What interventions reduce all-cause mortality in patients with heart failure (HF) and diabetes mellitus (DM)?

All-Cause Mortality Reducing Interventions for Heart Failure and Diabetes

SGLT2 inhibitors are the single most important intervention to reduce all-cause mortality in patients with both heart failure and diabetes, with proven benefits across the spectrum of heart failure phenotypes. 1

Primary Pharmacologic Interventions

SGLT2 Inhibitors (First-Line Priority)

SGLT2 inhibitors reduce all-cause mortality, cardiovascular mortality, and heart failure hospitalization in patients with diabetes regardless of whether they have established cardiovascular disease. 1

• Dapagliflozin specifically reduces all-cause mortality by 31% (HR 0.69,95% CI 0.53-0.88) in patients with chronic kidney disease and diabetes. 2
• In heart failure with reduced ejection fraction (HFrEF) and diabetes, dapagliflozin reduces all-cause mortality by 41% (HR 0.59,95% CI 0.40-0.88). 3
• The mortality benefit is most pronounced in patients with HFrEF (EF <45%), where cardiovascular death is reduced by 45% (HR 0.55,95% CI 0.34-0.90). 3
• SGLT2 inhibitors reduce heart failure hospitalization by 36% (HR 0.64,95% CI 0.43-0.95) in patients with HFrEF and by 24% (HR 0.76,95% CI 0.62-0.92) in those without reduced ejection fraction. 3

Beta-Blockers (Essential for HFrEF)

Beta-blockers (carvedilol, metoprolol succinate, or bisoprolol) are mandatory for all patients with HFrEF and diabetes to reduce mortality. 4

• Metoprolol succinate reduces all-cause mortality by 34% in heart failure patients (nominal p=0.00009). 5
• The combination of beta-blockers with SGLT2 inhibitors provides complementary mortality reduction through different mechanisms. 1

ACE Inhibitors or ARBs

ACE inhibitors (or ARBs if ACE inhibitors are not tolerated) reduce mortality and hospitalization in HFrEF patients with diabetes. 6

• These agents are fundamental elements of global risk reduction and should be used at maximally tolerated doses. 1
• In the DAPA-CKD trial, 97% of patients achieving mortality benefit were on background ACE inhibitor or ARB therapy. 2

Mineralocorticoid Receptor Antagonists (MRAs)

Spironolactone or eplerenone should be added for patients with HFrEF (EF ≤35%) who remain symptomatic despite ACE inhibitors and beta-blockers. 6, 4

• MRAs provide additional mortality reduction when combined with other guideline-directed medical therapy. 4

Sacubitril/Valsartan

Consider sacubitril/valsartan as a replacement for ACE inhibitors in patients who remain symptomatic despite optimal therapy with ACE inhibitors and beta-blockers. 6, 4

Cardiovascular Risk Factor Management

Blood Pressure Control

Antihypertensive therapy reduces cardiovascular events, heart failure, and microvascular complications in patients with diabetes. 1

• Target blood pressure is <130/80 mmHg (hypertension is defined as ≥130/80 mmHg). 1
• Use loop diuretics (not thiazides) for volume management in patients with heart failure and renal dysfunction, as thiazides are ineffective with eGFR <30 mL/min. 7

Lipid Management

Management of dyslipidemia is a fundamental element of global risk reduction to decrease cardiovascular mortality. 1

• Statin therapy should be incorporated as part of comprehensive cardiovascular risk reduction. 1

Glycemic Control

Moderate glycemic control (HbA1c 7.0-8.0%) is optimal for most patients with heart failure and diabetes, as intensive glycemic control does not reduce all-cause mortality. 1

• The ACCORD, ADVANCE, VADT, and UKPDS trials showed no mortality benefit from intensive glycemic control (HbA1c 6.4-7.0% vs 7.3-8.4%). 1
• The mortality benefits of SGLT2 inhibitors are independent of glycemic control and occur regardless of HbA1c reduction. 1
• Avoid both hypoglycemia and extreme hyperglycemia in acute ischemic heart conditions. 8

Lifestyle Interventions

Exercise Training

Exercise training reduces heart failure hospitalizations and improves quality of life, though its effect on all-cause mortality is less certain when large trials are included. 1

• Meta-analysis of 19 trials (excluding HF-ACTION) showed mortality reduction with exercise (RR 0.91,95% CI 0.39-0.98). 1
• Exercise reduces plasma norepinephrine, inflammation, and improves endothelial function and skeletal muscle metabolism. 1
• Aerobic exercise at 70-80% of peak VO2 is recommended, with programs ranging from supervised sessions to home-based training. 1

Dietary Modification

The sodium-restricted DASH diet reduces blood pressure, arterial stiffness, and oxidative stress while improving diastolic function in heart failure patients with treated hypertension. 1

Medications to Avoid

Contraindicated Agents

NSAIDs and COX-2 inhibitors (ibuprofen, celecoxib) are contraindicated as they increase sodium and water retention, worsening heart failure and increasing mortality risk. 6, 4

Thiazolidinediones (pioglitazone, rosiglitazone) are contraindicated due to increased risk of heart failure worsening and hospitalization. 4

Non-dihydropyridine calcium channel blockers (diltiazem, verapamil) increase the risk of heart failure worsening and hospitalization. 6

Agents Without Mortality Benefit

• Nutritional supplements (coenzyme Q10, carnitine, taurine, antioxidants) and hormonal therapies are not recommended. 6
• The combination of ARB or renin inhibitor with both ACE inhibitor and MRA increases risk of renal dysfunction and hyperkalemia without mortality benefit. 6

Treatment Algorithm for Mortality Reduction

Step 1: Initiate SGLT2 Inhibitor Immediately

• Start dapagliflozin 10 mg daily regardless of heart failure phenotype (HFrEF, HFmEF, or HFpEF). 1, 2
• This provides the most robust all-cause mortality reduction. 1, 3

Step 2: Optimize Neurohormonal Blockade (for HFrEF)

• Ensure maximally tolerated doses of ACE inhibitor or ARB. 1, 2
• Titrate beta-blocker (carvedilol, metoprolol succinate, or bisoprolol) to target dose. 4, 5
• Add MRA (spironolactone or eplerenone) if EF ≤35% and symptomatic. 4

Step 3: Consider Sacubitril/Valsartan

• Replace ACE inhibitor with sacubitril/valsartan if patient remains symptomatic despite Steps 1-2. 6, 4

Step 4: Manage Cardiovascular Risk Factors

• Control blood pressure to <130/80 mmHg using loop diuretics for volume management. 1, 7
• Initiate statin therapy for lipid management. 1
• Target HbA1c 7.0-8.0% (avoid intensive glycemic control). 1

Step 5: Implement Lifestyle Modifications

• Prescribe aerobic exercise at 70-80% peak VO2. 1
• Recommend sodium-restricted DASH diet. 1

Critical Pitfalls to Avoid

Do not delay SGLT2 inhibitor initiation while optimizing other therapies—the mortality benefit is immediate and independent of other medications. 1, 3

Do not use thiazide diuretics in patients with eGFR <30 mL/min—they are ineffective and potentially harmful. 7

Do not pursue intensive glycemic control (HbA1c <6.5%) as it does not reduce mortality and may increase hypoglycemia risk. 1

Do not prescribe NSAIDs, thiazolidinediones, or non-dihydropyridine calcium channel blockers—these directly increase mortality and heart failure events. 6, 4

Monitor renal function and electrolytes closely when combining ACE inhibitors, MRAs, and SGLT2 inhibitors, checking at 1 and 4 weeks, then at 8 and 12 weeks. 7