Among the interesting studies announced at the American Diabetes Association (ADA) Scientific Sessions 2010 was a head-to-head comparison of two new incretin-based drugs for type 2 diabetics. The full, one-year data presented at the meeting showed that Novo Nordisk’s GLP-1 analog Victoza outperformed Merck & Co’s DPP-4 inhibitor Januvia. These findings were consistent with the 26-week results of this trial which were featured earlier this year in The Lancet.
Given these promising results, I was pleased to be able to ask Dr. Alan Moses, Novo Nordisk’s Chief Medical Officer, a few questions about Victoza and its use in the treatment of type 2 diabetes.
What are incretins?
Incretins are natural hormones made by special cells in the intestine that enhance insulin secretion in response to glucose. Incretin-based therapies work on the beta cell of the pancreas to increase insulin secretion which, in turn, lowers blood sugar. There are two major classes of incretin-based diabetes therapies are GLP-1 agonists like Victoza®, and DPP-4 inhibitors.
How does an incretin-based diabetes treatment differ from other treatments for type 2 diabetes?
Because incretin-based treatments target the beta cell and enhance the release of insulin based on the amount of glucose in the blood, they have some potential advantages over other currently available treatments.
- First, they address one of the underlying problems of type 2 diabetes by directly working on the beta cell. Because of this, drugs like Victoza® have a major ability to lower glucose concentrations.
- Second, since their action depends on the level of glucose in the blood, they have a very low risk of causing low blood sugar (hypoglycemia) which distinguishes them from some other commonly used diabetes medications.
- Third, and unlike most other diabetes medications, they do not increase weight. And Victoza actually promotes weight loss.
What symptoms would suggest the use of incretin-based treatment? Is it (or could it be) used as a first line treatment?
Consensus statements from the American Diabetes Association and the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists, and the American College of Endocrinology recognized GLP-1 analogs as an effective add-on treatment for patients who are not responding to metformin and lifestyle changes alone. That is, when blood sugar remains high for patients taking metformin, Victoza® or other GLP-1 analogs are appropriate choices for treatment. Victoza is not currently recommended for first line treatment.
What is a GLP-1 analog?
GLP-1 is a naturally occurring body hormone that helps to maintain normal blood sugar levels.Unfortunately, patients with type 2 diabetes have defects in their GLP-1 system that contribute to inadequate insulin release that, in turn, result in increased glucose levels. Human GLP-1 is broken down very quickly by the body and cannot be used as an effective medication.GLP-1 analogs, like Victoza®, mimic the action of naturally-occurring GLP-1 in the body and work to help the pancreas produce more insulin in response to the presence of elevated blood sugar. Victoza® lasts for more than 24 hours and has a potent effect in reducing elevated glucose levels, but with a very low risk of hypoglycemia.
How does Victoza compare with the other GLP-1 analog, exenatide?
Victoza® differs from exenatide or Byetta in a number of ways. Victoza can be administered once a day, at any time of day and not related to meals while exenatide should be administered twice a day and before each of the two major meals. Besides convenience, a recent study published in the journal Lancet in conjunction with the 2009 American Diabetes Association meeting (6/8/09) demonstrated that Victoza produced a greater decrease in fasting blood glucose and overall glucose levels as measured by hemoglobin A1c than exenatide. It also was associated with a lower rate of low blood glucose levels. Both drugs promoted weight loss.
There appears to be some confusion about whether Victoza is a weight-loss drug– the marketing material boasts that Victoza has the “added benefit of weight loss,” but footnotes that with “Victoza is not a weight loss product.” Similarly, Martin Jernigan of Novo Nordisk made the curious statement at the Victoza launch that Victoza is “really about getting A1c under control, so patients can also get the benefit of weight loss.” Is Victoza a weight loss drug? If so, in what way does it aid weight loss? If not, how do patients get the “benefit of weight loss” from Victoza?
Victoza® is approved by the U.S. Food & Drug Administration for the treatment of type 2 diabetes. In addition, to lowering blood sugar, in clinical trials, type 2 diabetes patients treated with Victoza also demonstrated weight loss superior to comparator agents including, sulfonyreas, TZDs and insulin. So some type 2 diabetes patients taking Victoza may also get the added benefit of weight loss – an important factor since 85% of people with type 2 diabetes are also overweight or obese. However, Victoza was approved for use as type 2 diabetes treatment because of its substantial effects to lower HbA1c– this was the primary basis for its approval. The studies that led to the FDA approval of Victoza for diabetes were not designed to prove that the drug produced weight loss, although weight loss was seen in the majority of those who took the drug. It is, however, important to note that because of the weight loss benefits we’ve seen with Victoza patients, liraglutide (the active molecule in Victoza) is currently in Phase III development for the treatment of obesity in non-diabetic patients.
For the studies that indicated patients lost weight as a result of taking Victoza, how long were patients followed? Was the weight loss persistent for the course of the study and any follow-ups, or did patients regain weight over time?
Some individuals with diabetes who were treated with Victoza in the clinical trial program were followed for up to two years. During that time, they lost the majority of weight within the first 12 weeks, but maintained weight loss for the duration of their treatment. There was no evidence of substantial weight regain during continued treatment with Victoza.
What about Victoza as a weight loss drug in non-diabetics? Are there studies planned for that?
Yes. Victoza® is currently in Phase III development for the treatment of obesity in individuals without diabetes, but these studies will take several years to complete.
What were the main side effects of Victoza? Did many people drop out of the study because of them?
The most common adverse reactions reported in patients treated with Victoza® are headache, nausea, diarrhea, and anti-liraglutide antibody formation. Immunogenicity-related events, including urticaria, were more common among Victoza-treated patients than among comparator-treated patients in clinical trials. The nausea that occurs with Victoza is relatively mild in intensity and disappears quite rapidly after starting treatment.
Is the fact that this is an injection a hindrance for patients?
No one likes to take injections but Victoza® is easy to administer because it comes in a prefilled disposable pen-like device with a very small needle attached. The dose can be adjusted on the device by dialing it up or down and the injection is easy and virtually painless to administer. Since Victoza can be administered any time of day at the convenience of the patient, it does not have to interfere with activities of daily living making it somewhat easier to use.
Can Victoza be used to treat type 1 diabetics? Can it be used in patients taking insulin?
Victoza® is not indicated for the treatment of type 1 diabetes. Rather, it is approved only for the treatment of type 2 diabetes.
Your safety information states that Victoza has been found to cause thyroid tumors in some rats and mice and that it is unknown whether this could be the case in humans as well. What are the benefits of Victoza that outweigh such a potentially heavy risk?
While Victoza® does carry a boxed warning about its effects on a very specific kind of cell in the thyroid gland of rats and mice, there has been no evidence to date that Victoza causes the same problem in humans. Novo Nordisk conducted extensive experiments to see if Victoza had any effect in humans on a marker of thyroid C-cell disease known as calcitonin. In nearly 4,000 individuals treated with Victoza, many for up to two years, there was no evidence that Victoza produced a consistent duration-dependent or dose-dependent increase in this marker. Thus, at this time, although we cannot rule out an effect in humans, we have no evidence to suggest that an effect occurs. We are confident that the benefit/risk profile of Victoza favors its use in the treatment of type 2 diabetes. The animal findings mean that Victoza is contraindicated in people who have a history of thyroid C-cell tumors, a very rare condition.
The drug warnings for Victoza note that in clinical trials, at least 8.6% of patients treated with Victoza developed anti-liraglutide antibodies (in other words, anti-Victoza antibodies). More concerning still, in the 52-week trial, 6.9% of patients treated with Victoza also developed antibodies against native GLP-1. Is there a risk that a type 2 diabetic patient treated with synthetic incretins will develop a previously absent autoimmune reaction to native peptides like GLP-1, further impairing insulin production and pancreatic performance?
Compared to the other GLP-1 agonist currently available, Victoza® produces a low rate of antibodies and there is no clear evidence that these antibodies affect the action of Victoza in controlling blood glucose. We have no evidence that blood glucose worsens in people taking Victoza which might happen if strong antibodies against native GLP-1 were to form.
Given the risk seen in these studies of developing antibodies against both native and analog GLP-1, are there any symptoms or warning signs that patients taking Victoza should look out for that would indicate they were developing an autoimmune reaction to the drug?
There is no evidence at this time to suggest that patients taking Victoza have experienced an “autoimmune reaction to the drug.”
Alan C. Moses, MD is board certified by the American Board of Internal Medicine and has subspecialty certification in Endocrinology and Metabolism. He is a Fellow of the American College of Physicians. In April 2004, Dr. Moses joined Novo Nordisk, Inc as Associate Vice President for Clinical Research and Medical Affairs – Endocrinology and in 2007 was named Chief Medical Officer, North America. In January of 2008, he was named Corporate Vice President and Global Chief Medical Officer. In this role, he is involved in the full spectrum of the diabetes focus of Novo Nordisk from drug discovery, through drug development, brand messaging, and the implications of diabetes for the company and for patients, healthcare professionals and for healthcare systems.
He has written over 100 papers and articles on the treatment of diabetes, is an Editor of the Fourteenth edition of Joslin’s Diabetes Mellitus, and has been recognized both locally and nationally for clinical care in diabetes and for his research in diabetes and growth factors.