Over the past decade, clinical development and regulatory review of investigational drugs for diabetes and obesity have been guided by heightened standards for pre- and post-marketing assessment of cardiovascular safety. In high-risk patients with type 2 diabetes, several large multicentre cardiovascular outcome trials (CVOTs) have confirmed non-inferiority, i.e. cardiovascular safety for several glucose-lowering agents. More recent diabetes CVOTs have demonstrated major cardiovascular benefits for drugs representing two newer classes, sodium–glucose cotransporter (SGLT)-2 inhibition and glucagon-like peptide (GLP)-1 receptor agonists. Collectively, hard endpoint data from diabetes CVOTs have ushered in a new era of type 2 diabetes drug development and clinical care. Moreover, some unexpected cardiovascular side-effects have been unearthed for certain drugs. With respect to the history of obesity pharmacotherapy, there have been several instances over the years in which weight-reducing medications were withdrawn from the market because of unacceptable cardiotoxicity, including aminorex, fenfluramine and dexfenfluramine, phenylpropanolamine, and sibutramine. Development programmes for novel anti-obesity drugs are also now required to provide evidence of cardiovascular safety. However, while weight reduction with more recently approved anti-obesity medications has been shown to improve multiple cardiometabolic risk factors, more definitive demonstration of cardiovascular risk/benefit through completion of CVOTs is still awaited. Thus, a marked disparity exists between the CVOT evidence bases for cardiovascular safety of newer glucose-lowering and weight-reducing medications. We believe that in this modern era of metabolic drug development cardiovascular effects of new drug candidates can and should be more rigorously assessed during the early phases of development, to inform go-/no-go decisions. Incorporating advanced imaging-, circulating-, and/or functional biomarkers into early phase development has the potential to identify early signals of cardiovascular risk or benefit, that may not be readily apparent through routine monitoring of traditional risk factors that have been relied upon to date.