Objective · To investigate the effects of different blood glucose (BG), blood pressure (BP) control levels and atrial fibrillation (AF) control strategies on the risk of the new-onset heart failure with preserved ejection fraction (HFpEF) in patients with type 2 diabetes mellitus (T2DM), hypertension and AF. Methods · A total of 418 patients with T2DM, hypertension and AF, but without clinical signs or symptoms of heart failure, admitted to the Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine from January 2008 to December 2012 were enrolled. The participants were followed up for 7 years to examine the effects of BG control [glycosylated hemoglobin (HbA1c): <7.0%, 7.0%–8.0% and >8.0%), BP control [24 h systolic BP (SBP): <120 mmHg (1 mmHg=0.133 kPa), 120–140 mmHg and >140 mmHg] and rhythm or rate control for AF on new-onset HFpEF. Univariate and multivariate Cox regression models were used to estimate the related risk factors of new-onset HFpEF. Results · With a 7-year follow-up, the new-onset HFpEF occurred in 67 of 418 enrolled patients. In different control levels for diabetes mellitus, hypertension and AF, the intensive control of BG (HbA1c<7.0%), poor control of BP (24 h SBP>140 mmHg) and rate control of AF had the highest risk (37.9%), and the conservative control of BG (HbA1c 7.0%–8.0%), intensive control of BP (24 h SBP<120 mmHg) and rhythm control of AF had the lowest risk of new-onset HFpEF (4.8%). Multivariable Cox regression analysis showed that rate control for AF (HR=1.727, 95%CI 1.079–2.997, P=0.036) was independently associated with the presence of new-onset HFpEF. Conclusion · Conservative control of BG, besides intensive control of BP and rhythm control of AF, is found to be a crucial factor to delay the progression of HFpEF among patients with T2DM, hypertension and AF.