Metformin Treatment in Heart Failure With Preserved Ejection Fraction: A Systematic Review and Meta Regression Analysis

Abstract

Background: Observational series suggest a mortality benefit from metformin in the heart failure (HF) population. However, the benefit of metformin in HF with preserved ejection fraction (HFpEF) has yet to be explored. We performed a systematic review and meta-analysis to identify whether variation in EF impacts mortality outcomes in HF patients treated with metformin. Methods: MEDLINE and EMBASE were searched up to October 2019. Observational studies and randomised trials reporting mortality in HF patients and the proportion of patients with an EF > 50% at baseline were included. Other baseline variables were used to assess for heterogeneity in treatment outcomes between groups. Regression models were used to determine the interaction between metformin and subgroups on mortality. Results: Four studies reported the proportion of patients with a preserved EF and were analysed. Metformin reduced mortality in both preserved or reduced EF after adjustment with HF therapies such as angiotensin converting enzyme inhibitors (ACEi) and beta-blockers (β = − 0.2 [95% CI − 0.3 to − 0.1], p = 0.02). Significantly greater protective effects were seen with EF > 50% (p = 0.003). Metformin treatment with insulin, ACEi and beta-blocker therapy were also shown to have a reduction in mortality (insulin p = 0.002; ACEi p < 0.001; beta-blocker p = 0.017), whereas female gender was associated with worse outcomes (p < 0.001). Conclusions: Metformin treatment is associated with a reduction in mortality in patients with HFpEF.

Diabetic phenotype and prognosis of patients with heart failure and preserved ejection fraction in a real life cohort

“…On the other hand, treatment reducing nutrient overload might be beneficial and should be preferred. Metformin, for example, which has shown beneficial effect on mortality in HF patients [ 49 ], although often referred to as insulin sensitizer, has its main glucose-lowering effect via reducing hepatic glucose production. Similarly, SGLT-2 inhibitors lower blood glucose by promoting glycosuria.…”

Metformin and the heart: Update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure

“…Strong pathogenic links have emerged between diabetes and HF with preserved ejection fraction (HFpEF) [41]. A meta-analysis of four studies in patients with T2D and HFpEF demonstrated a significant reduction in mortality with metformin, especially for those with LVEF > 50% [42]. A recent retrospective study of patients with type 2 diabetes and HFpEF demonstrated reduced mortality associated with metformin only in patients with sub-optimal glycaemic control (HbA1c ≥ 7%) [43].…”

“…HFpEF, in particular, is regarded increasingly as a hitherto under recognised cardiovascular complication of diabetes, and is associated with a severely adverse prognosis [41]. The EMPEROR Preserved trial [130] recently identified a SGLT2 inhibitor as the first pharmacologic intervention to improve hard clinical outcomes in this populationthe suggestion of improved outcomes in metformin-treated patients with HFpEF from a metaanalysis [42] and retrospective studies [43,44], described above, merits further study.…”

The effects of antidiabetic agents on heart failure

“…A more recent meta-analysis by Halabi et al that specifically investigated all-cause mortality in diabetic patients with heart failure did stratify results according to HFrEF and HFpEF [12]. In this meta-analysis, which pooled data of 22,469 patients from four observational studies (including three that were also included by Crowley et al), metformin reduced allcause mortality in patients with HFpEF (β = -2.3 (95% CI -3.3 to -1.3)) but not HFrEF (β = 0.2 (95% CI -0.2 to 0.6)).…”