Januvia (sitagliptin) is an oral Type 2 diabetes medication manufactured by Merck & Co. The U.S. Food and Drug Administration (FDA) approved the drug in 2006, and it is one of the most popular Type 2 diabetes drugs on the market. In 2007, the FDA approved a variation of Januvia called Janumet, which is a combination of sitagliptin and metformin. Janumet also comes in an extended release formula called Janumet XR.
Januvia and Janumet are known as dipeptidyl peptidase 4 (DPP-4) inhibitors that work by helping the body produce more insulin.
Both Januvia and Janumet belong to a class of drugs called dipeptidyl peptidase 4 (DPP-4) inhibitors that work by helping the body produce more insulin. Januvia was the first DPP-4 approved by the FDA and is the top-selling brand in its class. With two million prescriptions written in 2011, analysts expected Januvia to eventually produce multi-billion dollar sales numbers. Januvia brought in about $6 billion in 2014. Merck stands to benefit from the patent on the drug until 2022.
In clinical trials Januvia proved effective in controlling blood sugar levels. However, some studies reported rare and serious side effects, including acute pancreatitis, severe joint pain, pancreatic cancer and thyroid cancer.
How Do Januvia and Janumet Work?
Januvia is designed to work with other Type 2 diabetes medications, like Byetta, to increase their effectiveness. It helps lower blood sugar in two ways. It helps the body increase insulin to stabilize blood sugar and decrease sugars that are made in the liver. It is a part of the class of diabetes medications called DPP-4 inhibitors. DPP-4 is a protein made by the body that plays a role in glucose metabolism.
The process works like this: After a person eats and blood sugar rises, intestinal cells release hormones called incretin hormones. Incretin stimulates pancreatic cells called beta cells to release insulin to metabolize sugar and signals the liver to stop making excess sugar. In people without diabetes, DPP-4 breaks down incretin to keep blood sugar and insulin levels balanced. For people with diabetes, too much sugar is already in the blood.
These drugs block DPP-4, allowing incretin to stay in the blood longer and to continue stimulating the pancreas into make more insulin to remove excess sugar.
Janumet is similar to Januvia, except it contains metformin. So, in addition to stimulating the body to produce more insulin like Januvia does, the metformin in Janumet decreases the glucose produced by the liver and decreases the absorption of glucose by the intestines.
How Effective are Januvia and Janumet?
About 5,200 people participated in the initial clinical trials for Januvia. The majority of study participants were white and the average age was 55 years. Both Januvia and Janumet reduced blood sugar in clinical trials.
An A1C (glucose level in the blood) measurement of 7 percent or lower is ideal for people with Type 2 diabetes. In one study with 1,262 patients who took Januvia for 18 weeks or 24 weeks, researchers found 100 mg daily lowered A1C, a measurement of glucose in the blood, by .7 percent and .8 percent respectively.
An A1C (glucose level in the blood) measurement of 7 percent or lower is ideal for people with Type 2 diabetes.
Januvia also reduced fasting plasma glucose (FPG) by about 13 points in people who started with an FPG of 180. A normal FPG is 100 or lower.
In clinical studies for Janumet, researchers did not actually use Janumet. They obtained their data by administering sitagliptin and metformin. They found using both drugs lowered AIC and FPG more than using either drug alone.
A1C levels dropped about 1.4 percent in patients with a starting A1C of 8.8 percent who took 50 mg sitagliptin and 500 mg of metformin twice daily. It dropped 1.9 percent in those with a starting A1C of 8.8 percent who took 50 mg sitagliptin and 1000 mg metformin twice daily.
Dosage Strengths and Recommendations
Januvia and Janumet come in a variety of dosages, depending on each individual's needs for glucose control. These drugs are not meant to treat people with Type 1 diabetes. People who have excess toxins known as ketones in the blood or urine — a condition known as diabetic ketoacidosis — should not take Januvia or Janumet.
The recommended starting dose of Januvia is 100 mg once daily with or without food. Depending on the patient, the prescribing health care provider may adjust the dose. People with a history of serious allergic reactions to sitagliptin should not take Januvia.
Because the kidneys filter Januvia out of the body, people whose kidneys are not fully functioning should not take Januvia. The recommended dose for people with moderate kidney insufficiency is 50 mg and 25 mg for patients with end-stage kidney disease that requires dialysis. Health care providers should test a patient's kidney function before starting Januvia.
Janumet dosages are customized for each patient, but should not exceed 100 mg sitagliptin/2000 mg metformin. The recommended starting dose is 50 mg sitagliptin/500 mg metformin. Patients should take Janumet twice daily with meals, and dose increases should be gradual to minimize gastrointestinal side effects from metformin.
If patients are already taking metformin, doctors should continue them on that dose plus 50 mg sitagliptin. Patients already taking 850 mg of metformin should take 50 mg sitagliptin/1000 mg metformin.
Like Januvia, the proper functioning kidneys are necessary to filter Janumet out of the body. Patients with severe kidney problems should not take Janumet.
In clinical trials, researchers reported the most common side effects that occurred in five percent or more of patients taking Januvia include nasopharyngitis (common cold), respiratory tract infections and headaches. Januvia may also come with more rare but serious side effects.
Patients should consult their doctor immediately if they experience any serious Januvia side effects. This is not a complete list of side effects. Always speak to a doctor or health care provider for more information.
Common side effects of Januvia include:
- Elevated liver enzymes
- Swelling of hands or legs
- Upper respiratory infection
- Stuffy or runny nose
- Sore throat
- Back pain
Serious Januvia side effects include:
- Pancreatitis (swelling of the pancreas that can cause vomiting, fast heart rate, nausea, stomach and back pain)
- Allergic reactions (hives, difficulty breathing, swelling of the lips, face, tongue or throat)
- Weight gain
- Shortness of breath
- Severe skin reaction (rash, blistering or peeling, burning in eyes, swelling of the face)
- Hypoglycemia (low blood sugar)
- Fatal and nonfatal necrotizing pancreatitis (tissue in the pancreas dies and causes an infection, usually a more severe form of acute pancreatitis)
Janumet Side Effects and Black Box Warning
Because Janumet is a combination medication, it has the side effect risks of Januvia plus metformin. In people who took Janumet, the most common side effects that occurred in five percent or more of clinical trial participants include diarrhea, headache and respiratory infections. More people who took Janumet instead of Januvia experienced low blood sugar (hypoglycemia) and gastrointestinal issues such as gas, indigestion and abdominal discomfort.
Because Janumet is made with metformin, it carries a black box warning for lactic acidosis. This condition occurs when lactic acid accumulates in the bloodstream. Symptoms of lactic acidosis include feeling cold in hands and feet, dizziness, irregular heartbeat, weakness and nausea. People who suffer from lactic acidosis should seek medical care immediately.
FDA Warnings and Post-Market Safety Studies
The most serious side effects associated with Januvia and Janumet are acute pancreatitis, pancreatic cancer and thyroid cancer. While there may have been some signals of these side effects in initial clinical trials, it wasn't until independent researchers studied these side effects and more patients reported issues that the FDA began to look into the potential risks.
In 2011, the FDA received almost 200 reports of acute and chronic pancreatitis linked to Januvia and Janumet — some of which were fatal. In March 2013, the agency announced it was gathering more data on Januvia's link to pancreatitis and possible pancreatic cancer. In July 2013, the FDA said it there was no cause for concern with safety risks in a new study linking Januvia and other DPP-4's to pancreatitis. But the agency said its review was ongoing.
In 2015, the FDA warned that Januvia and Janumet could cause severe joint pain.
Pancreatitis is an inflammation of the pancreas. It can cause the body's digestive enzymes to attack the pancreas. In severe cases, the disease can cause tissue damage, infection, cyst formation and bleeding. The damage can spread to other organs like the heart, kidneys and lungs, and the mortality rate is 10 to 30 percent.
Cases of pancreatitis associated with Januvia and Janumet tend to be acute, meaning the disease occurs quickly and over a short period of time, and it can be fatal. A UCLA clinical study published in the journal Gastroenterology revealed that taking Januvia increases the risk of pancreatitis six-fold, and cases usually develop in less than two months.
Nearly 100 cases of acute pancreatitis caused by Januvia, including necrotizing pancreatitis, were reported to the FDA between 2006 and 2009. Necrotizing pancreatitis occurs when digestive hormones produced by the pancreas begin to digest the pancreatic tissue, killing it. This can lead to infection and death.
In 2009, the FDA issued a safety alert that linked sitagliptin, the active ingredient in Januvia and Janumet, to acute pancreatitis. There were no safety studies conducted in people who have a history of pancreatitis, and the agency warned that it is not known whether these people are at an increased risk if they take sitagliptin. Pancreatitis can also lead to pancreatic cancer.
The FDA issued an updated alert in 2013, saying it was still investigating Januvia and similar drugs for evidence that they caused pancreatitis or pancreatic cancer.
According to a study published in February 2013 in JAMA Internal Medicine, patients taking Januvia or Byetta were twice as likely as those who took other drugs to end up in the hospital with pancreatitis — inflammation of the pancreas that can be fatal. Research found that the inflammation results from pancreatic lesions caused by the drugs.
Januvia and Janumet are also linked to pancreatic cancer. Pancreatic tumors can grow without symptoms and may not be detected until the cancer reaches a later stage. People taking sitagliptin have more than double the risk of developing pancreatic cancer, according to a UCLA study. The risk of developing cancer increases the longer someone takes Januvia or Janumet.
Dr. Peter Butler, the study's lead investigator, said it can be difficult to discover the extent of the damage done to the pancreas without removing it and examining it. As a result, pancreatic cancer may be diagnosed late. The American Cancer Society says the average rate of survival for pancreatic cancer is 18 to 20 months, and the overall five-year survival rate is four percent.
In a 2015 review of current literature, researchers summarized the results of FDA adverse event reports. They found a high incidence of pancreatic cancer in patients who took DPP-4 inhibitors like Januvia and Janumet. The researchers concluded further studies were needed, but the benefits of the drugs might outweigh the risks.
There have also been reports of patients developing thyroid cancer after taking Januvia. The UCLA study found a very minor increase in thyroid cancer, with only two cases reported out of the sample group. The 2015 analysis of FDA adverse event reports also found an increase in thyroid cancer in people who took incretin-based therapies like Januvia, although glucagonlike peptide-1 (GLP-1) receptor agonists like Victoza had a much higher incidence of thyroid cancer.
According to the ACS, the death rate of thyroid cancer is relatively low compared to other cancers. However, it can cause many serious side effects including swelling of the neck, pain, voice changes and hoarseness, trouble swallowing or breathing, and a constant cough.
According to the medication inserts of Januvia and Janumet, there are few drug interactions. But these drugs were not tested with every drug that could react with them.
Possible drug interactions include:
- Digoxin (Januvia)
- Alcohol may increase risk of lactic acidosis (Janumet)
- Carbonic anhydrase inhibitors such as topiramate, zonisamide, acetazolamide or dichlorphenamide (Janumet)
- Insulin may increase risk of low blood sugar (Janumet)