Reducing Circulating Sphingolipid Levels to Optimise Cardiometabolic Health - The SphingoFIT Randomised Controlled Trial

Overnutrition, reduced energy expenditure and chronic inflammation stimulate triglyceride storage. Once the triglyceride stores are saturated, lipids in excess are redirected to form sphingolipids. However, sphingolipid accumulation drives complex molecular alterations, which promote peripheral insulin resistance and atherosclerosis. Failure to manage this sphingolipid overload eventually results in diabetes mellitus and coronary artery diseases. In the last decade, these pathophysiological findings found resonance in milestone clinical studies. In primary prevention, a score combining the blood level of four sphingolipids outperformed the 2019 SCORE of the European Society of Cardiology in terms of cardiovascular risk prediction. The same score predicted cardiovascular mortality beyond low-density lipoprotein cholesterol in secondary prevention. Remarkably, sphingolipids are not limited to cardiovascular risk prediction, as they were shown to predict diabetes mellitus onset ten years before the disease was diagnosed. While the utility of sphingolipid profiling to stratify cardiometabolic risk is well-established, little is known about therapeutic modalities to lower sphingolipid levels. If circulating sphingolipids are to be measured in clinical practice, providing patients with evidence-based sphingolipid-lowering interventions is essential. As exercise is a powerful means to prevent and treat cardiometabolic diseases, exercise interventions are ideal candidates for mitigating sphingolipid levels in a cost-effective, safe, and patient-empowering manner. This 2-arm, monocentric, randomised controlled trial explores whether and to what extent an 8-week fitness-enhancing training programme can lower serum sphingolipid levels of middle-aged adults at elevated cardiometabolic risk (n= 98, 50% females). The exercise intervention will consist of supervised high-intensity interval training (three sessions weekly), while the control group will receive physical activity counselling based on current guidelines. Maximal cardiopulmonary exercise tests will be performed before and after the 8-week programme to verify patients' fitness has improved. Blood will be sampled early in the morning in a fasted state before and after the 8-week programme. Participants will be provided with individualised, pre-packaged meals for the two days preceding blood sampling to minimise potential confounding. An 'omic-scale sphingolipid profiling, using high-coverage reversed-phase liquid chromatography coupled to tandem mass spectrometry, will be applied to capture the circulating sphingolipidome. Classical biomarkers of cardiometabolic health (total cholesterol, low- and high-density density lipoprotein cholesterol, triglycerides, glycated haemoglobin, and the homeostatic model assessment for insulin resistance) and retinal vessel diameters, a novel surrogate of microvascular health, will also be assessed pre-and post-intervention. This study will inform clinicians whether and to what extent exercise can be used as an evidence-based treatment to lower circulating sphingolipid levels.