What is the role of linagliptin (DPP-4 inhibitor) in managing type 2 diabetes in patients with heart failure, particularly those with reduced ejection fraction and impaired renal function?

Linagliptin in Heart Failure

Linagliptin is safe to use in patients with heart failure and does not increase the risk of heart failure hospitalization, making it an acceptable DPP-4 inhibitor choice when glycemic control is needed in this population, though SGLT2 inhibitors remain the preferred first-line agents for patients with heart failure due to their proven mortality and morbidity benefits. 1, 2

Evidence for Linagliptin's Safety in Heart Failure

The CARMELINA trial specifically evaluated linagliptin in 6,979 patients with type 2 diabetes at high cardiovascular and renal risk, including 1,873 (26.8%) with a history of heart failure at baseline 2. Over a median follow-up of 2.2 years, linagliptin demonstrated:

• No increase in heart failure hospitalization risk (HR 0.90,95% CI 0.74-1.08) compared to placebo 1, 2
• Neutral effect on the composite of cardiovascular death/heart failure hospitalization (HR 0.94,95% CI 0.82-1.08) 2
• No increase in recurrent heart failure events (rate ratio 0.94,95% CI 0.75-1.20) 2

This neutral safety profile was consistent across subgroups, including patients with and without baseline heart failure, across the spectrum of renal impairment, and regardless of left ventricular ejection fraction 2.

Distinguishing Linagliptin from Other DPP-4 Inhibitors

Not all DPP-4 inhibitors have the same heart failure safety profile—this is a critical distinction. The 2022 ADA guidelines emphasize that saxagliptin showed a 27% relative increase in heart failure hospitalization risk in the SAVOR-TIMI 53 trial 1. In contrast, linagliptin (CARMELINA), sitagliptin (TECOS), and alogliptin (EXAMINE) showed no significant increase in heart failure hospitalization 1.

The 2019 AHA/HFSA scientific statement concludes that the risk-benefit balance for most DPP-4 inhibitors does not justify their use in patients with established heart failure or those at high risk for heart failure 1. However, this statement was published before the full CARMELINA results were available, and the guidelines acknowledge that linagliptin data were still pending at that time 1.

Advantages of Linagliptin in Heart Failure with Renal Impairment

Linagliptin has a unique pharmacokinetic advantage: it requires no dose adjustment regardless of renal function, including in severe renal impairment (eGFR <30 mL/min/1.73 m²). 3 This is particularly relevant for heart failure patients, who frequently have concomitant chronic kidney disease.

• In severe renal impairment, steady-state exposure increases by only 40-42%, which is not clinically significant and does not necessitate dose adjustment 3
• Renal excretion accounts for less than 7% of the administered dose 3
• The standard 5 mg once-daily dose is maintained across all levels of renal function 3

Common pitfall: The FDA label warns that the use of linagliptin in combination with insulin in patients with severe renal impairment was associated with a higher rate of hypoglycemia 3. Therefore, when combining linagliptin with insulin in this population, consider reducing the insulin dose to mitigate hypoglycemia risk 3.

Clinical Positioning: When to Use Linagliptin vs. SGLT2 Inhibitors

SGLT2 inhibitors remain the preferred first-line glucose-lowering agents for patients with heart failure. The 2022 ADA guidelines strongly recommend SGLT2 inhibitors with demonstrated cardiovascular benefit to reduce major adverse cardiovascular events and heart failure hospitalization 1. SGLT2 inhibitors have shown:

• 35% reduction in heart failure hospitalization with empagliflozin 1
• 39% reduction in heart failure hospitalization with canagliflozin 1
• Consistent benefits across multiple large outcomes trials 1

However, linagliptin has a role when:

1. SGLT2 inhibitors are contraindicated or not tolerated (e.g., recurrent genital mycotic infections, volume depletion concerns, or patient intolerance) 1
2. Additional glycemic control is needed beyond SGLT2 inhibitors and other guideline-directed therapies 1
3. Severe renal impairment exists where dosing simplicity is advantageous (no adjustment needed) 3
4. The patient is already on metformin and requires add-on therapy but SGLT2 inhibitors or GLP-1 receptor agonists are not appropriate 1

FDA Safety Warnings for Linagliptin

The FDA label includes a specific warning about heart failure: "An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class." 3 The label recommends:

• Consider the risks and benefits prior to initiating treatment in patients at risk for heart failure, such as those with prior history of heart failure and renal impairment 3
• Observe patients for signs and symptoms of heart failure during therapy 3
• Advise patients of characteristic symptoms of heart failure and to immediately report such symptoms 3
• If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation 3

Practical Algorithm for Using Linagliptin in Heart Failure

Step 1: Optimize guideline-directed medical therapy for heart failure

• Ensure patient is on appropriate doses of ACE inhibitors/ARBs/ARNI, beta-blockers, and mineralocorticoid receptor antagonists 1

Step 2: Prioritize SGLT2 inhibitors for glycemic control

• Initiate empagliflozin or dapagliflozin as first-line glucose-lowering agent if not contraindicated 1

Step 3: Consider linagliptin if:

• SGLT2 inhibitors are contraindicated, not tolerated, or insufficient for glycemic control 1
• Patient has severe renal impairment (eGFR <30 mL/min/1.73 m²) and dosing simplicity is desired 3
• Additional glucose lowering is needed beyond metformin and SGLT2 inhibitors 1

Step 4: Dosing

• Linagliptin 5 mg once daily, regardless of renal function 3
• If combining with insulin or sulfonylureas, reduce the dose of these agents to minimize hypoglycemia risk 3

Step 5: Monitoring

• Monitor for signs/symptoms of worsening heart failure (dyspnea, orthopnea, peripheral edema, weight gain) 3
• Assess glycemic control (HbA1c) within 3 months 1
• Monitor renal function, though dose adjustment is not required 3

Important Caveats

• Linagliptin provides no cardiovascular benefit—it is cardiovascularly neutral, not protective 1, 2
• Avoid saxagliptin in heart failure patients due to increased hospitalization risk 1
• Thiazolidinediones should be avoided in patients with symptomatic heart failure due to strong association with increased heart failure risk 1
• Metformin remains safe in stable heart failure as long as renal function is adequate (eGFR ≥30 mL/min/1.73 m²) 1
• The FDA label warns of rare but serious adverse effects including pancreatitis, severe arthralgia, bullous pemphigoid, and hypersensitivity reactions 3