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 th ...
s that
block
Block or blocked may refer to:
Arts, entertainment and media Broadcasting
* Block programming, the result of a programming strategy in broadcasting
* W242BX, a radio station licensed to Greenville, South Carolina, United States known as ''96.3 ...
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
Dipeptidyl peptidase-4 (DPP4), also known as adenosine deaminase complexing protein 2 or CD26 (cluster of differentiation 26) is a protein that, in humans, is encoded by the ''DPP4'' gene. DPP4 is related to FAP, DPP8, and DPP9. The enzyme was d ...
(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 ...
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
Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certa ...
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
Vildagliptin, sold under the brand name Galvus and others, is an oral anti-hyperglycemic agent (anti-diabetic drug) of the DPP-4 inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin inhibits the inactivation of Glucag ...
(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
Saxagliptin, sold under the brand name Onglyza, is an oral hypoglycemic ( anti-diabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Early development was solely by Bristol-Myers Squibb; in 2007 AstraZeneca joined with Bristol-My ...
(FDA approved in 2009, marketed as Onglyza)
*
Linagliptin
Linagliptin, sold under the brand name Tradjenta among others, is a medication used to treat type 2 diabetes (but not type 1) in conjunction with exercise and diet. It is generally less preferred than metformin and sulfonylureas as an initial tr ...
(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
Gemigliptin ( rINN), sold under the brand name Zemiglo, is an oral anti-hyperglycemic agent ( anti-diabetic drug) of the dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitor) class of drugs. Glucose lowering effects of DPP-4 inhibitors are mainly m ...
(approved in Korea in 2012, marketed by
LG Life Sciences
LG Corporation (or LG Group) (), formerly Lucky-Goldstar from 1983 to 1995 (Korean: ''Leokki Geumseong''; ), is a South Korean multinational conglomerate founded by Koo In-hwoi and managed by successive generations of his family. It is t ...
) Marketed as Zemiglo
*
Anagliptin
Anagliptin (INN; trade name Suiny) is a pharmaceutical drug for the treatment of type 2 diabetes mellitus. It is approved for use in Japan. It belongs to the class of anti-diabetic drugs known as dipeptidyl peptidase-4 inhibitor
Inhibitors of ...
(approved in Japan in 2012, marketed by Sanwa Kagaku Kenkyusho Co., Ltd. and
Kowa Company, Ltd.)
*
Teneligliptin
Teneligliptin (INN; trade name Tenelia) is a pharmaceutical drug for the treatment of type 2 diabetes mellitus. It belongs to the class of anti-diabetic drugs known as dipeptidyl peptidase-4 inhibitors or "gliptins".
Creation
It was created by M ...
(approved in Japan in 2012)
*
Alogliptin
Alogliptin, sold under the brand names Nesina and Vipidia,) is an oral anti-diabetic drug in the DPP-4 inhibitor (gliptin) class. Alogliptin does not decrease the risk of heart attack and stroke. Like other members of the gliptin class, it caus ...
(FDA approved 2013, marketed by
Takeda Pharmaceutical Company
The is a Japanese multinational pharmaceutical company, with partial American and British roots. It is the largest pharmaceutical company in Asia and one of the top 20 largest pharmaceutical companies in the world by revenue (top 10 followin ...
)
*
Trelagliptin (approved for use in Japan in 2015)
*
Omarigliptin (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), '' Hyd ...
, 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
''Berberis'' (), commonly known as barberry, is a large genus of deciduous and evergreen shrubs from tall, found throughout Temperateness, temperate and subtropical regions of the world (apart from Australia). Species diversity is greatest in S ...
'', 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
Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...
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
Saxagliptin, sold under the brand name Onglyza, is an oral hypoglycemic ( anti-diabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Early development was solely by Bristol-Myers Squibb; in 2007 AstraZeneca joined with Bristol-My ...
,
linagliptin
Linagliptin, sold under the brand name Tradjenta among others, is a medication used to treat type 2 diabetes (but not type 1) in conjunction with exercise and diet. It is generally less preferred than metformin and sulfonylureas as an initial tr ...
, and
alogliptin
Alogliptin, sold under the brand names Nesina and Vipidia,) is an oral anti-diabetic drug in the DPP-4 inhibitor (gliptin) class. Alogliptin does not decrease the risk of heart attack and stroke. Like other members of the gliptin class, it caus ...
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
Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. ...
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
Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. ...
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 Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) are enzyme inhibitors that inhibit the enzyme dipeptidyl peptidase-4 (DPP-4). They are used in the treatment of type 2 diabetes mellitus. Inhibition of the DPP-4 enzyme prolongs and enhances the a ...
References
{{DEFAULTSORT:Dipeptidyl Peptidase-4 Inhibitor