Utility of invasive and non-invasive cardiovascular research methodologies in drug development for diabetes, obesity and NAFLD/NASH

Mounting evidence supports the existence of clinically important mechanistic intersections between prevalent metabolic and cardiovascular disorders. Novel pharmacotherapies that may simultaneously impact metabolism and vascular function are being developed. While medications for diabetes and obesity are closely scrutinized for cardiovascular safety and efficacy, methodologies for the early phase assessment of vascular function remain underutilized. This consideration extends to drugs being developed for nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), which is associated with an increased risk of atherothrombotic cardiovascular disease. Available cardiovascular methodologies may be classified as either invasive or non-invasive. Invasive methodologies are recommended for the characterization of direct interactions with a target vessel or the vasculature more generally. Various invasive methods that are very selective and precise in their targets are suitable for proof of concept or proof of mechanism studies. Non-invasive methods tend to be more suitable for large cohorts or for screening activities selecting subpopulations of subjects with cardiovascular disease for participation in clinical studies. Thus, a balance exists between the scalable properties of non-invasive methodologies for screening and patient selection on one hand, and the precision of invasive methods as primary or exploratory endpoints when designing a clinical study on the other. B Objective, precise and specific methodologies that are widely available can usefully inform the clinical development strategy of new drugs and devices with predicted or unexpected cardiometabolic effects. An informed decision of particular methods should be based on the molecular, cellular or mechanistic targets of the drug to be evaluated. Consideration should be given to the application of methodologies in early phase and mechanistic clinical trials to identify cardiovascular signals of efficacy and safety. Such methodologies should have levels of sensitivity and reproducibility appropriate for the specific study. The selection of methodologies will depend in part on factors such as cost, availability, and operator expertise. Early identification of safety/efficacy cardiovascular signals can be helpful in de-risking the decision-making process of drug development and/or the informed selection of mandatory cardiovascular endpoints in later phases of the drug lifecycle. These timely insights may save resources such as time and development costs that might otherwise be spent in large and expensive mandatory phase 3/4 cardiovascular outcome trials (CVOTs). This strategy may help to improve the safety profiles of novel drugs and the efficient spending on the planning and execution of cardiometabolic drug development.