Review of Type-2 Diabetes Medication Liraglutide (VICTOZA)

In January 2010, the Food and Drug Administration (FDA) approved the injectable drug liraglutide (VICTOZA) to be used in combination with diet and exercise to improve blood sugar control in adults with type-2 diabetes. Public Citizen is categorizing liraglutide as a “Do Not Use” drug because of serious safety questions about the drug, as well as the lack of conclusive evidence that it reduces the risk of heart attacks and strokes in patients with type-2 diabetes.

There are two major safety issues with liraglutide: 1) possible thyroid tumors, which may be cancerous; and 2) inflammation of the pancreas, called pancreatitis, which may be severe and lead to death.

The FDA pharmacologists who reviewed the preapproval animal studies of liraglutide recommended that the drug not be approved, as did the medical officer who conducted the safety review for the agency. One of her main concerns was the possibility of thyroid tumors. Liraglutide is the only FDA-approved drug that causes thyroid tumors in male and female rats and mice. Thyroid tumors were seen in patients as well: There was a three-fold increase in thyroid cancer in patients on liraglutide vs. a comparable drug.

The other major safety issue, pancreatitis, was increased four-fold in patients on liraglutide vs. a comparator; one patient taking liraglutide died.

The number of drugs and families of drugs approved by the FDA for type-2 diabetes is growing. There are now 11 families of these drugs, involving more than 22 different products. The table accompanying this article contains the families and drugs currently available in the U.S. to control blood sugar in patients with type-2 diabetes along with our recommendations for use (see Table 1).

Liraglutide and the other drugs marketed to improve blood sugar control will help with the symptoms of type-2 diabetes, such as frequent urination and thirst. However, no type-2 diabetes drug on the market is allowed to claim that it can reduce the major risks associated with this disease: heart attack and stroke.

In fact, the FDA-approved professional product label, or package insert, for liraglutide says, “There have been no clinical studies establishing conclusive evidence of macrovascular [heart attack and stroke] risk reduction with VICTOZA or any other antidiabetic drug.”

Liraglutide is the second member of the new family of antidiabetic drugs known as incretin mimetics (or glucagon-like peptide-1 (GLP-1) agonists). We reviewed the first member of this family, exenatide (BYETTA), in the November 2009 Worst Pills, Best Pills News. We warned readers not to use it for seven years after its approval (April 2012). However, an article in the February 2011 Gastroenterology found that exenatide increased the odds of pancreatitis six-fold compared to four other drugs prescribed for diabetes. With increasing reports of serious adverse events, we now think that exenatide, as well as liraglutide, should be classified as a “Do Not Use” drug.

There were more than 2 million prescriptions dispensed for exenatide in 2009. We expect the same level of sales for liraglutide in the future. It all depends on how much the drugmaker invests in advertising.

The FDA’s approval of liraglutide

There are no laws or regulations that require a new drug to be either safer or more effective than older drugs already on the market for it to be granted FDA approval.

The FDA’s approval of a type-2 diabetes drug depends on the drug’s ability to reduce a blood chemical called hemoglobin A1c (HbA1c), which is a measure of blood sugar control, compared to a placebo. The drug must be statistically better than the placebo to be granted approval for marketing. HbA1c is reported as a percentage, and it is now thought that a value of between 7.0 and 7.5 percent is an acceptable goal, since higher levels caused increases in overall mortality.

Comparative efficacy: liraglutide versus other antidiabetic drugs

Liraglutide is approved for use by itself and in combination with other antidiabetic drugs. The basis for its approval when used alone is the result of a 52-week randomized clinical trial that compared liraglutide to the older drug glimepiride (AMARYL) in type-2 diabetic patients. There were about 250 patients per group. A dose of 1.8 milligrams of liraglutide lowered HbA1c by 0.6 percent more than 8 milligrams of glimepiride. The result was statistically significant, but the clinical importance of this difference is unknown.

The professional product label for liraglutide describes a 26-week clinical trial comparing liraglutide (plus metformin) with glimepiride (plus metformin). There was no difference in efficacy between the two groups, but the liraglutide plus metformin group had substantially more adverse effects, e.g., nausea: 15 vs. 3.3 percent, diarrhea: 11 vs. 3.7 percent, and vomiting: 6.5 vs. 0.4 percent.

Liraglutide medication guide

The FDA has the regulatory authority to require pharmacists to distribute written information with each new and refill prescription for drugs that pose significant public health concerns. This FDA-approved information is called a medication guide.

Liraglutide is among the growing list of drugs that require a medication guide. The liraglutide medication guide and other drugs’ medication guides can be found on the FDA’s website at www.fda.gov/Drugs/DrugSafety/UCM085729.

Exercise and type-2 diabetes

Study results published in the Nov. 24, 2010, Journal of the American Medical Association add to what we know and underscore the importance of exercise in preventing and managing type-2 diabetes. The study was a gold-standard randomized clinical trial that examined the benefits of aerobic exercise and resistance training (lifting weights) on HbA1c levels in people with type-2 diabetes. The study involved 262 inactive women and men in Louisiana with type-2 diabetes and HbA1c levels of 6.5 percent or higher. They were enrolled in a nine-month exercise program between April 2007 and August 2009.

At the end of the study, the average change in HbA1c level in the group doing both aerobic and resistance exercise was a statistically significant drop of 0.34 percent, comparable to some drug therapies.

What You Can Do

You should not use liraglutide. The drug modestly reduces HbA1c with no evidence that it reduces the major risks of type-2 diabetes — heart attack and stroke. Other serious safety questions also remain unanswered regarding increases in cases of cancer and pancreatitis and increased rates of nausea, diarrhea and vomiting in liraglutide users.

Evolving evidence shows that a combination of aerobic and resistance training and a healthy diet can prevent and treat type-2 diabetes. If these are insufficient, drugs for diabetes that we consider appropriate for use are in the table.

Consumers may report serious adverse events with products to the FDA’s MedWatch Adverse Event Reporting program either online or by regular mail, fax or phone.

• Online: https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
• Regular mail: Use postage-paid, pre-addressed FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
• Fax: (800) FDA-0178
• Phone: (800) FDA-1088

Table 1. Drugs Approved for Type-2 Diabetes

*Do Not Use
**Limited Use

Updated 4/4/2012