Glargine Insulin Is Expensive: Is Compounded Insulin an Acceptable Alternative?

After reading your last post about the escalating costs of insulin analogs, such as glargine and detemir, I wanted to ask your opinion about compounded insulin products. Compared to the human glargine preparation (Lantus), some compounding pharmacies offer a compounded glargine product at only about 25% of the regular price as sold by human pharmacies.

Any comments? Why not use these compounded insulin products?

My Response:

I would never use a compounded insulin product in my cat or dog patients unless there was absolutely not other option. I know it sounds tempting, but experience (especially with compounded PZI insulin), shows that the potency of these compounded insulin products can vary greatly from bottle to bottle (1). As we all know, it's difficult enough to regulate a diabetic cat without the additional variable of the insulin changing its potency every time the owner buys a new bottle. I feel that it’s far better to get manufactured FDA-approved insulin that has external quality control standards applied to it.

How insulin glargine is made (or how it should be!)
Making insulin glargine is not a simple process. Remember that glargine is an insulin analog (2). With insulin glargine, the chemical structure of the insulin protein is changed to make it have a relatively constant release over 24 hours with no pronounced peaks (at least in man).

So how do they make this insulin? Synthesizing human insulin is a multi-step biochemical process that depends on basic recombinant DNA techniques, and an understanding of the insulin gene (3-5). For insulin glargine and other insulin analogs, instead of synthesizing the exact DNA sequence for insulin, manufacturers synthesize an insulin gene where the sequence is slightly altered. These changes in resultant amino acid sequence are responsible for glargine's prolonged duration of action.

DNA carries the instructions for how the body works and one small segment of the DNA—the insulin gene— codes for the protein insulin. Manufacturers manipulate the biological precursor to insulin so that it grows inside simple bacteria. While manufacturers each have their own variations, this recombinant DNA process is the basis for manufacturing human insulin (Figure 1).

Figure 1: A diagram of the complicated manufacturing steps for insulin (from reference 4).

Quality control must play a very important aspect of insulin production (3-5). After synthesizing the insulin glargine, the structure and purity of the insulin batches are tested through several different methods. High performance liquid chromatography is used to determine if there are any impurities in the insulin. Other separation techniques, such as X-ray crystallography, gel filtration, and amino acid sequencing, may also be performed. Manufacturers also test the vial's packaging to ensure it is sealed properly. Manufacturing for human insulin must comply with National Institutes of Health procedures for large-scale operations. The United States Food and Drug Administration must approve all manufactured insulin preparation.

Practical and legal problems with using compounded insulin
As detailed above, making insulin entails a complicated manufacturing process, and I do not know how any compounding pharmacy could possibly produce a reliable insulin product. Compounded insulin products fall into a legally gray area that is the subject of current scrutiny by the FDA (6,7). It is important to recognize the limitations about safety, effectiveness, and stability of compounded insulin preparations.

Pet owners should be informed of the risks of failure associated with using a compounded insulin product. They should consent to therapy based on disclosure that the use of the insulin product is scientifically unproven (i.e., there are no published scientific papers concerning the use and effectiveness of compounded insulins).  Overall, it is the responsibility of the veterinarian to ensure the safety and therapy of any prescribed insulin treatment, including compounded insulin products — and failure to do otherwise places the patient and pet owner, as well as the veterinarian, at risk.

References:

1. Scott-Moncrieff JC, Moore GE, Coe J, et al. Characteristics of commercially manufactured and compounded protamine zinc insulin. J Am Vet Med Assoc 2012;240:600-605. 
2. Owens DR, Griffiths S. Insulin glargine (Lantus). Int J Clin Pract 2002;56:460-466. 
3. Gebel E. Making insulin: A behind-the-scenes look at producing a lifesaving medication. Diabetes Forecast 2013;July issue. 
4. Website. How Products are Made: Insulin. 
5. Owens DR, Landgraf W, Schmidt A, et al. The emergence of biosimilar insulin preparations--a cause for concern? Diabetes Technol Ther 2012;14:989-996. 
6. Boothe DM. Veterinary compounding in small animals: a clinical pharmacologist's perspective. Vet Clin North Am Small Anim Pract 2006;36:1129-1173. 
7. Lust E. Compounding for animal patients: contemporary issues. J Am Pharm Assoc 2004;44:375-384.