Onglyza & Kombiglyze XR

The U.S. Food and Drug Administration approved AstraZeneca’s Onglyza in 2009 and Kombiglyze XR in 2010. Along with diet and exercise, these medications help control high blood sugar in people with Type 2 diabetes. The medicines are not approved to treat people with Type 1 diabetes or diabetic ketoacidosis.

The active ingredient in Onglyza is saxagliptin. Kombiglyze XR combines saxagliptin with metformin in an extended release pill. In February 2017, the FDA approved a new oral Type 2 diabetes medication called Qtern that combines Onglyza and Farxiga (dapagliflozin).

Saxagliptin is a popular medication, partly because it effectively controls blood sugar and does not encourage weight gain like other diabetes medications.

Prescription drug prices in the U.S. have been rising for several years. Some drugs in 2022 increased by more than $20,000 or 500%.

Between July 2021 and July 2022, there were 1,216 products whose price increases exceeded the inflation rate of 8.5% for that period. The average price increase for these drugs was 31.6%.

In 2017, Onglyza made $611 million for AstraZeneca.

These medications belong to a group of Type 2 diabetes medications called incretin-based therapies. Specifically, they belong to a class of drugs called DPP-4 inhibitors. These drugs help the pancreas secrete more insulin and stop the liver from making excess sugar. Other drugs in the same class include: Januvia (sitagliptin), Tradjenta (linagliptin) and Nesina (alogliptin).

Saxagliptin may have disadvantages compared to other drugs in its class. Of all the DPP-4 drugs, saxagliptin lowered HbA1c the least, according to a 2014 article by researcher Paul Craddy and colleagues in Diabetes Therapy.

When compared to people treated with other DPP-4 drugs, fewer people who took saxagliptin were able to achieve an HbA1c below 7 percent, the researchers concluded. It’s important to note the researchers either worked for Takeda Pharmaceuticals International GmbH or for a company sponsored by Takeda.

In 2016, the FDA warned that people who take drugs that contain saxagliptin or alogliptin may have a greater risk for heart failure. This is especially the case for patients with kidney or heart disease, the agency said. Some patients who suffered heart problems filed Onglyza lawsuits against AstraZeneca.

Saxagliptin inhibits DPP-4, an enzyme that naturally occurs in the body. DPP-4’s job is to break down an incretin hormone called GLP-1. After a person eats, the body releases GLP-1 into the blood. The hormone signals the pancreas to make insulin.

People with diabetes secrete less GLP-1, which causes the pancreas to produce less insulin. This results in too much sugar in the blood. Because DPP-4 breaks down GLP-1, inhibiting DPP-4 allows GLP-1 to remain in the body longer. This signals the pancreas to make more insulin after meals.

In addition to producing too little insulin, the pancreas of a person with Type 2 diabetes also releases too much glucagon, a hormone that tells the liver to produce more glucose. Saxagliptin helps control the amount of glucagon in the blood.

Onglyza comes in 5 mg and 2.5 mg tablets. Kombiglyze XR tablets can contain 2.5 mg or 5 mg of saxagliptin combined with 500 mg or 1,000 mg of metformin.

The maximum daily dose of Kombiglyze XR is 5 mg of saxagliptin/2,000 mg of metformin a day. Patients should swallow the tablets whole without crushing or chewing them.

Patients can take Onglyza once a day with or without food, but patients who use Kombiglyze XR must take the drug with their evening meal.

Doctors will decide the dose based on how a patient responds to treatment, and it may need adjusting after. In people with severe kidney impairment, the medication insert recommends the lowest dose of saxagliptin, which is 2.5 mg.

If a patient is taking a cytochrome inhibitor such as ketoconazole, doctors will also limit the saxagliptin dose. If kidney function worsens, doctors may discontinue the medication and recommend another anti-diabetic drug.

Who Should Not Take Saxagliptin?

As with most medications, people with certain medical conditions should not take Onglyza or Kombiglyze XR. People who have suffered lactic acidosis or ketoacidosis should not take these drugs.

Respiratory tract infections, urinary tract infections and headaches were the most common saxagliptin side effects that affected 5% or more clinical trial participants.

Onglyza and Kombiglyze XR are oral medications for the treatment of Type 2 diabetes. Saxagliptin is the active ingredient in Onglyza, whereas Kombiglyze XR combines saxagliptin with metformin extended-release. Metformin is another diabetes drug.

Saxagliptin has a range of common side effects. Researchers have documented most of these effects in clinical trials and post-marketing reports.

Researchers observed these side effects in 5% or more of the clinical trial participants. The data is from five clinical trials involving 882 participants, primarily white adults aged 55, who took saxagliptin for about 21 weeks.

The more serious side effects, such as heart failure, acute pancreatitis and joint pain are detailed below.

Onglyza and Heart Failure

As of June 2024, the FDA had received 748 reports of heart failure associated with Onglyza use. Its label has carried a warning about heart failure since 2016.

“When I am making prescribing decisions, I consider the advantages of glycemic control over possible harmful effects when selecting saxagliptin or other agents used to treat diabetes,” McKinney said.

A 2022 study in the Journal of the American College of Cardiology reaffirmed that saxagliptin increases the risk of hospitalization for heart failure. Another 2022 study in Biomedicines found that saxagliptin may worsen heart failure by disrupting a protective mechanism in the heart involving the protein dipeptidyl peptidase-4 (DPP4) and specific neuropeptides.

In April 2016, the FDA released a Drug Safety Communication warning about an increased risk of heart failure with saxagliptin which stated “Type 2 diabetes medicines containing saxagliptin and alogliptin may increase the risk of heart failure, particularly in patients who already have heart or kidney disease. 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 found that more people taking saxagliptin or alogliptin ended up in the hospital for heart failure compared to those who took a placebo. This led to Onglyza lawsuits from individuals who allege the manufacturer failed to provide sufficient warning about the associated risks.

Onglyza and Acute Pancreatitis

A review of three cardiovascular outcome studies showed a small risk of acute pancreatitis with DPP-4 inhibitors, such as Onglyza, as reported by Elsevier, a Dutch company that specializes in publishing scientific, technical and medical content.

Their online article from 2024 stated that the increased risk amounts to about 1 to 2 additional cases per 1,000 patients treated for two years. However, several other studies did not find this increased risk.

After examining the data, the FDA and European Medical Agencies declared that DPP-4 inhibitors do not significantly elevate the risk of pancreatitis or pancreatic cancer in patients with type 2 diabetes. Nonetheless, the agencies recommended continued monitoring to ensure safety.

Post-marketing reports have linked Onglyza usage to acute pancreatitis, prompting the drug’s label to recommend close monitoring for signs of this condition. One study found that 0.2% of Onglyza users developed acute pancreatitis, compared to 0.1% of those who received a placebo. Notably, most Onglyza users and all placebo-treated participants had pre-existing risk factors for pancreatitis.

According to a case report in Practical Diabetes, a 33-year-old man developed acute pancreatitis after switching from Onglyza to Kombiglyze XR. He had symptoms such as dizziness, vomiting, palpitations and breathlessness and was diagnosed with acute pancreatitis. After replacing Kombiglyze XR with insulin and metformin, staff discharged the patient who was now in stable condition.

“I look into their past medical history of pancreatic disease; also I inquire about gallstones and alcohol use,” McKinney said. “As a result, I enlighten individuals affected by this condition about its symptoms such as severe abdominal pain together with throwing up.”

Arthralgia: Severe, Disabling Joint Pain and Onglyza

DPP-4 inhibitors, including Onglyza, can lead to serious joint pain that might even require a hospital stay, according to Elsevier. The symptoms can appear anytime between 1 day and a few years after starting the treatment.

Doctors aren’t sure why this happens, but inflammation triggered by certain proteins in the body could be the cause.
Post-marketing studies found that patients experienced relief upon stopping the drug. Still, some had symptoms return when they restarted the same or a different DPP-4 inhibitor, according to the medication’s label.

If severe joint pain occurs after you start taking Onglyza, you should immediately talk to your doctor.

Latest Onglyza Side Effects Information

As of October 2025, 58% of Onglyza side effects reported to the U.S. Food and Drug Administration were considered severe, according to the agency. Heart failure, increased blood glucose and pancreatitis were the most common Onglyza side effects reported.

These three conditions accounted for over a quarter of all side effects reported to the FDA. Heart failure accounted for 17% of all reports.

Disclaimer: Reports submitted to the FDA do not necessarily indicate that the medication caused an adverse event. It is important to consult a healthcare professional before changing your medication.

Reports have been decreasing over the years, with only 11 reports so far for 2024. Despite this, patients should still talk to their doctor about potential heart and pancreatitis risks before taking Onglyza.

“Before putting a patient on saxagliptin, I want to understand their history of these conditions and other risk factors they possess for them,” Dr. Michael O. McKinney, a doctor who practices at the medical weight loss center Healthy Outlook, told Drugwatch.

“For example, patients who have had heart failure or are known to have chronic pancreatitis are usually started on different medications.”

The FDA released drug safety communications related to Onglyza and Kombiglyze XR in 2013, 2015 and 2016. The agency ordered AstraZeneca to add updated safety information to the drugs’ labels.

Drug Interactions

Some drugs and substances — including grapefruit juice — can increase or decrease the effectiveness of Onglyza and Kombiglyze XR, according to the medication labels. Patients should tell their doctors about all medications they take before starting treatment.

This is not a complete list of interactions. Consult your doctor and the medication labels regarding other potential drug interactions.

Researchers studied the effects of saxagliptin in six clinical trials involving 4,148 people with Type 2 diabetes. These studies examined the effectiveness of the drug alone or with other anti-diabetic medications.

People who took Onglyza alone had a decrease of 0.4 to 0.5 in hemoglobin A1C measurements and a decrease of 9 to 15 in fasting plasma glucose. Participants who took a placebo experienced an increase of 0.2 in hemoglobin A1C measurements and an increase of 6 in fasting plasma glucose.

Researchers did not actually test Kombiglyze XR in clinical trials. Instead, they gave patients saxagliptin and metformin immediate-release tablets together. In these trials, people who took 5 mg of saxagliptin and 500 mg of metformin had a reduction of 2.5 in hemoglobin A1C and a decrease of 60 in fasting plasma glucose. Participants who took a placebo and metformin experienced a decrease of 2 in hemoglobin A1C and a decrease of 47 in fasting plasma glucose.

Pharmacist Karen Whalen reviewed Onglyza in American Family Physician shortly after the medication hit the market. She said it would not be her first choice for treating patients because it has “a more significant drug interaction profile than sitagliptin and offers little cost advantage.” It also did not lower A1C as well as metformin as a first-line therapy.

“For these reasons, saxagliptin should be reserved as an alternative therapy for patients who cannot tolerate other treatments for Type 2 diabetes or in whom other treatments fail,” Whalen wrote.