Discussion
epilepsy, inflammation, ketosis, diabetes, heart failure, metabolic migraine, migraine
MIGRAINE, INFLAMMATION, KETOSIS, EPILEPSY
Classifying sub-groups of migraineurs based on objective biomarkers is essential for improving clinical study designs, developing novel treatments and ultimately, improving clinical care. Hereby, we documented metabolic markers in BHB supplementation responders differed from those who did not respond. To our knowledge, this is the first work proposing blood biomarkers for predicting treatment response to migraine prophylaxis and could help pave the way not only for testing future anti-inflammatory/metabolic interventions, but also for reassessing already existing solutionsHowever, there were several limitations to this analysis. At trial onset, only the racemic BHB was available, which has ½ of the potency of the bioidentical D- BHBDespite the trial’s limitations, we could find potentially useful and easily available predictors (and their potentially useful cut-offs) for identifying whether a person belongs to the responder group or not based on the independent markers of inorganic phosphorous, HS-CRP (a marker for inflammation) and Hba1C (long-term blood sugar) and this result is highly significant—despite our small sample size but should be prospectively validated in future studies.In contrast, several markers of metabolism and inflammation were worse in the BHB responder group while no pharmacokinetic differences were found. Additionally, most of these markers improved or started looking more like the non-responder group after the intervention. Most notably hs-CRP (inflammation) more than halved and this change was significant, despite the small sample size (n = 9), thus, it is likely the rest of the paired analyses were underpowered. Together, these findings suggest that responders were responding because of their baseline pathophysiological differences and not because they were exposed to higher doses of BHB.While the connection to energy metabolism with glucose, insulin, KBs, HbA1c and triglycerides seems evident, the other markers also have a strong connection to metabolism. Hs-CRP has been found to be a marker of impaired energy metabolism, in addition to a marker of acute systemic inflammationIt is necessary to mention we are not the first ones to find an association between treatment response to a metabolic migraine therapeutic and a biomarker. Over a decade ago the therapeutic response to high-dose riboflavin was shown to be associated with specific mitochondrial DNA (mtDNA) haplogroups (non- H mitochondrial DNA haplotypes)We should highlight that the utility of these individual predictors is context dependant and we provided data for cost–benefit assessments. For example, as shown in Table Finally, it is possible that these potentially relevant metabolic predictors are not migraine specific and could be useful for studies on other illnesses for which ketosis has been hypothesized to be beneficial such as diabetes, heart failure and epilepsy.