Advanced glycation end product (AGE) formation is characterized by the glycation of plasma proteins during longstanding hyperglycemia. These AGEs then stimulate transmembrane receptors of advanced glycation end products (rAGE) on somatic cells including cardiac myocytes resulting in the alteration of intracellular signaling, gene expression, and release of proinflammatory molecules and free radicals. These processes are thought to play a role in the development of diabetic cardiomyopathy. Much of the evidence for starting SGLT2 inhibitors to modify the pathology noted above focuses on advanced indications such as greater than-stage A heart failure, end-stage kidney disease, and elevated HbA1c diabetes. This evidence has firmly entrenched the SGLT2 inhibitors inside the treatment armamentarium of symptomatic heart failure and diabetes care. However, a subset of non-diabetic patients inside these trials who had preserved systolic function showed decreased heart failure morbidity with the same SGLT2 inhibitor therapies. We seek to present evidence that SGLT2 inhibitors may be a consideration for early heart failure prevention in Stage A patients. As an early

glycation end product itself, HbA1c is nicely positioned as an early hemodynamic risk marker inside this mechanism.

In light of this, we are presenting evidence that:

1. Confirms a relationship between HBA1c and subtle and graduated levels of cardiac dysfunction portending the use of HBA1c as an early/subclinical disease marker in heart failure. (published data)

2. Confirms a meta-analytic review of the literature which shows an association between SGLT2 inhibitor use and decreased morbidity and mortality inside of earlier forms of heart failure. (preparing to publish data)

3. Reminds us to be careful in the widespread application of these principles due to unexpected side effects of SGLT2 inhibitor therapy in the setting of masked autoimmune diabetes (LADA). (published data)

Dr. Doug Duffee MD MDiv FACP is a Fellow of the American College of Physicians and an American Board of Internal Medicine certified General Internist with over 25 years of patient care, hospital administrative, academic teaching, and community volunteer experience. While currently serving as the Program Director for Parkview Medical Center’s Internal Medicine Residency Program and as an Adjunct Associate Professor of Medicine at Rocky Vista University, his academic interests include Diabetic cardiomyopathy and point-of-care ultrasound. Clinically, in addition to his current role in resident teaching, he has worked in a large multispecialty group practice and later built a solo traditional Internal Medicine practice. He trained in Internal Medicine at the Mayo Clinic in Rochester Minnesota, USA and as part of that training published the original clinical description of PVC-induced cardiomyopathy. As a generalist, the overlap between preventive cardiovascular care, diabetes, and spiritual lifestyle is an active interest.