Comparison of Cardiovascular Effects of Sitagliptin and Empagliflozin

DPP-4 Inhibitors (Gliptins) and Their Impact on the CV System

The mechanism of action of gliptins is the inhibition of dipeptidyl peptidase 4 (DPP-4), which is involved in the degradation of glucagon-like peptide 1 (GLP-1) and other incretin and peptide hormones and cytokines. This results in increased insulin secretion and decreased glucagon release. Inhibition of DPP-4 also leads to reduced degradation of stromal cell-derived chemokine factor 1α (SDF-1α), thereby improving the function of progenitor endothelial cells. Besides their direct impact on glycemia levels, gliptins also influence endothelial function, reduce oxidative stress, decrease inflammatory markers, assist in weight reduction, and lower blood pressure, collectively achieving a cardioprotective effect.

The cardiovascular safety and effect of gliptins on the CV system in T2D patients have been investigated in several placebo-controlled studies in recent years: EXAMINE with alogliptin, SAVOR-TIMI 53 with saxagliptin, and TECOS with sitagliptin. These studies have proven the noninferiority of gliptins, i.e., CV safety, yet failed to demonstrate their superiority in reducing CV event occurrence compared to placebo among T2D patients with high CV risk.

CV Effects of SGLT2 Inhibitors (Gliflozins)

Gliflozins increase glucose, sodium, and water excretion through the kidneys. Glycosuria supports weight reduction, improves beta-cell function, and enhances insulin sensitivity. Increased diuresis and sodium excretion lead to blood pressure reduction and increased hematocrit, resulting in positive hemodynamic effects. Better glycemic and blood pressure control positively affect the CV system and have nephroprotective properties as well.

The cardiovascular efficacy and safety of gliflozins in T2D patients were first evaluated in the randomized placebo-controlled EMPA-REG OUTCOME study with empagliflozin. This study included 7020 T2D patients with CV disease. Empagliflozin significantly reduced the incidence of major adverse CV events (including myocardial infarction, stroke, and CV death), CV mortality, overall mortality, and hospitalizations due to heart failure. Given that chronic kidney disease represents an independent CV risk factor, empagliflozin's proven renoprotective effects are also considered a CV benefit.

When to Use Sitagliptin and When to Use Empagliflozin?

According to current recommendations, based on the results of the cited studies, empagliflozin is preferred over sitagliptin in treating T2D, especially in patients with high CV risk. However, diabetologists must also consider other aspects of individual medications. Thus, the best approach is an individualized evaluation of each diabetic patient's characteristics.

Professional recommendations have reconsidered the previous approach to T2D management, which was primarily based on strict glycemic and hemoglobin A1c control. Current recommendations prioritize an individually established target value for hemoglobin A1c and also focus on preventing and treating CV complications.

Sitagliptin, given its favorable safety profile, can be beneficial for frail patients at high risk of hypoglycemia or dehydration. Its dosage can be adjusted according to kidney function and is also suitable for patients with renal insufficiency.

Empagliflozin is preferred primarily for patients at high risk of atherosclerotic cardiovascular disease, those with heart failure, and those with chronic kidney disease, where weight reduction or hypoglycemia risk reduction is desired. Empagliflozin can be administered to T2D patients with an eGFR of up to 30 ml/min/1.73m² who have CV disease. For patients with heart failure, it can be administered with an eGFR of up to 20 ml/min/1.73m². Since May 1, 2022, empagliflozin 10 mg (pack of 28 tablets) is reimbursed for heart failure indication with reduced EF LK ≤ 40% and simultaneously eGFR > 20 ml/min/1.73 m², in patients remaining symptomatic {NYHA Class II–III} despite optimal treatment, prescribed by specialists in cardiology, pediatric cardiology, angiology, and internal medicine.

Conclusion

New oral antidiabetic drugs have significantly expanded the options in modern diabetology. Besides glycemic control, these modern medications offer numerous benefits. In addition to the proven CV safety, some classes of antidiabetic drugs have shown CV benefits. Current recommendations incorporate these pieces of evidence within the algorithms for choosing the appropriate antidiabetic medication for each specific patient.

(kali)

Sources: 
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2. American Diabetes Association Professional Practice Committee, Draznin B., Aroda V. R., Bakris G. et al. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes − 2022. Diabetes Care 2022; 45 (Suppl. 1): S125–S143, doi: 10.2337/dc22-S009. 
3. SPC Jardiance. Available at: www.ema.europa.eu/en/documents/product-information/jardiance-epar-product-information_cs.pdf