Basics Actions Mechanism Regulators Diabetes Analogues Enhancers
The short half life of GLP-1 has prompted the development of modified GLP-1 molecules or analogues which are DPP-IV resistant with longer half lives. These "incretin mimetics" are predicted to become part of the therapeutic armamentarium for type 2 diabetes mellitus in the near future.
Exendin4 (1-39) isolated from the saliva of Gila monster [Gila Monster Pic] is a GLP 1 agonist and may have therapeutic potential as it extends the actions of GLP 1 from a few minutes to almost 24 hours. Am J Physiol Endocrinol Metab. 2003;284:E1072-E1079 It was named thus to signify its ability to EXtEND INsulin action or probably more aptly, EXocrine product with ENDocrINe actions. A glycine substitution confers resistance to degradation by DPP-IV peptidase enzyme. Diabetes. 1999 May;48(5):1026-34 Further Exendin has a greater ability to penetrate the blood brain barrier. Int J Obes Relat Metab Disord. 2003 Mar;27(3):313-8.
Exendin-4 is a potent and long-lasting insulinotropic agent in nondiabetic and diabetic subjects. HbA1C decreased from 9.1% to 8.3% over just 1 month treatment with Exendin 4. Am J Physiol Endocrinol Metab. 2003;284:E1072-E1079 The major side effect of exendin-4 is nausea and vomiting which seems dose-dependent. The half life of exenatide is prolonged by 36% in moderate renal failure (creatinine clearance 30-51 ml/min) and 84% in End stage renal disease. Exendin 9-39 is a GLP-1 J Biol Chem. 1993 Sep 15;268(26):19650-5. (and GIP Endocrinology. 1995 Oct;136(10):4629-39) antagonist at the receptors. Exendin 1-30 has been shown to have biological properties similar to Exendin-4 but with lesser potency. Endocrine. 2005 Jun;27(1):1-9.
Exendin 4 increases cAMP levels in human islets and Min6 cells, which promotes Irs2 expression and stimulates Akt phosphorylation. J Biol Chem. 2005 Nov 4 Although Exendin does not seem to arrest progression to diabetes, it seems to at least slow the progression which might be mediated through its actions on the IRS-2 branch of the Insulin-IGF signalling cascade. Exendin4 seems to have synergistic effects on food intake suppression when given with Peptide YY Endocrinology.2005 Sep;146(9):3748-56 which is no surprise as the former acts through GLP-1 receptor dependent sensory afferent pathways, while the latter acts through the Y2 receptors, and might indicate the need for combination therapies to target in obesity treatment. Exendin 4 treatment of cultured islets has been shown to improve glycaemic outcomes post islet transplantation in mice. Diabetologia. 2005 Oct;48(10):2074-9
Exenatide is the synthetic Exendin 4 manufactured by Amylin pharmaceuticals and Eli Lilly. Varying doses of subcutaneous exenatide (5 and 10 mcg) with Sulphonylurea, Diabetes Care. 2004 Nov;27(11):2628-35. Metformin Diabetes Care. 2005 May;28(5):1092-100 and a combination of the two Diabetes Care. 2005 May;28(5):1083-91. has been undertaken over a 30 week period as the three AMIGO studies. 480 (placebo), 483 (5 mcg exenatide bd) and 480 (10 mcg Exenatide bd) patients were included in the study. View PowerPoint presentation. A HbA1c reduction of 0.9% was achieved in the 10 mcg exenatide arm at 30 weeks which was sustained on study extension to 52 weeks. A 4-pound weight reduction at 30 weeks in the 10 mcg arm was improved to a total of 8 pounds weight loss by 52 weeks. Nausea and hypoglycaemia occurred in 20 and 44% respectively, but only a small proportion dropped out due to nausea. (4%) Despite its effectiveness in improving overall glycaemic control, normalisation of fasting glucose levels still remains to be achieved.
A subset of patients from these three different arms underwent open label label extension for a further 52 weeks (82 weeks total). Data from 393 patients presented at the ADA 2005, shows a HbA1c reduction of -1.1% and a mean weight reduction of -4.5 kgs at 82 weeks. View data on cardiovascular risk improvement in 265 subjects
Exenatide does not seem to decrease insulin degradation. Exenatide administered subcutaneously produces median peak plasma levels at 2.1 hours. Studies in type 2 diabetes patients suggest that exenatide effect is ideal if given with meals or within 1 hour before the meal itself. Diabet Med. 2006 Mar;23(3):240-5 Intravenously administered Exenatide improves both the first and second phase of insulin secretion in response to intravenous glucose administration in type 2 diabetics. Clin Endocrinol Metab. 2005 Nov;90(11):5991-7 Exenatide (Byetta) was approved as a twice daily subcutaneous injection by the US FDA in April 2005 , and is currently available in the UK. Studies in type I diabetics with and without immunosuppressive therapy is planned. A phase 2 study is in progress assessing a long acting preparation of exenatide (Exenatide LAR) which seems to be a promising compound in view of its long half life making the prospect of monthly subcutaneous injections possible. Drugs R D. 2004;5(1):35-40
A short term study suggests that Exenatide therapy in combination with thiazolidinediones or metformin seems to be safe and efficacious in improving glycaemic control. ADA 66th Scientific Sessions; June 9-13, 2006; Abstract 117-OR. Exenatide use has non-surprisingly improved hepatic steatosis as demonstrated by liver fat estimation using spectroscopy, and very likely represents the effect of improved glycaemia. Liver Int. 2006 Oct;26(8):1015-7 islet cell transplant patients seem to benefit with exenatide therapy during the transplant ADA 66th Scientific Sessions; June 9-13, 2006; Abstract 256-OR or following graft cell failure American Diabetes Association 66th Scientific Sessions; June 9-13, 2006; Abstract 1925-P with reduced insulin-dependence and improved islet cell grafts function.
A 10-fold overdose of exenatide which happened accidentally [in three individuals] resulted in severe nausea and vomiting with severe hypoglycaemia in one and full recovery. Clin Ther. 2005 Feb;27(2):210-5. Other side effects reported with treatment dose were mild to moderate nausea (36%), headache (25%), vomiting (21%), and dizziness (18%). Antibody development has been noted in up to 30% of subjects receiving long term exenatide, Diabetes Care. 2003 Aug;26(8):2370-7.but this did not seem to be associated with loss of efficacy or cross reaction with human GLP-1. Exenatide use has been reported to have produced acute pancreatitis in a 69 year old man who was already on three drugs (infliximab?, gabapentin, and mevacor) known to produce pancreatitis. Diabetes Care 29:471, 2006 Symptoms of pancreatic pain started within 24 hours of initiating Exenatide at 5 mg bd. The pancreatitis settled well with standard treatment. Concerns regarding exenatide altering drug actions through gastric emptying modulation have been ill-founded. J Clin Pharmacol. 2006 Oct;46(10):1179-87
Liraglutide (NN2211) [Novo Nordisk] is another long-acting derivative produced by covalently linking GLP-1 to a fatty acid. This fatty acyl-GLP-1 binds to serum albumin, which greatly increases the duration of action of GLP-1 by limiting metabolism by DPP-IV and delaying/prolonging absorption from the injection site as well as reducing renal clearance. The half-life of this compound is approximately 12 hours and hence once daily injections should be effective treatment .Diabetes.2002 Feb;51(2):424-9.
In patients with T2DM, a single subcutaneous injection of Liraglutide at bedtime for a week reduced nocturnal glucose levels, greatly reduced the glucose excursions during a standardized lunch, and increased meal-stimulated insulin secretion. Suppression of meal-stimulated glucagon levels and delay of gastric emptying were also observed. Diabetes. 2002 Feb;51(2):424-9. However, as with exendin-4 or native GLP-1, nausea and vomiting are dose-limiting side effects. But slow up-titration seems to facilitate tolerance of doses as high as 2 mg/day.
A 12 week double blind randomised study in 193 type 2 diabetes patients with a mean age of 56.6 years and mean HbA1c 7.6% using varying doses of Liraglutide or Glimiperide demonstrated a 0.75% decrease in HbA1c and 1.8 mmol/L decrease in FBS in the 0.75 mg Liraglutide group. Improvement in glycemic control was evident after 1 week. Body weight was reduced by 1.2 kg in the 0.45-mg Liraglutide group (P = 0.0184) compared with placebo. No safety issues were raised for Liraglutide. Diabetes Care. 2004 Jun;27(6):1335-42. As in the case of Exenatide, Liraglutide administration decreasesDiabetes. 2002 Feb;51(2):424-9. but does not normalise fasting glucose levels. View Glucose Insulin response to 10 mcg/kg Liraglutide
Phase III trials have been completed as the LEAD trials (Liraglutide Effect and Action in Diabetes} with Liraglutide in combination with sulphonylurea (LEAD-1SU), with sulphonylurea and metformin (LEAD-2) or with metformin and thiazolidinediones (LEAD-4 Met+TZD). A monotherapy trial conducted against glimeperide showed better efficacy for Liragutide with less hypoglycaemia (LEAD-3 Mono)
Albumin linking is a desirable therapeutic option to prolong the action of drugs, as albumin has a longer half life in circulation. Pharm Res. 2002 May;19(5):569-77. Albumin (HSA-human serum albumin) conjugated GLP-1 molecules are being explored as treatment modalities to prolong GLP-1 half life. CJC-1131 [Conju Chem pharmaceuticals] is an albumin conjugated GLP-1 analogue with a half life 15-19 days, Diabetes. 2003 Mar;52(3):751-9. demonstrating the full spectrum of GLP-1-dependent activities, with the possibility of at least once weekly injections. nPhase II monotherapy trial in Oct 2003 revealed a 0.8% reduction of HbA1c after a month with meaningful improvement of HbA1c levels being achieved in 80%. 27% reached target HbA1c < 7% . A significant reduction in body weight of a mean 2.3 kg was attained.
Albugon [GlaxoSmithKline] is an albumin like protein into which the GLP-1 amino acid sequence has been inserted twice. Diabetes. 2004 Sep;53(9):2492-500. Studies in humans are pending.
Other potential agents acting in a glucose dependent fashion
A GLP-1 receptor agonist with glucagon receptor antagonistic properties (Dual-Acting Peptide for Diabetes (DAPD)), is being developed to address the insulin secretory defect as well as the glucagon mediated hyperglycaemic effect in type 2 diabetics. J Endocrinol. 2007 Feb;192(2):371-80 Pegylation of this compound (PEG-DAPD) results in prolonged action without the GI side effects due to reduction in gastric emptying time, and is being investigated as a euglycaemic agent.
GPR119 is a G alpha-coupled receptor found only in beta-cells of pancreatic islets. GPR119 functions as a glucose-dependent insulinotropic receptor. AR231453 is a GPR119-specific agonist which increases cyclic AMP accumulation and insulin release in rodent islets with improved oral glucose tolerance in wild-type mice and in diabetic KK/A(y) mice through insulin release in a glucose dependent fashion. Endocrinology. 2007 Feb 8 In contrast to the incretin mimetics above, agonists at this receptor could be developed as orally acting agents in treating diabetes.
Molecules as Exenatide and Liraglutide which act like incretins (incretin mimetics) thus offer advantages over existing therapeutic modalities. The reduced risk of hypoglycaemia, the decreased weight gain or in fact weight loss induction, Diabetes Care. 2004 Nov;27(11):2628-35. the absence of a need for titration of doses (universal dosing), Regul Pept. 2005 Jun 15;128(2):135-48. the very low incidence of side effects, and the potential for preserving or increasing beta cell mass and secretory function, Diabetes. 1999 Dec;48(12):2270-6. without depleting insulin stores make these an exciting new development in the treatment of type 2 diabetes. Prolonging the action of these drugs with further modifications Drugs R D.2004;5(1):35-40 could make their acceptability even higher than that for insulin, and elevate their role from a mere bridge-to-insulin after oral medication failure, to even stand alone therapy at best. The effectiveness of combination therapy with oral medications and insulin will be demonstrated as clinical use becomes widespread and prolonged. Implications of the modulation of gastric emptying on the timing of administration of short acting insulins, the optimal combination therapy regimens, the effect on cardiovascular endpoints, the effects of antibody development to exogenous peptides, as well as the consequences of prolonged pancreatic stimulation (as nesidioblastosis) will need to be clarified.
Exendin4 (1-39) isolated from the saliva of Gila monster [Gila Monster Pic] is a GLP 1 agonist and may have therapeutic potential as it extends the actions of GLP 1 from a few minutes to almost 24 hours. Am J Physiol Endocrinol Metab. 2003;284:E1072-E1079 It was named thus to signify its ability to EXtEND INsulin action or probably more aptly, EXocrine product with ENDocrINe actions. A glycine substitution confers resistance to degradation by DPP-IV peptidase enzyme. Diabetes. 1999 May;48(5):1026-34 Further Exendin has a greater ability to penetrate the blood brain barrier. Int J Obes Relat Metab Disord. 2003 Mar;27(3):313-8.
Exendin-4 is a potent and long-lasting insulinotropic agent in nondiabetic and diabetic subjects. HbA1C decreased from 9.1% to 8.3% over just 1 month treatment with Exendin 4. Am J Physiol Endocrinol Metab. 2003;284:E1072-E1079 The major side effect of exendin-4 is nausea and vomiting which seems dose-dependent. The half life of exenatide is prolonged by 36% in moderate renal failure (creatinine clearance 30-51 ml/min) and 84% in End stage renal disease. Exendin 9-39 is a GLP-1 J Biol Chem. 1993 Sep 15;268(26):19650-5. (and GIP Endocrinology. 1995 Oct;136(10):4629-39) antagonist at the receptors. Exendin 1-30 has been shown to have biological properties similar to Exendin-4 but with lesser potency. Endocrine. 2005 Jun;27(1):1-9.
Exendin 4 increases cAMP levels in human islets and Min6 cells, which promotes Irs2 expression and stimulates Akt phosphorylation. J Biol Chem. 2005 Nov 4 Although Exendin does not seem to arrest progression to diabetes, it seems to at least slow the progression which might be mediated through its actions on the IRS-2 branch of the Insulin-IGF signalling cascade. Exendin4 seems to have synergistic effects on food intake suppression when given with Peptide YY Endocrinology.2005 Sep;146(9):3748-56 which is no surprise as the former acts through GLP-1 receptor dependent sensory afferent pathways, while the latter acts through the Y2 receptors, and might indicate the need for combination therapies to target in obesity treatment. Exendin 4 treatment of cultured islets has been shown to improve glycaemic outcomes post islet transplantation in mice. Diabetologia. 2005 Oct;48(10):2074-9
Exenatide is the synthetic Exendin 4 manufactured by Amylin pharmaceuticals and Eli Lilly. Varying doses of subcutaneous exenatide (5 and 10 mcg) with Sulphonylurea, Diabetes Care. 2004 Nov;27(11):2628-35. Metformin Diabetes Care. 2005 May;28(5):1092-100 and a combination of the two Diabetes Care. 2005 May;28(5):1083-91. has been undertaken over a 30 week period as the three AMIGO studies. 480 (placebo), 483 (5 mcg exenatide bd) and 480 (10 mcg Exenatide bd) patients were included in the study. View PowerPoint presentation. A HbA1c reduction of 0.9% was achieved in the 10 mcg exenatide arm at 30 weeks which was sustained on study extension to 52 weeks. A 4-pound weight reduction at 30 weeks in the 10 mcg arm was improved to a total of 8 pounds weight loss by 52 weeks. Nausea and hypoglycaemia occurred in 20 and 44% respectively, but only a small proportion dropped out due to nausea. (4%) Despite its effectiveness in improving overall glycaemic control, normalisation of fasting glucose levels still remains to be achieved.
A subset of patients from these three different arms underwent open label label extension for a further 52 weeks (82 weeks total). Data from 393 patients presented at the ADA 2005, shows a HbA1c reduction of -1.1% and a mean weight reduction of -4.5 kgs at 82 weeks. View data on cardiovascular risk improvement in 265 subjects
Exenatide does not seem to decrease insulin degradation. Exenatide administered subcutaneously produces median peak plasma levels at 2.1 hours. Studies in type 2 diabetes patients suggest that exenatide effect is ideal if given with meals or within 1 hour before the meal itself. Diabet Med. 2006 Mar;23(3):240-5 Intravenously administered Exenatide improves both the first and second phase of insulin secretion in response to intravenous glucose administration in type 2 diabetics. Clin Endocrinol Metab. 2005 Nov;90(11):5991-7 Exenatide (Byetta) was approved as a twice daily subcutaneous injection by the US FDA in April 2005 , and is currently available in the UK. Studies in type I diabetics with and without immunosuppressive therapy is planned. A phase 2 study is in progress assessing a long acting preparation of exenatide (Exenatide LAR) which seems to be a promising compound in view of its long half life making the prospect of monthly subcutaneous injections possible. Drugs R D. 2004;5(1):35-40
A short term study suggests that Exenatide therapy in combination with thiazolidinediones or metformin seems to be safe and efficacious in improving glycaemic control. ADA 66th Scientific Sessions; June 9-13, 2006; Abstract 117-OR. Exenatide use has non-surprisingly improved hepatic steatosis as demonstrated by liver fat estimation using spectroscopy, and very likely represents the effect of improved glycaemia. Liver Int. 2006 Oct;26(8):1015-7 islet cell transplant patients seem to benefit with exenatide therapy during the transplant ADA 66th Scientific Sessions; June 9-13, 2006; Abstract 256-OR or following graft cell failure American Diabetes Association 66th Scientific Sessions; June 9-13, 2006; Abstract 1925-P with reduced insulin-dependence and improved islet cell grafts function.
A 10-fold overdose of exenatide which happened accidentally [in three individuals] resulted in severe nausea and vomiting with severe hypoglycaemia in one and full recovery. Clin Ther. 2005 Feb;27(2):210-5. Other side effects reported with treatment dose were mild to moderate nausea (36%), headache (25%), vomiting (21%), and dizziness (18%). Antibody development has been noted in up to 30% of subjects receiving long term exenatide, Diabetes Care. 2003 Aug;26(8):2370-7.but this did not seem to be associated with loss of efficacy or cross reaction with human GLP-1. Exenatide use has been reported to have produced acute pancreatitis in a 69 year old man who was already on three drugs (infliximab?, gabapentin, and mevacor) known to produce pancreatitis. Diabetes Care 29:471, 2006 Symptoms of pancreatic pain started within 24 hours of initiating Exenatide at 5 mg bd. The pancreatitis settled well with standard treatment. Concerns regarding exenatide altering drug actions through gastric emptying modulation have been ill-founded. J Clin Pharmacol. 2006 Oct;46(10):1179-87
Liraglutide (NN2211) [Novo Nordisk] is another long-acting derivative produced by covalently linking GLP-1 to a fatty acid. This fatty acyl-GLP-1 binds to serum albumin, which greatly increases the duration of action of GLP-1 by limiting metabolism by DPP-IV and delaying/prolonging absorption from the injection site as well as reducing renal clearance. The half-life of this compound is approximately 12 hours and hence once daily injections should be effective treatment .Diabetes.2002 Feb;51(2):424-9.
In patients with T2DM, a single subcutaneous injection of Liraglutide at bedtime for a week reduced nocturnal glucose levels, greatly reduced the glucose excursions during a standardized lunch, and increased meal-stimulated insulin secretion. Suppression of meal-stimulated glucagon levels and delay of gastric emptying were also observed. Diabetes. 2002 Feb;51(2):424-9. However, as with exendin-4 or native GLP-1, nausea and vomiting are dose-limiting side effects. But slow up-titration seems to facilitate tolerance of doses as high as 2 mg/day.
A 12 week double blind randomised study in 193 type 2 diabetes patients with a mean age of 56.6 years and mean HbA1c 7.6% using varying doses of Liraglutide or Glimiperide demonstrated a 0.75% decrease in HbA1c and 1.8 mmol/L decrease in FBS in the 0.75 mg Liraglutide group. Improvement in glycemic control was evident after 1 week. Body weight was reduced by 1.2 kg in the 0.45-mg Liraglutide group (P = 0.0184) compared with placebo. No safety issues were raised for Liraglutide. Diabetes Care. 2004 Jun;27(6):1335-42. As in the case of Exenatide, Liraglutide administration decreasesDiabetes. 2002 Feb;51(2):424-9. but does not normalise fasting glucose levels. View Glucose Insulin response to 10 mcg/kg Liraglutide
Phase III trials have been completed as the LEAD trials (Liraglutide Effect and Action in Diabetes} with Liraglutide in combination with sulphonylurea (LEAD-1SU), with sulphonylurea and metformin (LEAD-2) or with metformin and thiazolidinediones (LEAD-4 Met+TZD). A monotherapy trial conducted against glimeperide showed better efficacy for Liragutide with less hypoglycaemia (LEAD-3 Mono)
Albumin linking is a desirable therapeutic option to prolong the action of drugs, as albumin has a longer half life in circulation. Pharm Res. 2002 May;19(5):569-77. Albumin (HSA-human serum albumin) conjugated GLP-1 molecules are being explored as treatment modalities to prolong GLP-1 half life. CJC-1131 [Conju Chem pharmaceuticals] is an albumin conjugated GLP-1 analogue with a half life 15-19 days, Diabetes. 2003 Mar;52(3):751-9. demonstrating the full spectrum of GLP-1-dependent activities, with the possibility of at least once weekly injections. nPhase II monotherapy trial in Oct 2003 revealed a 0.8% reduction of HbA1c after a month with meaningful improvement of HbA1c levels being achieved in 80%. 27% reached target HbA1c < 7% . A significant reduction in body weight of a mean 2.3 kg was attained.
Albugon [GlaxoSmithKline] is an albumin like protein into which the GLP-1 amino acid sequence has been inserted twice. Diabetes. 2004 Sep;53(9):2492-500. Studies in humans are pending.
Other potential agents acting in a glucose dependent fashion
A GLP-1 receptor agonist with glucagon receptor antagonistic properties (Dual-Acting Peptide for Diabetes (DAPD)), is being developed to address the insulin secretory defect as well as the glucagon mediated hyperglycaemic effect in type 2 diabetics. J Endocrinol. 2007 Feb;192(2):371-80 Pegylation of this compound (PEG-DAPD) results in prolonged action without the GI side effects due to reduction in gastric emptying time, and is being investigated as a euglycaemic agent.
GPR119 is a G alpha-coupled receptor found only in beta-cells of pancreatic islets. GPR119 functions as a glucose-dependent insulinotropic receptor. AR231453 is a GPR119-specific agonist which increases cyclic AMP accumulation and insulin release in rodent islets with improved oral glucose tolerance in wild-type mice and in diabetic KK/A(y) mice through insulin release in a glucose dependent fashion. Endocrinology. 2007 Feb 8 In contrast to the incretin mimetics above, agonists at this receptor could be developed as orally acting agents in treating diabetes.
Molecules as Exenatide and Liraglutide which act like incretins (incretin mimetics) thus offer advantages over existing therapeutic modalities. The reduced risk of hypoglycaemia, the decreased weight gain or in fact weight loss induction, Diabetes Care. 2004 Nov;27(11):2628-35. the absence of a need for titration of doses (universal dosing), Regul Pept. 2005 Jun 15;128(2):135-48. the very low incidence of side effects, and the potential for preserving or increasing beta cell mass and secretory function, Diabetes. 1999 Dec;48(12):2270-6. without depleting insulin stores make these an exciting new development in the treatment of type 2 diabetes. Prolonging the action of these drugs with further modifications Drugs R D.2004;5(1):35-40 could make their acceptability even higher than that for insulin, and elevate their role from a mere bridge-to-insulin after oral medication failure, to even stand alone therapy at best. The effectiveness of combination therapy with oral medications and insulin will be demonstrated as clinical use becomes widespread and prolonged. Implications of the modulation of gastric emptying on the timing of administration of short acting insulins, the optimal combination therapy regimens, the effect on cardiovascular endpoints, the effects of antibody development to exogenous peptides, as well as the consequences of prolonged pancreatic stimulation (as nesidioblastosis) will need to be clarified.