Applying metabolomics to cardiometabolic intervention studies and trials: past experiences and a roadmap for the future: Table 1.

Abstract

Metabolomics and lipidomics are emerging methods for detailed phenotyping of small molecules in samples. It is hoped that such data will: (i) enhance baseline prediction of patient response to pharmacotherapies (beneficial or adverse); (ii) reveal changes in metabolites shortly after initiation of therapy that may predict patient response, including adverse effects, before routine biomarkers are altered; and( iii) give new insights into mechanisms of drug action, particularly where the results of a trial of a new agent were unexpected, and thus help future drug development. In these ways, metabolomics could enhance research findings from intervention studies. This narrative review provides an overview of metabolomics and lipidomics in early clinical intervention studies for investigation of mechanisms of drug action and prediction of drug response (both desired and undesired). We highlight early examples from drug intervention studies associated with cardiometabolic disease. Despite the strengths of such studies, particularly the use of state-of-the-art technologies and advanced statistical methods, currently published studies in the metabolomics arena are largely underpowered and should be considered as hypothesis-generating. In order for metabolomics to meaningfully improve stratified medicine approaches to patient treatment, there is a need for higher quality studies, with better exploitation of biobanks from randomized clinical trials i.e. with large sample size, adjudicated outcomes, standardized procedures, validation cohorts, comparison witth routine biochemistry and both active and control/placebo arms. On the basis of this review, and based on our research experience using clinically established biomarkers, we propose steps to more speedily advance this area of research towards potential clinical impact.

Metabolic profiling–multitude of technologies with great research potential, but (when) will translation emerge?

“…In another review in this issue, Sattar and colleagues discuss the applications and use of metabolomics in cardiometabolic intervention studies and trials 88 . They express their concerns regarding the small scale and focus on surrogate outcomes in most metabolomics studies in the area.…”

“…They express their concerns regarding the small scale and focus on surrogate outcomes in most metabolomics studies in the area. Advancing a list of recommendations for future biomarker studies, they call for multi-expertise research coalitions to work together for rigorous experimental study designs, with an early focus on truly relevant clinical questions: 88 the latter an issue recently elaborated in relation to clinical research in general by Ioannidis 89 . They also present an interesting and critical discussion on the potential role of metabolomics in predicting drug responses, and elaborate this in the case of statins.…”

“…Generally, the idea of individual metabolic phenotypes is alluring 90–92 and might in some cases provide additional and predictive value, for not only drugs but dietary substances as well 41 , 93 . However this does not necessarily translate into clinical relevance or applicability and, as the review by Sattar and colleagues 88 indicates, applications of metabolomics in clinical trials are scarce. Recently Würtz and co-workers published a proof-of-concept study 17 –a, “natural”, clinical trial of statin effects 94 –in which they overcame the lack of metabolomics data in randomized controlled trials by using serially collected blood samples in population-based cohorts, in which a subset of individuals had started to use statins during follow-up.…”

Clinical metabolomics: a pivotal tool for companion diagnostic development and precision medicine

“…Clinical metabolomics has also appeared within the pharmaceutical industry as an independent assay in toxicology and disease pathology. In addition, there is an augmented role for metabolomics in drug discovery and preclinical studies contributing to pharmacokinetic and pharmacodynamic characterization of drug candidates [4,6,7].…”

“…This is mandatory in terms of model interpretation and biochemical relevance. Additionally, clinical metabolomics offers a layer of understanding that bridges socioeconomic barriers, and may identify the needs of underserved populations that may also influence response to therapeutic intervention and outcome based on their metabolic phenotype [6,7,10]. For example, urinary metabolite excretion patterns were found to be different between East Asian and Western populations, Japanese individuals living in Japan or in the USA, and Chinese participants living in the northern and southern parts of China.…”