ヒトiPS細胞を用いてヒト心不全モデルを試験管の中で再現糖尿病治療薬SGLT2阻害薬による新しい治療効果の機序を解明

Modeling Heart Failure with Human iPS Cells

While patients with HFpEF maintain their heart's contraction strength, they suffer from a diminished ability of the heart to expand, which prevents it from pumping blood effectively. Historically, research relied on a mouse model reported in 2019 using high-fat diets and nitric oxide (NO) production inhibitors.

This breakthrough allowed them to investigate the underlying mechanisms of the disease and test the efficacy of various medications, specifically focusing on the SGLT2 inhibitor class of diabetes drugs.

Mechanism of Action for SGLT2 Inhibitors

The study, published in the journal Cell Stem Cell (August 6, 2026 issue) and online on July 16, 2026, at 11:00 a.m. (EDT), provides new insight into why SGLT2 inhibitors improve outcomes for HFpEF patients. Researchers identified that the eNOS-NO-cGMP-PKG pathway—a critical system for regulating heart function—becomes dysfunctional in HFpEF. The investigation found that SGLT2 inhibitors activate the eNOS protein within vascular endothelial cells, effectively restoring this pathway toward a normal state.

Beyond this signaling restoration, the findings indicate that these drugs mitigate cellular stress. The study revealed that SGLT2 inhibitors prevent excessive sodium and calcium influx into cells, which otherwise triggers inflammation. By reducing this burden, the medication helps prevent the further deterioration of heart function. The researchers confirmed these results by observing that when eNOS function was intentionally lost in cells, SGLT2 inhibitors failed to improve heart function or reduce inflammation.

Clinical Impact on Diabetic Kidney Disease Patients

The protective effects of SGLT2 inhibitors extend into clinical practice, particularly for patients with chronic kidney disease (CKD) and diabetes. According to research published in Diabetes Research and Clinical Practice on June 15, 2026, a large-scale analysis of 1,818 patients with diabetic nephropathy demonstrated that SGLT2 inhibitors are effective in reducing cardiac stress.

The study analyzed data from the J-CKD-DB-Ex database to track levels of B-type natriuretic peptide (BNP)—a hormone secreted by the heart that serves as a primary marker for cardiac workload.

This reduction in BNP levels was observed regardless of the patient’s age, sex, or baseline kidney function. While the study noted that the effect was slightly less pronounced in patients already taking diuretics, the positive impact on cardiac load remained consistent across other demographic variables.

Future Directions for Heart Failure Treatment

For patients with diabetic nephropathy, the researchers emphasize that treatment strategies must now account for preventing the progression of heart failure as much as protecting kidney function.

The development of the iPS cell-based HFpEF model is expected to provide a robust platform for future drug discovery, potentially addressing the lack of established, effective treatments for this specific form of heart failure.