Combination therapy improves heart failure measures in retrospective Chinese cohort

A single-centre retrospective cohort study of 150 adults with heart failure found that adding the SGLT2 inhibitor dapagliflozin to sacubitril-valsartan was associated with larger improvements in cardiac function, neuroendocrine and inflammatory biomarkers, quality of life and safety measures than sacubitril-valsartan alone. The analysis, conducted at The First People’s Hospital of Jiande in China between October 2023 and October 2025, compared 75 patients receiving sacubitril-valsartan with 75 who received the combination regimen. Serum markers were assessed three months after treatment began, while echocardiographic outcomes and follow-up data extended to six months.

The groups had similar baseline characteristics, including age, sex, body mass index, New York Heart Association functional class, causes of heart failure, diabetes, hypertension, coronary artery disease and background use of beta-blockers or mineralocorticoid-receptor antagonists. Both groups also received routine heart-failure management, including health education, medication adherence support, individualized dietary advice, exercise recommendations, smoking cessation, alcohol restriction, weight control and monthly home-care sessions. These measures were part of clinical care rather than interventions assigned specifically for the retrospective analysis. Treatment was selected in routine practice, so the study compared outcomes associated with different regimens rather than randomly allocating patients to a drug combination.

Both treatment pathways were associated with improved cardiac measures. In the sacubitril-valsartan group, mean left-ventricular ejection fraction rose from 37.42% to 48.47%, left-ventricular end-diastolic diameter fell from 56.54 to 50.11 millimetres, left-ventricular end-systolic diameter decreased from 43.83 to 37.98 millimetres, and cardiac output increased from 3.19 to 4.09 litres per minute. The corresponding changes in the combination group were larger: ejection fraction increased from 37.06% to 53.08%, end-diastolic diameter decreased from 56.28 to 46.68 millimetres, end-systolic diameter fell from 43.63 to 35.62 millimetres, and cardiac output rose from 3.32 to 4.96 litres per minute. All between-group post-treatment differences were reported as statistically significant.

The biological markers pointed in the same direction. Three months after treatment, N-terminal pro-B-type natriuretic peptide, or NT-proBNP, declined from 1,791.43 to 882.26 picograms per millilitre in the sacubitril-valsartan group and from 1,775.19 to 380.14 picograms per millilitre in the combination group. Cardiotrophin-1 fell from 321.17 to 221.35 pg/mL with sacubitril-valsartan and from 323.73 to 152.97 pg/mL with combination therapy. Beta-endorphin decreased from 143.19 to 108.21 pg/mL and from 140.99 to 72.67 pg/mL, respectively. The combination group therefore had lower post-treatment values for all three markers, with reported intergroup P values below 0.01.

Combination therapy was also associated with a larger reduction in circulating inflammatory cytokines. Interleukin-1 beta fell from 65.14 to 42.89 nanograms per litre in the sacubitril-valsartan group and from 63.72 to 34.22 ng/L in the combination group. Interleukin-6 declined from 35.25 to 22.37 ng/L with sacubitril-valsartan and from 34.76 to 12.77 ng/L with combination treatment. Tumor necrosis factor alpha decreased from 29.52 to 15.72 ng/L and from 29.87 to 10.72 ng/L, respectively. The post-treatment differences were significant, but the measurements cannot establish a direct molecular mechanism: lower cytokines might reflect an anti-inflammatory effect, improved haemodynamics, or both, and circulating concentrations do not directly reveal the pathways operating in heart tissue.

Researchers classified patients as having an obvious effect, an effective response or no response by combining changes in ejection fraction, ventricular diameters, cardiac output, NT-proBNP, cardiotrophin-1, beta-endorphin and inflammatory markers. On that composite definition, 63 of 75 patients in the sacubitril-valsartan group responded, giving a response rate of 84.00%. Seventy of 75 patients in the combination group responded, producing a rate of 93.33%. The difference was significant by a chi-square test. The Minnesota Living with Heart Failure Questionnaire also showed a larger improvement in the combination group: the mean score declined from 50.66 to 25.37 with sacubitril-valsartan and from 49.42 to 20.14 with combination therapy. Because lower scores indicate less heart-failure-related distress, the result suggests better reported quality of life in the combination arm.

Safety outcomes were numerically more favourable among patients who received combination therapy. Complications occurred in 11 of 75 patients in the sacubitril-valsartan group, or 14.67%, and in four of 75 in the combination group, or 5.33%. The total difference was significant, although individual event categories were not. The combination group had one sudden cardiac death, one heart-failure readmission, one acute myocardial infarction, no stroke and one severe arrhythmia; the sacubitril-valsartan group had two sudden deaths, three readmissions, two acute myocardial infarctions, two strokes and two severe arrhythmias. Drug-related adverse reactions affected 15 patients receiving sacubitril-valsartan alone, or 20.00%, and seven receiving combination therapy, or 9.33%, a significant overall difference. Recorded reactions included dizziness, orthostatic hypotension, urinary frequency, nausea, diarrhoea, liver dysfunction, muscle pain and hyperkalemia.

The results are consistent with the complementary pharmacology of the two treatments. Sacubitril-valsartan blocks angiotensin II receptors while inhibiting neprilysin, the enzyme that degrades natriuretic peptides; the combination therefore combines suppression of the renin-angiotensin-aldosterone system with enhanced natriuretic, vasodilatory and diuretic effects. Dapagliflozin inhibits glucose reabsorption in proximal renal tubules, producing osmotic diuresis and potentially reducing preload. The study also describes effects on myocardial energy metabolism, oxidative stress, inflammation and remodelling. Together, these pathways could plausibly contribute to the observed changes, although the retrospective design and biomarker-only measurements cannot determine whether the benefits arose from pharmacologic synergy, differences in other care, or unmeasured patient characteristics.

Several limitations constrain the findings. The study recruited patients from one hospital, and its 150-person sample may not represent the wider population with heart failure. Treatment was not randomized, and although recorded baseline variables were balanced, the analysis did not include multivariate adjustment for potential confounders. Only outcome assessors were blinded; patients and treating clinicians knew which regimen they received. The follow-up was short, with laboratory outcomes measured at three months and echocardiographic outcomes at six months, so the study did not establish long-term effects on mortality, sustained remodelling, repeated hospitalization or quality of life. There were also few cardiovascular events and no stratified analyses by dose, heart-failure subtype, functional class or age. The results therefore show an association with better outcomes, not definitive proof that adding dapagliflozin causes the improvements or reduces major cardiovascular risk. Larger multicentre studies with longer follow-up and prespecified adjustment would be needed to determine how broadly the findings apply.

Subject of Research: Retrospective comparison of sacubitril-valsartan with and without dapagliflozin in 150 Chinese heart-failure patients

Article Title: Mechanisms and clinical outcomes of sacubitril-valsartan and SGLT2 inhibitors in heart failure patients: a retrospective cohort study

Article References: Zhong, X., Xia, L., Li, L., & Tang, B. (2026). Mechanisms and clinical outcomes of sacubitril-valsartan and SGLT2 inhibitors in heart failure patients: a retrospective cohort study. Frontiers in Cardiovascular Medicine, 13, Article 1931636. https://doi.org/10.3389/fcvm.2026.1931636

Image Credits: AI Generated

DOI: 10.3389/fcvm.2026.1931636

Keywords: heart failure, sacubitril-valsartan, dapagliflozin, SGLT2 inhibitors, cardiac function, inflammation, neuropeptide biomarkers, retrospective cohort, Mechanisms, clinical, outcomes, SGLT2