DPP-4 inhibitors in human subjects

DPP-4 compounds approved for the treatment of type 2 diabetes include Vildagliptin (Galvus) (LAF237), Sitagliptin (Januvia), Saxagliptin and Linagliptin (Tradjenta)  Alogliptin is approved in Japan.

Januvia (Sitagliptin) was approved for the treatment of type 2 diabetes in the United States on Oct 17 2006, for use as monotherapy, or combination therapy, with either metformin or a thiazolidinedione.  Subsequenly, multiple DPP4 inhibitors havebeen approved worldwide, including saxagliptin, linagliptin, alogliptin, vildagliptin, and other gliptins in Asian markets.

Administration of the first generation Novartis compound 1-[[[2-[(5-cyanopyridin-2-yl)amino] ethyl]amino]acetyl]-2- cyano-(S)- pyrrolidine (NVP DPP728) over a 4 week period to 93 patients with Type 2 diabetes (mean HbA1c of 7.4%) reduced levels of plasma glucose, insulin, and HbA1c over the 4 week study period. See Inhibition of Dipeptidyl Peptidase IV Improves Metabolic Control Over a 4-Week Study Period in Type 2 Diabetes. Diabetes Care. 2002 May;25(5) :869-875

Is metformin an inhibitor of DPP-4? Patients receiving metformin have also been noted to exhibit additive glucose lowering benefits following institution of GLP-1 therapy. See Additive glucose-lowering effects of glucagon-like peptide-1 and metformin in type 2 diabetes. Diabetes Care. 2001 Apr;24(4):720-5. In a study of 10 obese non-diabetic male patients, metformin administration was associated with increased levels of circulating GLP-1 following oral glucose-loading, and in experiments using pooled human plasma, metformin (0.1-0.5 microg/ml) significantly inhibited degradation of GLP-1(7-36)amide after a 30-min incubation at 37 degrees C, in the presence or absence of DPP-4. The authors of this study raised the possibility that metformin may inhibit the enzymatic breakdown of GLP-1 both in vitro and in vivo. See Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care. 2001 Mar;24(3):489-94

Nevertheless,  analysis of the relationship between DPP-4, and GLP-1 degradation using biochemical analyses in vitro, Demuth and colleagues found no direct effect of metformin on the DPP-4-mediated degradation of GLP-1 using a variety of sources of human DPP-4. See Metformin Effects on Dipeptidylpeptidase IV Degradation of Glucagon-like Peptide-1. Biochem Biophys Res Commun. 2002 Mar 15;291(5):1302-8  

Selectivity of DPP-4 Inhibition

As DPP-4 is a member of a large class of related proteases, there has been considerable attention focused on the importance of "selectivity" of DPP-4 inhibitors. Lankas and colleagues generated a series of DPP-8/9 or QPP-preferring inhibitors, and observed widespread organ toxicities. Pathological findings included alopecia, thrombocytopenia, reticulocytopenia, enlarged spleen, multiorgan histopathological changes, and mortality in rodents and in dogs, gastrointestinal toxicity. The QPP inhibitor produced reticulocytopenia in rats. The DPP-8/9 inhibitor also impaired human T cell activation in vitro Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes. 2005 Oct;54(10):2988-94. In contrast, Burkey and colleagues administered vildagliptin orally to mice and rats chronically for 13 weeks, producing systemic exposures well above that required to inhibit the related enzymes DPP-8 and DPP-9, with mean plasma levels of 2279 nM and 5729 nM in mice and rats, respectively. No evidence for multiple organ toxicity was observed, raising questions about the previous toxicity attributed to DPP-8/9 inhibition. See Adverse effects of dipeptidyl peptidases 8 and 9 inhibition in rodents revisited. Diabetes Obes Metab. 2008 Apr 17. [Epub ahead of print]

DPP-4 inhibition and angioedema

There has long been interest as to whether DPP-4 inhibition will lead to potentiation of the biological action of pepttides with vasoactive or pro-inflammatory properties, thereby increasing the risk of local inflammation or angioedema. Brown and colleagues addressed this issue through analysis of the vildagliptin phase 3 clinical trial database. Analysis of angioedema specifically in patients who were also using ACE inhibitors revealed an odds ratio of 4.57, linking vildagliptin use to an increased risk of angioedema. See Dipeptidyl Peptidase-IV Inhibitor Use Associated With Increased Risk of ACE Inhibitor-Associated Angioedema Hypertension. 2009 Jul 6. [Epub ahead of print]

   DPP-4 Inhibitors: Potential for Adverse Events

Some of the safety issues raised in regard to the biology of GLP-1R agonists, principally the relationship between GLP-1, DPP-4, and pancreatitis, may be reviewed in the section GLP-1 SAFETY

                                                                                               DPP-4 Inhibitors: Actions on bone

GLP-1, GIP, PYY, and GLP-2, are all DPP-4 substrates, changes, specifically reduction of DPP-4 activity, may result in potential perturbation in bone biology perhaps through indirect modulation of active peptide hormone activity. As patients with type 2 diabetes exhibit increased fracture rates due to a reduction in bone quality, Kyle and colleagues examined multiple parameters of bone strength and bone quality in Dpp4+/+ vs Dpp4-/- mice, with or without estrogen deficiency induced by ovariectomy (OVX). Kyle also studied the same parameters in wildtype mice placed on a high fat diet, with or without OVX, and treated with the DPP-4 inhibitor sitagliptin, or the thiazolidinedione, pioglitazone. The degree of glucose control achieved with the two different anti-diabetic agents was comparable for sitagliptin vs. pioglitazone, as assessed by glucose tolerance and HbA1c, however pioglitazone-treated mice exhibited enhanced insulin sensitivity, significant weight gain and fat accumulation. Consistent with previous reports, the TZD pioglitazone reduced bone mineral density, and bone mineral volume, and decreased bone quality as demonstrated by significant adverse changes in vertebral compression parameters. Pioglitazone also reduced the mineral apposition rate and increased bone marrow adiposity. In contrast, sitagliptin treatment of WT mice was largely neutral on multiple parameters of bone mineral density and bone quality, however modest increases in bone mineral density, trabecular bone mineralization profiles and trabecular architecture were observed with sitagliptin. Similarly, Dpp4-/- mice exhibited very little perturbation in bone mineral density or quality, however both sitagliptin-treated or Dpp4-/- mice did experience further reductions in BMD and bone quality following OVX. See Kyle, K.A., Willett, T.L., Baggio, L.L., Drucker, D. J., Grynpas, M. Differential Effects of PPAR-g Activation vs. Chemical or Genetic reduction of DPP-4 Activity on Bone Quality in Mice Endocrinology 2011 Feb;152(2):457-67.

Monami and colleagues carried out a meta-analysis of clinical trials carried out with DPP-4 inhibitors in 11,880 patients exposed to a DPP-4 inhibitor vs 9,175 control subjects for at least 24 weeks. The biological plausability of inducing changes in bone strength/density over 24 weeks that would lead to a fracture remains uncertain. DPP-4 inhibitors were associated with a significantly lower reported fracture rate, even after correcting for exposure to TZD use. 16/54 trials did not disclose the number of bone fractures and several trials reported no fracture events. Furthermore, 20 of the 28 trials compared DPP-4 inhibitor relative to placebo. 63 total fractures were reported, 26 with DPP-4 inhbitor use. Only 7 trials were 52 weeks or greater. Dipeptidyl Peptidase-4 Inhibitors and Bone Fractures: A meta-analysis of randomized clinical trials Diabetes Care. 2011 Nov;34(11):2474-6