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 helps control blood sugar in two ways:

• It stops the liver from making too much glucose by reducing the amount of glucagon secreted by the pancreas.
• It helps the body produce more insulin after meals by inhibiting DPP-4 and allowing GLP-1 to remain in the body longer.

Kombiglyze XR also contains metformin, so it helps reduce blood sugar in four ways:

• It decreases sugar absorbed in the gut.
• It reduces sugar made by liver.
• It makes the body more sensitive to insulin.
• It increases the amount of insulin the body produces after meals.

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.

Before taking Onglyza and Kombiglyze XR, tell your doctor if you:

• Know you are allergic to any of the drugs’ ingredients
• Have had previous heart failure of kidney problems
• Are pregnant or plan to become pregnant (it is not known if saxagliptin may harm the baby)
• Plan to breastfeed (it is not known if saxagliptin may be passed through breast milk)
• Have had pancreatitis or have risk factors for pancreatitis

In clinical trials, Onglyza and Kombiglyze XR caused a number of side effects. Because Kombiglyze XR combines the active ingredient of Onglyza with metformin, the drug carries the side effects of Onglyza and the possible complications of metformin.

In addition, Kombiglyze XR has a black box warning for lactic acidosis, a rare condition where too much lactic acid builds up in the blood. It can cause respiratory distress, abdominal pain and weakness. Some cases have been fatal.

FDA Safety Warnings

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.

Examples of interactions:

• Iodine used in the contrast dye for certain radiographic procedures may cause renal failure. Doctors may discontinue Kombiglyze XR before the procedure because the risk of lactic acidosis is high in people with poor kidney function.
• CYP3A4/5 inhibitors such as ketoconazole, rifampicin, grapefruit juice, Prozac (fluoxetine) and tamoxifen increase the concentration of saxagliptin.
• Anolazine, vandetanib, dolutegravir, cimetidine and other carbonic anhydrase inhibitors increase the concentration of metformin.
• Alcohol may increase the risk of lactic acidosis when used with Kombiglyze XR.

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.