Recent Cardiology Trials: Key Findings and Clinical Implications
SGLT2 Inhibitors: Transformative Cardiovascular Benefits
SGLT2 inhibitors, particularly empagliflozin and dapagliflozin, represent the most significant advancement in cardiovascular medicine, demonstrating mortality reduction and heart failure benefits that extend far beyond glucose control. 1, 2
Empagliflozin (EMPA-REG OUTCOME)
Empagliflozin reduced cardiovascular death by 38% (HR 0.62,95% CI 0.49-0.77, p<0.001) and the composite of MI, stroke, and cardiovascular death by 14% (HR 0.86,95% CI 0.74-0.99, p=0.04) in patients with type 2 diabetes and established cardiovascular disease over 3.1 years median follow-up. 1
The cardiovascular mortality benefit emerged remarkably early—reaching statistical significance by Day 59 after treatment initiation—and was sustained throughout the trial. 3
Hospitalization for heart failure was reduced by 35%, with this benefit appearing even earlier at Day 17 after starting treatment. 3
These benefits were consistent across the entire spectrum of cardiovascular risk, from low to highest risk patients, regardless of prior myocardial infarction or stroke history. 4
Dapagliflozin (DAPA-HF and DELIVER)
Dapagliflozin 10 mg daily reduced cardiovascular death and heart failure hospitalizations by 26% in patients with heart failure and reduced ejection fraction (HFrEF), completely independent of diabetes status. 2
In the DELIVER trial for heart failure with preserved ejection fraction (HFpEF), dapagliflozin reduced the combined risk of cardiovascular death or worsening heart failure by 18% (HR 0.82,95% CI 0.73-0.92, p<0.001) in patients with LVEF >40%. 2
Dapagliflozin is the only medication proven to improve both clinical outcomes AND functional capacity/quality of life in HFpEF patients, with significant improvements in Kansas City Cardiomyopathy Questionnaire scores and 6-minute walk distance in the PRESERVED-HF trial. 2
The drug provides incremental benefit regardless of background medical therapy, including ACE inhibitors/ARBs, beta-blockers, mineralocorticoid receptor antagonists, and ARNI. 2
Canagliflozin (CANVAS Program)
Canagliflozin significantly reduced the composite outcome of cardiovascular death, MI, or stroke versus placebo (26.9 vs. 31.5 participants per 1,000 patient-years; HR 0.86,95% CI 0.75-0.97) in 10,142 participants with type 2 diabetes followed for 3.6 years. 1
Critical safety concern: Canagliflozin increased the risk of lower-limb amputation (HR 1.97,95% CI 1.41-2.75), though this was not observed in other canagliflozin trials. 1
Heart Failure Management: Guideline-Directed Medical Therapy
First-Line Therapy for Heart Failure with Reduced Ejection Fraction
For patients with HFrEF (ejection fraction ≤40%), the optimal treatment regimen consists of four pillars: SGLT2 inhibitor, ACE inhibitor/ARB, beta-blocker, and mineralocorticoid receptor antagonist. 5
SGLT2 inhibitors are now recommended as first-line therapy for all patients with heart failure and diabetes to reduce hospitalization risk and improve outcomes, regardless of ejection fraction. 5, 1
Beta-blockers (specifically metoprolol, bisoprolol, or carvedilol) remain first-line therapy in diabetic patients with heart failure, with proven mortality benefit. 5
For patients with severe heart failure who remain symptomatic despite optimal therapy, sacubitril/valsartan should replace ACE inhibitors. 5
Sacubitril/Valsartan (PARADIGM-HF)
In the PARADIGM-HF trial of 8,442 adults with symptomatic chronic heart failure (NYHA class II-IV) and ejection fraction ≤40%, sacubitril/valsartan was superior to enalapril in reducing the composite endpoint of cardiovascular death or hospitalization for heart failure (HR 0.8,95% CI 0.73-0.87, p<0.0001). 6
The treatment effect reflected reductions in both cardiovascular death and heart failure hospitalization, with improved overall survival (HR 0.84,95% CI 0.76-0.93, p=0.0009). 6
Sudden death accounted for 45% of cardiovascular deaths, followed by pump failure at 26%. 6
Ivabradine (SHIFT Trial)
In the SHIFT trial of 6,558 adults with stable NYHA class II-IV heart failure, left ventricular ejection fraction ≤35%, and resting heart rate ≥70 bpm, ivabradine reduced the composite endpoint of hospitalization for worsening heart failure or cardiovascular death (HR 0.82,95% CI 0.75-0.90, p<0.0001). 7
The treatment effect reflected only a reduction in hospitalization for worsening heart failure; there was no favorable effect on cardiovascular mortality. 7
Most patients (89%) were taking beta-blockers, with only 26% on guideline-defined target daily doses, primarily due to hypotension (45%), fatigue (32%), and dyspnea (14%). 7
Heart Failure with Preserved Ejection Fraction: Emerging Therapies
Dapagliflozin stands alone as the only medication with proven benefits for both clinical outcomes and functional capacity in HFpEF patients, making it the preferred first-line agent. 2
Comparative Efficacy in HFpEF
Sacubitril/valsartan showed no significant improvement in exercise capacity in HFpEF patients, with a mean difference in 6-minute walk distance of only 2.5 meters (p=0.42). 2
Spironolactone failed to improve exercise capacity in HFpEF trials, and the FDA issued no final determination on its use for HFpEF. 2
Both dapagliflozin (DELIVER) and empagliflozin (EMPEROR-PRESERVED) demonstrated reductions in the combined risk of heart failure hospitalizations or cardiovascular death in HFpEF, establishing a class effect for SGLT2 inhibitors. 2
Medications to Avoid in Heart Failure
Thiazolidinediones (pioglitazone and rosiglitazone) are contraindicated in heart failure patients with NYHA class III-IV due to increased risk of fluid retention. 5
Saxagliptin (DPP-4 inhibitor) is not recommended due to increased risk of heart failure hospitalization. 5
Aliskiren (direct renin inhibitor) is not recommended for patients with heart failure and diabetes due to risks of hypotension, worsening renal function, and hyperkalemia. 5
DPP-4 Inhibitors: Neutral Cardiovascular Effects
Cardiovascular outcomes trials of DPP-4 inhibitors have consistently shown no cardiovascular benefits relative to placebo. 1
- The CAROLINA study demonstrated noninferiority between linagliptin (DPP-4 inhibitor) and glimepiride (sulfonylurea) on cardiovascular outcomes, despite lower rates of hypoglycemia in the linagliptin group. 1
Finerenone: Novel Mineralocorticoid Receptor Antagonist
People with type 2 diabetes and chronic kidney disease should be considered for treatment with finerenone to reduce cardiovascular outcomes and the risk of CKD progression. 1
- Finerenone should be considered for diabetic patients with chronic kidney disease to reduce cardiovascular events and heart failure hospitalization. 5
Peripheral Artery Disease Screening
The VIVA trial demonstrated that combined vascular screening for abdominal aortic aneurysm, PAD, and hypertension in 50,156 participants was associated with increased pharmacologic therapy, reduced in-hospital time for PAD and coronary artery disease, and reduced mortality. 1
- Screening for asymptomatic PAD using ankle-brachial index is recommended in people with diabetes who are age ≥65 years, diabetes duration ≥10 years, microvascular disease, clinical evidence of foot complications, or any end-organ damage from diabetes. 1
Clinical Implementation Priorities
In-Hospital Initiation of SGLT2 Inhibitors
SGLT2 inhibitors should be initiated during hospitalization for heart failure, not deferred to outpatient follow-up, as clinical benefits accrue within days to weeks. 2
Dapagliflozin has a strong safety profile with minimal blood pressure effects and no excess kidney adverse events, making it suitable for in-hospital initiation. 2
Standard dosing is dapagliflozin 10 mg once daily with no titration required and no dose adjustment needed for age, sex, or background therapy. 2
Mechanism of Cardiovascular Benefit
The reduction in cardiovascular mortality with SGLT2 inhibitors is unlikely to be explained solely by metabolic effects (HbA1c reduction, weight loss, blood pressure lowering); hemodynamic effects, specifically reduced blood pressure and decreased extracellular volume, are more likely responsible for the reduction in cardiovascular mortality and heart failure hospitalization. 8
- The EMPA-VISION trial is investigating the effects of empagliflozin on cardiac energy metabolism using magnetic resonance spectroscopy, with the primary endpoint being change in resting phosphocreatine-to-adenosine triphosphate ratio. 9
2024 Updates in Cardiology Practice
Recent evidence from 2024 has challenged several established practices in cardiology, including the routine use of beta-blockers after myocardial infarction and the practice of holding renin-angiotensin system inhibitors before noncardiac surgery. 10
New evidence addresses the timing of valve intervention in severe aortic stenosis in relation to symptom development. 10
The role of invasive treatment strategies for older adults with non-ST-segment elevation MI has been clarified. 10
Research into tirzepatide for heart failure with preserved ejection fraction represents an emerging area of investigation. 10