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Min et al. Metab Target Organ Damage 2023;3:6 https://dx.doi.org/10.20517/mtod.2023.09 Page 5 of 10

further research is needed to establish this. Of interest, Suzuki et al. demonstrated that there was no
significant difference in the risk of developing heart failure, angina, MI, stroke, and atrial fibrillation in
[23]
25,315 patients with T2DM who were taking SGLT-2 inhibitors . SGLT-2 inhibitors included in this study
were empagliflozin, dapagliflozin, canagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin. Of note, the
latter three are not approved by the FDA . An overview of SGLT-2 inhibitor CVOTs is shown in Table 2.
[23]
Heart failure benefits of SGLT-2 inhibitors
A consistent finding from all SGLT-2 inhibitor CVOTs was a reduction in HHF in people with T2DM.
Empagliflozin produced a 35% RRR in HHF, canagliflozin a 33% RRR, dapagliflozin a 27% RRR, and
ertugliflozin a 30% RRR respectively. Following these findings, dedicated heart failure outcome trials of
[24]
[25]
[26]
dapagliflozin (DAPA-HF and DELIVER ) and empagliflozin (EMPEROR-Reduced and EMPEROR-
Preserved ) have been performed in people with or without comorbid T2D. The heart failure trials of
[27]
SGLT-2 inhibitors are summarised in Table 3.
The DAPA-HF trial investigated dapagliflozin versus placebo, added to standard of care therapy in people
with reduced ejection fraction (rEF) on echocardiogram (41.8% had already an established diagnosis of
T2DM). The primary outcome of the trial was a composite of CV death or worsening heart failure
(hospitalization or an emergency room urgent visit resulting in intravenous diuretic therapy). Dapagliflozin
resulted in a 26% RRR in the composite heart failure outcome (HR 0.74; 95%CI: 0.65- 0.85; P < 0.001), an
18% RRR in CV mortality (HR 0.82; 95%CI: 0.69- 0.98) and a 17% RRR in all-cause mortality (HR 0.83;
95%CI: 0.71- 0.97). The impact of dapagliflozin on HF was consistent irrespective of the presence or absence
of T2DM . The EMPEROR-Reduced study of empagliflozin in people with rEF illustrated similar findings;
[24]
empagliflozin produced a 25% RRR in the composite heart failure outcome (HR 0.75; 95%CI: 0.65 - 0.86; P <
0.001) and a 30% RRR in HHF (HR 0.70; 95%CI: 0.58 - 0.85; P < 0.001). Results in those with T2DM had
similar HF benefits: a RRR of 31% in HHF for all trial subjects and 33% in the subgroup of people with
T2DM . Based on these data, dapagliflozin and empagliflozin gained approval for the management of
[26]
chronic heart failure with rEF, irrespective of diabetes mellitus.

Following this impressive evidence from heart failure rEF outcome trials, two trials (EMPEROR-Preserved;
Empagliflozin) and (DELIVER; Dapagliflozin) were performed in people with chronic heart failure and
preserved ejection fraction (pEF). In early 2022, the FDA extended the licensed indication of empagliflozin
[28]
for the treatment of heart failure with pEF based on findings from the EMPEROR-Preserved trial. Similar
to the EMPEROR-Reduced trial observations, empagliflozin produced a significant reduction in the
composite heart failure outcome (HR 0.79; 95%CI: 0.69 - 0.90; P < 0.001) in people with chronic heart failure
with pEF. This effect was largely due to the reduction in risk of HHF in the empagliflozin cohort (RRR of
27%; HR 0.73; 95%CI: 0.61 - 0.88; P < 0.001) . The recently published DELIVER trial confirmed the benefit
[27]
of SGLT2-inhibitors for the treatment of heart failure with pEF . It investigated dapagliflozin (10 mg) in
[25]
individuals with pEF (n = 6,263) and reported an 18% RRR in the composite heart failure outcome (HR 0.82;
95%CI: 0.73 - 0.92; P < 0.001); this effect was mainly related to a reduction in worsening of heart failure
rather than CV mortality.

Renal benefits of SGLT-2 inhibitors
There are consistent reports of reno-protection afforded by SGLT-2 inhibitors in the CVOTs [Table 2]. A
secondary analysis of all four SGLT-2 inhibitor CVOTs (empagliflozin, canagliflozin, dapagliflozin, and
ertugliflozin) demonstrated a RRR (> 35%) in renal function decline and a slowing of progression of
albuminuria. These findings were confirmed by dedicated renal outcome studies, CREDENCE, and DAPA-
CKD [Table 4].