Metformin has been a cornerstone in diabetes treatment since the 1960s, still serving as a first-line pharmacological therapy for type 2 diabetes in most clinical guidelines. However, the impact of timing on the drug’s efficacy has not been fully explored. A recent study lead by EASD members and published in Diabetologia demonstrates that the glucose-lowering effect of metformin is enhanced when taken before, rather than with, a nutrition load. The observations provide compelling evidence to support the concept that a “preload” of metformin before a meal has the potential to enhance its efficacy in postprandial glucose-lowering, as stated by Cong Xie from the Royal Adelaide Hospital, Australia, and his colleagues in their paper. Interestingly, this is associated with an enhanced secretion of the incretin hormone glucagon-like peptide 1 (GLP-1).
 

The benefits of pre-meal administration
In their proof-of-concept study, the authors analysed the gastrointestinal effects of metformin in sixteen participants already using a stable dose of the drug. Their results demonstrate that administering metformin 30 to 60 minutes before a meal reduces plasma glucose levels while increasing plasma GLP-1 and insulin levels. To control for individual variations in gastric emptying, metformin was administered via a nasoduodenal catheter, followed by an intraduodenal glucose infusion. Plasma glucose, insulin and total GLP-1 were measured every 30 minutes, starting an hour before glucose administration until two hours afterward.


Revisiting the mechanisms of metformin
“Metformin is effective to suppress hepatic glucose production and lower fasting hyperglycaemia in people with type 2 diabetes. Amounting evidence in recent decades has shown that metformin also exerts multiple gastrointestinal actions,” says Dr Xie. This includes stimulating the secretion of GLP-1, slowing gastric emptying, suppressing intestinal glucose absorption, inhibiting bile acid resorption and modulating the gut microbiota. In addition, it has been shown that enteral administration of metformin is more effective than intravenous or intraportal routes. Delayed-release forms with minimal systemic exposure have also been shown to work well.  


Stimulating GLP-1: direct or indirect effects?
While GLP-1 may play a major role in the efficacy of metformin, the authors hypothesise that the incretin hormone is stimulated indirectly by the drug rather than directly. In their study, plasma GLP-1 levels increased only when metformin was given before, but not at the same time as, glucose infusion. This suggests that GLP-1 levels are primarily affected by changes in the glucose-gut interaction, Xie and colleagues state. They propose that metformin acts on glucose transporters by reducing the rate of glucose absorption in the upper small intestine. This increases the glucose exposure of GLP-1-secreting L-cells in the distal intestine, resulting in higher plasma GLP-1 levels.  


Challenging current recommendations
Although it is typically recommended to take metformin with meals to minimise gastrointestinal side effects, the study found no difference in nausea scores between different administration times, which were consistently low. Consequently, the benefits of pre-meal administration should be considered. “The findings of our study suggest that the empirical recommendation for ingestion of metformin with meals may have compromised its efficacy to improve blood glucose control after meals,” says Associate Professor Tongzhi Wu, principal investigator of the study. “Modification of the timing of metformin ingestion in relation to meals could be a cost-effective approach to improve glycaemic control in people living with type 2 diabetes,” he concludes, highlighting the clinical implications of their findings. 


Key Points:

  • Usually, metformin is taken with meals to reduce gastrointestinal side effects. However, the impact of metformin timing on its efficacy has not been fully explored.
  • In a recent study published in Diabetologia, participants experienced greater glucose reduction together with increased GLP-1 and insulin levels when metformin was administered 30 to 60 minutes before a meal.
  • The results challenge current recommendations, suggesting pre-meal administration of metformin may improve postprandial glucose control without increased nausea.

Author: Hanna Gabriel, BA MSc. Any opinions expressed in this article are the responsibility of EASD e-Learning.

To read this paper visit: Xie, C., Iroga, P., Bound, M.J. et al. Impact of the timing of metformin administration on glycaemic and glucagon-like peptide-1 responses to intraduodenal glucose infusion in type 2 diabetes: a double-blind, randomised, placebo-controlled, crossover study. Diabetologia (2024).
https://doi.org/10.1007/s00125-024-06131-6