# Efficacy and safety of soluble guanylate cyclase stimulators or activators for chronic kidney disease: a systematic review and meta-analysis

## TL;DR

This study reviews preclinical evidence suggesting that drugs targeting the NO-sGC-cGMP pathway may help treat chronic kidney disease by improving kidney function and reducing harmful markers.

## Contribution

The study provides a meta-analysis of preclinical data on sGC stimulators and activators for CKD, highlighting their renoprotective effects and potential for future clinical development.

## Key findings

- sGC stimulators and activators significantly reduced kidney weight, blood pressure, and serum uric acid levels in preclinical studies.
- Renal function improved as indicated by reduced serum creatinine and blood urea nitrogen levels.
- Treatment efficacy was consistent across sGC types but may vary depending on the type of chronic kidney disease.

## Abstract

Chronic Kidney Disease (CKD) poses a major global health burden, leading to serious complications and death. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling axis regulates various kidney functions. sGC stimulators (sGCs) and activators (sGCa) are emerging as a potential new approach for the treatment of renal disorders. However, there is still a lack of large-scale research on CKD.

We systematically searched the PubMed, Embase, Web of Science, and Cochrane Library databases from January 1971 to December 2025 to identify studies examining the effects of sGCs or sGCa on CKD. Pooled standardized mean differences (SMDs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for study outcomes.

Ten studies were included in the final analysis. The administration of sGCs or sGCa was associated with significant reductions in kidney weight (SMD = −1.55, 95%CI: −2.19, −0.90), systolic blood pressure (SMD = −3.52, 95%CI: −6.48, −0.56), and serum uric acid levels (SMD = −3.82, 95%CI: −4.84, −2.80), alongside improved renal function (serum creatinine: SMD = −3.24, 95%CI: −4.94, −1.55; blood urea nitrogen: SMD = −3.53, 95%CI: −5.30, −1.76). However, no significant impact on body weight was observed (SMD = −0.24, 95%CI: −1.17, 0.68). Subgroup analysis indicated that treatment efficacy remained consistent regardless of the specific sGC type but may vary across different forms of chronic kidney disease.

This preclinical meta-analysis indicates that sGC stimulators and activators exert renoprotective effects in CKD, with efficacy potentially influenced by disease etiology. By restoring impaired NO–sGC–cGMP signaling through distinct mechanisms, these agents may offer complementary therapeutic options for different CKD types and inform future clinical trial design.

The present study has been registered on PROSPERO (Registration No. CRD420251162902).