Basics Actions Mechanism Regulators Diabetes Analogues Enhancers
DPP-IV (Dipeptidyl Peptidase) enzyme metabolizes a wide range of regulatory peptides including GIP, GLP2, Neuropeptide Y, endorphin, Peptide YY, Growth hormone releasing hormone (GHRH), stromal cell-derived factor, eotaxin, macrophage-derived chemokine, Regul Pept. 1999 Nov 30;85(1):9-24. as well as GLP-1. Eur J Biochem. 1993 Jun 15;214(3):829-35. GLP-1 (7-36) and (7-37) are cleaved to form GLP-1 (9-36) and (9-37) amide. DPP-IV inactivates GLP-1 and converts it to GLP(9-36 amide) which like Exendin (9-39 ) is an antagonist at the GLP-1 receptor to which it strongly binds. Inhibition of DPP-IV can thus increase GLP-1 levels, potentiating its action and duration. The possibility of once daily oral administration of these agents seems to be an encouraging feature. Since the side effects of GLP-1 are dose dependent, GLP-1 and its agonists tend to produce nausea and vomiting at supra physiological levels (>60 pmol/L), an effect that is less likely to be produced by DPP-IV inhibitors. DPP-IV inhibition increases the proportion of active GLP-1 rather than the total concentration with typical values of 30 pmol/L after a meal.
Rats seem to have higher DPP-IV activity than mice. Nat Biotechnol. 1997 Jul;15(7):673-7. Plasma DPP-IV activity was not increased in diabetic patients, but it is possible that tissue activity of DPP-IV could be higher. While studies in DPP-IV mutant rats have produced variable results with regard to improvement in glycaemia, Metabolism. 1996 Nov;45(11):1335-41 ; Proc Natl Acad Sci USA 2000 97(12): 6874-6879 in humans, LAF237 (Vildagliptin) a DPP-IV inhibitor, [Novartis] has been shown to improve post prandial sugar levels predominantly by glucagon suppression rather than by increasing insulin response. J Clin Endocrinol Metab. 2004 May;89(5):2078-84. Although insulin levels remain unchanged with Vildagliptin therapy, more complex assessments of beta cell function show that insulin secretory rate is significantly increased at a glucose level of 7 mmol/L, [increased insulin secretory tone] despite the secretory slope remaining unchanged. J Clin Endocrinol Metab. 2005 Aug;90(8):4888-94. Interestingly infrequent occurrences of hypoglycaemia and nausea has been noted. Phase II b trials in 44 patients over 12 weeks with 100 mg Vildagliptin has shown a reduction of HbA1c of 0.68 % from a mean of 7.7% . In the same trial, combination with Metformin reduced the HbA1c by 0.82% from a mean of 7.8% -although only 12 patients were in the 100mg arm as opposed to 50 in the placebo arm. The beneficial effects of Vildagliptin on HbA1c seem to be sustained at 1 year. Diabetes Care. 2004 Dec;27(12):2874-80 Vildagliptin in combination with metformin has shown improvement in beta cell function with improved post meal insulin sensitivity and maintenance of the improved glycaemic control. Diabetes Care. 2005 Aug;28(8):1936-40.
A 2 week study in Zucker fa/fa rats (rat models for DM and IGT) using bd metformin or a DPP-IV inhibitor or a combinationdemonstrated that the combination caused a significant GLP-1 rise , with reduction in food intake and body weight gain. Separately neither of them had effects on appetite or body weight gain. J Pharmacol Exp Ther. 2004 Aug;310(2):614-9.
Saxagliptin [Bristol Myers Squibb] and Sitagliptin [Merck] are DPP-IV inhibitors presently under development.
While DPP-IV inhibition can decrease degradation of GLP-1, it seems likely that an increase in the non-degraded GLP-1 levels exert a negative feedback on the L cells to decrease production of new GLP-1. J Endocrinol. 2002 Feb;172(2) :355-362. Combining DPP-IV inhibitors with incretins has been shown to increase the efficacy of the incretin significantly (GLP-1 or PACAP action by 75-80% and GIP action by 40%), Endocrinology. 2005 Apr;146(4):2055-9 and soon might become a part of the polypharmacy approach to diabetic treatment in the not-so-distant future. Since DPP-IV is not present in the CNS, clearance of GLP-1 in the CSF may be through other mechanisms as simple diffusion. J Mol Neurosci. 2002 Feb-Apr;18(1-2):7-14. The same mechanisms may apply to the DPP-IV resistant Exendin-4 which has high CNS penetration. Int J Obes Relat Metab Disord. 2003 Mar;27(3):313-8.
Concerns regarding DPP-IV inhibitors
Plasma levels of GLP-1 that can be achieved using DPP-IV inhibitors are very much dependent on normal GLP-1 secretion rates and hence their sustained effect as the diabetic state progresses remains to be seen. It is possible as demonstrated in studies that the increased fraction of active intact GLP-1 with its pro-pancreatic effects might decrease the rate of progression of beta cell failure with sustained effectiveness. DPP-IV is a pleiotropic enzyme involved in the degradation of hormones and peptides other than GLP-1 as mentioned above, including GIP, GLP2, Neuropeptide Y, endorphin, Peptide YY, Growth hormone releasing hormone (GHRH), stromal cell-derived factor, eotaxin, macrophage-derived chemokine, Regul Pept. 1999 Nov 30;85(1):9-24. DPP-IV also plays a role in the modification of antigens for immune recognition as it is expressed as CD26 on the surface of T-lymphocytes with inactivation of chemokines as RANTES, Scand J Immunol. 2001 Sep;54(3):249-64. Hence there is the concern that inhibition could affect other physiologic systems, in the form of increases in blood pressure due to decreased Neuropeptide Y degradation, increased inflammation and allergic reactions due to chemokine excess, and neurogenic inflammation mediated by non-degraded substance P and neuropeptide Y. Int Rev Cytol.2004;235:165-213. Despite this, DPP-IV knock out mice do not show any immunological dysfunction. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6874-9. DPP-IV belongs to a group of serine proteases, many of whose function is not yet characterised (DPP-7, DPP-8, DPP-9, Fibroblast activation protein-alpha [FAP]). Inhibition of DPP-8 and DPP-9 enzymes is thought to contribute to the side effects of DPP-IV inhibitors including alopecia, thrombocytopenia, and splenomegaly. Diabetologia.2005 Apr;48(4):616-20 It is hence very crucial that highly specific DPP-IV inhibitors are developed to ensure long term safety.
Rats seem to have higher DPP-IV activity than mice. Nat Biotechnol. 1997 Jul;15(7):673-7. Plasma DPP-IV activity was not increased in diabetic patients, but it is possible that tissue activity of DPP-IV could be higher. While studies in DPP-IV mutant rats have produced variable results with regard to improvement in glycaemia, Metabolism. 1996 Nov;45(11):1335-41 ; Proc Natl Acad Sci USA 2000 97(12): 6874-6879 in humans, LAF237 (Vildagliptin) a DPP-IV inhibitor, [Novartis] has been shown to improve post prandial sugar levels predominantly by glucagon suppression rather than by increasing insulin response. J Clin Endocrinol Metab. 2004 May;89(5):2078-84. Although insulin levels remain unchanged with Vildagliptin therapy, more complex assessments of beta cell function show that insulin secretory rate is significantly increased at a glucose level of 7 mmol/L, [increased insulin secretory tone] despite the secretory slope remaining unchanged. J Clin Endocrinol Metab. 2005 Aug;90(8):4888-94. Interestingly infrequent occurrences of hypoglycaemia and nausea has been noted. Phase II b trials in 44 patients over 12 weeks with 100 mg Vildagliptin has shown a reduction of HbA1c of 0.68 % from a mean of 7.7% . In the same trial, combination with Metformin reduced the HbA1c by 0.82% from a mean of 7.8% -although only 12 patients were in the 100mg arm as opposed to 50 in the placebo arm. The beneficial effects of Vildagliptin on HbA1c seem to be sustained at 1 year. Diabetes Care. 2004 Dec;27(12):2874-80 Vildagliptin in combination with metformin has shown improvement in beta cell function with improved post meal insulin sensitivity and maintenance of the improved glycaemic control. Diabetes Care. 2005 Aug;28(8):1936-40.
A 2 week study in Zucker fa/fa rats (rat models for DM and IGT) using bd metformin or a DPP-IV inhibitor or a combinationdemonstrated that the combination caused a significant GLP-1 rise , with reduction in food intake and body weight gain. Separately neither of them had effects on appetite or body weight gain. J Pharmacol Exp Ther. 2004 Aug;310(2):614-9.
Saxagliptin [Bristol Myers Squibb] and Sitagliptin [Merck] are DPP-IV inhibitors presently under development.
While DPP-IV inhibition can decrease degradation of GLP-1, it seems likely that an increase in the non-degraded GLP-1 levels exert a negative feedback on the L cells to decrease production of new GLP-1. J Endocrinol. 2002 Feb;172(2) :355-362. Combining DPP-IV inhibitors with incretins has been shown to increase the efficacy of the incretin significantly (GLP-1 or PACAP action by 75-80% and GIP action by 40%), Endocrinology. 2005 Apr;146(4):2055-9 and soon might become a part of the polypharmacy approach to diabetic treatment in the not-so-distant future. Since DPP-IV is not present in the CNS, clearance of GLP-1 in the CSF may be through other mechanisms as simple diffusion. J Mol Neurosci. 2002 Feb-Apr;18(1-2):7-14. The same mechanisms may apply to the DPP-IV resistant Exendin-4 which has high CNS penetration. Int J Obes Relat Metab Disord. 2003 Mar;27(3):313-8.
Concerns regarding DPP-IV inhibitors
Plasma levels of GLP-1 that can be achieved using DPP-IV inhibitors are very much dependent on normal GLP-1 secretion rates and hence their sustained effect as the diabetic state progresses remains to be seen. It is possible as demonstrated in studies that the increased fraction of active intact GLP-1 with its pro-pancreatic effects might decrease the rate of progression of beta cell failure with sustained effectiveness. DPP-IV is a pleiotropic enzyme involved in the degradation of hormones and peptides other than GLP-1 as mentioned above, including GIP, GLP2, Neuropeptide Y, endorphin, Peptide YY, Growth hormone releasing hormone (GHRH), stromal cell-derived factor, eotaxin, macrophage-derived chemokine, Regul Pept. 1999 Nov 30;85(1):9-24. DPP-IV also plays a role in the modification of antigens for immune recognition as it is expressed as CD26 on the surface of T-lymphocytes with inactivation of chemokines as RANTES, Scand J Immunol. 2001 Sep;54(3):249-64. Hence there is the concern that inhibition could affect other physiologic systems, in the form of increases in blood pressure due to decreased Neuropeptide Y degradation, increased inflammation and allergic reactions due to chemokine excess, and neurogenic inflammation mediated by non-degraded substance P and neuropeptide Y. Int Rev Cytol.2004;235:165-213. Despite this, DPP-IV knock out mice do not show any immunological dysfunction. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6874-9. DPP-IV belongs to a group of serine proteases, many of whose function is not yet characterised (DPP-7, DPP-8, DPP-9, Fibroblast activation protein-alpha [FAP]). Inhibition of DPP-8 and DPP-9 enzymes is thought to contribute to the side effects of DPP-IV inhibitors including alopecia, thrombocytopenia, and splenomegaly. Diabetologia.2005 Apr;48(4):616-20 It is hence very crucial that highly specific DPP-IV inhibitors are developed to ensure long term safety.