Drugs targeting the NO-sGC-cGMP pathway in the treatment of patients with COPD-associated pulmonary hypertension: a systematic review

Abdullah A. Alqarni^1*Sara Alghamdi²Abdulelah Aldhahir³Jaber S Alqahtani⁴Rayan A Siraj⁵Ahmed H Alasimi⁶Heba Bintalib⁷Abdulkareem A Algarni⁸Mansour S. Majrshi⁹Adel M Alshabasy¹⁰Hassan Alwafi¹¹

• ¹Department of Respiratory Therapy, Faculty of Medical Rehabilitation Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
• ²AlSalama Hospital, Jeddah, Saudi Arabia
• ³Jazan University, Jazan, Saudi Arabia
• ⁴Prince Sultan Military College of Health Sciences, Dhahran, Saudi Arabia
• ⁵King Faisal University, Al Ahsa, Saudi Arabia
• ⁶Georgia State University, Atlanta, United States
• ⁷King Saud bin Abdulaziz University for Health Sciences College of Nursing, Jeddah, Saudi Arabia
• ⁸King Saud bin Abdulaziz University for Health Sciences College of Nursing, Al Ahsa, Saudi Arabia
• ⁹Imperial College London, London, United Kingdom
• ¹⁰King Abdulaziz Hospital, Jeddah, Saudi Arabia
• ¹¹Umm Al-Qura University, Mecca, Saudi Arabia

Background: Pulmonary hypertension (PH) due to chronic obstructive pulmonary disease (COPD) is categorized as group 3 PH and is associated with increased mortality and morbidity. Currently, there are no approved therapies for those who have PH secondary to COPD due to conflicting evidence. Therefore, this systematic review aims to summarize the current evidence on the effectiveness of drugs targeting the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway on clinical outcomes among patients with COPD-associated PH.We conducted a comprehensive search of electronic databases, including Embase, Medline, Cochrane, and Scopus, from inception to February 1, 2024. Studies investigating the efficacy of drugs targeting the NO-sGC-cGMP pathway on clinical outcomes in patients with COPD-associated PH were included. Exclusion criteria encompassed case reports, systematic reviews, review articles, conference abstracts with no full text, non-full-text articles, non-English manuscripts, opinion articles, and book chapters. Two distinct Cochrane risk-of-bias tools designed for randomized and non-randomized clinical trials were used to evaluate the risk of bias within the selected studies for inclusion.Results: Fourteen studies, comprising a total of 567 adult patients diagnosed with PH secondary to COPD, met the inclusion criteria and were included in this systematic review. Among these, nine studies reported significant improvements in clinical parameters related to pulmonary hemodynamics. Improvement in exercise capacity was observed in four out of seven studies. Three studies evaluated dyspnea severity and quality of life following treatment with agents targeting the NO-sGC-cGMP pathway. Of these, three demonstrated improvement in dyspnea severity while two reported enhancements in health-related quality of life. Substantial heterogeneity was evident regarding the potential of pharmacological agents targeting the NO-sGC-cGMP pathway to enhance gas exchange, lung function, and arterial oxygenation in COPD patients with concurrent PH.The short-term use of oral drugs targeting the NO-sGC-cGMP pathway, particularly sildenafil, demonstrates promising potential for enhancing pulmonary hemodynamics, exercise capacity, dyspnea severity, and health-related quality of life but not lung function and oxygenation status in adult patients with COPD-associated PH. Further double-blind, randomized, placebocontrolled trials are needed to assess the therapeutic benefits of agents targeting the NO-sGC-cGMP pathway, particularly inhaled therapies for managing PH due to COPD.