Sitagliptin, sold under the brand name Januvia among others, is an anti-diabetic medication used to treat

type 2 diabetes Type 2 diabetes (T2D), 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 ...

. It is in the dipeptidyl peptidase-4 (DPP-4) inhibitor class and works by increasing the production of

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

and decreasing the production of

glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the 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 (medic ...

by the pancreas. In the United Kingdom it is listed as less preferred than metformin or a

sulfonylurea Sulfonylureas or sulphonylureas are a class of organic compounds used in medicine and agriculture. The functional group consists of a sulfonyl group (-S(=O)2) with its sulphur atom bonded to a nitrogen atom of a ureylene group (N,N-dehydrourea ...

. It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. It is also available in the fixed-dose combination medication sitagliptin/metformin (Janumet, Janumet XR). Common side effects include headaches, swelling of the legs, and upper respiratory tract infections. Serious side effects may include angioedema, low blood sugar, kidney problems,

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormone A hormone (from the Ancient Greek, Greek participle , "se ...

, and

joint pain Arthralgia () literally means 'joint pain'. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication Medication (also called medicament, medicine, pharmaceutic ...

. Whether use in

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...

is safe is unclear. Sitagliptin was developed by Merck & Co. and approved for medical use in the United States in 2006. In 2022, it was the 86th most commonly prescribed medication in the United States, with more than 7million prescriptions. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

, but not in the United States.

Medical uses

Sitagliptin is used to treat type 2 diabetes. It is generally less preferred than metformin or sulfonylureas. It is taken by mouth. It is also available as the fixed-dose combinations of sitagliptin/metformin (Janumet, Janumet XR) and sitagliptin/simvastatin (Juvisync). Sitagliptin should not be used to treat type 1 diabetes. In December 2020, the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) approved labeling changes stating that Januvia (sitagliptin), Janumet (sitagliptin and metformin hydrochloride), and Janumet XR (sitagliptin and metformin hydrochloride extended-release) are not proven to improve glycemic (blood sugar) control in children aged 10 to 17 with type 2 diabetes. The drugs are approved to improve blood sugar control in adults aged 18 and older with type 2 diabetes.

Adverse effects

Adverse effects from sitagliptin are similar to

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

, except for rare

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

common cold The common cold, or the cold, is a virus, viral infectious disease of the upper respiratory tract that primarily affects the Respiratory epithelium, respiratory mucosa of the human nose, nose, throat, Paranasal sinuses, sinuses, and larynx. ...

-like symptoms, and photosensitivity. It does not increase the risk of diarrhea. No significant difference exists in the occurrence of

hypoglycemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes 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 tria ...

between placebo and sitagliptin. In those taking sulphonylureas, the risk of low blood sugar is increased. The existence of rare case reports of

kidney failure Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...

and hypersensitivity reactions is noted in the United States prescribing information, but a causative role for sitagliptin has not been established. Several postmarketing reports of

(some fatal) have been made in people treated with sitagliptin and other DPP-4 inhibitors, and the US FDA package insert carries a warning to this effect, although the causal link between sitagliptin and pancreatitis has not yet been fully substantiated. One study with lab rats published in 2009 concluded that some of the possible risks of pancreatitis or pancreatic cancer may be reduced when it is used with metformin. However, while DPP-4 inhibitors showed an increase in such risk factors, as of 2009, no increase in pancreatic cancer has been reported in individuals taking DPP-4 inhibitors. In 2015, the US Food and Drug Administration (FDA) added a new warning and precaution about the risk of "severe and disabling" joint pain to the labels of all DPP-4 inhibitor medicines.

Mechanism of action

Sitagliptin works to competitively inhibit the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

dipeptidyl peptidase 4 (DPP-4). This enzyme breaks down the

incretin Incretins are a group of metabolic hormones that decrease Blood sugar level, blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from Pancreas, pancreatic beta cells of the islets of Langerhans ...

GLP-1 Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certai ...

and GIP, gastrointestinal hormones released in response to a meal. By preventing breakdown of GLP-1 and GIP, they are able to increase the secretion of insulin and suppress the release of glucagon by the alpha cells of the pancreas. This drives blood glucose levels towards normal. As the blood glucose level approaches normal, the amounts of insulin released and glucagon suppressed diminishes, thus tending to prevent an "overshoot" and subsequent low blood sugar (hypoglycemia), which is seen with some other oral hypoglycemic agents. Sitagliptin has been shown to lower HbA1c level by about 0.7% points versus placebo. It is slightly less effective than metformin when used as a monotherapy. It does not cause weight gain and has less hypoglycemia compared to sulfonylureas. Sitagliptin is recommended as a second-line drug (in combination with other drugs) after the combination of diet/exercise and metformin fails.

History

Sitagliptin was approved by the US

(FDA) in October 2006, and is sold under the brand name Januvia. In April 2007, the FDA approved an oral combination of sitagliptin/metformin sold under the brand name Janumet. In October 2011, the FDA approved an oral combination of sitagliptin/simvastatin sold under the brand name Juvisync. The extended release version of sitagliptin/metformin was approved in February 2012.

External links

References

{{Authority control Dipeptidyl peptidase-4 inhibitors Carboxamides Trifluoromethyl compounds Fluoroarenes Triazoles Drugs developed by Merck & Co. Wikipedia medicine articles ready to translate