Are U-shaped relationships between risk factors and outcomes artifactual?

A study evaluated whether the observed nadir in a U- or J-shaped relationship between a particular risk factor and a future health outcome is a function of the distribution of the risk factor in the sample being analyzed.
Data from the ORIGIN trial were used to assess the relationship between three risk factors (weight, systolic blood pressure, and serum insulin) and the hazard of a major cardiovascular event comprising a nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Three spline curves were generated for each risk factor. The first was based on all available data, the second for a subgroup with a higher mean risk factor level, and the third for a subgroup with a lower mean risk factor level. Nadir levels of the risk factor (i.e., risk factor levels predicting the lowest hazard) were then identified for each spline curve.
When compared to the nadir values based on all available data, nadir values for all three risk factors were higher for the subgroups with higher mean levels and lower for those with lower mean levels.
The researchers conclude that the distribution of a risk factor in the population is an important determinant of its nadir value. Populations with high or low values may have high and low nadirs, respectively. Identification of a nadir for a modifiable risk factor from epidemiologic relationships may therefore arise from this distribution bias and is therefore unrelated to therapeutic targets.
Source: Shah, R, Thabane, L, Gerstein, HC. Are U-shaped relationships between risk factors and outcomes artifactual? Journal of Diabetes. 2022; 1- 7.