What medications, such as SGLT2 (sodium-glucose cotransporter 2) inhibitors, can reduce mortality in patients at risk of cardiogenic shock or with a history of heart failure with reduced ejection fraction?

Mortality-Reducing Medications in Cardiogenic Shock and Heart Failure

SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) are the most important mortality-reducing medications for patients at risk of cardiogenic shock or with established heart failure, demonstrating consistent reductions in cardiovascular death (12-18%), all-cause mortality (8%), and heart failure hospitalizations (27-39%) across all ejection fraction ranges. 1, 2, 3

Primary Recommendation: SGLT2 Inhibitors as Foundational Therapy

For patients with heart failure with reduced ejection fraction (HFrEF, LVEF ≤40%), initiate either dapagliflozin 10 mg daily or empagliflozin 10 mg daily immediately—these are Class I, Level A recommendations that reduce cardiovascular death by 18% and heart failure hospitalizations by 30%. 4, 1, 2

Evidence Hierarchy for HFrEF:

• Dapagliflozin: Reduced composite outcome of worsening heart failure or cardiovascular death by 26% (HR 0.74,95% CI 0.65-0.85) in the DAPA-HF trial with 4,744 patients, regardless of diabetes status 1, 2
• Empagliflozin: Reduced cardiovascular death or heart failure hospitalization by 25% (HR 0.75,95% CI 0.65-0.86) in EMPEROR-Reduced trial with 3,730 patients 1, 2
• Canagliflozin: Reduced heart failure hospitalization by 33% in CANVAS program 4

Critical Implementation Points:

Initiate SGLT2 inhibitors during hospitalization in stabilized patients (no increase in IV diuretics for 6 hours, no IV vasodilators or inotropes for 24 hours)—deferring initiation results in most eligible patients never receiving the medication within 1 year. 1, 2

Benefits appear within 12 days of initiation, with empagliflozin showing 58% relative risk reduction at just 12 days. 1, 2

No dose titration required, unlike ACE inhibitors or beta-blockers, and minimal effects on blood pressure, heart rate, or potassium levels. 1, 2

Expanded Indications Beyond HFrEF

Heart Failure with Preserved Ejection Fraction (HFpEF, LVEF >40%):

For HFpEF patients with NYHA class II-IV symptoms, use empagliflozin or dapagliflozin (Class 2a, Level B-R recommendation)—empagliflozin reduced cardiovascular death or heart failure hospitalization by 21% in EMPEROR-Preserved trial. 1, 2

Dapagliflozin reduced worsening heart failure or cardiovascular death by 18% in the DELIVER trial with 6,263 HFpEF patients. 1, 2

Acute Decompensated Heart Failure:

In patients hospitalized for acute heart failure, empagliflozin initiated after clinical stabilization (median 3 days from admission) improved clinical benefit with a win ratio of 1.36 (95% CI 1.09-1.68, P=0.0054) over 90 days in the EMPULSE trial. 5

This benefit occurred regardless of whether heart failure was acute de novo or decompensated chronic, and regardless of ejection fraction or diabetes status. 5

Renal Function Considerations

Do not withhold SGLT2 inhibitors for mild-to-moderate renal impairment—dapagliflozin can be used with eGFR as low as 25 mL/min/1.73m², and empagliflozin with eGFR ≥30 mL/min/1.73m². 1, 6

A transient eGFR decline after initiation is expected and provides long-term kidney protection—do not discontinue for this reason. 1, 2

In very high-risk CKD patients, SGLT2 inhibitors decrease all-cause mortality by 48 per 1000 patients (95% CI 84 fewer to 6 fewer) and kidney failure by 58 per 1000 (95% CI 72 fewer to 42 fewer). 4

Contraindications include eGFR <20 mL/min/1.73m² for dapagliflozin, eGFR <45 mL/min/1.73m² for initiation of empagliflozin, and patients on dialysis. 1, 6

Mortality Benefits Across All Risk Strata

Meta-Analysis of Five Major Trials (21,947 patients):

SGLT2 inhibitors reduced cardiovascular death by 13% (HR 0.87,95% CI 0.79-0.95), all-cause mortality by 8% (HR 0.92,95% CI 0.86-0.99), and first heart failure hospitalization by 28% (HR 0.72,95% CI 0.67-0.78). 3

These benefits were consistent across all ejection fraction ranges, care settings, and regardless of diabetes status. 3

Cardiovascular Mortality Reductions by Risk Strata:

• High-risk CKD patients: 6 fewer cardiovascular deaths per 1000 (95% CI 10 fewer to 1 fewer) 4
• Very high-risk CKD patients: 10 fewer cardiovascular deaths per 1000 (95% CI 17 fewer to 3 fewer) 4
• HFrEF patients: 18% reduction in cardiovascular death 1, 2

Safety Profile and Monitoring

Common adverse events include genital mycotic infections (1.5-1.7%), urinary tract infections (2.3-2.7%), and hypotension (5.7%), but serious adverse events are actually lower than placebo (32.3% vs 43.6% in EMPULSE trial). 1, 5

Monitor for euglycemic ketoacidosis in diabetic patients, volume depletion (especially with concurrent diuretics), and signs of urinary tract infections or urosepsis. 2, 6

Symptomatic hypotension occurred in only 0.3% of dapagliflozin patients versus 0.5% of placebo patients in DAPA-HF, despite concurrent use with ACE inhibitors/ARBs and mineralocorticoid receptor antagonists. 2

Critical Pitfalls to Avoid

Do not use ertugliflozin for heart failure—it lacks dedicated heart failure outcome trials and has no evidence for mortality or hospitalization reduction. 1

Do not discontinue existing guideline-directed medical therapy (ACE inhibitors, ARBs, beta-blockers, mineralocorticoid receptor antagonists)—SGLT2 inhibitors provide additive benefit on top of optimal therapy. 1, 2

Do not avoid SGLT2 inhibitors in patients with low blood pressure—they have minimal blood pressure effects and no excess symptomatic hypotension compared to placebo. 1, 2

Avoid thiazolidinediones (pioglitazone, rosiglitazone) and saxagliptin in heart failure patients—these increase heart failure risk (Class III recommendation). 4

Mechanism of Mortality Benefit

SGLT2 inhibitors work through multiple mechanisms beyond glucose lowering: enhanced natriuresis improving diuretic efficacy, tubuloglomerular feedback causing afferent arteriolar vasoconstriction preventing glomerular hyperfiltration, metabolic shift toward ketone utilization improving myocardial energetics, and reduction in cardiac fibrosis and adverse remodeling. 2

The cardiovascular benefits are independent of glucose-lowering effects, representing direct cardiovascular protection. 1, 2

Complementary Medications (Not Primary Focus but Important)

GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide) have neutral effects on heart failure hospitalization and may be considered for diabetes management in heart failure patients, but they do not reduce heart failure mortality. 4

Metformin should be considered in heart failure patients with stable eGFR >30 mL/min/1.73m² (Class IIa, Level C recommendation). 4