GROUNDBREAKERS: SGLT2 INHIBITORS

What are SGLT2 inhibitors?

SGLT2 (sodium-glucose cotransporter-2) inhibitors block SGLT2 found on the epithelial cells of the proximal convoluted
tubule of the kidneys to prevent reabsorption of glucose from glomerular filtration.

Why the hype about SGLT2 inhibitors?

SGLT2 inhibitors were initially intended as oral hypoglycemic agents for patients with diabetes mellitus. However, recent
trial results have shown cardiovascular and renal benefits beyond the effects of glycemic improvement, suggesting a
therapeutic role in patients with heart failure and chronic kidney disease, even in the absence of diabetes mellitus. SGLT2
inhibitors also appears to promote weight loss.

Evidence?
CANVAS DECLARE-TIMI58 EMPA-REG (n=7,020) DAPA-HF CREDENCE
(n=10,142) (n=17,160) (n=4,744) (n=4,401)

Publication NEJM, 2017 NEJM, 2019 NEJM, 2015 NEJM, 2019 NEJM, 2019

Intervent Canagliflozin Dapagliflozin Empagliflozin Dapagliflozin Canagliflozin

Population CVD ≥ 30 or >2 CVRF CVD or risk factors for Pre-existing CVD HFrEF EF ≤ 40% eGFR 30-90 or uACR
≥ 50 ASCVD >30 + on ACE

% CVD 65.6% 40.6% 99% 100% 50.4%

% DM 100% 100% 100% 42% 100%

Mean eGFR 76.5 85.3 74.1 66 56.2

Pri outcome MACE: 0.86 (0.76- MACE: 0.93 (0.84-1.03) MACE: 0.86 (0.74- HF, CV mortality Composite kidney
0.97) 0.99) 0.74 (0.65-0.85) and CV 0.70 (0.59-
0.82)

Renal Progression of ≥40% decrease in Doubling of Cr, RRT, Worsening renal ESRD, doubling of Cr,
outcome albuminuria 0.73 eGFR, ESKF or related or related death 0.54 function 0.71 relative death 0.66
(0.67-0.79) death 0.53 (0.43-0.66) (0.40-0.75) (0.44-1.16) (0.53-0.81)
40% reduction eGFR,
RRT, renal death 0.60
(0.47-0.77)

Adverse Increase in LL Risk of DKA, genital Risk of genital No change in Risk of DKA, genital
effects amputation, genital infections infections amputation or infections
infections DKA risk

When to use?
• Diabetes Mellitus: Usually as a second agent for patients on metformin not reaching glycemic targets with
o Overt artherosclerotic CVD
o Heart failure
o Nephropathy
• Evidence for use in cardiovascular or renal disease in the absence of DM is emerging however this has yet to be
formalized into practice guidelines

Caution?
• Contraindications: eGFR < 45, prior DKA
• Caution in: Concomitant diuretic use
• Adverse effects: Euglycemic DKA, genitourinary infections,

Spaces to watch?
There are 2 ongoing SGLT2 inhibitor trials looking at renal benefits as a primary outcome (DAPA CKD and EMPA Kidney).
SGLT2 inhibitors might also benefit patients with non-alcoholic fatty liver disease.