Heart Failure in diabetes – getting more complicated?

10th February 2020, Dr Chee L Khoo

Diabetes can either be the sole perpetrator of the heart failure or be an accomplice to other cardiac disease such as coronary artery disease or myocarditis. Diabetic cardiomyopathy can manifest itself either as a restrictive cardiomyopathy with heart failure with preserved ejection fraction (HFpEF) or as a dilated cardiomyopathy with heart failure wth reduced ejection fraction (HFrEF). HFpEF is a lot more common and usually occurs in T2D whereas, HFrEF appears to be more common in T1D. The mechanisms, co-morbidities that lead to either phenotype, their biochemical signs and their treatment are very different (1,2). Thus, it’s worthwhile understanding the pathophysiology of both types of heart failure.


In HFpEF, systemic inflammation from the various metabolic derangements (including Advanced Glycation End-products (AGE), obesity, hyperlipidaemia) causes coronary artery endothelial inflammation and dysfunction which leads to paracrine signalling errors from the endothelium (3,4). This results in leukocyte infiltration of the myocardium. Increased myofibroblasts and increased interstitial collagen deposition results in scarred (stiffened) myocardium without loss of cardiomyocytes.

A stiffened myocardium leads to reduced diastolic filling. While the ejection fraction is “preserved”, the actual diastolic volume ejected is reduced. It is still heart failure because there is a reduction in ejection.


Hyperglycaemia causes increased protein kinase C in fibroblasts leading to increase collagen production and deposition in cardiomyocyte but as replacement fibrosis instead of interstitial fibrosis (5). Accumulation of triglycerides within myocytes in hyperlipidaemia causes myocyte death contributing reduction of functional myocardial fibres. AGE also attached to AGE receptors in the myocardium leading to cardiomyocyte death exacerbating the replacement fibrosis.

Instead of a stiffened myocardium from interstitial fibrosis, replacement fibrosis leads to a dilated myocardium. There is diastolic dysfunction but here, the diastolic volume is increased. Because of the larger diastolic volume, the ejection fraction is reduced. It is still heart failure.

Therapeutic implications in diabetes therapy

Patients with diabetes who develop heart failure has a much higher mortality than patients with diabetes that don’t have heart failure. To diagnose diabetic cardiomyopathy, we need to exclude CAD or hypertensive cardiomyopathy both of which are common in patients with diabetes.

Diet significantly improved peak oxygen consumption (VO2) and quality-of-life scores (6). Furthermore, the combination of diet and exercise training was additive and produced a larger increase in peak VO2 than the increases most drug treatments produced in HFrEF. Interestingly, the increase in peak VO2 was strongly correlated with lower biomarkers of inflammation, which is consistent with obesity driving HFpEF through systemic inflammation (7).

In patients with DM, metformin improved both tissue Doppler long-axis lengthening velocity (e0) and isovolumic relaxation time (8). LVEF is increased. This effect is not seen in patients with diabetes.

Insulin, DPP-4 inhibitors, and GLP-1 analogues all force glucose to enter the myocytes. Forced glucose entry into cells leads to acidosis, myofilamentary desensitisation and reduction in contractile performance. This is particularly deleterious in HFrEF.

Sodium glucose cotransporter-2 inhibitors lower glycaemia through blocked renal glucose reabsorption and enhanced glucosuria. In the SGLT2 inhbitor cardiovascular outcome trials, use of empagliflozin, dapagliflozin and canagliflozin resulted in 30-35% reduction in heart failure hospitalisation. How that is achieve is still unclear.

The DAPA-HF trial recently demonstrated that patients with HFrEF benefit more in patients with HFpEF. There are more dedicated heart failure trials reporting over the next 12 months and we might be clearer as to which agent is better suited for which type of HF (9).


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  2. Ather S, Chan W, Bozkurt B, et al. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol 2012;59:998–1005.
  3. 6. Paulus WJ, Tschoepe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodelling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013;62:263–71.
  4. Redfield MM. Heart Failure with Preserved Ejection Fraction. N Engl J Med 2016;375:1868–77.
  5. Asburn J, Villareal FJ. The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy. J Am Coll Cardiol 2006;47: 693–700.
  6. 50. Kitzman DW, Brubaker P, Morgan T, et al. Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2016;315:36–46.
  7. Santhanakrishnan R, Chong JP, Ng TP, et al. Growth differentiation factor 15, ST2, high-sensitivity troponin T, and N-terminal pro brain natriuretic peptide in heart failure with preserved vs. reduced ejection fraction. Eur J Heart Fail 2012;14:1338–47.
  8. Andersson C, Søgaard P, Hoffmann S, et al. Metformin is associated with improved left ventricular diastolic function measured by tissue Doppler imaging in patients with diabetes. Eur J Endocrinol 2010;163:593–9
  9. Kato ET, Silverman MG, Mosenzon O, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation 2019;139:2528–2536