Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes Therapy
The prevalence of type 2 diabetes is rising dramatically, and some predictions state that the worldwide number of subjects with diabetes by 2030 will be 370 million, along with a concomitant rise in prediabetic conditions.1 Since type 2 diabetes is increasing and most patients do not reach their therapeutic goals, novel treatment options are needed.
While insulin resistance is constant in the course of type 2 diabetes, islet function declines continuously over time, and disease progression of type 2 diabetes is characterised by a loss of islet function. Hyperglycaemia, free fatty acids, cytokines, adipokines and toxic metabolic products may lead to a loss of β-cell function and β-cell mass in the islets. The α cells in the islet additionally develop a disturbance of glucagon secretion. In healthy subjects, glucagon secretion is suppressed under hyperglycaemic conditions, whereas in type 2 diabetes glucagon secretion is elevated, leading to excessive glucose production by the liver.2
The therapeutic options currently available do not address the problem of islet-cell dysfunction. Both sulfonylureas and glinides stimulate insulin secretion from the β cells, metformin and glitazones act on insulin resistance and α-glucosidase inhibitors delay the digestion of sucrose and the breakdown of complex carbohydrates. Exogenous insulin replaces the endogenous secretory insulin deficit, although it potentially causes weight gain and hypoglycaemia. The progressive loss of islet function observed in type 2 diabetes is not ameliorated by any of the current therapeutic options.3
Incretin Hormones and Incretin-based Therapies
The incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) stimulate insulin secretion after a meal.4 The incretin effect – which leads to an enhanced insulin response after oral glucose compared with intravenous glucose – is reduced or even absent in patients with type 2 diabetes,5 but can be restored by raising concentrations of the incretin hormones.
The promising therapeutic potential of GLP-1 as a pharmacological tool for treating type 2 diabetes was discovered in the 1990s. In contrast to other insulinotropic agents, e.g. the sulfonylureas, the insulinotropic effect of GLP-1 depends even more closely on the actual glucose concentration, which allows the possibility of glucose normalisation without the risk of hypoglycaemia. In patients with type 2 diabetes, exogenous GLP-1 increases insulin secretion and normalises both fasting and post-prandial blood glucose. Furthermore, it has the ability to restore the blunted first phase of insulin secretion in type 2 diabetes.6
Besides the glucose-lowering effects, GLP-1 has a variety of additional ‘non-insulinotropic’ physiological actions that may be advantageous in type 2 diabetes therapy, i.e. it suppresses glucagon secretion from the α cells and slows gastric emptying. Therefore, it contributes to satiety and to a slower passage and resorption of carbohydrates. Additionally, GLP-1 acts as a mediator of satiety in the hypothalamus, where it is also found as a neurotransmitter.3 Patients with type 2 diabetes having received GLP-1 as a continuous infusion have lost bodyweight.7 Furthermore, GLP-1 stimulates β-cell formation from precursor cells and also inhibits their apoptosis, leading to an increase in β-cell mass and to an improvement in β-cell function.8
- Smyth S, Heron A, Diabetes and obesity: the twin epidemics, Nat Med, 2006;12:75–80.
- Prentki M, Nolan CJ, Islet beta cell failure in type 2 diabetes, J Clin Invest, 2006;116:1802–12.
- Gallwitz B, Therapies for the treatment of type 2 diabetes mellitus based on incretin action, Minerva Endocrinol, 2006; 31:133–47.
- Creutzfeldt W, The incretin concept today, Diabetologia, 1979; 16:75–85.
- Nauck MA, Heimesaat MM, Orskov C, et al., Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus, J Clin Invest, 1993;91:301–7.
- Drucker DJ, Nauck MA, The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes, Lancet, 2006;368:1696–1705.
- Zander M, Madsbad S, Madsen JL, Holst JJ, Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallelgroup study, Lancet, 2002;359:824–30.
- Drucker DJ, The biology of incretin hormones, Cell Metab, 2006;3:153–65.
- Mentlein R, Dipeptidyl-peptidase IV (CD26) – role in the inactivation of regulatory peptides, Regul Pept, 1999;85:9–24.
- Deacon CF, Alogliptin, a potent and selective dipeptidyl peptidase-IV inhibitor for the treatment of type 2 diabetes, Curr Opin Investig Drugs, 2008;9:402–13.
- Thomas L, Eckhardt M, Langkopf E, et al., (R)-8-(3-aminopiperidin- 1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazoli n- 2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors, J Pharmacol Exp Ther, 2008; 325:175–82.
- Rosenstock J, Sankoh S, List JF, Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naïve patients with type 2 diabetes, Diabetes Obes Metab, 2008; 10:376–86.
- Gallwitz B, Sitagliptin: Profile of a novel DPP-4 inhibitor for the treatment of type 2 diabetes, Drugs Today (Barc), 2007;43: 13–25.
- Ristic S, Bates PC, Vildagliptin: a novel DPP-4 inhibitor with pancreatic islet enhancement activity for treatment of patients with type 2 diabetes, Drugs Today (Barc), 2006;42:519–31.
- Madsbad S, Krarup T, Deacon CF, Holst JJ, Glucagon-like peptide receptor agonists and dipeptidyl peptidase-4 inhibitors in the treatment of diabetes: a review of clinical trials, Curr Opin Clin Nutr Metab Care, 2008;11:491–9.
- Williams-Herman D, Round E, Luo E, et al., The combination of sitagliptin and metformin is well tolerated in patients with type 2 diabetes: pooled analysis of 3028 patients in clinical trials for up to 2 years, Diabetes, 2008;57(Suppl. 1):A592.
- Conarello SL, Li Z, Ronan J, et al., Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance, Proc Natl Acad Sci U S A, 2003;100:6825–30.
- Williams-Herman D, Xu L, Davies MJ, et al., Substantial improvement in beta-cell function with initial combination therapy of sitagliptin and metformin in patients with type 2 diabetes after 1 yeat of treatment, Diabetes, 2008;57 (Suppl. 1):A161.
- Dobs A, Goldstein BJ, Wieczorek L, et al., Triple combination therapy with sitagliptin, metformin, and rosiglitazone improves glycemic control in patients with type 2 diabetes, Diabetes, 2008;57(Suppl. 1):A-152.
- Scherbaum WA, Schweizer A, Mari A, et al., Evidence that vildagliptin attenuates deterioration of glycaemic control during 2-year treatment of patients with type 2 diabetes and mild hyperglycaemia, Diabetes Obes Metab, 2008; Epub ahead of print.
- Aschner P, Kipnes MS, Lunceford JK, Set al., Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes, Diabetes Care, 2006;29:2632–7.
- Nauck MA, Meininger G, Sheng D, et al., Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial, Diabetes Obes Metab, 2007; 9:194–205.
- Charbonnel B, Karasik A, Liu J, et al., Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone, Diabetes Care, 2006;29:2638–43.
- Raz I, Chen Y, Wu M, et al., Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes, Curr Med Res Opin, 2008;24:537–50.
- Goldstein BJ, Feinglos MN, Lunceford JK, et al., Effect of Initial Combination Therapy with Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, and Metformin on Glycemic Control in Patients with Type 2 Diabetes, Diabetes Care, 2007;30(8):1979–87.
- Hermansen K, Kipnes M, Luo E, et al., Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin, Diabetes Obes Metab, 2007;9(5):733–45.
- Ahren B, What mediates the benefits associated with dipeptidyl peptidase-IV inhibition?, Diabetologia, 2005;48: 605–7.
- Rosenstock J, Brazg R, Andryuk PJ, et al., Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebocontrolled, parallel-group study, Clin Ther, 2006;28:1556–8.
- Raz I, Hanefeld M, Xu L, et al., Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus, Diabetologia, 2006; 49:2564–71.
- Scott R, Loeys T, Davies MJ, Engel SS, Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes, Diabetes Obes Metab, 2008; Epub ahead of print.
- Ahren B, Gomis R, Standl E, et al., Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes, Diabetes Care, 2004;27:2874–80.
- Rosenstock J, Baron MA, Camisasca RP, et al., Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes, Diabetes Obes Metab, 2007;9: 175–85.
- Garber AJ, Schweizer A, Baron MA, et al., Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study, Diabetes Obes Metab, 2007;9:166–74.
- Garber AJ, Foley JE, Banerji MA, et al., Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea, Diabetes Obes Metab, 2008; Epub ahead of print.
- Pi-Sunyer FX, Schweizer A, Mills D, Dejager S, Efficacy and tolerability of vildagliptin monotherapy in drug-naive patients with type 2 diabetes, Diabetes Res Clin Pract, 2007;76:132–8.
- Fonseca V, Schweizer A, Albrecht D, et al., Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes, Diabetologia, 2007;50:1148–55.
- Bosi E, Camisasca RP, Collober C, et al., Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin, Diabetes Care, 2007;30:890–95.
- Rosenstock J, Baron MA, Dejager S, et al., Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial, Diabetes Care, 2007;30:217–23.
- Schweizer A, Couturier A, Foley JE, Dejager S, Comparison between vildagliptin and metformin to sustain reductions in HbA(1c) over 1 year in drug-naive patients with type 2 diabetes, Diabet Med, 2007;24:955–61.
- Bolli G, Dotta F, Rochotte E, Cohen SE, Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind study, Diabetes Obes Metab, 2008;10:82–90.
- Dejager S, Razac S, Foley JE, Schweizer A, Vildagliptin in drugnaive patients with type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled, multiple-dose study, Horm Metab Res, 2007;39:218–23.