New directions in diagnosis and treatment for heart failure in patients with type 2 diabetes are discussed by Dr Swoboda and Professor Plein from Leeds, UK Patients with type 2 diabetes mellitus have a two- to three-fold increased risk of developing heart failure independently of conventional risk factor such as age, sex, coronary artery disease and hypertension. When patients with diabetes develop heart failure, they have substantially worse outcomes than those without diabetes, making this combination of diseases a pressing clinical problem. The pathophysiology of diabetic heart failure is complex and includes adverse effects of hyperglycaemia, hyperinsulinaemia, insulin resistance, and altered lipid metabolism on the myocardium, as well as endothelial dysfunction and autonomic neuropathy. Despite these numerous contributors to diabetic heart failure, its current treatment follows similar principles to that of non-diabetic populations, partly because specific therapies for diabetic heart failure have been elusive. An obvious disease-specific target for the condition would be to improve glycaemic control. Indeed, large observational studies have shown that poor control of blood glucose increases the risk of heart failure, in particular in female patients. However, initial trials failed to show a reduction in the risk of heart failure hospitalization in patients with diabetes despite improved glucose control. To compound matters some agents such as the peroxisome proliferator-activated receptor gamma (PPARγ) agonists, even increased heart failure events. New directions in treating diabetic heart failure Two recently published trials of sodium-glucose co-transporter-2 (SGLT2) inhibition have shown promising results and suggest a new direction for more disease-specific therapy of patients with diabetic heart failure. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) was published in 2015 and included 7020 patients with type 2 diabetes who were randomized to empagliflozin or placebo and The Canagliflozin Cardiovascular Assessment Study (CANVAS), in which 10 142 patients with type 2 diabetes were randomized to canagliflozin or placebo, was published in 2017. Both studies specifically recruited patients with increased cardiovascular risk and included a proportion of patients with existing heart failure at randomization (10.1% in EMPA-REG OUTCOME and 14.4% in CANVAS). Furthermore, all patients in EMPA-REG OUTCOME had established cardiovascular disease: coronary artery disease (75%), myocardial infarction (47%), prior coronary artery bypass (25%), stroke (23%), and peripheral artery disease (21%). In CANVAS, the prevalence of cardiovascular disease at baseline was 72% including coronary artery disease (56%), stroke (19%), and peripheral artery disease (21%). Both studies reported rates of heart failure admission as a secondary endpoint and in both there were significant reductions (35% and 33%, respectively), making SGLT2 inhibitors the first class of hypoglycaemic agent that has been shown to reduce the risk of heart failure in type 2 diabetes. Given the poor prognosis of patients with both diabetes and heart failure there is an urgent need to understand how to improve heart failure risk stratification in patients with diabetes and to identify which patients are most likely to benefit from treatment with SGLT-2 inhibition. A sub-analysis of EMPA-REG OUTCOME was published in this journal (doi: 10.1093/eurheartj/ehx511) and demonstrated that empagliflozin reduced the risk of heart failure in all patients irrespective of the baseline estimated risk of heart failure. The risk of heart failure was estimated using the Health ABC HF Risk score derived from age, coronary artery disease, systolic blood pressure, heart rate, left ventricular hypertrophy (assessed by electrocardiogram), smoking, serum albumin, fasting blood glucose, and creatinine. Cardioprotective mechanisms of SGLT2 inhibitors Despite the high burden of established cardiovascular disease in both EMPA-REG OUTCOME and CANVAS, neither of them included formal baseline cardiac imaging assessment. This was a missed opportunity to provide further insight into the mechanism of heart failure in diabetes and the mechanisms that underpin the beneficial effects of SGLT2-inhibition in diabetic heart failure. Several such mechanisms have been postulated. In addition to their antiglycaemic effects, SGLT2 inhibitors promote natriuresis and osmotic diuresis, reducing preload and blood pressure, as well as arterial stiffness and afterload. Improved cardiac metabolism and subendocardial blood flow have been proposed as cardioprotective mechanisms. Advanced imaging to improve the understanding of heart failure in diabetes Non-invasive imaging can detect multiple pathological processes in patients with type 2 diabetes. Echocardiography studies have shown that type 2 diabetes is associated with impairment of diastolic and systolic (particularly global longitudinal strain) function which both appear to increase the risk of heart failure. Using nuclear imaging such as single-photon emission computed tomography (SPECT) or positron emission tomography both occult ischaemia and global impairment of cardiac microvasculature can be detected in type 2 diabetes. With cardiovascular magnetic resonance (CMR) both focal fibrosis by late gadolinium enhancement and diffuse fibrosis by T1 mapping have been reported and appear to be related to heart failure outcomes. These imaging tests are widely available and are performed routinely in clinical cardiology. Other, more advanced imaging is beginning to improve our understanding of diabetic heart failure. For example, studies using exercise magnetic resonance spectroscopy have shown that energetic reserve is reduced in these patients. At present, however, it remains unclear which are the most powerful predictors of heart failure events in type 2 diabetes and whether any imaging biomarker can identify those most likely to benefit from pharmacological intervention. Cardiac imaging in future trials of hypoglycaemic agents Non-invasive imaging can detect early and late abnormalities in both asymptomatic and symptomatic patients with type 2 diabetes mellitus. Inclusion of baseline imaging in clinical trials would help identify not only the mechanism by which SGLT2 inhibitors and other novel hypoglycaemic agents decrease risk of heart failure but would also answer the greater questions of how diabetes itself leads to heart failure independently of other risk factors. In the past decade, there has been a dramatic transformation in clinical trials in diabetes so that they now routinely report cardiovascular outcomes. We would advocate that future trials should also include detailed baseline imaging phenotyping in at least a subset of randomized patients. Echocardiography, SPECT or focused CMR can be conducted quickly with minimal inconvenience to the patient. The inclusion of cardiac imaging in future clinical trials would generate valuable data on the potential of imaging biomarkers to describe mechanisms of diabetic heart failure and guide therapy. In the future cardiac imaging might have a role in stratifying heart failure risk, helping clinicians to provide personalized care. With the ever-increasing range of hypoglycaemic agents in type 2 diabetes, we advocate that non-invasive cardiac imaging has an important potential role in identifying and targeting treatment those at the highest risk. Conflict of interest: none declared. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: firstname.lastname@example.org. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
European Heart Journal – Oxford University Press
Published: May 21, 2018
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