Sitagliptin
Encyclopedia
Sitagliptin is an oral antihyperglycemic (antidiabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. It was developed, and is marketed, by Merck & Co.
This enzyme-inhibiting drug is used either alone or in combination with other oral antihyperglycemic agents (such as metformin
or a thiazolidinedione
) for treatment of diabetes mellitus type 2
. The benefit of this medicine is its fewer side effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose values. While safety is its advantage, efficacy is often challenged as it is often recommended to be combined with other agents like metformin. Exenatide
(Byetta) also works by its effect on the incretin
system.
s, adverse effects
were as common with sitagliptin (whether used alone or with metformin
or pioglitazone
) as they were with placebo
, except for extremely rare nausea
and common cold
-like symptoms. There is no significant
difference in the occurrence of hypoglycemia
between placebo and sitagliptin.
There have been several postmarketing reports
of pancreatitis
(some fatal) in people treated with sitagliptin, 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.
The hypothetical risk of cancer activation with DPP-4 down-regulation applies to all the DPP-4 inhibitors on the market (saxagliptin and vildagliptin) in addition to sitagliptin.
and is marketed in the US as Januvia by Merck & Co.
On April 2, 2007, the FDA approved an oral combination of sitagliptin and metformin
marketed in the US as Janumet.
the enzyme
dipeptidyl peptidase 4 (DPP-4). This enzyme breaks down the incretin
s GLP-1 and GIP, gastrointestinal hormone
s released in response to a meal. By preventing GLP-1 and GIP inactivation, they are able to increase the secretion of insulin and suppress the release of glucagon by 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.
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...
This enzyme-inhibiting drug is used either alone or in combination with other oral antihyperglycemic agents (such as metformin
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
or a thiazolidinedione
Thiazolidinedione
The thiazolidinediones , also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2. They were introduced in the late 1990s.- Mechanism of action :...
) for treatment of 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 benefit of this medicine is its fewer side effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose values. While safety is its advantage, efficacy is often challenged as it is often recommended to be combined with other agents like metformin. Exenatide
Exenatide
Exenatide is a medication approved in April 2005 for the treatment of diabetes mellitus type 2. It belongs to the group of incretin mimetics and is manufactured by Amylin Pharmaceuticals and Eli Lilly and Company....
(Byetta) also works by its effect on the 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...
system.
Adverse effects
In clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s, adverse effects
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
were as common with sitagliptin (whether used alone or with metformin
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
or pioglitazone
Pioglitazone
Pioglitazone is a prescription drug of the class thiazolidinedione with hypoglycemic action.Pioglitazone is marketed as trademarks Actos in the USA, Canada, the UK and Germany, Glustin in Europe,"Glizone" and "Pioz" in India by Zydus CND and USV respectively and Zactos in Mexico by Takeda...
) as they were with placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
, except for extremely rare nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and 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...
-like symptoms. There is no significant
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
difference in the occurrence of hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
between placebo and sitagliptin.
There have been several postmarketing reports
Postmarketing surveillance
Postmarketing surveillance is the practice of monitoring the safety of a pharmaceutical drug or device after it has been released on the market and is an important part of the science of pharmacovigilance...
of pancreatitis
Pancreatitis
Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...
(some fatal) in people treated with sitagliptin, 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.
Cancer risk of DPP-4 inhibitors
The DPP-4 enzyme is known to be involved in the suppression of certain malignancies, particularly in limiting the tissue invasion of these tumours. Inhibiting the DPP-4 enzymes may allow some cancers to progress. A study of DPP-4 inhibition in human nonsmall cell lung cancer (NSCLC) concluded "DPPIV functions as a tumor suppressor, and its downregulation may contribute to the loss of growth control in NSCLC cells.The hypothetical risk of cancer activation with DPP-4 down-regulation applies to all the DPP-4 inhibitors on the market (saxagliptin and vildagliptin) in addition to sitagliptin.
History
Sitagliptin was approved by the U.S. Food and Drug Administration (FDA) on October 17, 2006,and is marketed in the US as Januvia 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...
On April 2, 2007, the FDA approved an oral combination of sitagliptin and metformin
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
marketed in the US as Janumet.
Mechanism of action
Sitagliptin works to competitively inhibitCompetitive inhibition
Competitive inhibition is a form of enzyme inhibition where binding of the inhibitor to the active site on the enzyme prevents binding of the substrate and vice versa.-Mechanism:...
the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
dipeptidyl peptidase 4 (DPP-4). This enzyme breaks down the 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...
s GLP-1 and GIP, gastrointestinal hormone
Gastrointestinal hormone
The gastrointestinal 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...
s released in response to a meal. By preventing GLP-1 and GIP inactivation, they are able to increase the secretion of insulin and suppress the release of glucagon by 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.
External links
- Official website
- Januvia Prescribing Information Merck & Co.
- Sitagliptin Pharmacokinetics – PubPK
- Merck Announces FDA Acceptance of New Drug Application for JANUVIA - Merck press release.
- The race to get DPP-4 inhibitors to market - Forbes.com
- Merck's March Madness - Forbes.com – Sitagliptin – About DPP-4
- U.S. National Library of Medicine: Drug Information Portal - Sitagliptin