What are the key outcomes of the CARMELINA trial regarding linagliptin (Dipeptidyl peptidase-4 (DPP-4) inhibitor) in patients with type 2 diabetes and impaired renal function?

Key Outcomes of the CARMELINA Trial for Linagliptin in Type 2 Diabetes with Impaired Renal Function

The CARMELINA trial demonstrated that linagliptin is cardiovascular and renally safe in patients with type 2 diabetes and impaired renal function, showing no increased risk of major adverse cardiovascular events compared to placebo (HR 0.98; 95% CI 0.84-1.14) and no worsening of kidney outcomes (HR 1.04; 95% CI 0.89-1.22). 1

Primary Cardiovascular Outcomes

The CARMELINA trial was specifically designed to evaluate linagliptin in patients with type 2 diabetes who had high cardiovascular and renal risk. Key findings include:

• Primary 3-point MACE outcome (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke): HR 0.98 (95% CI 0.84-1.14), demonstrating cardiovascular safety 1, 2
• Cardiovascular death: HR 1.00 (95% CI 0.81-1.24), showing no increase in mortality 1
• Myocardial infarction: HR 1.03 (95% CI 0.82-1.29) 1
• Stroke: HR 0.86 (95% CI 0.66-1.12) 1

Renal Outcomes

The trial included important renal endpoints, particularly relevant given the study population:

• Key secondary kidney composite outcome (renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR): HR 1.04 (95% CI 0.89-1.22), showing no adverse impact on kidney function 2
• Progression of albuminuria: Reduced with linagliptin compared to placebo (HR 0.86; 95% CI 0.78-0.95) 3, 4
• Consistent renal safety across all eGFR categories, including patients with severely reduced kidney function 4

Heart Failure Outcomes

• Hospitalization for heart failure: HR 1.21 (95% CI 0.92-1.59), showing no statistically significant increase 1
• Unlike saxagliptin in the SAVOR-TIMI 53 trial which showed increased heart failure hospitalization risk, linagliptin did not demonstrate this safety concern 1

Study Population Characteristics

CARMELINA specifically targeted patients with high cardiorenal risk:

• Mean age: 65.8 years 5
• Mean eGFR: 54.6 mL/min/1.73 m² 2
• Albuminuria: Present in 80.1% of participants 2
• Chronic kidney disease: 73.8% of participants had prevalent kidney disease (defined as eGFR <60 mL/min/1.73 m² or macroalbuminuria) 5
• Established cardiovascular disease: 57.2% of participants 5
• Median follow-up: 2.2 years 1

Glycemic Control and Safety

• HbA1c reduction: Linagliptin effectively reduced HbA1c compared to placebo across all eGFR categories 4
• Hypoglycemia: No increased risk of hypoglycemia compared to placebo 3, 2
• Pancreatitis: Low incidence with 9 events (0.3%) in the linagliptin group vs 5 events (0.1%) with placebo 2

Clinical Implications

1. Cardiovascular safety: Unlike some cardiovascular outcome trials that have shown benefits with SGLT2 inhibitors, linagliptin demonstrated cardiovascular neutrality (neither harm nor benefit) 1

2. Renal function: Linagliptin can be safely used across all stages of kidney function without dose adjustment, making it particularly valuable for patients with impaired renal function 6, 4

3. Comparison to other DPP-4 inhibitors: All DPP-4 inhibitors tested in cardiovascular outcome trials (linagliptin, saxagliptin, sitagliptin, alogliptin) have shown cardiovascular safety, but linagliptin specifically included a higher proportion of patients with kidney disease 1

4. Positioning in therapy: For patients with type 2 diabetes and established cardiovascular disease or chronic kidney disease, SGLT2 inhibitors with proven cardiovascular benefits are recommended as first-line agents for risk reduction 1. Linagliptin represents a safe alternative when SGLT2 inhibitors cannot be used.

Limitations

• The trial was designed to demonstrate non-inferiority (safety) rather than superiority (benefit)
• The median follow-up of 2.2 years may be insufficient to detect long-term effects
• The trial did not show cardiovascular or renal benefits, unlike some SGLT2 inhibitor and GLP-1 receptor agonist trials

In conclusion, CARMELINA established linagliptin as a cardiovascularly and renally safe option for patients with type 2 diabetes and impaired renal function, without demonstrating specific cardiovascular or renal protective benefits beyond glycemic control.