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Incretin mimetics

Last reviewed dd mmm yyyy. Last edited dd mmm yyyy

Authoring team

  • 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%
      • GLP-1 stimulates insulin secretion, glucose-dependently
      • GLP-1 decreases glucagon secretion, glucose-dependently
      • 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.


  • 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)


  1. Curr Opin Pharmacol. 2006 Dec;6(6):598-605.
  2. MHRA (December 2014). Exenatide: risk of severe pancreatitis and renal failure
  3. MHRA (June 2019). GLP-1 receptor agonists: reports of diabetic ketoacidosis when concomitant insulin was rapidly reduced or discontinued
  4. Klein KR et al. Occurrence of Gastrointestinal Adverse Events Upon GLP-1 Receptor Agonist Initiation With Concomitant Metformin Use: A Post Hoc Analysis of LEADER, STEP 2, SUSTAIN 6, and PIONEER 6. Diabetes Care 2023; dc231791.

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