Onglyza and Kombiglyze XR are well-known anti-diabetic medications manufactured and marketed by multinational pharmaceutical giants, AstraZeneca AB and Bristol-Meyers Squibb respectively. Both drugs function by lowering blood sugar levels through active influencing of the pancreatic hormone GLP-1. Although these drugs offer many promises for those suffering from Type 2 Diabetes Mellitus (T2DM), in recent years they have also come under increasing scrutiny for a litany of issues tied to the cardiac health of patients and uncertainty over longer-term side effects.
Prescription Name and Overview
Onglyza is the product name for the drug saxagliptin, an oral tablet that regulates the level of insulin production in the pancreas. Kombiglyze XR is the product name for medication combining saxagliptin and metformin hydrochloride, which together act to help control blood sugar levels in adults battling T2DM by decreasing glucose production in the liver and absorption of glucose in the intestines. Onglyza was approved by the U.S. Food and Drug Administration (FDA) in 2009 and Kombiglyze in 2010. Kombiglyze has proven to be a profitable success story for the global pharmaceutical giant, AstraZeneca, AB. Both drugs have been noted for several side effects which may be mild, moderate, or severe.
Generic Name and Overview
Neither Onglyza or Kombiglyze XR have a generic equivalent on the market.
OTC Name and Overview
Manufacturer
Onglyza (Saxagliptin)
Manufacturer: AstraZeneca AB (Cambridge, United Kingdom)
Kombiglyze XR (Saxagliptin and Metformin HCL)
Manufacturer: Bristol-Myers Squibb, Inc. (New York, New York)
Labeled Indications
Both Onglyza and Kombiglyze XR are typically prescribed to combat T2DM in conjunction with patient lifestyle changes which include: diet, exercise, and weight control. They are also used with other medications as part of a broader treatment strategy. Neither drug is used for treating Type 1 diabetes.
Onglyza’s recommended dosage is heavily dependent upon the condition of the patient but typically is either 2.5mg or 5mg taken orally on a daily basis. Kombiglyze is typically prescribed in a daily oral dose of either 2.5mg or 5mg saxagliptin/with varying levels of metformin dependent upon the condition of the patient and other medications.
Active Ingredients
Active Ingredients
The primary active agent in both Onglyza and Kombiglyze is saxagliptin, a type of medication known as an “incretin mimetic” that belongs to a class of drugs called “DDP-4 Inhibitors”. DDP-4 Inhibitors’ primary function is to influence the pancreatic hormone known as GLP-1 and in turn, manipulate insulin production.
What Is It Used For?
Both Onglyza and Kombiglyze XR are used as treatments in a larger strategy to combat T2DM.
How Does it Work?
Onglyza and Kombiglyze XR both feature the drug saxagliptin as their primary source of action. Saxagliptin is an “incretin memetic” and is part of a larger family of approved diabetes medications called DDP-4 Inhibitors. Simply put, these drugs work by increasing the levels of incretin hormone released by the intestines, thereby regulating insulin levels in the body. When saxagliptin is combined with metformin, the combination can manipulate both insulin and blood sugar within the framework of one medication.
What are the Approved Uses?
Onglyza is approved for helping to control high blood sugar in patients with T2DM; in combination with a proper regimen of diet and exercise.
Kombiglyze XR contains a combination of saxagliptin and metformin. Accordingly, it is also approved for the control of high blood sugar (with proper diet and exercise) as well as lowering blood sugar to help restore the body’s balanced response to insulin.
Production Anecdotes / History
AstraZeneca and Bristol-Myers Squibb jointly submitted the New Drug Application (NDA) for saxagliptin in June 2008 to the FDA. The FDA first approved the use of saxagliptin alone under the brand name Onglyza in 2009, and later approved the use of saxagliptin in combination with metformin under the brand name Kombiglyze XR in 2010. In recent years, Onglyza accounted for $543 million in sales for AstraZeneca.
Precautions
The following warnings are associated with standard precautions when prescribing saxagliptin:
- Avoid taking if you suffer from a state of diabetic ketoacidosis.
- Advise your physician if you suffer from any of the following:
- kidney disease
- heart disease
- pancreatitis
- gallstones
- high triglycerides
- a history of alcoholism
- Saxagliptin is contraindicated in patients with a history of a serious hypersensitivity reaction to saxagliptin, such as anaphylaxis, urticaria, angioedema, or exfoliative dermatitis or other serious skin conditions (serious rash), including Stevens-Johnson Syndrome.
- Acute pancreatitis has been reported in a randomized clinical trial and in postmarketing reports in patients taking saxagliptin or other members of the dipeptidyl peptidase-4 (DPP4) inhibitors class.
- Conditions that predispose patients to develop hyperglycemia may alter saxagliptin efficacy. Hyperglycemia related conditions include drug interactions, female hormonal changes, high fever, severe psychological stress, and uncontrolled hypercortisolism, or hyperthyroidism. More frequent blood glucose monitoring may be necessary for patients with these conditions.
- Conditions that predispose patients to develop hypoglycemia may alter antidiabetic agent efficacy. Conditions associated with hypoglycemia include debilitated physical condition, drug interactions, malnutrition, uncontrolled adrenal insufficiency, pituitary insufficiency, or hypothyroidism.
- An increased risk of hospitalization for heart failure has been reported in patients receiving saxagliptin in a randomized, placebo-controlled postmarketing trial (SAVOR). The study included 16,492 patients with type 2 diabetes who had either a history of cardiovascular events or risk for cardiovascular events.
- A saxagliptin dosage adjustment is required in patients with moderate or severe renal impairment including renal failure and those patients on dialysis.
- Cases of severe, sometimes disabling, arthralgia (joint pain) have been reported with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors, including saxagliptin.
Drug Interactions
Can interact with the following:
- Furosemide
- Glimepiride
- Glipizide
- Hydroclorothiazide
- Insulin
- Levothyroxine
- Lisinopril
Note: This list is not intended as a complete list of all possible drug interactions. Please consult your physician for a more thorough analysis of any potential drug interactions in your prescription regimen.
Long Term Side Effects
The following are possible side effects from prescription use of saxagliptin:
- Sore Throat
- Headache
- Joint Pain
- Rash
- Hives
- Skin Peeling
- Itching
- Swelling of the Face, Lips, Tongue, or Throat
- Difficulty Breathing or Swallowing
- Hoarseness
- Vomiting
- Loss of Appetite
- Excessive Tiredness
- Shortness of Breath
- Swelling of the Feet, Ankles, or Legs
- Sudden Weight Gain
FDA Warnings (History Of)
Pancreatitis and Pancreatic Cancer Risk
In 2013, the FDA issued a public warning concerning incretin mimetics prescribed for T2DM, among which are: Onglyza and Kombiglyze XR. The FDA’s warning was prompted following medical studies linking increased risk of pancreatitis and pancreatic cancer with incretin mimetics. Specifically, the warning came in the form of an announcement that the Agency would be investigating post-market reports of increased risk of pancreatitis and pre-cancerous cellular changes called “pancreatic duct metaplasia” in patients who were prescribed these particular incretin mimetics.
Severe Joint Pain
The FDA warned patients and medical professionals in 2015 that saxagliptin, among other drugs, may cause joint pain that can be “severe and disabling”. Furthermore, the FDA required new warnings and precautions about this risk to the labels of all medicines in the DPP-4 inhibitor drug class.
Risk of Heart Failure
In 2015, a comprehensive study entitled “Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus” (SAVOR) found that saxagliptin may increase the risk of hospitalization for heart failure by about 27%. Furthermore, in 2015 an FDA advisory panel concluded that individuals who take this saxagliptin may face an increased risk of heart failure. Accordingly, in April 2016 the FDA released a drug safety communication warning concerning the increased risk of heart failure with saxagliptin. The FDA then required AstraZeneca to add warnings to the medication labels.
Lawsuits
Over the past few years, plaintiffs from across the United States have filed suits in both state and federal court alleging injury from saxagliptin. In particular, they allege that the manufacturers – AstraZeneca and Bristol-Myers Squibb, knew or should have known about the link between saxagliptin and heart failure and failed to warn patients and their doctors. With a few minor exceptions, these lawsuits have been consolidated into a federal “multi-district litigation” (MDL) proceeding coordinated in the courtroom of Judge Karen K. Caldwell in the U.S. District Court for the Eastern District of Kentucky.
Sources Cited (11)
“Saxagliptin and Metformin in Fixed Combination for the Treatment of Type 2 Diabetes in Adults” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738378/
2. “Saxagliptin” https://medlineplus.gov/druginfo/meds/a610003.html
3. “Metformin and Saxagliptin (Kombiglyze XR)” https://www.emedicinehealth.com/drug-metformin_and_saxagliptin/article_em.htm
4. “Kombiglyze XR” https://www.nps.org.au/medicine-finder/kombiglyze-xr-5-mg-1000-mg-modified-release-tablets
5. “MEDICATION GUIDE KOMBIGLYZE® XR (kom-be-glyze X-R) (saxagliptin and metformin HCl extended-release) tablets” https://www.fda.gov/downloads/Drugs/DrugSafety/UCM280360.pdf
6. “FDA Drug Safety Communication: FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes” https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-investigating-reports-possible-increased-risk-pancreatitis-and-pre
7. “FDA Drug Safety Communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin” https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-adds-warnings-about-heart-failure-risk-labels-type-2-diabetes
8. “FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain” https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-dpp-4-inhibitors-type-2-diabetes-may-cause-severe-joint-pain
9. “AstraZeneca Full-Year and Q4 2018 Results” https://markets.ft.com/data/announce/detail?dockey=1323-13968777-4AP8IJBFD886BB97HNFQ9PHR1H
10. “Saxagliptin” https://pillbox.nlm.nih.gov/
11. “5:18-md-02809KKC – Eastern District of Kentucky” http://www.kyed.uscourts.gov/518-md-02809-kkc
Tracy Everhart
Tracy Everhart is the Editor for Drug Law Journal. A highly-trained and certified medical professional, Tracy is also an accomplished medical writer. After spending years on the front lines of the medical profession, Tracy now devotes her expertise and skills to researching and reporting on new drugs and devices that enter the market, as well as their side-effects and the real-life stories involved. Prior to joining Drug Law Journal, Tracy wrote for benchmark online healthcare resources focused on families and, in particular, women’s health issues. Tracy holds post-graduate degrees from both the American College of Healthcare Sciences and the Yale School of Nursing. She is also a graduate of both Hampshire College, where she studied microbiology and the University of South Carolina school of nursing.
