SGLT2 Inhibitors in Heart Failure Management

Introduction to SGLT2 Inhibitors

• SGLT2 inhibitors significantly reduce cardiovascular mortality, heart failure hospitalizations, and improve quality of life across the spectrum of heart failure patients regardless of ejection fraction or diabetes status, as demonstrated in the DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, and DELIVER trials 1, 2

Trial Results

• The DAPA-HF trial enrolled 4,744 patients with heart failure with reduced ejection fraction (HFrEF) ≤40%, NYHA class II-IV, with 45% having type 2 diabetes, and found that dapagliflozin 10mg daily reduced the primary composite outcome of worsening heart failure or cardiovascular death by 26% (HR 0.74 [95% CI 0.65-0.85]) 1, 3
• The EMPEROR-Reduced trial enrolled 3,730 patients with HFrEF ≤40%, NYHA class II-IV, with approximately 50% having type 2 diabetes, and found that empagliflozin 10mg daily reduced the primary composite outcome of cardiovascular death or hospitalization for worsening heart failure by 21% (HR 0.79 [95% CI 0.69-0.90]; P < 0.001) 1, 3
• The DELIVER trial enrolled 6,263 patients with heart failure and ejection fraction >40%, and found that dapagliflozin reduced the primary outcome of worsening heart failure (hospitalization or urgent visit) or cardiovascular death by 18% (HR 0.82 [95% CI 0.73-0.92]; P < 0.001) 1, 3

Clinical Guidelines

• The American College of Cardiology strongly recommends SGLT2 inhibitors for all patients with symptomatic heart failure regardless of ejection fraction or diabetes status 2
• Benefits of SGLT2 inhibitors appear independent of glucose-lowering effects 2, 4

Safety and Economic Considerations

• Safety considerations for SGLT2 inhibitors include monitoring for euglycemic ketoacidosis, genital and soft tissue infections, and volume depletion, especially when combined with diuretics 2
• Cost-effectiveness analyses of dapagliflozin found costs per QALY between $60,000 and $90,000, consistent with intermediate value 2

Empagliflozin for Diastolic Heart Failure

Efficacy and Recommendations

• The American College of Cardiology recommends SGLT2 inhibitors, including empagliflozin, for patients with established HFpEF or HFrEF to reduce the risk of worsening heart failure and cardiovascular death 5, 6
• The European Society of Cardiology guidelines recommend empagliflozin in patients with type 2 diabetes and cardiovascular disease to reduce cardiovascular events and risk of death 7
• Empagliflozin 10mg daily reduced the composite outcome of cardiovascular death or hospitalization for heart failure by 21% (HR 0.79 [95% CI 0.69-0.90]; P < 0.001) in patients with heart failure and ejection fraction >40% 5
• A large meta-analysis confirmed reduced risk for cardiovascular death, hospitalization for heart failure, and all-cause mortality across the spectrum of heart failure patients 6

Clinical Application

• Treatment with empagliflozin improves symptoms, physical limitations, and quality of life in patients with heart failure 6
• The benefits of empagliflozin in heart failure appear independent of its glucose-lowering effects, representing a direct cardiovascular benefit, although the exact mechanism is not fully understood 5, 6

Empagliflozin vs Dapagliflozin for Type 2 Diabetes: Cardiovascular and Renal Outcomes

Cardiovascular Benefits

• Both empagliflozin and dapagliflozin are effective across the ejection fraction spectrum (HFrEF and HFpEF) for heart failure benefits 8, 9
• Natriuretic peptide screening (BNP ≥50 pg/mL or NT-proBNP ≥125 pg/mL) can identify patients who would benefit most from SGLT2 inhibitor therapy, including empagliflozin and dapagliflozin 8, 9

Renal Protection

• Dapagliflozin provides robust renal protection, reducing the composite renal outcome by 44% (HR 0.56, 95% CI 0.45-0.68) 10, 11
• The renoprotective effects of SGLT2 inhibitors, including dapagliflozin, are independent of diabetes status 10, 11

Dapagliflozin in Heart Failure Management

Benefits and Implementation

• The American College of Cardiology recommends initiating dapagliflozin during heart failure hospitalization in stabilized patients, as deferring initiation is associated with a high likelihood that eligible patients will never receive the medication within 1 year 12
• Dapagliflozin provides incremental benefit regardless of whether patients are on optimal guideline-directed medical therapy (GDMT), reducing the primary outcome by 26% (HR 0.74, 95% CI 0.59-0.93) in patients already on ACE inhibitor/ARB, beta-blocker, and mineralocorticoid receptor antagonist 12
• The American College of Cardiology suggests that dapagliflozin works independently of glucose-lowering effects, representing direct cardiovascular benefit through mechanisms beyond glycemic control, and has minimal blood pressure effects, no excess risk of symptomatic hypotension, and numerically fewer serious adverse events than placebo 12
• The American College of Cardiology recommends continuing existing GDMT, including ACE inhibitors, ARBs, beta-blockers, or MRAs, as dapagliflozin provides additive benefit 12
• Dapagliflozin preserves kidney function rather than causing adverse renal effects, with benefits observed even in patients with eGFR as low as 25 mL/min/1.73 m², reducing the composite of ≥50% sustained eGFR decline, progression to end-stage kidney disease, or cardiovascular/renal death by 39% (HR 0.61, 95% CI 0.51-0.72) 12

Dapagliflozin in Heart Failure Quadruple Therapy

Mechanism of Action and Effects

• Dapagliflozin inhibits proximal tubular sodium-glucose reabsorption, leading to glucosuria and natriuresis that enhances diuretic efficacy when combined with loop diuretics, and triggers tubuloglomerular feedback through increased distal tubule sodium delivery, causing afferent arteriolar vasoconstriction that prevents glomerular hyperfiltration and provides long-term kidney protection in patients with heart failure 13
• Dapagliflozin shifts cardiac metabolism toward ketone utilization, which requires less oxygen than glucose or fatty acid metabolism, directly improving myocardial energetics, and reduces cardiac fibrosis and adverse remodeling through mechanisms that complement the effects of RAAS inhibitors and beta-blockers in patients with heart failure 13

Guideline Recommendations and Clinical Implementation

• The American College of Cardiology recommends SGLT2 inhibitors, such as dapagliflozin, for all patients with symptomatic HFrEF in addition to ACEi/ARB/ARNI, beta-blockers, and MRAs, with a Class I recommendation 14
• The European Society of Cardiology recommends dapagliflozin or empagliflozin for patients with HFmrEF or HFpEF to reduce cardiovascular death and heart failure hospitalizations, with a Class I recommendation 15

Safety Profile and Contraindications

• Dapagliflozin has minimal blood pressure effects, particularly in patients with lower baseline blood pressure, and symptomatic hypotension occurred in only 0.3% of dapagliflozin patients vs 0.5% of placebo patients in DAPA-HF, with no excess kidney adverse events despite use with ACEi/ARB/ARNI and MRAs 16
• Dapagliflozin should be used with caution when combined with high-dose loop diuretics due to enhanced natriuresis, and is contraindicated in patients with eGFR <25 mL/min/1.73 m² or on dialysis 13

Empagliflozin for Heart Failure with Reduced Ejection Fraction

Primary Recommendation

• The American College of Cardiology and American Diabetes Association provide Class I recommendations for SGLT2 inhibitors in all patients with symptomatic HFrEF, independent of diabetes status or need for additional glucose lowering 17
• The American College of Cardiology recommends initiating empagliflozin during hospitalization once clinically stable, with a standard dose of 10 mg once daily, as it provides additive benefit on top of optimal guideline-directed medical therapy 17

Safety Profile in HFrEF

• Symptomatic hypotension occurred in 5.7% with empagliflozin versus 5.5% with placebo, with minimal BP reduction in patients with baseline SBP 100-110 mmHg, and an increasing BP trend over time reflecting improved cardiac function 18
• Empagliflozin preserves kidney function, reducing eGFR decline over time, and is contraindicated only if eGFR <25 mL/min/1.73 m² or on dialysis 18

Renal Protection and Heart Failure Outcomes with SGLT2 Inhibitors

Renal Protection

• The American College of Cardiology and European Society of Cardiology provide Class I recommendations for dapagliflozin and empagliflozin in patients with advanced chronic kidney disease, with dapagliflozin reducing the composite of ≥50% sustained eGFR decline, ESKD, or cardiovascular/renal death by 39% (HR 0.61, 95% CI 0.51-0.72) in patients with mean baseline eGFR 43 mL/min/1.73 m² 19
• Empagliflozin in EMPA-KIDNEY reduced kidney disease progression and cardiovascular death by 28% (HR 0.72, 95% CI 0.64-0.82) in patients with eGFR as low as 20 mL/min/1.73 m² 19
• Dapagliflozin was studied in patients with median UACR 949 mg/g and reduced the kidney composite outcome by 44% (HR 0.56, 95% CI 0.45-0.68) 19

Heart Failure Outcomes

• Dapagliflozin reduced worsening heart failure or cardiovascular death by 18% (HR 0.82, 95% CI 0.73-0.92) in the DELIVER trial, with benefits observed in patients with heart failure with preserved ejection fraction 19
• The American College of Cardiology and European Society of Cardiology provide Class I recommendations for both dapagliflozin and empagliflozin across the entire ejection fraction spectrum, with equivalent efficacy for heart failure and renal protection 19

Empagliflozin for Heart Failure in Type 2 Diabetes

Cardiovascular Benefits

• Empagliflozin reduces heart failure hospitalizations by 35% compared to placebo in patients with type 2 diabetes and high cardiovascular risk, representing a number needed to treat of 35 over 3 years to prevent one heart failure hospitalization or cardiovascular death 20
• Empagliflozin reduces the composite outcome of cardiovascular death or hospitalization for heart failure by 21% (HR 0.79, 95% CI 0.69-0.90; P < 0.001) in both HFrEF and HFpEF populations 20
• The TECOS trial demonstrated that sitagliptin is cardiovascular neutral, showing non-inferiority to placebo for major adverse cardiovascular events but providing no reduction in heart failure hospitalizations or cardiovascular death 20
• Sitagliptin offers no cardiovascular benefit beyond glucose control, making it an inferior choice when empagliflozin provides substantial cardiovascular risk reduction 20

Safety Profile

• Sitagliptin is generally well-tolerated with a neutral cardiovascular safety profile 20
• No increased risk of heart failure hospitalization demonstrated in TECOS with sitagliptin 20

Cardioprotective Role of Dapagliflozin and Empagliflozin

Primary Cardiovascular Benefits

• The European Society of Cardiology recommends empagliflozin to reduce the risk of death in patients with type 2 diabetes and cardiovascular disease, with a reduction in cardiovascular death by 38% (HR 0.62; 95% CI 0.49-0.77) and all-cause mortality by 32% (HR 0.68; 95% CI 0.57-0.82) 21, 22
• Both dapagliflozin and empagliflozin provide equivalent cardioprotection in patients with type 2 diabetes and obesity at high cardiovascular risk, with either agent reducing major cardiovascular events, heart failure hospitalizations, and cardiovascular mortality by approximately 14-26% 21, 22, 23
• SGLT2 inhibitors, including empagliflozin and dapagliflozin, are recommended to lower the risk of heart failure hospitalization with Class I evidence 21, 22

Renal Protection

• SGLT2 inhibitors are recommended to reduce the progression of diabetic kidney disease 21, 22

Clinical Implementation

• The American Heart Association and European Society of Cardiology suggest initiating either dapagliflozin 10 mg or empagliflozin 10 mg daily in patients with type 2 diabetes and obesity who have established cardiovascular disease or very high/high cardiovascular risk 21, 22, 23

SGLT2 Inhibitors in Heart Failure with Preserved Ejection Fraction (HFpEF)

Clinical Trial Evidence

• Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death by 18% (hazard ratio 0.82, 95 % CI 0.73‑0.92; p < 0.001) in the DELIVER trial, which enrolled 6,263 patients with HFpEF (EF > 40 %). 24
• Empagliflozin lowered the composite of cardiovascular death or heart‑failure hospitalization by 21 % (hazard ratio 0.79, 95 % CI 0.69‑0.90; p < 0.001) in the EMPEROR‑Preserved trial, which enrolled 5,988 patients with HFpEF (EF > 40 %). 24
• The reduction in the EMPEROR‑Preserved trial was driven primarily by a 27 % decrease in heart‑failure hospitalizations (hazard ratio 0.73, 95 % CI 0.61‑0.88; p < 0.001). 24
• Both trials demonstrated consistent efficacy across the preserved‑ejection‑fraction spectrum (EF ≥ 60 % and EF 50‑59 %). 24
• The therapeutic benefit of dapagliflozin and empagliflozin was independent of diabetes status; roughly 44‑50 % of participants had type 2 diabetes, yet outcomes were similar in diabetic and non‑diabetic subgroups. 24

Guideline Recommendations

• The American College of Cardiology and the American Diabetes Association assign a Class I recommendation to SGLT2‑inhibitor therapy for all symptomatic HFpEF patients to reduce cardiovascular death and heart‑failure hospitalizations. 24
• Both dapagliflozin and empagliflozin are approved for heart‑failure treatment irrespective of diabetes status and should be started at a fixed dose of 10 mg once daily without titration. 24

Implementation Strategies

• Initiate SGLT2‑inhibitor therapy during a heart‑failure hospitalization once the patient is hemodynamically stable (no increase in IV diuretics for ≥ 6 h and no IV vasodilators or inotropes for ≥ 24 h). 25
• Therapy can be started in patients with estimated glomerular filtration rates as low as 20‑25 mL/min/1.73 m² and should be continued even if eGFR declines modestly after initiation. 25

Safety Considerations

• Euglycemic ketoacidosis is a rare adverse event that warrants prompt recognition, especially in diabetic patients who are fasting or have reduced insulin dosing. 24
• Volume depletion, symptomatic hypotension (≈ 0.3‑5.7 % of patients), genital mycotic infections (≈ 1.5‑1.7 %), and urinary‑tract infections (≈ 2.3‑2.7 %) are the most common side‑effects and are generally manageable. 24

Practical Pitfalls to Avoid

• Do not withhold SGLT2‑inhibitors solely because a patient lacks diabetes; cardiovascular benefits are independent of glucose‑lowering effects. 24
• Do not postpone initiation until after hospital discharge, as delayed treatment leads to many eligible patients never receiving the medication within the first year. 24
• Restrict use to dapagliflozin or empagliflozin, as other SGLT2 inhibitors lack dedicated HFpEF outcome‑trial data. 24