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Page 4 of 10 Min et al. Metab Target Organ Damage 2023;3:6 https://dx.doi.org/10.20517/mtod.2023.09

Renal benefits of GLP-1RAs
Unlike SGLT-2 inhibitors, the kidney protective effect of GLP-1RAs has not been fully evaluated.
[15]
Exploratory analyses of renal outcomes from the CVOTs of GLP-1RAs suggest a reno-protective effect .
However, these studies were not designed to assess hard endpoints such as a decline in eGFR, end-stage
renal disease (ESRD) or kidney-related mortality. A meta-analysis reported that GLP-1RAs achieved a 17%
RRR in the broad kidney consisting of new occurrence of macroalbuminuria, doubling of serum creatinine
or decline in estimated glomerular filtration rate (eGFR) of 40% or more, renal replacement therapy (RRT)
and renal death (HR 0.83; 95%CI: 0.78 -0.89; P < 0.0001), this occurring over a median follow-up of 3.2
years . Supportive of this analysis, the recently published AMPLITUDE-O trial demonstrated a 32% RRR
[16]
in a composite renal outcome with efpeglenatide against placebo . The exploratory analysis of this trial
[13]
also illustrated the CV and renal safety of efpeglenatide, and this was independent of the concomitant
[17]
administration of SGLT-2 inhibitors .

Cardiovascular benefits of SGLT-2 inhibitors
To date, there have been four published CVOTs of SGLT-2 inhibitors: CANVAS and CANVAS-R
(canagliflozin) , DECLARE-TIMI 58 (dapagliflozin) , EMPA-REG OUTCOME (empagliflozin) and
[19]
[20]
[18]
VERTIS CV (ertugliflozin) , which all demonstrated CV safety. The EMPA-REG OUTCOME trial was the
[21]
first CVOT of an SGLT-2 inhibitor not only to illustrate CV safety but also to reduce CV outcomes (3P-
MACE) compared to placebo in people with T2DM and documented CVD. The impressive findings of a
14% RRR in the primary composite endpoint (HR 0.86; 95%CI: 0.74- 0.99; P = 0.04), a 38% RRR in CV death
(HR 0.62 ; 95%CI: 0.49- 0.77; P < 0.001) and a 32% RRR in all-cause mortality (a pre-specified secondary
outcome) were seen with empagliflozin . However, no significant benefits in non-fatal MI or non-fatal
[20]
stroke were noted . Two years later, the CANVAS program was presented in 2017, reporting a lower risk
[20]
of CV events in people receiving canagliflozin in a cohort with T2DM and established CVD or an elevated
[18]
risk of CVD (HR 0.86; 95%CI: 0.75- 0.97; P < 0.001 for non-inferiority; P = 0.02 for superiority) .
Canagliflozin, however, did not result in any significant differences for each component of the 3P-MACE
(CV death, non-fatal MI, non-fatal stroke) or for mortality from any cause. Of concern, an increased risk of
toe or metatarsal amputation and risk of bony fracture was observed with canagliflozin (HR 1.97; 95%CI:
1.41-2.75 and HR 0.80; 95%CI: 0.49-1.29, respectively).

In contrast, the DECLARE-TIMI 58 (dapagliflozin CVOT) did not demonstrate a superior CV benefit. In
the co-primary event analysis, dapagliflozin did not significantly reduce the 3P-MACE endpoint (HR 0.93;
95%CI: 0.84-1.03; P = 0.17), or CV death. However, dapagliflozin did result in a lower rate of CV death or
hospitalisation for heart failure (HHF) (HR 0.83; 95%CI: 0.73- 0.95; P = 0.005), a finding reflected by a lower
rate of hospitalisation for heart failure (HR 0.73; 95%CI:, 0.61 to 0.88), not by CV death (HR 0.98 ; 95%CI:
0.82- 1.17) . (The impact of the SGLT-2 inhibitor class on heart failure is discussed in the next section).
[19]
Similarly, the ertugliflozin CVOT in the VERTIS-CV trail did not show a benefit in 3P-MACE (HR 0.97;
95.6%CI: 0.85-1.11) nor in each component of the 3P-MACE . Of interest, VERTIS-CV included an
[21]
additional primary endpoint (CV death or HHF); however, ertugliflozin also failed to show superiority (HR
0.88; 95%CI: 0.75-1.03; P = 0.11) for this endpoint .
[22]

It is essential to be aware that the study designs and baseline CV status of trial populations differ between
the SGLT-2 inhibitor CVOTs. The proportions of trial participants with known CVD were 99%, 65%, 41%,
and 100% in EMPA-REG OUTCOME, CANVAS trial program, DECLARE-TIMI 58, and VERTIS CV,
respectively. It has been speculated that differences in CV outcomes between empagliflozin/ canagliflozin
and dapagliflozin were due to heterogeneity of trial design rather than drug-specific effects. With the recent
findings from VERTIS CV, which had comparable baseline CV status to EMPA-REG OUTCOME, it is
possible that the CV benefit of SGLT-2 inhibitors might not be applicable to all agents within the class, but