Incretin mimetics

• 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 disease, kidney disease and GLP-1 mimetics:
    • review (11 RCTs; 85,373 patients) found that GLP-1 receptor agonists significantly reduce clinically important kidney events, kidney failure, and cardiovascular events. No difference in risk of serious adverse events seen between GLP-1s and placebo (RR 0.95, 95%CI 0.90-1.01) (2):
      • study authors concluded that:
        • evidence that GLP-1 receptor agonists significantly reduce clinically important kidney events, kidney failure, and cardiovascular events
    • a further meta-analysis of long-acting GLP-1 receptor agonists and oral GLP-1 receptor agonists in individuals with type 2 diabetes (3)
      • included data from the Semaglutide cardiOvascular oUtcomes triaL (SOUL) (oral semaglutide) and Evaluate Renal Function with Semaglutide Once Weekly (FLOW) trial
      • found long-acting GLP-1R agonists reduced incidence of MACE (HR 0.86 [95% CI 0.81 to 0.90]), hospitalisation for heart failure (0.86 [0.79 to 0.93]), kidney events (0.83 [0.75 to 0.92) and all-cause mortality (0.88 [0.82 to 0.93])

Notes:

• pancreatitis
  • 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 (4)
    
    
• GLP-1 receptor agonists: reports of diabetic ketoacidosis when concomitant insulin was rapidly reduced or discontinued (5)
  • 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 (6)
    
    
• GLP-1 receptor agonists and diabetic retinopathy
  • data suggest that the strongest relationship between GLP-1 receptor agonists treatment and early worsening of retinopathy after drug initiation is via their impact on HbA1c (7)
    
    
• GLP-1 receptor agonists and muscle loss
  • studies suggest muscle loss with these medications (as indicated by decreases in fat-free mass [FFM]) ranges from 25% to 39% of the total weight lost over 36–72 weeks (8)
    • this substantial muscle loss can be largely attributed to the magnitude of weight loss, rather than by an independent effect of GLP-1 receptor agonists, although this hypothesis must be tested
    • by comparison, non-pharmacological caloric restriction studies with smaller magnitudes of weight loss result in 10–30% FFM losses

Reference:

1. Curr Opin Pharmacol. 2006 Dec;6(6):598-605.
2. Badve, Sunil V et al. Effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials. Lancet Diabetes & Endocrinology November 25th 2024.
3. Lee MMY et al, SOUL Trial Investigators; Cardiovascular and Kidney Outcomes and Mortality With Long-Acting Injectable and Oral Glucagon-Like Peptide 1 Receptor Agonists in Individuals With Type 2 Diabetes: A Systematic Review and Meta-analysis of Randomized Trials. Diabetes Care 2025
4. MHRA (December 2014). Exenatide: risk of severe pancreatitis and renal failure
5. MHRA (June 2019). GLP-1 receptor agonists: reports of diabetic ketoacidosis when concomitant insulin was rapidly reduced or discontinued
6. 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.
7. Bethel MA et al. HbA1c Change and Diabetic Retinopathy During GLP-1 Receptor Agonist Cardiovascular Outcome Trials: A Meta-analysis and Meta-regression. Diabetes Care. 2021 Jan;44(1):290-296.
8. Prado CM et al. Muscle matters: the effects of medically induced weight loss on skeletal muscle. Lancet Diabetes and Endocrinology 2024; 11 (12):785-78.