Victoza and the Incretin System Modulator Medications for Diabetes

Victoza is among what is becoming an increasingly crowded market for drugs that affect the incretin system of pancreatic beta cell function and control of insulin release.  The whole incretin system has been a bit more confusing to me than it needs to be primarily because of the nearly unpronounceable terms and similar acronyms.  I’ve figured out the basics of this system and will share that with readers first as the use of Victoza and the other drugs aimed at this whole process makes a lot more sense if you have a cursory handle on how the system works:

Eating –> Gut release of GLP-1 –> (DPP-4 rapidly degrades GLP-1) –> Stimulates Insulin release and Inhibits Glucagon release –>Lowers Blood Sugar.

GLP-1 analogues like Victoza and Byetta act on the GLP -1 pancreatic beta cells like GLP-1, to lead to lower blood sugar, especially after meals.  DPP-4 inhibitors like Januvia, Onglyza and Tradjenta inhibit the function of DPP-4 which otherwise very quickly, within about 2 minutes, degrades GLP-1.  This very short effect of natural GLP-1 due to very rapid DPP-4 degradation makes this system very agile and responsive to keep blood sugars controlled in the non-diabetic.  The GLP-1 analogues, Victoza and Byetta, can achieve somewhat higher GLP-1 like activity than is possible with the DPP-4 inhibitors, and generally have a modestly greater effect on reducing blood sugars than the DPP-4 inhibitors.

That said the orally administered DPP-4 inhibitors are often used first simply because they don’t require injection.   Despite its distinct advantage of a longer half life and so once daily injections instead of twice daily, Victoza has struggled to gain popularity likely because Byetta was first to market and had the advantage of being novel and more exciting than a second to market drug.  In addition the FDA release of a black-box warning about rodent research showing an increased risk of thyroid C-cell cancer in rats administered Victoza may have hurt Victoza in an attempt to gain market share. Those concerns seem at most minor, as this is a very rare cancer, and no evidence of higher risk in humans has come to light.

Type 2 diabetes is a gigantic problem that is increasing as our population grows older and fatter.  The GLP-1 analogues have a very attractive side-effect of modest weight loss making their adoption by patients with type 2 diabetes who are struggling to both control their blood sugars and to lose weight easier.  It is recommended that Victoza be initiated at 0.6 mg per day as a single subcutaneous injection at any time of the day, regardless of meals, and after 1 week the dose be increased to 1.2 mg daily.  If the desired reduction in blood sugar is not achieved the dose can be increased to 1.8 mg daily.

Side effects with Victoza are relatively uncommon, with only nausea, headache and diarrhea more common than with placebo and occurring in at least 5% of patients.  Pancreatitis is the most common serious Victoza side effect.

I side effect of Victoza that is desirable is modest weight loss.  Both alone and in combination with metformin Victoza led to an average weight loss of about 5-6 pounds over a year of use as compared to about a 2 pound weight gain in control patients treated with glimepiride (an older alternative oral diabetes medication in the sulfonylurea class).

As an interesting side note GLP-1 is a polypeptide, meaning it is made up of a string of amnio acids linked together.  Many hormones like thyroid hormone, insulin and others are polypeptides.  Scientists have learned how to analyze the sequence of amino acids in various polypeptides, and also to reproduce these polypeptides.  By doing this and making various modifications modern laboratories have devised synthetic polypeptides like Victoza which can function like the naturally occurring polypeptide but be resistant to the natural degradation process.  Victoza is a nice example of bench science paying dividends in new and unique medications.

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