Ketones, SGLT2, HFrEF

The study team will examine the effects of elevated plasma ketones caused by 12-week treatment with an SGLT2i (empagliflozin) treatment in participants with T2DM and HF. The study team will focus on three possible mechanisms of action for these effects and test the following: (i) Skeletal muscle bioenergetics. Using 31P-MRS, the team will quantify phosphocreatine \[PCr\], ATP, inorganic phosphate, phosphodiester, and intracellular pH. With 1H-MRS, and will measure intramyocellular lipid content at rest and ATPmax production after exercise. The team will examine the relationships between phosphorous metabolite concentrations, intramyocellular lipid content, and ATP generation before and after 12 weeks of SGLT2 inhibition. (ii) LV systolic and diastolic function using cardiac MRI in type 2 diabetic patients with Class II-III NYHA heart failure and reduced EF. (iii) To examine the contribution of the SGLT2i-induced increase in plasma ketone concentration on myocardial function and myocardial blood flow by inhibiting the rise in plasma ketone concentration with acipimox while continuing empagliflozin. (iv) Improvements in Patient-Reported Outcomes (PRO). Kansas City Cardiomyopathy Questionnaire ( KCCQ) scoring will be used to evaluate self-reported physical function and well-being. This tool is a well-developed and validated method to obtain patient self-reported parameters of health in adults.