Onglyza and Kombiglyze XR (Saxagliptin)

Onglyza and Kombiglyze XR are indicated, in conjunction with diet and exercise, to improve blood sugar control in adults with type 2 diabetes. They are not approved for use in type 1 diabetics. The active ingredient in Onglyza is saxagliptin, part of a class of drugs called dipeptidyl peptidase-4 (DPP-4) inhibitors.

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DPP-4 inhibitors block the action of the enzyme DPP-4, which destroys incretin in the body. Incretins are hormones that are naturally released throughout the day, though levels increase after meals. In a healthy person, these hormones help the pancreas produce insulin only when it is needed while reducing the amount of blood sugar (glucose) the liver produces when glucose is not needed.

Kombiglyze XR combines saxagliptin with another diabetes drug, metformin.

In 2013, a major company-sponsored clinical trial found that people in the trial taking saxagliptin had a statistically significantly higher risk of being hospitalized for heart failure. In 2016, the U.S. Food and Drug Administration (FDA) added a warning about heart failure risks to the labels of Onglyza and Kombiglyze XR.

The warning instructs health care professionals to “[c]onsider the risks and benefits” of the drugs in patients who have known risk factors for heart failure,  counsel patients regarding symptoms of heart failure, and observe patients for “signs and symptoms of heart failure.”

If you or a relative were prescribed Onglyza or Kombiglyze XR and were diagnosed with heart failure (also called congestive heart failure), or were hospitalized due to existing heart failure while taking these drugs, you may be able to seek compensation for these injuries. The same is true if you have a relative who died from heart failure while on Onglyza or Kombiglyze XR. Weitz & Luxenberg can help you understand your options, beginning with a free consultation.

Insurer Drops Coverage for Onglyza and Kombiglyze XR

Bristol-Myers Squibb received FDA approval for Onglyza in 2009. The agency approved Kombiglyze XR in 2010. In 2014, AstraZeneca acquired Bristol-Myers Squibb’s diabetes drug portfolio and continues to manufacture both drugs. In its 2016 annual report, AstraZeneca reported $376 million in annual sales from Onglyza in the U.S. The report also noted this $376 million represented a 10% decline in sales over the previous year, as the company “prioritized” another of its diabetes drugs acquired from Bristol-Myers Squibb, Farxiga. 

In August 2015, Express Scripts, the largest standalone pharmacy benefit manager (PBM) in the U.S., announced it would exclude both Onglyza and Kombiglyze XR from its 2016 preferred formulary of drugs, or those for which it is willing to cover costs. The PBM’s announcement came less than four months after an FDA advisory committee recommended the agency require warnings on labels for Onglyza and Kombiglyze XR that the medicines may increase the risk of heart failure.

“We look at the formulary first from a clinical perspective to ensure that it provides access to safe and effective medications in all therapy classes,” Express Scripts said online about its 2016 formulary exclusions.

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Studies Find Increased Risk of Hospitalization for Heart Failure

The FDA Advisory Committee and the agency itself evaluated two studies that found higher rates of hospitalization for heart failure in patients taking certain DPP-4 inhibitors.

One of those studies looked specifically at saxagliptin, the active ingredient in both Onglyza and Kombiglyze XR. That trial, which collected data from May 2010 through December 2011 at 788 sites in 26 countries, involved 16,492 patients. The patients in the trial all had type 2 diabetes and either had cardiovascular disease or were at high risk for it.  This trial, named SAVOR-TIMI 53, found “a 27% increase in the rate” of first-event hospitalization for heart failure among its saxagliptin-treated subjects when compared to placebo-treated subjects.

“DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased,” the researchers wrote.

A second study found another DPP-4 inhibitor, alogliptin, also presented a heightened risk for heart failure requiring hospitalization among patients taking it — 3.9% taking alogliptin versus 3.3% given a placebo.

FDA Launches Safety Review of Onglyza, Kombiglyze XR, Other DPP-4 Inhibitors

Results of the saxagliptin trial prompted an FDA safety review starting in February 2014. At the time, the FDA told patients prescribed Onglyza or Kombiglyze XR and other DPP-4 inhibitors to continue taking the drugs and address their questions or concerns to their health care professionals, while also encouraging patients and health care professionals to “report side effects involving saxagliptin products to the FDA MedWatch program…”

In 2016, the FDA announced its safety review had “found that 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.”

The FDA said people taking the medicines should contact their health care professionals if they develop heart failure symptoms such as:

  • 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

The FDA also announced it was “adding new warnings to the drug labels about this safety issue.” Consult your doctor before stopping any prescribed medication.

Weitz & Luxenberg wants to hear from people who were prescribed Onglyza or Kombiglyze XR, and were later diagnosed with or hospitalized for heart failure. If you have a relative who died due to heart failure while on either of the drugs, we also want to hear from you. You may be able to seek compensation.

The Relationship Between Diabetes and Heart Disease

Adults with diabetes are nearly two times more likely to die from heart disease than people who don’t have diabetes. The high blood sugar levels from diabetes can slowly damage blood vessels or the nerves that control the heart. 

Because of this relationship, it is important that diabetes medicines not exacerbate risks of cardiovascular problems.

In 2007, two years before Onglyza was approved by the FDA, a study of an earlier diabetes drug, rosiglitazone, published in The New England Journal of Medicine, led the FDA to issue new guidelines on cardiovascular risk for diabetes drugs, in which new drugs “must include a demonstration of no unacceptable increase in CV risk” during the approval process. The rosiglitazone study found a statistically significant 43% increased risk of myocardial infarction and a nearly 64% increased likelihood of cardiovascular death in people taking rosiglitazone, though the latter was not statistically significant.

The FDA’s “Guidance for Industry” issued in 2008 presented “recommendations” to drug and biologic manufacturers on how to “demonstrate that a new antidiabetic therapy to treat type 2 diabetes is not associated with an unacceptable increase in cardiovascular risk.” 

Though the guidance was legally nonbinding, by May 2016, at least 17 large clinical trials involving more than 140,000 subjects had been completed or were ongoing under the 2008 guidance. These included the SAVOR – TIMI 53 trial that found the 27% increased risk in patients taking saxagliptin.

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  10. 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#
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  17. Scirica, B.M., et al. (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#t=article
  18. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. (2015, April 14). Briefing Material; Endocrinologic and Metabolic Drugs Advisory Committee Meeting; Executive Summary (pg. 8) Retrieved from https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM442060.pdf
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  20. White, W.B., et al. (2013, October 3). Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes. Retrieved from http://www.nejm.org/doi/full/10.1056/NEJMoa1305889#t=article
  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. (2014, February 11). FDA Drug Safety Communication: FDA to review heart failure risk with diabetes drug saxagliptin (marketed as Onglyza and Kombiglyze XR) Retrieved from https://www.fda.gov/Drugs/DrugSafety/ucm385287.htm
  23. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. (2015, April 14). Briefing Material; Endocrinologic and Metabolic Drugs Advisory Committee Meeting; Executive Summary (pg. 8) Retrieved from https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM442060.pdf
  24. 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
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  28. Bae, J.C. (2016, June 10). Diabetes Drugs and Cardiovascular Safety. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923407/
  29. U.S. Food and Drug Administration. (2008, December). Guidance for Industry; Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes (pg. 1) Retrieved from https://www.fda.gov/downloads/Drugs/.../Guidances/ucm071627.pdf
  30. Smith, R.J., Goldfine, A.B., and Hiatt, W.R. (2016, May). Evaluating the Cardiovascular Safety of New Medications for Type 2 Diabetes: Time to Reassess? Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27208377
  31. Smith, R.J., Goldfine, A.B., and Hiatt, W.R. (2016, May). Evaluating the Cardiovascular Safety of New Medications for Type 2 Diabetes: Time to Reassess? Retrieved from http://care.diabetesjournals.org/content/39/5/738.figures-only

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