Lantus admissions to EMA (European Medical Agency) - cancer risk from genetically engineered glargine.
Aside from the fact that the E. coli bacteria used in the production of Lantus "human" insulin (which is not even a true insulin and is less "human" in structure than beef or pork) is, according to the patents, raised in an animal brain and heart tissue based agar which could give rise to BSE (according to the US FDA) while pancreatic tissue from infected cattle could not (according to the US FDA), the 17 page Aventis EMA 2000 application to the European Medical Agency (EMA) notes 7 areas of concern to diabetics and physicians considering the use of Lantus (insulin glargine or HOE901) in the management of diabetes mellitus. The longest clinical studies lasted only 52 weeks and most of the studies (5 of 6 studies done) lasted only 28 weeks.
All studies were done against the intermediate action (~13 hours duration) human NPH (aka "the insulin from hell" according to many endocrinologists). All human trials were done in groups of 349 to 619 subjects, roughly 1/2 on human NPH and 1/2 on Lantus (glargine). Only 349 pediatric cases were done while 2,327 adult cases including 1,563 Type 2 cases. One adult Type 1 study used Lispro, all other studies used R (neutral) insulin for bolus doses. The results reflect, essentially NO A1c benefit from the use of glargine and substantially increased insulin doses. Due to the difference in daily dosing requirements, all studies were done "open label" since there is no way to blind or double blind such studies.
In view of the toxicity indications, we do not view Lantus as a reasonable alternative to human NPH, much less as a reasonable alternative to Beef Ultralente or Beef PZI as a basal insulin for the treatment of diabetes mellitus of either Type 1 or Type 2.
Note: in vitro means in a test tube on cell cultures, in vivo means in a living animal.
1. Single dose toxicity - High doses of glargine resulted in death due to excessive hypoglycemia.
2. Repeated dose toxicity - Repeated dose toxicity studies were performed by subcutaneous administration of insulin glargine in mice, rats and dogs. The animals suffered from dose dependent hypoglycaemia ( hypoglycemia , insulin shock, insulin reaction ), hypoglycaemic shock, and coma. These effects are due to the excessive pharmacodynamic action of the product. Haemorrhage, inflammation and fibrosis were observed at the injection site. Pancreatic beta-cell degranulation was observed in both dogs and rats. This reversible beta-cell degranulation was probably due to the down regulation of insulin synthesis due to a compound over-stimulation, and would therefore also occur during long-term treatment with human NPH as well. [NB This likely explains why Type 2 diabetics required increasing doses of glargine in the Type 2 studies done. ed]
3. Reproduction studies - Effects on reproduction occurred at high doses inducing hypoglycemia and maternal toxicity. At low doses reproduction was not affected.
4. Mutagenic potential - The mutagenic potential of insulin glargine was investigated using 3 bacterial assays and one in vitro point mutation assay in mammalian cells, one in vitro V79 Chinese hamster chromosome aberration assay, all with and without metabolic activation. In addition, an in vivo bone marrow chromosome aberration assay in Chinese hamsters following single subcutaneous doses of 0 and 750 IU insulin glargine/kg was performed. These studies demonstrated that insulin glargine is not mutagenic. [NB Typical dosage for humans taking insulin is less than 1 IU per kg and hamsters on this regimen likely died of hypoglycemia before mutagenic changes could have had a chance to occur. ed]
5. Oncogenic and carcinogenic potential [cancer ed] - The carcinogenic potential was studied in mice and rats. Malignant Fibrous Histiocytomas at the injection site were the predominant findings in both mice and rats. This effect was not related to the dose but correlated to the low pH [acidity ed] of the insulin glargine solution [this is the primary reason that glargine has the action it has according to some texts on the subject ed]. Malignant Fibrous Histiocytomas is a type of tumour commonly found in subcutaneous tissues of laboratory rats and mice when solutions with non-neutral pH are used. In both mice and rats, there was no evidence for treatment related neoplastic findings other than Malignant Fibrous Histiocytomas. However, the affinity of insulin glargine for the IGF-1 [insulin like growth factor 1 ed] receptor was a particular concern, especially because of the fact that published results for the B10-Asp have raised concern about the mitogenicity.
Insulin Glargine Non-neoplastic changes including subcutaneous fibrosis, sclerosis and inflammation, squamous cell hyperplasia, epidermititis and haemorrhage were observed at the injection site.
6. Local tolerance - Local tolerance in a number of rabbit studies was good for single intravenous, paravenous and subcutaneous injections of doses similar to those intended to be used in humans and moderate to good for single intramuscular injection. The formulations used in repeated dose toxicity studies in mice and rats elicited tissue damage caused by the low pH of these formulations (see above). [cute trick, how many diabetics use a single injection in a lifetime of diabetes? ed]
7. Antigenic potential - The antigenicity of insulin glargine was evaluated in rats and dogs. Antibody formation was noted in rats. However, due to the differences in structure between rat insulin and human insulin, this finding is not relevant for humans. In dogs, antibody formation against insulin glargine was not observed. Since human and dog insulin share high structural homology it is likely that insulin glargine has low antigenic potential in humans. [since glargine is a totally different protein from any insulin known in the natural world, and since human insulin causes insulin antibody production and allergies in humans, this seems to be pure nonsense. ed]
Based on Aventis' admissions to the EMA, I cannot, in good faith, recommend that anyone even consider Lantus insulin. There is more than plenty of beef insulin available to make the gold standard for basal insulins, Beef Ultralente, but no one is doing it. The only reasonable substitute is Beef PZI from CP Pharmaceuticals in the UK. Beef R or Neutral, Beef NPH or Isophane, and Beef Lente are all available by import.
Why be a guinea pig when less expensive, proven, better, non-prescription products are available and can be made?