Metabolic modulation has been an attractive therapeutic approach to heart failure as scientific evidence for an altered metabolic state in the failing heart has been demonstrated for decades. However, the ability to safely alter the substrate metabolism in the myocardium without adverse effects while at the same time be able to provide long-term benefits have not been widely investigated. Meanwhile, the ability to alter long-term molecular, cellular, and hormonal changes as a result of progressive cardiac dysfunction has been directly associated with improvement in clinical outcomes. Among the drugs that have been studied, glucagon-like peptide-1 (GLP-1) analogs and trimetazidine have demonstrated promise in this area. Data on GLP-1, although promising, remain to show short-term improvements. In contrast, trimetazidine has extensive long-term experience with favorable effects on reverse remodeling. However, the appropriate candidate to receive such therapies and the appropriate targets of therapy remain unclear, which may warrant further investigations.