Tradjenta and Jentadueto are DPP-4 inhibitors used to treat patients with Type 2 diabetes. Both medications have been associated with serious, sometimes fatal, side effects, including pancreatitis, pancreatic cancer and possible heart failure. Jentadueto also contains metformin. Metformin-use has been associated with an increased risk of the development of lactic acidosis.
Linagliptin is the active ingredient in two anti-diabetes drugs, Tradjenta and Jentadueto, that has been linked to several serious, potentially deadly, side effects, including inflammation of the pancreas called pancreatitis, the development of precancerous cells (metaplasia) in the pancreas and possibly pancreatic cancer.
Heart failure is also a concern that is still being studied with the treatment of DPP-4 inhibitors, a class of drugs to which both Tradjenta and Jentadueto belong. The risk of heart failure may be greater in patients with existing heart complications and kidney impairment.
Additionally, Jentadueto contains metformin, which has been linked to an increased risk of the development of lactic acidosis, especially in high-risk patients.
In 2013, the FDA began an evaluation of unpublished findings by a group of academic researchers that suggested an increased risk of pancreatitis (or inflammation of the pancreas) as well as precancerous cellular changes called pancreatic duct metaplasia in patients with Type 2 diabetes being treated with incretin mimetics (a class of drugs including Tradjenta and Jentadueto). The FDA reported that the findings were based on an examination of a small number of pancreatic tissue specimens taken from patients who died of unknown causes.
The FDA stated that it had “not reached any new conclusions about safety risks” associated with the drugs and that the communication was simply intended to inform the public and health care professionals of the federal agency’s intent to obtain and further evaluate the information. While the FDA said it would communicate its final conclusions and recommendations when its evaluation was complete or when any new information was available to report, the FDA has not updated the public as to the status of its investigation to date.
Prior to this communication, the FDA had previously warned the public about post-marketing reports that showed acute pancreatic inflammation, including cases leading to death, linked to the use of incretin mimetics.
In June 2013, a British Medical Journal (BMJ) article discussed concerns and evidence regarding the same. It concluded, based on the results of animal studies and reports from regulatory agencies, such as the FDA, that “it does appear that there may be an increased risk of these drugs having adverse effects.”
The FDA did note in its 2013 safety announcement that although the risk for pancreatitis may have previously been known, the FDA had never “previously communicated about the potential risk of pre-cancerous findings of the pancreas with [the use of] incretin mimetics,” such as Tradjenta and Jentadueto. However, the agency declined to definitely conclude at that time if these drugs may actually cause or contribute to the development of pancreatic cancer.
Pancreatitis is inflammation of the pancreas, the large gland (organ) situated behind the stomach and close to the first part of the small intestine called the duodenum. The serious condition occurs when digestive enzymes produced by the pancreas start digesting the gland itself.
The pancreas is an organ made up of two glands, one of which has exocrine cells that help digest food by way of enzymes released into pancreatic ducts, and the other composed of endocrine cells that release hormones directly into the bloodstream. Pancreatic cancer usually begins in the exocrine cells, with more than 90 percent of metaplastic changes found to take place in the ductal system.
Metaplasia, or a change in cells to a form that does not normally occur in the tissue in which it is found, is often reversible. It is not considered cancer, however. It is usually associated with cancer, or seen as a precursor to cancer, thereby requiring immediate medical or surgical attention and intervention. Chronic pancreatitis, or pancreatitis that does not heal or improve, is considered a risk factor for the development of certain types of pancreatic cancer, usually affecting the pancreatic ducts.
For most patients with pancreatic cancer beginning in the exocrine cells, there is no cure.
Acute pancreatitis happens suddenly. The main symptom of the serious condition is pain felt in the upper left side or middle of the abdomen. This pain can often be severe. Patients may also look ill and experience fever, nausea, vomiting and sweating.
Unlike pancreatitis, pancreatic cancer does not always show symptoms, especially in the early stages. However, when symptoms are present, they are very similar to those of pancreatitis, including upper abdominal pain that can spread to the back and jaundice.
Treatment of pancreatitis often requires a hospital stay. During that time, intravenous (IV) fluids, antibiotics and pain medications may be administered to the patient. Food and fluid by mouth may also be stopped to limit the activity of the pancreas.
In the most severe cases of pancreatitis, surgery is usually needed to remove damaged, dead or infected pancreatic tissue.
When metaplasia (abnormal tissue change) occurs in pancreatic tissue, the cells may progress to develop dysplasia, or the enlargement of an organ or tissue by the rapid increase of abnormal cells. This can then lead to malignant neoplasia, or cancer. When metaplasia is detected, it is usually best to remove the irritant causing the cellular changes, thereby decreasing a person’s risk of the eventual development of cancer.
Pancreatic cancer is hard to detect in its early stages. This is primarily due to the fact that the pancreas is located deep within the body and cannot be felt by doctors during a routine exam. Imaging tests, such as an endoscopic ultrasound, or a thin tube with a camera at the end that is passed through the mouth into the stomach, can help doctors see the pancreas through the stomach wall and find a tumor when pancreatic cancer is suspected. A biopsy, or tissue sample, can be retrieved during the procedure as well.
Because pancreatic cancer is often found late and it can spread quickly, it can be difficult to treat. Treatment of pancreatic cancer in its later stages is not likely to be effective.
Patients with pancreatic cancer typically have a very low chance of survival. When surgery can be done, the five-year survival rate is usually somewhere between 10 to 25 percent. When surgery is not possible, the survival rate drops to about 6 percent after five years.
A link between DPP-4 inhibitors, such as Tradjenta and Jentadueto, and heart failure has been found in cardiovascular outcomes trials for two other drugs in the DPP-4 inhibitor class (saxagliptin and alogliptin), according to drug labeling. The trials evaluated patients with Type 2 diabetes and those with atherosclerotic cardiovascular disease (ASVD). ASVD is a condition in which an artery wall thickens as a result of an influx and accumulation of white blood cells and smooth muscle cells thereby creating a plague that is both fibrous and fatty.
However, a study published in 2016, regarding the safety and effectiveness of linagliptin in Type 2 diabetes patients with kidney and cardiovascular risk factors, showed that treatment with drugs containing linagliptin, such as Tradjenta and Jentadueto, does not increase a patient’s cardiovascular risk and may even have a cardiovascular benefit.
The FDA requires evidence that diabetic therapies do not cause unacceptable increases in cardiovascular risk.
Patients at risk for heart failure, or those with a history of kidney impairment, should consider the risks and benefits of treatment with Tradjenta and Jentadueto. Patients should be observed for signs and symptoms of heart failure after starting treatment with one of the anti-diabetes drugs. Where heart failure develops, discontinuation of treatment should be considered after the patient is evaluated.
Postmarketing cases of lactic acidosis have been reported in patients using medications containing metformin, such as Jentadueto. Metformin-use decreases liver uptake of lactate (or lactic acid) increasing levels of the chemical substance in the blood, which may lead to an increased risk of lactic acidosis.
Some of the reported cases have resulted in death. The onset of metformin-associated lactic acidosis is often subtle and accompanied by nonspecific symptoms.
Severe cases of lactic acidosis can result in abnormally low body temperature, low blood pressure and resistant bradyarrhythmias (slow heartbeat so that the pulse rate is less than 60 per minute).
Please seek the advice of a medical professional before making health care decisions.
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