dipeptidyl peptidase-4 inhibitor
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Inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors or gliptins) are a class of
oral hypoglycemic Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exceptions of insulin, most GLP receptor agonists (liraglutide, exenatide, and others), and pramlintide, all are administered orally and are thus ...
s that block the
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
dipeptidyl peptidase-4 (DPP-4). They can be used to treat
diabetes mellitus type 2 Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
. The first agent of the class –
sitagliptin Sitagliptin, sold under the brand name Januvia among others, is an anti-diabetic medication used to treat type 2 diabetes. In the United Kingdom it is listed as less preferred than metformin or a sulfonylurea. It is taken by mouth. It is also a ...
– was approved by the
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
in 2006.
Glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...
increases
blood glucose Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals. Approximately 4 grams of glucose, a simple sugar, is present in the blo ...
levels, and DPP-4 inhibitors reduce glucagon and blood glucose levels. The mechanism of DPP-4 inhibitors is to increase
incretin Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood-gl ...
levels ( GLP-1 and GIP), which inhibit
glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...
release, which in turn increases
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
secretion, decreases gastric emptying, and decreases
blood glucose Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals. Approximately 4 grams of glucose, a simple sugar, is present in the blo ...
levels. A 2018
meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
found no favorable effect of DPP-4 inhibitors on all-cause mortality, cardiovascular mortality,
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
or
stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
in patients with type 2 diabetes.


Examples

Drugs belonging to this class are: *
Sitagliptin Sitagliptin, sold under the brand name Januvia among others, is an anti-diabetic medication used to treat type 2 diabetes. In the United Kingdom it is listed as less preferred than metformin or a sulfonylurea. It is taken by mouth. It is also a ...
(FDA approved 2006, marketed by Merck & Co. as Januvia) * Vildagliptin (EU approved 2007, marketed in the EU by
Novartis Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...
as Galvus) * Saxagliptin (FDA approved in 2009, marketed as Onglyza) * Linagliptin (FDA approved in 2011, marketed as Tradjenta by
Eli Lilly and Company Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Colonel ...
and
Boehringer Ingelheim C.H. Boehringer Sohn AG & Co. is the parent company of the Boehringer Ingelheim group, which was founded in 1885 by Albert Boehringer in Ingelheim am Rhein, Germany. As of 2018, Boehringer Ingelheim is one of the world's largest pharmaceutical ...
) * Gemigliptin (approved in Korea in 2012, marketed by LG Life Sciences) Marketed as Zemiglo * Anagliptin (approved in Japan in 2012, marketed by Sanwa Kagaku Kenkyusho Co., Ltd. and Kowa Company, Ltd.) * Teneligliptin (approved in Japan in 2012) * Alogliptin (FDA approved 2013, marketed by Takeda Pharmaceutical Company) *
Trelagliptin Trelagliptin (trade name Zafatek) is a pharmaceutical drug used for the treatment of type 2 diabetes (diabetes mellitus). Indications It is a highly selective dipeptidyl peptidase-4 inhibitor that is typically used as an add on treatment when ...
(approved for use in Japan in 2015) *
Omarigliptin Omarigliptin (MK-3102) is a potent, long-acting oral antidiabetic drug of the DPP-4 inhibitor class used for once-weekly treatment of type 2 diabetes and currently under development by Merck & Co. It inhibits DPP-4 to increase incretin levels (G ...
(MK-3102) (approved in Japan in 2015, developed by Merck & Co.; research showed that omarigliptin can be used as once-weekly treatment and generally well tolerated throughout the base and extension studies) * Evogliptin (approved for use in South Korea) * Gosogliptin (approved for use in Russia) * Dutogliptin (being developed by Phenomix Corporation), Phase III Other chemicals which may inhibit DPP-4 include: *
Berberine Berberine is a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in such plants as ''Berberis vulgaris'' (barberry), ''Berberis aristata'' (tree turmeric), ''Mahonia aquifolium'' (Oregon grape), ''Hydra ...
, an
alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...
found in plants of the genus '' Berberis'', inhibits dipeptidyl peptidase-4 which may at least partly explains its antihyperglycemic activity.


Adverse effects

In those already taking
sulphonylurea Sulfonylureas (UK: sulphonylurea) are a class of organic compounds used in medicine and agriculture, for example as antidiabetic drugs widely used in the management of diabetes mellitus type 2. They act by increasing insulin release from the bet ...
s, there is an increased risk of low blood sugar when taking a medicine in the DPP-4 drug class. Adverse effects include nasopharyngitis,
headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
,
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
, hypersensitivity and skin reactions. The U.S. Food and Drug Administration (FDA) is warning that the type 2 diabetes medicines like
sitagliptin Sitagliptin, sold under the brand name Januvia among others, is an anti-diabetic medication used to treat type 2 diabetes. In the United Kingdom it is listed as less preferred than metformin or a sulfonylurea. It is taken by mouth. It is also a ...
, saxagliptin, linagliptin, and alogliptin may cause joint pain that can be severe and disabling. FDA has added a new Warning and Precaution about this risk to the labels of all medicines in this drug class, called dipeptidyl peptidase-4 (DPP-4) inhibitors. However, studies assessing risk of rheumatoid arthritis among DPP-4 inhibitor users have been inconclusive. A 2014 review found increased risk of
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
with saxagliptin and alogliptin, prompting the FDA in 2016 to add warnings to the relevant drug labels. A 2018 meta analysis showed that use of DPP-4 inhibitors was associated with a 58% increased risk of developing acute pancreatitis compared with placebo or no treatment. A 2018 observational study suggested an elevated risk of developing inflammatory bowel disease (specifically, ulcerative colitis), reaching a peak after three to four years of use and decreasing after more than four years of use. A 2020 Cochrane systematic review did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
, non-fatal
stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
or
end-stage renal disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vom ...
when comparing metformin monotherapy to dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes.


Cancer

In response to a report of precancerous changes in the pancreases of rats and organ donors treated with the DPP-4 inhibitor sitagliptin, the United States FDA and the European Medicines Agency each undertook independent reviews of all clinical and preclinical data related to the possible association of DPP-4 inhibitors with pancreatic cancer. In a joint letter to the New England Journal of Medicine, the agencies stated that they had not yet reached a final conclusion regarding a possible causative relationship. A 2014 meta-analysis found no evidence for increased
pancreatic cancer Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of t ...
risk in people treated with DPP-4 inhibitors, but owing to the modest amount of data available, was not able to completely exclude possible risk.


Combination drugs

Some DPP-4 inhibitor drugs have received approval from the FDA to be used with metformin concomitantly with additive effect to increase the level of glucagon-like peptide 1 (GLP-1) which also decreases
hepatic The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
glucose production.


See also

* Development of dipeptidyl peptidase-4 inhibitors


References

{{DEFAULTSORT:Dipeptidyl Peptidase-4 Inhibitor