Byetta, Victoza, and Januvia are medications used for the treatment of Type 2 Diabetes Mellitus (T2DM). They are classified as “Incretin Mimetics” and are medications normally prescribed for individuals who are not able to control their diabetic condition with typical front-line management tools alone. Incretin Mimetics are also commonly referred to as “Glucagon-like Peptide 1 (GLP-1) receptor agonists.

Prescription Name and Overview

Byetta

Byetta is the trade name of Exenatide. Initially manufactured by Amylin Pharmaceuticals in a joint-venture/alliance with Eli Lilly & Co., Amylin was eventually acquired by Bristol-Myers Squibb and marketed jointly with AstraZeneca Pharmaceuticals. In 2013, AstraZeneca bought exclusive ownership and control from Bristol-Myers. Byetta is commonly used in combination with insulin glargine but is not itself a substitute for insulin.

Victoza

Victoza is the trade name of Liraglutide and is manufactured by the Danish firm, Novo Nordisk A/S (also the world’s largest producer of insulin). Victoza was approved by the U.S. Food and Drug Administration (FDA) for use as a medication to lower blood sugar levels when coupled with diet and other medications in 2010. Victoza was seen as a profit-center for Novo Nordisk as it enjoys certain dosing advantages over competitor Byetta – generally only requiring a single daily injection.

Januvia

Januvia is the trade name of Sitagliptin and is manufactured by Merck & Co. Januvia was approved by the FDA in October 2016 as the first in a new class of diabetes medications are known as dipeptidyl peptidase-4 (DPP-4) inhibitors.  Januvia is taken orally as opposed to other similar medications that are injected.

What Are They Used For?

Drugs in the Incretin Mimetic class work by mimicking the incretin hormones that the body usually produces naturally to stimulate the release of insulin in response to a meal. They are used along with diet and exercise to lower blood sugar in adults with type 2 diabetes.

How Do They Work?

Incretin Mimetics typically perform their primary function in patients through the following avenues of operation:

• Stimulating the release of insulin by the pancreas after eating, even before blood sugars start to rise.
• Inhibiting the release of glucagon by the pancreas. Glucagon is a hormone that causes the liver to release its stored sugar into the bloodstream.
• Slowing glucose absorption into the bloodstream by reducing the speed at which the stomach empties after eating, thus making you feel more satisfied after a meal.

These effects are in direct response to the presence of carbohydrate in the digestive system and therefore the chance of significant hypoglycemia occurring is unlikely unless used in combination with other hypoglycemic drugs.

What Are the Approved Uses?

Byetta

Amylin’s application for Byetta was approved by the FDA in 2005 for its use to improve glycemic control in patients with T2DM who have not achieved sufficient glycemic control on metformin, a sulfonylurea, or a combination of metformin or sulfonylurea. Byetta is marketed as capable of lowering blood glucose levels in the blood and being safe to prescribe with other diabetic drugs. It is commonly used in combination with insulin glargine. Byetta is not a substitute for insulin in insulin-requiring individuals. Furthermore, Byetta should not be taken by individuals with type 1 diabetes or for the treatment of diabetic ketoacidosis. 

Victoza

The initial application Novo Nordisk submitted for Victoza was approved by the FDA in January 2010 but limited in scope to help lower blood sugar levels when coupled with diet, exercise, and other diabetes medicines. It was not recommended as initial therapy for patients who have not been able to control their diabetes with diet and exercise alone. Since then, Victoza has been approved for the reduction of the risk of a three-component endpoint consisting of cardiovascular death, non-fatal heart attack, or non-fatal stroke (2017); and for injection for the treatment of pediatric patients 10 years or older with type 2 diabetes (2019). Victoza is the first non-insulin drug approved to treat type 2 diabetes in pediatric patients since metformin was approved for pediatric use in 2000.

Januvia

The FDA has approved Jauviua tablets for use with diet and exercise to improve glycemic control in adult patients with T2DM. The once-daily agent can be used alone or in combination with metformin or the thiazolidinediones pioglitazone HCl and rosiglitazone maleate when treatment with either drug alone provides inadequate glucose control.

Precautions

Byetta

• Byetta should be used with caution in patients with kidney problems and or who have kidney transplants.
• Severe allergic reactions can happen with Byetta.
• The FDA categorizes medications based on safety for use during pregnancy. Five categories – A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy. Byetta falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans, though. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.
• Byetta may cause inflammation of the pancreas (pancreatitis), a potentially life-threatening condition. Tell your doctor right away if you have severe stomach pain and vomiting.

Victoza

• Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with Victoza. Patients should be observed carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Victoza should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, Victoza should not be restarted.
• There have been reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis in Victoza-treated patients.
• Serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) are a possibility in patients treated with Victoza.
• 3.1% of Victoza-treated patients versus 1.9% of placebo-treated patients reported an acute event of gallbladder diseases, such as cholelithiasis or cholecystitis.
• In animal studies, Victoza was found to cause thyroid tumors (abnormal growths) and thyroid cancer.

Januvia

• May cause joint pain that can be severe and disabling.
• Possibility of increased risk of pancreatitis and pre-cancerous cellular changes called pancreatic duct metaplasia in patients with type 2 diabetes.
• Januvia doesn’t typically cause skin rashes. However, skin rashes can be a symptom of an allergic reaction to Januvia.
• People who have taken Januvia with other diabetes drugs did, in some cases, exhibit edema. Symptoms of edema can include swelling in some parts of your body, such as your hands and legs.
• Some patients experience Hyperglycemia if they miss/skip a dosage or do not follow their meal plan.

Possible Drug Interactions

Byetta

Victoza

Januvia

Long Term Side Effects

Byetta

Victoza

Januvia

History of FDA Warnings

Pancreatitis and Pancreatic Cancer Risk

In 2013, the FDA issued a public warning concerning incretin mimetics prescribed for T2DM, among which are: Byetta/Bydureon, Victoza, and Januvia/Janumet. 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. Following this warning, the FDA required Victoza’s manufacturer, Novo Nordisk, to include a warning about pancreatitis on prescription labels. 

Thyroid Cancer

Victoza

Following-up on concerns the agency developed concerning the linkage between Victoza and thyroid cancer, the FDA required Novo Nordisk to include a “black box” warning on Victoza labels. This is the most serious form of FDA warning as it indicates a potentially serious health risk or life-threatening complication resulting from the medication. The FDA’s concern stemmed primarily from studies in laboratory mice evidencing that Victoza causes cancerous tumors. No studies involving humans have yielded conclusive discoveries of tumors.

Bydureon

Bydureon evolved as an enhancement from Byetta and is manufactured by the same firm, AstraZeneca. Like Byetta, Bydureon contains the same active incretin mimetic, but in a longer-lasting format that only requires once-a-week injections. Like Victoza, the FDA has substantial concerns regarding the potential for the development of thyroid cancer, although no human linkage between the drug and thyroid cancer has been proven. Accordingly, the FDA requires Bydureon to feature a “black box” label warning that it may cause thyroid tumors and cancer.

Lactic Acidosis

Janumet is a further evolution of Januvia, and like Bydureon, contains the same active ingredient as its predecessor, Januvia plus metformin. The FDA requires Janumet to carry a “black box” label warning concerning a condition known as Lactic Acidosis – a dangerous build-up of lactic acid in the blood associated with metformin.

Lawsuits

Several plaintiffs from across the United States have filed individual lawsuits claiming pancreatic injuries and pancreatic cancer diagnosis linked with incretin mimetic-based pharmaceuticals such as Januvia/Janumet, Victoza, and Byetta/Bydureon. In 2013, these cases were consolidated under the rubric of Multi-District Litigation (MDL) in the Federal District Court for the Southern District of California.  Since then the class has grown to over 980 cases.

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