Sitagliptin, sold under the brand name Januvia among others, is an

anti-diabetic medication 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 ...

used to treat

type 2 diabetes 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 urinatio ...

. In the United Kingdom it is listed as less preferred than

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. ...

or a

sulfonylurea 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 ...

. It is taken

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...

. It is also available in the

fixed-dose combination A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form. Terms like "combination drug" or "combination drug product" can be common shorthand for a FDC pr ...

medication sitagliptin/metformin (Janumet, Janumet XR). Common side effects include headaches, swelling of the legs, and

upper respiratory tract infections An upper respiratory tract infection (URTI) is an illness caused by an acute infection, which involves the upper respiratory tract, including the nose, sinuses, pharynx, larynx or trachea. This commonly includes nasal obstruction, sore throat, to ...

. Serious side effects may include

angioedema Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are ...

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 bel ...

kidney problems Kidney failure, also known as end-stage kidney disease, 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 failure is classified as eit ...

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 hormones. There are two main types: acute pancreatitis, and chronic pancr ...

, and

joint pain Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication. According to MeSH, ...

. Whether use in

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

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...

is safe is unclear. It is in the dipeptidyl peptidase-4 (DPP-4) inhibitor class and works by increasing the production of insulin and decreasing the production of glucagon by the pancreas. Sitagliptin was developed by Merck & Co. and approved for medical use in the United States in 2006. In 2020, it was the 74th most commonly prescribed medication in the United States, with more than 9million prescriptions.

Medical uses

Sitagliptin is used to treat type 2 diabetes. It is generally less preferred than

or sulfonylureas. It is taken by mouth. It is also available as the

s of sitagliptin/metformin (Janumet, Janumet XR) and sitagliptin/simvastatin (Juvisync). Sitagliptin should not be used to treat type 1 diabetes. In December 2020, the U.S.

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 respon ...

(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 ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. In general, placebos can af ...

, except for rare

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 ...

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

hypoglycemia 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 bel ...

between placebo and sitagliptin. In those 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, the risk of

is increased. The existence of rare case reports of

kidney failure Kidney failure, also known as end-stage kidney disease, 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 failure is classified as eit ...

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 U.S. 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 U.S. 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 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 ...

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

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 ...

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,

gastrointestinal hormone The gastrointestinal hormones (or gut hormones) constitute a group of hormones secreted by enteroendocrine cells in the stomach, pancreas, and small intestine that control various functions of the digestive organs. Later studies showed that most o ...

s 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 Glycated hemoglobin, also known as HbA1c, glycohemoglobin, hemoglobin A1c, A1C, is a form of hemoglobin (Hb) that is chemically linked to a sugar. Most monosaccharides, including glucose, galactose and fructose, spontaneously (i.e. non-enzymati ...

level by about 0.7% points versus placebo. It is slightly less effective than metformin when used as a

monotherapy Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can also ...

. 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 U.S.

(FDA) in October 2006, and is marketed in the US as Januvia by Merck & Co. On April 2, 2007, the FDA approved an oral combination of sitagliptin/metformin sold in the US under the brand name Janumet. On October 7, 2011, the FDA approved an oral combination of sitagliptin/simvastatin marketed in the US as Juvisync.

References

External links

* * {{Portal bar , Medicine Wikipedia medicine articles ready to translate Dipeptidyl peptidase-4 inhibitors Carboxamides Trifluoromethyl compounds Fluoroarenes Triazoles Merck & Co. brands