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Effect of Delayed Release Metformin on Plasma Glucose Level

Is once-daily delayed release metformin better than the other forms of metformin?

Metformin is used for the management of type 2 diabetes (T2DM), with its mechanism still being debated. The glucose lowering actions of metformin have been credited for its effects on mitochondrial function, AMPK, and glucagon receptor stimulated adenylate cyclase in the liver and skeletal muscle. Antihyperglycemic actions of metformin were attributable to organized coverage, leading to a reduction in liver gluconeogenesis, including increased insulin mediated glucose uptake in peripheral tissue. Metformin actions in the gut include increased secretion of the endocrine L cell hormones, glucagon-like peptide-1 (GLP-1) and peptide YY (PYY); also an intestinal 5’ AMP –activated protein kinase (AMPK) – dependent pathway, microbiome and bile acid metabolism.

Available metformin formulations include immediate release metformin [Met IR] and extended release metformin [Met XR]. They have about 50% bioavailability with most occurring in the duodenum and jejunum. Therapeutic dose collects in the gut mucosa which increases its concentration up to 300 times greater. It is believed that higher doses of metformin are necessary to overpower the transporters in the proximal small intestine and supply optimally effective doses of metformin to the lower bowel. Met DR was designed to release at pH 6.5, which is connected with lower jejunum and ileum. Major metformin sites are therefore bypassed which results in about 50 % plasma exposure.

Two studies were done to know the effects of Met DR and Met IR on gut hormones, FPG and post prandial plasma glucose reductions. Study 1 investigated Met DR treatment regimen on pharmacokinetic and pharmacodynamics regimen. 24 subjects were randomized and given 2x daily Met IR 1000 mg, DR 1000 mg or 500 mg. They had a washout period of 9-12 days. Samples for PYY, GLP-1, and insulin were collected and PK and PD were estimated. 26 participants were randomized in study 2 and administered 1000 mg Met DR once daily AM, 1000mg Met DR once daily PM or 500 mg twice daily. Plasma PK, urine PK and PD were determined. For study 1 plasma metformin concentrations for 1000 mg Met DR dose were higher than for 500 mg dose. All treatment drastically reduced plasma glucose AUC at day 5 by 10%. AUC at day 5 increased by 62-87% for GLP-1 and by 38-55% for PYY. For study 2, the peak plasma concentration after a once daily PM administration resulted in a right shift as compared to once daily AM dose. Total metformin exposure was also lower for the once daily AM compared to the once daily PM and twice daily dosing. Peak concentration for metformin was 33% higher for once daily PM than twice daily. For safety and tolerability, the major side effects in both studies was gastrointestinal, specifically vomiting.

Another similar study was conducted in which 240 subjects with T2DM were randomized for 12 weeks. It was a placebo controlled dose response study. Subjects were randomized (1:1:1:1:1:1) to one of six treatment arms in a sensible manner stratified HbA1c level < 8%. Double blind treatment consisted of placebo, 600, 800, 1000 mg Met DR once daily every morning. 2000mg Met XR dose was titrated over 3 weeks. The primary end point was the change in FPG with secondary end point being changes in HbA1c and FPG levels. Data was collected for 12 weeks and the statistical analysis used was the ANCOVA model.  There were 40 subjects per treatment group. Subjects exhibited relatively good glycemic control at baseline; other features were mostly similar.

All treatment groups had improvements in FPG level compared to placebo. There were dose dependent reductions in median FPG, and median reductions for 1000 and 2000 mg Met XR at week 4 were statistically significant. 800 mg Met DR dose was also statistically significant. Met XR groups compared with placebo (all P < 0.05). Steady state metformin concentration were achieved by week 2 for all Met DR groups and the 1000 mg Met XR group by week 4 for the 2000 mg Met XR group. For safety and tolerability, it was mostly gastrointestinal in nature.

In conclusion, delivery of metformin to the lower bowel with DR resulted in a glucose lowering efficacy comparable to that with Met XR. Also, metformin works in the gut and DR could provide a means of administering metformin to patients who have renal impairment.

Practice Pearls:

  • The glucose lowering actions of metformin have been credited for its effects on its mitochondrial function, AMPK, and glucagon receptor stimulated adenylate cyclase in the liver and skeletal muscle.
  • It is believed that higher doses of metformin are necessary to overpower the transporters in the proximal small intestine and supply optimally effective doses of metformin to the lower bowel.
  • Metformin works in the gut and DR could provide a means of administering metformin to patients who have renal impairment.

References:

DeFronzo, Ralph A. et al. “Once-Daily Delayed-Release Metformin Lowers Plasma Glucose and Enhances Fasting and Postprandial GLP-1 and PYY: Results from Two Randomized Trials.” Diabetologia 59 (2016): 1645–1654. PMC. Web. 20 July 2016.

Buse John B et al. “The Primary Glucose-Lowering Effect of Metformin Resides in the Gut, Not the Circulation: Results from Short-term Pharmacokinetic and 12-Week Dose-Ranging Studies”. American Diabetes Association. 39 (2016). Web. 20 July 2016.