How to unlock GLP-1 drugs’ full glucose-lowering potential….
The current subcutaneous delivery method of GLP-1 agonist drugs for patients with type 2 diabetes may not be the most effective.
According to Michael Nauchk, MD, intravenously administered infusions of GLP-1 resulted in normalization of blood glucose without gastrointestinal upset, while subcutaneous injections and infusions resulted in lowering of blood sugar but not within normal range and with associated nausea and vomiting.
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Only when the peptide is administered intravenously does it “appear to exploit the full glucose-lowering potential inherent in the mechanism of enhanced GLP-1 receptor stimulation,” they wrote. “In contrast, subcutaneous administration … does not fully exploit this glucose-lowering potential.”
The researchers stated that during the development of GLP-1, proof-of-concept studies displayed that short-term intravenous infusions lowered glucose concentrations in hyperglycemic patients into the normal fasting glucose range — typically between 4 and 6.5 mmol/L.
These glucose lowering effects were seen at doses of 1 to 1.2 pmol/kg-1/min-1 or even lower, reaching a steady-state plasma level of total GLP-1 approximately 60-150 pmol/L corresponding with steady state plasma concentrations of intact, biologically active GLP-1 of 10 to 15 pmol/L without any gastrointestinal side effects.
However, in order to advance the compound, scientists created a subcutaneous form. Doses reaching as high as 1.5 nmol/kg had somewhat an effect on glycemia, but were not fully able to normalize blood glucose levels. Gastrointestinal side effects along with nausea and vomiting were also observed in a dose-dependent manner.
“Based on these results, a lower bioavailability of GLP-1 has to be suspected when the peptide is delivered into the subcutaneous compartment versus IV administration,” they wrote.
Following studies have evaluated whether a continuous subcutaneous infusion of GLP-1 could improve response and lessen side effects. Although continuous subcutaneous doses of 2.4 or 4.8 pmol/kg-1/min-1 led to better bioavailability of GLP-1, the glucose-lowering responses “were still much inferior” when compared to the intravenous infusions, Nauck and colleagues wrote.
The research team concluded in their literature review that the intravenous route may be a better means of normalizing blood glucose in patients with type 2 diabetes than the current route of subcutaneous administration.
Further investigation of these and other potential mechanisms that underlie the differences between IV and subcutaneous administration of GLP-1 agonists could lead to a “substantial improvement in incretin-based therapeutic agents,” Nauck and colleagues concluded.
Diabetologia, Sept. 2013