The following are key points to remember from this review on heart failure with preserved ejection fraction (HFpEF) and diabetes:

1. HFpEF is a heterogenous syndrome of multiple distinct phenotypes. It is more prevalent than heart failure with reduced ejection fraction (HFrEF) and is associated with higher mortality and readmission rates due to noncardiovascular causes. One important phenotype may be related to co-existing conditions such as diabetes mellitus (DM). About 45% of patients with HFpEF have DM.
2. Data from four large clinical trials of HFpEF patients (defined as EF >40% to ≥50%) showed that association of DM with all-cause and cardiovascular mortality and HF readmissions was stronger in HFpEF than in HFrEF patients. In addition, clinical trial data suggest that DM in HFpEF patients is associated with a greater burden of comorbidities, worse functional status, and elevated markers of inflammation with more signs of volume overload.
3. To reflect real-world outcomes, the authors examined baseline characteristics and short-term outcomes of 232,656 HFpEF patients from the Get With The Guidelines-Heart Failure registry. Patients with HFpEF and DM were younger but had more comorbidities compared to those without DM. In multivariable analyses, DM was not independently associated with in-hospital mortality. However, DM was associated with longer length of stay and lower likelihood of being discharged home. Furthermore, DM was associated with increased risk for 30-day all-cause and HF readmission.
4. The authors postulate that differences in hemodynamic mechanisms among patients with HFpEF and DM compared to those without DM may lead to volume overload faster, leading to earlier re-hospitalization. However, slower mechanisms leading to remodeling that increase mortality may not become evident at the 30-day interval assessed in this study.
5. Patients with DM have alterations in sodium handling predisposing them to congestion, cardiorenal syndrome, and decreased diuretic responsiveness. This includes up-regulation of sodium glucose cotransporter-2 (SGLT-2) receptors, leading to increased sodium absorption. In randomized trials among patients with established cardiovascular disease and DM, use of SGLT-2 inhibitors was associated with a reduction in major cardiovascular endpoints with reduction in HF hospitalizations. Studies assessing SGLT-2 inhibition in HFpEF are currently ongoing.
6. Increased adiposity seen with DM leads to release of pro-inflammatory cytokines. Accordingly, caloric restriction may have beneficial effects on inflammation by reducing adiposity in HFpEF patients with DM.
7. Other mechanisms leading to systemic inflammation in HFpEF patients with DM are mediated by fatty acid oxidation, lower nitric oxide levels, and advanced glycation end-products. Accordingly, targeting these pathways may inhibit reverse remodeling and reduce mortality in this population. For example, glucagon like peptide-1 receptor agonists reduce atherosclerotic burden, inflammation, and endothelial dysfunction. Studies with these agents are yet to be carried out in the HFpEF population. Neprilysin inhibition, which improves endothelial function and reduces myocyte stiffness, is currently being tested in the PARAGON-HF trial among HFpEF patients.
8. Poor functional status among DM patients with HFpEF is likely secondary to poor skeletal muscle function with change in composition, impaired oxygen delivery, and chronotropic incompetence. Functional capacity has been shown to increase in HFpEF following an exercise program. This may specifically have benefits in the DM population.
9. Higher burden of comorbidity in patients with DM and HFpEF reflects the need for a team-based approach between cardiologists, endocrinologists, and primary care physician. Early follow-up may help reduce re-hospitalization rates, and use of novel solutions such as seeing multiple providers at one visit may help improve quality of care provided.

Keywords: Adiposity, Caloric Restriction, Cardio-Renal Syndrome, Comorbidity, Diabetes Mellitus, Diuretics, Exercise Therapy, Fatty Acids, Glucagon-Like Peptide 1, Heart Failure, Hospital Mortality, Inflammation, Neprilysin, Obesity, Patient Readmission, Quality of Health Care, Secondary Prevention, Sodium-Glucose Transport Proteins, Stroke Volume, Up-Regulation

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