Dipeptidyl peptidase-4 inhibitors - AbsoluteAstronomy.com

Inhibitors of dipeptidyl peptidase 4, also DPP-4 inhibitors or gliptins, are a class of oral hypoglycemics that block DPP-4. They can be used to treat diabetes mellitus type 2

Diabetes mellitus type 2

Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...

.

The first agent of the class - sitagliptin

Sitagliptin

Sitagliptin is an oral antihyperglycemic of the dipeptidyl peptidase-4 inhibitor class. It was developed, and is marketed, by Merck & Co...

- was approved by the FDA in 2006.

Glucagon

Glucagon

Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...

increases blood glucose levels, and DPP-4 inhibitors reduce glucagon and blood glucose levels. The mechanism of DPP-4 inhibitors is to increase incretin

Incretin

Incretins are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating, even before blood glucose levels become elevated. They also slow the rate of absorption of nutrients into the blood stream by...

levels (GLP-1 and GIP), which inhibit glucagon

Glucagon

release, which in turn increases insulin

Insulin

Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

secretion, decreases gastric emptying, and decreases blood glucose levels.

Examples

Drugs belonging to this class are :

sitagliptin
Sitagliptin
Sitagliptin is an oral antihyperglycemic of the dipeptidyl peptidase-4 inhibitor class. It was developed, and is marketed, by Merck & Co...

(FDA approved 2006, marketed by Merck & Co.
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...

as Januvia),
vildagliptin
Vildagliptin
Vildagliptin is an oral anti-hyperglycemic agent of the new dipeptidyl peptidase-4 inhibitor class of drugs...

(EU approved 2008, marketed in the EU by Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...

as Galvus),
saxagliptin
Saxagliptin
Saxagliptin , previously identified as BMS-477118, is a new oral hypoglycemic of the new dipeptidyl peptidase-4 inhibitor class of drugs. Early development was solely by Bristol-Myers Squibb; in 2007 AstraZeneca joined with Bristol-Myers Squibb to co-develop the final compound and collaborate on...

(FDA approved in 2009, marketed as Onglyza),
linagliptin
Linagliptin
Linagliptin is a DPP-4 inhibitor developed by Boehringer Ingelheim for treatment of type II diabetes....

(FDA approved in 2011, marketed as Trajenta by Eli Lilly Co and Boehringer Ingelheim),
dutogliptin (being developed by Phenomix Corporation), Phase III
gemigliptin (being developed by LG Life Sciences,Korea)
alogliptin
Alogliptin
Alogliptin is an investigational anti-diabetic drug in the DPP-4 inhibitor class, being developed by Takeda Pharmaceutical Company. In January 2008, Takeda submitted a New Drug Application for alogliptin to the U.S. Food and Drug Administration, after positive results from Phase III clinical trials...

(developed by Takeda Pharmaceutical Company
Takeda Pharmaceutical Company
is the largest pharmaceutical company in Japan and Asia and a top 15 pharmaceutical company. The company has over 19,000 employees worldwide and achieved $15.7 billion USD in revenue during the 2008 fiscal year...

, whose FDA application for the product is currently under review)

Berberine

Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis Berberine is a quaternary...

, the common herbal dietary supplement, too inhibits dipeptidyl peptidase-4, which at least partly explains its antihyperglycemic activity.

Risks and side effects

Long-term effects of DPP-4 inhibitors on mortality and morbidity are so far inconclusive, although adverse effects, including nasopharyngitis (the common cold

Common cold

The common cold is a viral infectious disease of the upper respiratory system, caused primarily by rhinoviruses and coronaviruses. Common symptoms include a cough, sore throat, runny nose, and fever...

), headache, nausea, hypersensitivity and skin reactions, have been observed in clinical studies. Consistent with this FDA approval of Novartis

Novartis

Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...

' DPP-4 inhibitor vildagliptin

Vildagliptin

Vildagliptin is an oral anti-hyperglycemic agent of the new dipeptidyl peptidase-4 inhibitor class of drugs...

(Galvus®) was delayed because of skin lesions with blistering observed in nonhuman primate toxicology studies; one year later, Novartis CEO Dan Vasella remained uncertain as to their ability to ever file to market the drug in the United States. Other possible adverse effects, including hypersensitivity reactions and pancreatitis, have been reported. These effects may relate to DPP-4's function in restricting the inflammatory

Inflammation

Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

actions of the chemokine

Chemokine

Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...

CCL11

Chemokine ligand 11 is a small cytokine belonging to the CC chemokine family that is also known as eotaxin-1. CCL11 selectively recruits eosinophils by inducing their chemotaxis, and therefore, is implicated in allergic responses. The effects of CCL11 are mediated by its binding to a...

/eotaxin, so that inhibiting DPP-4 might unleash the recruitment of inflammatory cells.

Although one in vitro study found that DPP-4 inhibitors, together with GLP-2, increased proliferation and migration of colon cancer cells, which might encourage cancer cells to metastasize, carcinogenicity has not been confirmed in long-term, preclinical studies of the major DPP-4 inhibitors.

DPP-4 appears to work as a suppressor in the development of cancer

Cancer

Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

and tumours.

Examples

Risks and side effects

Further reading