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Onglyza and Kombiglyze XR

Onglyza and Kombiglyze XR are prescription drugs taken orally and used along with diet and exercise to improve control of blood sugar in adults with type 2 diabetes. (1)

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In a healthy person, the pancreas releases two hormones, insulin and glucagon, to control blood sugar levels. Insulin lowers the levels of blood sugar while glucagon raises them, keeping blood sugar in balance. (2) A person with diabetes doesn’t use insulin properly, which allows blood sugar levels to rise to levels that can be harmful to the body. (3)

Saxagliptin, the active ingredient in Onglyza, is part of a class of drugs called dipeptidyl peptidase-4 (DPP-4) inhibitors. (4) DPP-4 inhibitors block DPP-4, an enzyme that counteracts hormones called incretins, which stimulate the pancreas to make more insulin and lower the amount of glucagon produced by the liver based on the body’s blood glucose levels. (5)

Kombiglyze XR combines saxagliptin with metformin, another diabetes drug.

A Brief History of Onglyza and Kombiglyze XR

The U.S. Food and Drug Administration (FDA) approved Onglyza (saxagliptin) in 2009. (6) Onglyza’s manufacturer, Bristol-Myers Squibb, received FDA approval for the saxagliptin-metformin combination Kombiglyze XR in 2010. (7) Afterwards, the pharmaceutical company AstraZeneca acquired Bristol-Myers Squibb’s diabetes drug business in a multibillion dollar deal. (8) In 2016, Onglyza was responsible for $376 million in sales for AstraZeneca. (9)

Onglyza and Kombiglyze XR Concerns

Onglyza and Kombiglyze XR are not indicated for use by patients with type 1 diabetes or those with diabetic ketoacidosis (DKA). In April 5, 2016, the FDA mandated an additional label warning that saxagliptin and alogliptin (another DPP-4 inhibitor drug) use may increase a person’s risk of heart failure.

The FDA’s April 5, 2016 Safety Communication advises patients taking these drugs to contact their health care professional if they developed signs or symptoms of heart failure, which can include: (11)

  • Unusual shortness of breath during daily activities
  • Trouble breathing when lying down
  • Tiredness, weakness, or fatigue
  • Weight gain with swelling in the ankles, feet, legs, or stomach

Labels for Onglyza and Kombiglyze XR also warn of postmarketing reports of pancreatitis in people taking the drugs. The warnings recommend that physicians should observe patients for “signs and symptoms of pancreatitis” after they start taking Onglyza or Kombiglyze XR, and to “promptly discontinue” the drugs and “initiate appropriate management” if pancreatitis is suspected. (12) (13) Signs and symptoms of pancreatitis may include: (14)

  • Persistent pain in the upper abdomen that may extend to the back
  • Swollen and tender abdomen
  • Nausea and vomiting
  • Fever
  • Rapid pulse

Some other adverse reactions reported in more than 5% of patients taking Onglyza and Kombiglyze XR during clinical trials include: (15) (16)

  • Upper respiratory tract infection
  • Urinary tract infection
  • Headache

Because Kombiglyze XR also contains metformin, people taking this drug should also be aware of possible side effects related to metformin, especially lactic acidosis. Symptoms of lactic acidosis may include: (17)

  • Feeling that hands or feet are cold
  • Dizziness or lightheadedness
  • Slow or irregular heartbeat
  • Weakness or tiredness
  • Unusual muscle pain
  • Trouble breathing
  • Sleepiness or drowsiness
  • Stomach pain, nausea, or vomiting

Manufacturer-Sponsored Study Finds Increased Risk of Hospitalization Due to Heart Failure

An AstraZeneca and Bristol-Myers Squibb supported study of patients with type 2 diabetes with a history of cardiovascular events (or significant cardiovascular risk factors) published in The New England Journal of Medicine in 2013, found 3.5% of patients given saxagliptin were hospitalized for heart failure versus 2.8% of those taking the placebo. This result equated to a 27% increased risk of hospitalization for heart failure in saxagliptin-treated patients. (19)

Heart Failure Risk Leads to FDA Analysis and Mandated Label Revisions

Following the study published in The New England Journal of Medicine, the FDA requested information from the manufacturer of Onglyza and Kombiglyze XR in 2014, so the agency could further investigate the study’s findings of an increased rate of hospitalization for heart failure in saxagliptin-treated patients. (20)

In 2016, at the conclusion of an FDA safety review, which included an Advisory Committee that evaluated cardiovascular studies related to saxagliptin and a different DPP-4 inhibitor alogliptin, the FDA announced that saxagliptin- or alogliptin-containing medicines may increase risk for heart failure, particularly in patients who have existing heart or kidney disease. The FDA required new warnings to be added to labels for all drugs containing saxagliptin and alogliptin. (21) (22) The list of drugs affected included:

  • Onglyza (saxagliptin)
  • Kombiglyze XR (saxagliptin and metformin extended release)
  • Nesina (alogliptin)
  • Kazano (alogliptin and metformin)
  • Oseni (alogliptin and pioglitazone)

The FDA advised patients to not stop taking the drugs without first talking to a health care professional. (23) Consult your doctor before stopping any prescribed medication.

  1. Pharmacy and Therapeutics. (2009, September). New Drugs; Onglyza for Type-2 Diabetes. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799138/
  2. Crosta, P. (2017, May 26) Pancreas: Functions and possible problems. Retrieved from: https://www.medicalnewstoday.com/articles/10011.php
  3. American Diabetes Association. (n.d.). Type 2. Retrieved from: http://www.diabetes.org/diabetes-basics/type-2/?loc=db-slabnav
  4. 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
  5. Diabetes.co.uk.DPP-4 Inhibitors (Gliptins). (n.d.) Retrieved from: http://www.diabetes.co.uk/diabetes-medication/dpp-4-inhibitors.html
  6. U.S. Food and Drug Administration. (2009, July 31). NDA Approval Letter. Onglyza. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/022350s000ltr.pdf
  7. U.S. Food and Drug Administration. (2010, November 5). Drug Approval Package. Kombiglyze XR. Retrieved from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/200678Orig1s000Approv.pdf
  8. AstraZeneca. (2014, February 3). AstraZeneca completes the acquisition of Bristol-Myers Squibb share of global diabetes alliance. Retrieved from: https://www.astrazeneca.com/media-centre/press-releases/2014/astrazeneca-aquisition-bristol-myers-squibb-global-diabetes-alliance-03022014.html
  9. AstraZeneca. (2016) What science can do; AstraZeneca Annual Report and Form 20-F Information 2016 (pg. 2). Retrieved from: https://www.astrazeneca.com/content/dam/az/Investor_Relations/Annual-report-2016/AZ_AR2016_Full_Report.pdf
  10. European Medicines Agency. (2016, March 6). Onglyza; saxagliptin. Retrieved from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001039/human_med_000947.jsp&mid=WC0b01ac058001d124
  11. 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
  12. Full Prescribing Information (Onglyza). (2017, February). Retrieved from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022350s018lbl.pdf
  13. . Full Prescribing Information (Kombiglyze XR). (2017, February). Retrieved from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/200678s018lbl.pdf
  14. National Pancreas Foundation. (n.d.). Acute Pancreatitis Causes and Symptoms. Retrieved from: http://pancreasfoundation.org/patient-information/acute-pancreatitis/acute-pancreatitis-diagnosis-and-treatment/
  15. Full Prescribing Information (Onglyza). (2017, February). Retrieved from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022350s018lbl.pdf
  16. . Full Prescribing Information (Kombiglyze XR). (2017, February). Retrieved from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/200678s018lbl.pdf
  17. . (Full Prescribing Information (Kombiglyze XR). (2017, February). Retrieved from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/200678s018lbl.pdf
  18. Scirica, B.M. (2013, October 3). Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. Retrieved from: http://www.nejm.org/doi/full/10.1056/NEJMoa1307684
  19. Scirica, B.M. (2013, October 3). Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. Retrieved from: http://www.nejm.org/doi/full/10.1056/NEJMoa1307684
  20. U.S. Food and Drug Administration. (2016, April 5). FDA Drug Safety Communication: FDA to review heart failure risk with diabetes drug saxagliptin (marketed as Onglyza and Kombiglyze XR). Retrieved from: https://wayback.archive%2Dit.org/7993/20170112031610/http://www.fda.gov/Drugs/DrugSafety/ucm385287.htm
  21. 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
  22. U.S. Food and Drug Administration Center for Drug Evaluation and Research. (2015, April 14). Summary Minutes of the Endocrinologic and Metabolic Drugs Advisory Committee Meeting. Retrieved from: https://wayback.archive%2Dit.org/7993/20170404151621/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM453900.pdf
  23. 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