first antidiabetic medication based on the incretin hormone glucagon-like peptide-1 (GLP-1) was approved in 2005 (exenatide) as an adjunctive therapy in diabetic patients in whom sulphonylurea, metformin or both had failed
since exenatide, there has been the introduction of subsequent incretin mimetics in the UK. Liraglutide is available to prescribe as a once daily preparation. There is also available a once weekly preparation of exenatide; as well as the other once weekly incretin mimetics - dulaglutide and semaglutide.
the ability of GLP-1 to enhance pancreatic ß-cell mass could delay progression of the disease - however, only several years of treatment in humans will confirm the long-term efficacy of GLP-1 mimetics and enhancers on glycemic control
gastrointestinal glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are 'incretin hormones' released from the gut after a meal and are responsible for 70% of postprandial insulin secretion
a 31 amino acid peptide - GLP-1 is cleaved from proglucagon in L-cells in the GI-tract (and neurons in hindbrain/hypothalamus)
secreted in response to meal ingestion (direct luminal and indirect neuronal stimulation)
there is impairment of GLP-1 secretion and GIP action in diabetic patients - incretin effect is decreased to 30%
delays gastric emptying, decreases food intake and body weight
GLP-1 can enhance pancreatic ß-cell mass through the stimulation of ß-cell proliferation and neogenesis in healthy and diabetic rodents
GIP
has a similar insulinotropic effect to GLP-1 at glucose concentrations between 5.5 mM and 7.8 mM
GIP does not suppress glucagon secretion, and its effects on feeding behavior, if any, are unknown
collectively, these characteristics render GLP-1 more attractive than GIP as a target for the treatment of type 2 diabetes
GLP-1 is rapidly degraded by dipeptidylpeptidase IV (DPPIV)
therefore two approaches to utilization of the incretin effect were undertaken:
development of GLP-1 analogues (GLP-1 mimetics) resistant to degradation by DPPIV or the development of DPPIV inhibitors
GLP-1 analogues (GLP-1 mimetics)
lead to delayed gastric emptying, body weight loss
circulating concentrations of GLP-1 that induce nausea can be reached after subcutaneous injection of GLP-1 mimetics, but are not seen with DPPIV inhibitors
GLP-1 mimetics, which slow gastric emptying, might not only reduce the extent and rate of absorption of nutrients but also that of orally administered drugs - therefore be used with caution in patients receiving oral medications that require rapid gastrointestinal absorption and threshold concentrations for efficacy
main advantage of GLP-1 mimetics is their induction of weight loss, in addition to improvements in glycaemic control
Cardiovascular endpoints and GLP-1 mimetics:
regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular safety of GLP-1 mimetics has therefore been investigated in formal clinical trials. Of note is that there is evidence of cardiovascular benefit with treatment with liraglutide (LEADER), dulaglutide (REWIND) and semaglutide (SUSTAIN-6). See linked items for details.
Notes:
pancreatitis and renal failure
there have been reports of necrotising and haemorrhagic pancreatitis in people taking exenatide some of which were fatal - stop exenatide treatment if pancreatitis is diagnosed (2)
GLP-1 receptor agonists: reports of diabetic ketoacidosis when concomitant insulin was rapidly reduced or discontinued (3)
diabetic ketoacidosis has been reported in patients with type 2 diabetes on a combination of a GLP-1 receptor agonist and insulin who had doses of concomitant insulin rapidly reduced or discontinued. GLP-1 receptor agonists are not substitutes for insulin, and any reduction of insulin should be done in a stepwise manner with careful glucose self-monitoring. Abrupt discontinuation or reduction in insulin doses can lead to poor glycaemic control, with a risk of diabetic ketoacidosis
GLP-1 receptor agonists and metformin
analysis (n=16,996) of four clinical trials investigating GLP-1 receptor agonists (RA) found concomitant metformin use did not increase the percentage of patients who developed GI adverse effects or their severity during GLP-1RA initiation or discontinuation (4)
Reference:
Curr Opin Pharmacol. 2006 Dec;6(6):598-605.
MHRA (December 2014). Exenatide: risk of severe pancreatitis and renal failure
MHRA (June 2019). GLP-1 receptor agonists: reports of diabetic ketoacidosis when concomitant insulin was rapidly reduced or discontinued
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