.006) without a significant reduction of risk in patients with eGFR < 60ml/min/1,73 m2 (HR 0.86, 95%CI 0.63–1.17; p = 0.211); however, no significant interaction was found among the two groups (p for interaction = 0.42) (Fig. 5A). No effects of SGLTi were found on the on the composite of CV death or HF hospitalization, reported in three CVOTs (7) (8) (9) in both patients with eGFR ≥60 ml/min/1,73 m2 or eGFR < 60 ml/min/1,73 m2 (HR 0.85, 95%CI 0.66–1.10, p = 0.110 vs. HR 0.77, 95%CI 0.45–1.33, p = 0.177, respectively; p for interaction = 0.49) (Fig. 5B).
Safety analysis (Figure S4).
Safety analysis showed no significant effect of SGLT2i on amputation (RR 1.1, 95%CI 0.99–1.22), bone fractures (RR 1.26, 95%CI 0.59–2.70), pancreatitis (RR 0.88, 95%CI 0.34–2.29), severe hypoglycemia (RR 0.97, 95%CI 0.45–2.11), urinary tract infections (RR 1.16, 95%CI 0.79–1.71), and volume depletion (RR 1.05, 95%CI 0.98–1.12). In contrast, SGLT2i had a significant effect on genital tract infections (RR 4.35, 95%CI 2.46–7.71) with a high degree of heterogeneity among trials (I2 = 54%) and on diabetic ketoacidosis (RR 2.25, 95%CI 1.21–4.19).