Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome.

AIMS/HYPOTHESIS: Diabetes is one of the cardinal features of thiamine-responsive megaloblastic anaemia (TRMA) syndrome. Current knowledge of this rare monogenic diabetes subtype is limited. We investigated the genotype, phenotype and response to thiamine (vitamin B1) in a cohort of individuals with TRMA-related diabetes. METHODS: We studied 32 individuals with biallelic SLC19A2 mutations identified by Sanger or next generation sequencing. Clinical details were collected through a follow-up questionnaire. RESULTS: We identified 24 different mutations, of which nine are novel. The onset of the first TRMA symptom ranged from birth to 4 years (median 6 months [interquartile range, IQR 3-24]) and median age at diabetes onset was 10 months (IQR 5-27). At presentation, three individuals had isolated diabetes and 12 had asymptomatic hyperglycaemia. Follow-up data was available for 15 individuals treated with thiamine for a median 4.7 years (IQR 3-10). Four patients were able to stop insulin and seven achieved better glycaemic control on lower insulin doses. These 11 patients were significantly younger at diabetes diagnosis (p = 0.042), at genetic testing (p = 0.01) and when starting thiamine (p = 0.007) compared with the rest of the cohort. All patients treated with thiamine became transfusion-independent and adolescents achieved normal puberty. There were no additional benefits of thiamine doses >150 mg/day and no reported side effects up to 300 mg/day. CONCLUSIONS/INTERPRETATION: In TRMA syndrome, diabetes can be asymptomatic and present before the appearance of other features. Prompt recognition is essential as early treatment with thiamine can result in improved glycaemic control, with some individuals becoming insulin-independent. DATA AVAILABILITY: SLC19A2 mutation details have been deposited in the Decipher database ( https://decipher.sanger.ac.uk/ ).

The Efficacy of vitamin C, thiamine, and corticosteroid therapy in adult sepsis patients: a systematic review and meta-analysis.

Previous studies have suggested favorable outcomes of hydrocortisone, ascorbic acid (vitamin C), and thiamine (HAT) therapy in patients with sepsis. However, similar results have not been duplicated in sequential studies. This meta-analysis aimed to reevaluate the value of HAT treatment in patients with sepsis. Electronic databases were searched up until October 2020 for any studies that compared the effect of HAT versus non-HAT use in patients with sepsis. Data from 15 studies (eight randomized controlled trials [RCTs] and seven cohort studies) involving 67,349 patients were included. The results from the RCTs show no significant benefit of triple therapy on hospital mortality (risk ratio [RR], 0.99; P=0.92; I2=0%); intensive care unit (ICU) mortality (RR, 0.77; P=0.20; I2=58%); ICU length of stay (weighted mean difference [WMD], 0.11; P=0.86; I2 =37%) or hospital length of stay (WMD: 0.57; P=0.49; I2=17%), and renal replacement therapy (RR, 0.64; P=0.44; I2=39%). The delta Sequential Organ Failure Assessment (SOFA) score favored treatment after a sensitivity analysis (WMD, -0.72; P=0.01; I2=32%). However, a significant effect was noted for the duration of vasopressor use (WMD, -25.49; P<0.001; I2=46%). The results from cohort studies have also shown no significant benefit of HAT therapy on hospital mortality, ICU mortality, ICU length of stay, length of hospital stay, the delta SOFA score, the use of renal replacement therapy, or vasopressor duration. HAT therapy significantly reduced the duration of vasopressor use and improved the SOFA score but appeared not to have significant benefits in other outcomes for patients with sepsis. Further RCTs can help understand its benefit exclusively.