Sglt2 inhibitors in heart failure

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"SGLT2 inhibitors"[MeSH Terms] AND "heart failure"[MeSH Terms]

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SGLT2 Inhibitors in Heart Failure

Overview

SGLT2 inhibitors (gliflozins) were originally developed as glucose-lowering agents but their cardiovascular and renal benefits were discovered incidentally in large cardiometabolic outcomes trials. They are now established as one of the four pillars of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF).

The two agents used in heart failure are:

Dapagliflozin 10 mg once daily (first approved for HF in the US in 2020)
Empagliflozin 10 mg once daily

Mechanism of Action

The SGLT2 transporter is located in the renal proximal tubule, where it is responsible for reabsorbing ~90% of filtered glucose. Inhibition produces:

Glycosuria - increased urinary glucose excretion (lowers blood glucose in diabetics)
Natriuresis and osmotic diuresis - sodium and water loss, reducing preload
Haemodynamic effects - modest blood pressure reduction, reduced left ventricular filling pressures
Haematocrit increase - likely from volume contraction and erythropoietin stimulation
Slowed GFR decline - renoprotective effect (after an initial small, transient dip in eGFR)

The exact mechanism of benefit in HF is not fully established. SGLT2 is not expressed in the heart, so off-target effects have been proposed:

Inhibition of the sodium-hydrogen exchanger (NHE-1) in cardiomyocytes, reducing intracellular sodium and calcium overload
Inhibition of late sodium influx
Ketone body metabolism shift (providing a more energy-efficient fuel for the failing heart)
Reduction in inflammation and oxidative stress
Goldman-Cecil Medicine, p. 484; Goodman & Gilman's, p. 2316-2318

Heart Failure with Reduced Ejection Fraction (HFrEF / LVEF ≤40%)

Key Trials

Trial	Drug	Population	Key Result
DAPA-HF	Dapagliflozin	HFrEF, ±T2DM	Reduced CV death + worsening HF by 26%
EMPEROR-Reduced	Empagliflozin	HFrEF, ±T2DM	Reduced CV death + HF hospitalization by 25%

Both trials showed benefit regardless of diabetes status, establishing these drugs as HF treatments independent of glycaemic effects.

Clinical Benefits in HFrEF

Decreases left ventricular size and improves ejection fraction
Reduces symptoms and NYHA functional class
Reduces HF hospitalisations
Prolongs survival (reduces cardiovascular mortality)
Slows the rate of decline in eGFR over time
Mitigates MRA-induced hyperkalemia (additive benefit when combined with spironolactone/eplerenone)
Goldman-Cecil Medicine, p. 484

Heart Failure with Preserved Ejection Fraction (HFpEF / LVEF ≥50%)

The EMPEROR-Preserved trial demonstrated that empagliflozin significantly reduced the composite of first HF hospitalisation or cardiovascular death in HFpEF patients. The benefit was predominantly driven by reduction in HF hospitalisation, and the magnitude of benefit declined with increasing ejection fraction. Similarly, the DELIVER trial with dapagliflozin confirmed benefit in HFpEF. These results represent the first disease-modifying therapies shown to improve outcomes in HFpEF.

Braunwald's Heart Disease, p. 483

Position in GDMT - The "Fantastic Four"

SGLT2 inhibitors are now the fourth pillar of HFrEF treatment alongside:

ARNI (sacubitril/valsartan) or ACE inhibitor / ARB
Beta-blocker (bisoprolol, carvedilol, metoprolol succinate)
MRA (spironolactone or eplerenone)
SGLT2 inhibitor (dapagliflozin or empagliflozin)

They should be introduced as early as possible, and unlike other HF medications, require no up-titration - they are started and maintained at the same dose (10 mg once daily).

Goldman-Cecil Medicine, p. 484

Practical Use

Dosing

Drug	Starting Dose	Target Dose
Dapagliflozin	10 mg once daily	10 mg once daily
Empagliflozin	10 mg once daily	10 mg once daily

Contraindications

Type 1 diabetes mellitus
Previous diabetic ketoacidosis (DKA)
eGFR < 20 mL/min/1.73 m² (absolute)

Cautions / Seek Specialist Advice

eGFR 20-30 mL/min/1.73 m² (significant renal dysfunction)
Recurrent hypoglycaemia
Insulin use with tight glycaemic control (HbA1c <7%)
Suspected pancreatic insufficiency
History of genital fungal infections
Excessive alcohol or ketogenic diet (raises DKA risk)

Monitoring

Check kidney function at 4-8 weeks after starting (earlier if baseline eGFR <30)
An initial small decline in eGFR is expected and not usually a clinical problem
Meaningful blood pressure changes are rare

Adverse Effects

Adverse Effect	Notes
Genital mycotic (fungal) infections	5-10% of patients; more common in women and uncircumcised men; treat with antifungal cream
Volume depletion / hypotension	Especially if on diuretics; transient diuresis on initiation
Urinary tract infection	Modestly increased risk
Hypoglycaemia	Only in T2DM patients on insulin or sulfonylureas
Diabetic ketoacidosis (DKA)	Rare but serious; may be euglycaemic - blood glucose may not be markedly elevated; highest risk in insulin users
Urogenital infections	(Fournier's gangrene - extremely rare)
Bone fractures	Rare, reported with some agents

Important sick-day rules: SGLT2 inhibitors should be temporarily withheld during:

Acute illness with reduced food/fluid intake
Elective surgery (stop 3 days pre-operatively)
Any situation that might trigger DKA

If DKA is suspected: discontinue immediately.

Lippincott Illustrated Reviews Pharmacology, p. 370; Goldman-Cecil Medicine, p. 484

SGLT2 Inhibitors in Acute / Decompensated HF

A meta-analysis of RCTs (Carvalho et al., Clin Res Cardiol, 2023) confirmed cardiovascular and renal benefits of SGLT2 inhibitor initiation in the acute HF setting. The 2025 DAPA ACT HF-TIMI 68 trial and accompanying meta-analysis (Berg et al., Circulation, 2025, PMID 40884036) further evaluated in-hospital initiation of dapagliflozin in hospitalised HF patients.

Special Population: HF + T2DM

When adding an SGLT2 inhibitor to a patient with HF and concurrent T2DM who is already on diuretics, sulfonylureas, or insulin:

If euvolaemic with well-controlled diabetes: consider reducing or stopping the diuretic / sulfonylurea / insulin dose first
If hypervolaemic or with poor glycaemic control: no adjustment required before starting
Do not decrease insulin dose by more than 25%; consult endocrinology if significant insulin adjustments are needed
Lippincott Illustrated Reviews Pharmacology, p. 370

Summary Table

Feature	Detail
Mechanism	SGLT2 inhibition in renal proximal tubule; glycosuria, natriuresis, osmotic diuresis; possible NHE-1 inhibition
Agents	Dapagliflozin 10 mg OD; Empagliflozin 10 mg OD
HFrEF benefit	Reduces mortality, HF hospitalisation, LV remodelling; improves symptoms
HFpEF benefit	Reduces HF hospitalisation (EMPEROR-Preserved, DELIVER)
GDMT position	Fourth pillar alongside ARNI/ACE-i/ARB, beta-blocker, MRA
Contraindications	T1DM, prior DKA, eGFR <20
No uptitration needed	Start at target dose
Key adverse effect	Genital mycotic infection; rare euglycaemic DKA
Perioperative	Stop 3 days before elective surgery

Recent Evidence (2024-2026):

A landmark Lancet Diabetes & Endocrinology meta-analysis (Usman et al., 2024, PMID 38768620) confirmed SGLT2 inhibitor benefits on HF outcomes and CV death across the entire cardiometabolic disease spectrum.
A 2026 JAMA meta-analysis (Neuen et al., PMID 41203232) further characterised kidney outcome benefits by eGFR and albuminuria subgroups.

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