Introduction CYP2C9, to less active metabolites which are

Introduction

 

Approximately 8.5 million sulphonylurea
prescriptions are filled annually in England for the management of type 2
diabetes (T2D)(1). Sulphonylureas are widely used anti-hyperglycaemic drugs which
stimulate insulin release from pancreatic ? cells in a
glucose-independent manner(2, 3). However, they have shown to demonstrate significant interpatient
variability in dose requirements, and have a narrow therapeutic index(3). Sulphonylureas can cause drug-associated hypoglycaemia, resulting
from duration of sulphonylurea action, excessive alcohol intake, irregular
eating patterns, age, mild baseline hyperglycaemia, and/or other mechanisms
beyond these clinical variables(3).

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Genetic variants that influence the activity
of the enzyme involved in sulphonylureas’ primary metabolism pathway,
cytochrome P450 2C9 (CYP2C9), have also been suggested among the predictors of sulphonylurea
efficacy and adverse events(3). Sulphonylureas are metabolised in the liver, principally by CYP2C9,
to less active metabolites which are subsequently excreted by the kidneys(3). In terms of drug-metabolising enzyme polymorphisms, CYP2C9*3 (Ile359Leu) and to a lesser
extent CYP2C9*2 (Arg144Cys),
influence the pharmacokinetics of many sulfonylureas(3). These CYP2C9
polymorphisms are loss-of-function variants which result in reduced enzyme
activity and impaired substrate metabolism, corresponding to increased blood
sulphonylureas levels(4).

 

Zhou et
al. conducted a large genotype-guided trial to examine the impact of
loss-of-function CYP2C9 variants on glycaemic
response to sulfonylureas(5). They found that patients with two copies of a loss-of-function
allele were more likely to achieve a treatment haemoglobin A1c (HbA1c)
level <7% compared to patients with two wild-type CYP2C9 alleles(5). In addition, *2 and *3 allele carriers were less likely to experience treatment failure with sulfonylurea monotherapy(5). Zhou et al. conclude that patients with of loss-of-function CYP2C9 variants have improved glycaemic control with sulfonylureas(5).   Methodological shortcomings   Unfortunately, the authors omitted any discussion or investigation regarding required dosing, time to stable dose and most importantly risk for hypoglycaemia with the different CYP2C9 polymorphisms, imperative factors to consider when assessing glycaemic response to sulphonylureas.   Assessing risk of hypoglycaemia in patients with CYP2C9 *2 and *3 polymorphisms is of importance as the loss-of-function phenotype, by increasing sulfonylurea levels, could exacerbate hypoglycaemia. A significant limitation is the exclusion of patients prescribed sulfonylureas who did not repeat their prescriptions (12.9%) and those who did not meet the requirement for at least 6 months of stable sulfonylurea therapy (25.3%), which prevents such assessment. Identifying patients at high risk for adverse effects through pharmacogenetic testing prior to treatment initiation would allow alternative treatments to be prescribed pre-emptively, ultimately reducing adverse effects. Zhou et al. makes no acknowledgement of the imperative consequences hypoglycaemic events have for long-term medication adherence, or the immediate and potentially serious injury instigated from severe hypoglycaemic reactions.   Another weakness of this study comes from the investigators not measuring glycaemic response themselves at standard intervals. Therefore, they used an 18-month period to assess whether subjects reached a HbA1c less than 7%. This prolonged period allows more opportunities for non-genetic modifiers of the outcome such as influences from changes in diet and exercise. Furthermore, using a threshold of 7% HbA1c for treatment failure does not take into account instances where patients have a marked response yet remain above the goal.   Finally, Zhou et al. exclusively used HbA1c to assess glycaemic control, with no implementation of the other widely used assessments for glycaemic control such as fasting glucose levels and the glucose tolerance test. It has been shown that HbA1C captures only chronic hyperglycaemia, not identifying patients with acute hyperglycaemia or patients who experience poor glycaemic control through fluctuations between hypo- and hyperglycaemic events(6). Furthermore, HbA1C levels fluctuate not only due to glycaemia, but also due to erythrocyte turnover rates (e.g. blood loss, anaemia, malaria and haemoglobinopathies) and other factors(6).   Conclusion   The results produced by Zhou et al. provide little clinical utility. Testing patients with type 2 diabetes for CYP2C9*2 and CYP2C9*3 would identify very few patients (~4.6%)(5). Although these patients may be more likely than those with two wild-type CYP2C9 alleles to achieve a treatment HbA1c level <7% from sulfonylurea therapy, comparable clinical results could be revealed more easily by simply initiating sulphonylurea treatment. Even though pharmacogenetic testing may not play a useful role in respect to the aforementioned point, it may be beneficial by identifying genetic predisposition towards adverse drug effects. Evidence is accumulating demonstrating an association between CYP2C9 polymorphisms and increased risk of hypoglycaemia. As such, there may be possibilities to pre-emptively adjust sulfonylurea dosage to avoid hypoglycaemic events while still maintaining its effectiveness. Additional studies in patients with T2D are necessary to determine the effectiveness of CYP2C9 genotyping as a tool to guide sulfonylurea dosing and treatment.