J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website https://www.jocmr.org

Review

Volume 16, Number 10, October 2024, pages 449-464

Comprehensive Benefits of Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure With Reduced Ejection Fraction: A Literature Review

**Table 1.** Summary of Pivotal Clinical Trials of SGLT2 Inhibitors in HFrEF
Study name	Population characteristics	Intervention details	Primary outcomes
SGLT2: sodium-glucose cotransporter 2; HFrEF: heart failure with reduced ejection fraction; RRR: relative risk reduction; CV: cardiovascular; HR: hazard ratio; CI: confidence interval.
DAPA-HF	4,744 patients with HFrEF; mean age: 66 years; 23% female	Dapagliflozin 10 mg daily; median follow-up: 18.2 months	26% RRR in CV death or worsening HF (HR: 0.74, 95% CI: 0.65 - 0.85); 16% RRR in all-cause mortality (HR: 0.84, 95% CI: 0.72 - 0.99)
EMPEROR-Reduced	3,730 patients with HFrEF; mean age: 67 years; 24% female	Empagliflozin 10 mg daily; median follow-up: 16 months	25% RRR in CV death or HF hospitalization (HR: 0.75, 95% CI: 0.65 - 0.86); 13% RRR in all-cause mortality (HR: 0.87, 95% CI: 0.77 - 0.98)

Table 1. Summary of Pivotal Clinical Trials of SGLT2 Inhibitors in HFrEF

Study name

Population characteristics

Intervention details

Primary outcomes

SGLT2: sodium-glucose cotransporter 2; HFrEF: heart failure with reduced ejection fraction; RRR: relative risk reduction; CV: cardiovascular; HR: hazard ratio; CI: confidence interval.

DAPA-HF

4,744 patients with HFrEF; mean age: 66 years; 23% female

Dapagliflozin 10 mg daily; median follow-up: 18.2 months

26% RRR in CV death or worsening HF (HR: 0.74, 95% CI: 0.65 - 0.85); 16% RRR in all-cause mortality (HR: 0.84, 95% CI: 0.72 - 0.99)

EMPEROR-Reduced

3,730 patients with HFrEF; mean age: 67 years; 24% female

Empagliflozin 10 mg daily; median follow-up: 16 months

25% RRR in CV death or HF hospitalization (HR: 0.75, 95% CI: 0.65 - 0.86); 13% RRR in all-cause mortality (HR: 0.87, 95% CI: 0.77 - 0.98)

**Table 2.** Key Impacts of SGLT2 Inhibitors in HFrEF
Aspect	Details	Impact of SGLT2 inhibitors
SGLT2: sodium-glucose cotransporter 2; HFrEF: heart failure with reduced ejection fraction; HF: heart failure; CV: cardiovascular.
Demographic influence	Age, sex, ethnicity	14% reduction in cardiovascular death; significant benefits in Whites and Asians
Geographic/environmental factors	Healthcare access, socioeconomic status, pollution	25% reduction in HF hospitalizations across diverse regions
Genetic factors	MYH7, MYBPC3, SCN5A, TTN mutations	Effective despite genetic predispositions
Comorbidities/lifestyle	Diabetes, hypertension, obesity, unhealthy habits	13% reduction in all-cause mortality; improved weight and blood pressure
Clinical outcomes	Cardiovascular death, all-cause mortality, HF hospitalizations	14% CV death, 13% all-cause mortality, 25% HF hospitalizations reduction

Table 2. Key Impacts of SGLT2 Inhibitors in HFrEF

Aspect

Details

Impact of SGLT2 inhibitors

SGLT2: sodium-glucose cotransporter 2; HFrEF: heart failure with reduced ejection fraction; HF: heart failure; CV: cardiovascular.

Demographic influence

Age, sex, ethnicity

14% reduction in cardiovascular death; significant benefits in Whites and Asians

Geographic/environmental factors

Healthcare access, socioeconomic status, pollution

25% reduction in HF hospitalizations across diverse regions

Genetic factors

MYH7, MYBPC3, SCN5A, TTN mutations

Effective despite genetic predispositions

Comorbidities/lifestyle

Diabetes, hypertension, obesity, unhealthy habits

13% reduction in all-cause mortality; improved weight and blood pressure

Clinical outcomes

Cardiovascular death, all-cause mortality, HF hospitalizations

14% CV death, 13% all-cause mortality, 25% HF hospitalizations reduction

**Table 3.** Mechanisms of Action of SGLT2 Inhibitors in HFrEF
Mechanism	Effect
SGLT2: sodium-glucose cotransporter 2; HFrEF: heart failure with reduced ejection fraction; RAAS: renin-angiotensin-aldosterone system; SNS: sympathetic nervous system.
Diuretic and natriuretic	Reduced plasma volume, decreased preload and afterload
Improved myocardial energetics	Enhanced ketone body utilization, reduced oxidative stress
Reduced RAAS activation	Decreased fibrosis and hypertrophy
Reduced SNS activation	Lower incidence of arrhythmias, improved myocardial function

Table 3. Mechanisms of Action of SGLT2 Inhibitors in HFrEF

Mechanism

Effect

SGLT2: sodium-glucose cotransporter 2; HFrEF: heart failure with reduced ejection fraction; RAAS: renin-angiotensin-aldosterone system; SNS: sympathetic nervous system.

Diuretic and natriuretic

Reduced plasma volume, decreased preload and afterload

Improved myocardial energetics

Enhanced ketone body utilization, reduced oxidative stress

Reduced RAAS activation

Decreased fibrosis and hypertrophy

Reduced SNS activation

Lower incidence of arrhythmias, improved myocardial function

**Table 4.** Clinical Manifestations and Management in HFrEF
Clinical manifestation	Description	Impact on patient	Management approach
SGLT2: sodium-glucose cotransporter 2; HFrEF: heart failure with reduced ejection fraction.
Dyspnea	Shortness of breath due to pulmonary congestion	Decreased quality of life, impaired exercise tolerance	Diuretics, SGLT2 inhibitors
Fatigue	General sense of tiredness due to reduced cardiac output	Difficulty in daily activities	Optimize heart failure therapy, SGLT2 inhibitors
Fluid retention	Peripheral edema, ascites, weight gain due to volume overload	Discomfort, swelling	Diuretics, SGLT2 inhibitors
Nocturia	Frequent urination at night due to fluid mobilization	Disrupted sleep	Fluid management, SGLT2 inhibitors
Cachexia	Weight loss and muscle atrophy in advanced stages	Poor prognosis	Nutritional support, SGLT2 inhibitors
Gastrointestinal symptoms	Nausea, abdominal discomfort due to gastrointestinal congestion	Decreased appetite, discomfort	Symptom management, SGLT2 inhibitors
Arrhythmias	Atrial fibrillation and ventricular tachycardia	Increased risk of morbidity and mortality	Antiarrhythmic medications, SGLT2 inhibitors

Table 4. Clinical Manifestations and Management in HFrEF

Clinical manifestation

Description

Impact on patient

Management approach

SGLT2: sodium-glucose cotransporter 2; HFrEF: heart failure with reduced ejection fraction.

Dyspnea

Shortness of breath due to pulmonary congestion

Decreased quality of life, impaired exercise tolerance

Diuretics, SGLT2 inhibitors

Fatigue

General sense of tiredness due to reduced cardiac output

Difficulty in daily activities

Optimize heart failure therapy, SGLT2 inhibitors

Fluid retention

Peripheral edema, ascites, weight gain due to volume overload

Discomfort, swelling

Diuretics, SGLT2 inhibitors

Nocturia

Frequent urination at night due to fluid mobilization

Disrupted sleep

Fluid management, SGLT2 inhibitors

Cachexia

Weight loss and muscle atrophy in advanced stages

Poor prognosis

Nutritional support, SGLT2 inhibitors

Gastrointestinal symptoms

Nausea, abdominal discomfort due to gastrointestinal congestion

Decreased appetite, discomfort

Symptom management, SGLT2 inhibitors

Arrhythmias

Atrial fibrillation and ventricular tachycardia

Increased risk of morbidity and mortality

Antiarrhythmic medications, SGLT2 inhibitors

**Table 5.** Diagnostic Criteria and Challenges in HFrEF
Diagnostic tool	Key findings
HFrEF: heart failure with reduced ejection fraction; NT-proBNP: N-terminal pro-B-type natriuretic peptide; BNP: B-type natriuretic peptide; LVEF: left ventricular ejection fraction; CMR: cardiovascular magnetic resonance.
Clinical symptoms	Dyspnea, fatigue, fluid retention
Physical examination	Jugular venous distension, pulmonary crackles, peripheral edema, S3 heart sound
Laboratory tests	Elevated BNP/NT-proBNP levels
Echocardiography	Reduced LVEF, ventricular dilation, wall motion abnormalities
Electrocardiography (ECG)	QRS prolongation, T-wave abnormalities, left ventricular hypertrophy or atrial enlargement
Advanced imaging	CMR for myocardial fibrosis, structural abnormalities

Table 5. Diagnostic Criteria and Challenges in HFrEF

Diagnostic tool

Key findings

HFrEF: heart failure with reduced ejection fraction; NT-proBNP: N-terminal pro-B-type natriuretic peptide; BNP: B-type natriuretic peptide; LVEF: left ventricular ejection fraction; CMR: cardiovascular magnetic resonance.

Clinical symptoms

Dyspnea, fatigue, fluid retention

Physical examination

Jugular venous distension, pulmonary crackles, peripheral edema, S3 heart sound

Laboratory tests

Elevated BNP/NT-proBNP levels

Echocardiography

Reduced LVEF, ventricular dilation, wall motion abnormalities

Electrocardiography (ECG)

QRS prolongation, T-wave abnormalities, left ventricular hypertrophy or atrial enlargement

Advanced imaging

CMR for myocardial fibrosis, structural abnormalities

**Table 6.** SGLT2 Inhibitors in Managing HFrEF Complications
Complication	SGLT2 inhibitors’ benefits
SGLT2: sodium-glucose cotransporter 2; HFrEF: heart failure with reduced ejection fraction.
Heart failure symptoms	Alleviate dyspnea, fatigue, fluid retention
Atrial fibrillation	Reduce incidence and severity
Sudden cardiac death	Stabilize cardiac electrophysiology, prevent arrhythmias
Conduction system disease	Improve conduction abnormalities

Table 6. SGLT2 Inhibitors in Managing HFrEF Complications

Complication

SGLT2 inhibitors’ benefits

SGLT2: sodium-glucose cotransporter 2; HFrEF: heart failure with reduced ejection fraction.

Heart failure symptoms

Alleviate dyspnea, fatigue, fluid retention

Atrial fibrillation

Reduce incidence and severity

Sudden cardiac death

Stabilize cardiac electrophysiology, prevent arrhythmias

Conduction system disease

Improve conduction abnormalities