Type 2 diabetes might be controlled by diet and exercise but getting people to do that is tough. As a practical matter, most people cannot change their lives for something bad that will happen 7 to 10 years down the road when today has its own challenges to overcome. Thus most diabetic patients rely on drugs to lower their blood glucose levels. Luckily, a host of new drugs are being developed and we are seeing continual improvements in how blood glucose is controlled.
The latest addition to our armamentarium is Liraglutide (trade name Victoza). It was developed by Novo-Nordisk and was approved by the FDA early in 2010. It is a member of the class of drugs known as Incretins. Incretins are hormones that do all sorts of wonderful things for the diabetic patient including increase insulin sensitivity, decrease the rate of glucose production by the liver, and slow the rate of food absorption (to read more about incretins click here). Normally these hormones are rapidly degraded by the body, so what Novo-Nordisk did was to create something that would activate the appropriate hormone receptor but not get degraded so rapidly. They did a good job. The Liraglutide sticks around long enough in the body that one only needs to take it once per day. These sorts of things really help with compliance since these drugs are administered by injection like insulin.
The LEAD-6 clinical trial comparing Liraglutide to Exenatide (Byetta) was headed by Dr John Buse from the University of North Carolina at Chapel Hill and the results published in the Lancet in 2009. Four hundred and sixty four type 2 diabetes patients who were taking metformin and did not have well controlled blood glucose levels were randomized to receive either Byetta or Liraglutide. They took the drug for 26 weeks. The patients were predominantly Caucasian with approximately equal numbers of male and female participants. They were significantly overweight with an average BMI of 32.9 (obese).
The results of the study were quite good. Both groups saw a decrease in blood sugar as measured both as fasting blood glucose levels and by glycosylated hemoglobin (HbA1c). Since sugar binds to hemoglobin (glycosylation) and hemoglobin sticks around for about 90 days (the life span of a red blood cell), measuring HbA1c is a good average of blood glucose control over the past 2 – 3 months. Fasting blood glucose just measures how you are doing at that point in time. At any rate, the patients taking Liraglutide dropped by about 1.2% (approximately) while the patients taking Exenatide dropped about 0.8% (approximately). Now medical researchers have done a lot of work establishing at what level of blood glucose a patient is at risk for complications and what is a safe level. The magic number appears to be 6.5%. If you have diabetes and your HbA1c level is less than 6.5% your chances of developing complications are virtually nill. In this study about 35% of patients taking Liraglutide decreased their HbA1c levels below 6.5% while about 20% of patients taking Exenatide achieved the same level of control.
Furthermore, in a study that was just published in Diabetes Care, the trial was extended for another 14 weeks and the Exenatide group was switched to Liraglutide. Interestingly, by week 14, the two groups appeared identical. Thus it seems that patients can easily and safely switch from Exenatide to Liraglutide as needed.
Another important issue is nausea. This is the big downside to using incretins. Many patients report significant nausea (see Catherine Price’s blog for a personal description). In the Lancet article, incidence of nausea was measured for the two groups and while the two groups started out the same (around 15 – 16%) the Liraglutide group dropped to 2% while the Exenatide group stayed around 10%. Thus it looks like patients get used to Liraglutide more easily than Exenatide.
There is more risk associated with Liraglutide. About 5.1% of patients taking Liraglutide experienced a serious adverse effect while about 2.6% of patients taking Exenatide experienced the same level of problems. These problems were primarily GI disorders for both groups – this is a bit surprising given that the main issue is nausea with this class of therapy and that Liraglutide seemed to cause less nausea than Exenatide. There was 1 incidence of cancer in the Liraglutide group and 1 incidence of heart attack. In comparison there were 2 heart attacks and no cancers in the Exenatide group. To what extent did these drugs cause these problems? As for the GI side effects, I think it is highly likely. As for the cardiac and cancer effects – the data is not very clear. We will need to look at thousands of patients (as we did with Avandia) to get some decent numbers.
At present, in my opinion, Liraglutide looks like a good addition to our current therapies.
Yes! Especially useful for type 2 diabetic patients with remaining pancreatic function.
not to mention that incretins might have the potential to increase beta cell replication….
You mentioned that incretins increase insulin sensitivity, decrease the rate of glucose production by the liver, and slow the rate of food absorption… that makes me wonder if Liraglutide could benefit type 1’s as well.