Tradjenta & Jentadueto Side Effects

Tradjenta and Jentadueto both contain the active ingredient linagliptin to treat Type 2 diabetes. Common side effects of linagliptin include diarrhea, cough, sore throat, and runny or stuffy nose. Serious side effects include pancreatitis, skin reactions and joint pain.

Tradjenta and Jentadueto pills
Tradjenta and Jentadueto Side Effects
  1. Black Box Warning lactic acidosis (Jentadueto only)
  2. Warnings and Precautions pancreatitis, heart failure, increased risk of hypoglycemia with insulin use, severe joint pain, skin reactions that require hospitalization
  3. Side Effects Reported Most Often to FDA pancreatitis (Tradjenta); diarrhea (Jentadueto)

Linagliptin is the active ingredient in two antidiabetic drugs made by Boehringer Ingelheim: Tradjenta and Jentadueto. Jentadueto combines linagliptin with metformin.

The most common side effects of linagliptin are minor and include runny nose, sore throat, diarrhea and cough, according to the Tradjenta Medication Guide. These side effects may change when combined with other antidiabetic drugs or insulin. When used with other diabetes drugs, the most common side effects are gastrointestinal problems.

In clinical trials, side effects of linagliptin included:
  • Urinary tract infection
  • Headache
  • Weight gain
  • Increased cholesterol
  • Back pain
  • Joint pain
  • Upper respiratory infection
  • Headache
  • Cough
  • Runny nose
  • Pain in extremities
  • Hypoglycemia
  • Allergic reactions
  • Pancreatitis
  • Increased uric acid

Jentadueto has these side effects plus those of metformin. The most common side effects of metformin are diarrhea, nausea and vomiting, flatulence, indigestion abdominal discomfort and headache.

After a drug hits the market, people may voluntarily report side effects or adverse events to the U.S. Food and Drug Administration. From 2011 to September 2018, the FDA’s Adverse Events Reporting System (FAERS) received 3,229 reports of adverse events for Tradjenta. Of these, 889 were serious and included 119 deaths. People reported 425 adverse events to FAERS for Jentadueto, including 12 deaths.

Fact
In FAERS, the most reported adverse event for Tradjenta is pancreatitis. For Jentadueto, diarrhea is the most reported adverse event.
Source: FDA Adverse Event Reporting System (FAERS) Public Dashboard

Overall, most studies show the drugs are safe and effective for most people. But, Jentadueto has a black box warning for lactic acidosis caused by metformin. Because metformin decreases the lactate processed by the liver, more of this compound stays in the blood and can be toxic. Symptoms of lactic acidosis include body pain, tiredness, respiratory distress, heart arrhythmias and low blood pressure.

Tradjenta and Jentadueto medication labels also warn about the risk of serious side effects, including inflammation of the pancreas (pancreatitis), hypoglycemia, joint pain and heart failure. Some people filed lawsuits against Boehringer Ingelheim claiming the company did not adequately warn about the risk of pancreatitis.

Studies on Pancreatitis

One of the biggest concerns for people who take Tradjenta or Jentadueto is pancreatitis. Inflammation of the pancreas can lead to hospitalization and turn fatal. The FDA has warned pancreatitis can be an issue with these drugs and others in the dipeptidyl peptidase 4 (DPP-4) inhibitors class.

People who took linagliptin during clinical trials reported pancreatitis upward four times more than those who took placebo (15.2 cases versus 3.7 cases in 10,000 patient years), according to Tradjenta and Jentadueto’s prescribing information.

An article published in the February 2017 issue of Diabetes Care found the risk of acute pancreatitis with DPP-4 inhibitor use was “rare but real.”

“We can conclude that pancreatitis is an established but rare side effect of DPP-4 inhibitors that occurs at a very low frequency,” the article said. “We should inform patients on this potential side effect.”

Authors J. Hans DeVries and Julio Rosenstock recommended running tests to rule out gallstones in patients with abdominal pain.

“In the linagliptin clinical trial program, pancreatitis occurred in 8 of 4,687 patients receiving linagliptin and in none of the 1,183 patients receiving placebo.”

Source: Doctor of pharmacy Maisha Kelly Freeman, Efficacy and Safety of Linagliptin (Tradjenta) in Adults With Type-2 Diabetes Mellitus

Researchers have assessed the clinical safety of linagliptin in more than 4,000 patients with Type 2 diabetes, Maisha Kelly Freeman, doctor of pharmacy, reported in a 2011 article in Pharmacy and Therapeutics.

“In the linagliptin clinical trial program, pancreatitis occurred in 8 of 4,687 patients receiving linagliptin and in none of the 1,183 patients receiving placebo,” Freeman said.

A 2014 study by Dr. Michael Lehrke and colleagues found little to no pancreatic risk with linagliptin. Out of 4,810 patients, only two developed pancreatitis. There were no reports of precancerous lesions on the pancreas. Lehrke disclosed he had been a paid speaker for several drug companies, including Boehringer Ingelheim.

Cardiovascular Safety of Linagliptin

Tradjenta and Jentadueto carry warnings about the risk of heart failure. Boehringer Ingelheim added the warnings in 2017 after the FDA found Onglyza (saxagliptin) and Nesina (alogliptin), two other DPP-4 drugs, could increase the risk of heart failure.

“Heart failure can result in the heart not being able to pump enough blood to meet the body’s needs. As a result, we are adding new warnings to the drug labels about this safety issue,” the FDA said in a 2016 Drug Safety Communication.

“Heart failure can result in the heart not being able to pump enough blood to meet the body’s needs. As a result, we are adding new warnings to the drug labels about this safety issue.”

Source: U.S. Food and Drug Administration

Prior to the warnings, Julio Rosenstock and colleagues had analyzed 19 clinical trials with a total of 9,459 participants to see if Tradjenta increased the risk of cardiovascular events, including heart failure. They found 12 people out of 5,847 who took linagliptin ended up in the hospital for heart failure versus 9 people in the placebo group.

They concluded linagliptin was not associated with an increase in cardiovascular risk, including heart failure.

It is important to note that Boehringer Ingelheim funded the study. The pharmaceutical industry funded most of the safety studies on linagliptin.

In addition, Rosenstock and colleagues said a limitation of their 2015 study was that patients only took linagliptin for 2.2 years and 1.5 years. This might not have been enough time to develop heart problems.

Severe Joint Pain

One of the latest warnings added to labels for Tradjenta, Jentadueto and other DPP-4 drugs is the risk of severe joint pain. According to an August 2015 FDA Drug Safety Communication, people have experienced joint pain in as little as one day after taking a DPP-4.

The FDA said it identified 33 cases of severe joint pain with DPP-4 use in its FAERS database over a seven-year period, but only two of those reports were associated with linagliptin specifically.

After the patients stopped taking the drugs, the symptoms vanished. Some people who re-started therapy with a DPP-4 experienced the symptoms again.

About a year after the FDA released its safety announcement, researchers in Japan published a study in Drug Target Insights that found no increase in joint pain among 20 people with advanced stage diabetic neuropathy who took linagliptin.

Still, Boehringer Ingelheim continues to warn that people who take the drugs may develop joint pain that can be severe. The drug maker advises people to call a doctor if they experience the side effect.

Skin Problems

Another rare but serious side effect associated with DPP-4 drugs is a skin condition called bullous pemphigoid (BP) that can cause erosion and blisters.

Illustration of bullous pemphigoid
Expand
Boehringer Ingelheim warns that Tradjenta and Jentadueto can cause bullous pemphigoid.

The labels for Tradjenta and Jentadueto caution that the skin reaction may need to be treated in a hospital. Boehringer Ingelheim says to tell a doctor right away if someone who takes one of the drugs develops blisters.

In a 2018 Letter to the Editor in the journal of Cutaneous Immunology and Allergy, Dr. Junko Mukaijo and colleagues described a 64-year-old man who had been taking linagliptin for about six months and suffered blisters and lesions on his head, torso and limbs. He also had lesions in his mouth. Doctors diagnosed him with BP after taking a skin biopsy.

“According to the data, the proportional reporting ratio for linagliptin and [bullous pemphigoid] was the second highest after that for vildagliptin.”

Source: Dr. Junko Mukaijo and colleagues, Linagliptin treatment‐associated bullous pemphigoid presenting severe mucosal erosions

In this case and other BP cases with linagliptin, stopping the drug cleared up the skin issues. Though, the man’s mouth lesions required steroid treatment.

“The number of reported cases of BP induced by linagliptin has been increasing during the past few years,” the authors wrote. “According to the data, the proportional reporting ratio for linagliptin and BP was the second highest after that for vildagliptin.”

Please seek the advice of a medical professional before making health care decisions.

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Michelle Llamas, Senior Content Writer
Written By Michelle Llamas Senior Writer

Michelle Llamas has been writing articles and producing podcasts about drugs, medical devices and the FDA for seven years. She specializes in fluoroquinolone antibiotics, vaccines and products that affect women’s health such as Essure birth control, transvaginal mesh and talcum powder. Michelle collaborates with experts, including board-certified doctors, patients and advocates, to provide trusted health information to the public. Some of her qualifications include:

  • American Medical Writers Association (AMWA) Engage Committee and Membership Committee member
  • Centers for Disease Control and Prevention (CDC) Health Literacy certificates
  • Original works published or cited in The Lancet, British Journal of Clinical Pharmacology and the Journal for Palliative Medicine
Edited By

13 Cited Research Articles

  1. U.S. Food and Drug Administration. (n.d.). FDA Adverse Event Reporting System (FAERS) Public Dashboard. Retrieved from https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/surveillance/adversedrugeffects/ucm070093.htm
  2. DailyMed. (2017, August 18). Tradjenta – linagliptin tablet, film coated. Retrieved from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c797ea5c-cab7-494b-9044-27eba0cfe40f&audience=consumer#Section_5.1
  3. Freeman, M.K. (2011). Efficacy and Safety of Linagliptin (Tradjenta) in Adults With Type-2 Diabetes Mellitus. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278179/
  4. Rosenstock, J. et al. (2015, March 21). Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events. Retrieved from https://cardiab.biomedcentral.com/articles/10.1186/s12933-015-0215-2
  5. Gomes, G. et al. (2018, May 28). Linagliptin safety profile: A systematic review. Retrieved from https://www.sciencedirect.com/science/article/pii/S1751991818300871
  6. DailyMed. (2017, August 10). Jentadueto – linagliptin and metformin hydrochloride tablet, film coated. Retrieved from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6dd9b86-0d18-95d4-2bc7-05591bfdd597&audience=consumer#Section_8.3
  7. U.S. Food and Drug Administration. (2015, August 28). FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. Retrieved from https://www.fda.gov/Drugs/DrugSafety/ucm459579.htm
  8. U.S. Food and Drug Administration. (2016, April 5). FDA Drug Safety Communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin. Retrieved from https://www.fda.gov/Drugs/DrugSafety/ucm486096.htm
  9. Lehrke, M. et al. (2014, August 1). Safety and Tolerability of Linagliptin in Patients With Type 2 Diabetes: A Comprehensive Pooled Analysis of 22 Placebo-controlled Studies. Retrieved from https://www.sciencedirect.com/science/article/pii/S0149291814003713
  10. Haber, R. et al. (2016). Bullous Pemphigoid Associated With Linagliptin Treatment. Retrieved from https://jamanetwork.com/journals/jamadermatology/fullarticle/2458755
  11. Mukaijo, J. et al. (2018, May 4). Linagliptin treatment‐associated bullous pemphigoid presenting severe mucosal erosions. Retrieved from https://onlinelibrary.wiley.com/doi/full/10.1002/cia2.12006
  12. Ueda, Y. (2016). Effects and Safety of Linagliptin as an Add-on Therapy in Advanced-Stage Diabetic Nephropathy Patients Taking Renin–Angiotensin–Aldosterone System Blockers. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019128/
  13. DeVries, J.H. & Rosenstock, J. (2017). DPP-4 Inhibitor–Related Pancreatitis: Rare but Real! Retrieved from http://care.diabetesjournals.org/content/40/2/161
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