Insulin glargine

Insulin glargine

Clinical data
Routes of administration	Subcutaneous
ATC code	A10AE04 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Identifiers
IUPAC name Recombinant human insulin
CAS Number	160337-95-1
DrugBank	BTD00045
CompTox Dashboard (EPA)	DTXSID0043927
ECHA InfoCard	100.241.126
Chemical and physical data
Formula	C267H408N72O77S6
Molar mass	6063 g/mol g·mol−1

Insulin glargine, marketed by Sanofi-Aventis under the name Lantus, is a long-acting basal insulin analogue, given once daily to help control the blood sugar level of those with diabetes. Its advantage is that it has a duration of action of 24 hours, with a "less peaked" profile than NPH. Thus, it more closely resembles the basal insulin secretion of the normal pancreatic beta cells. In type 2 diabetes and in combination with a short acting sulfonylurea (drugs which stimulate the pancreas to make more insulin), it can offer moderate control of serum glucose levels. In the absence of endogenous insulin (Type 1 diabetes or depleted type 2), Lantus needs the support of a fast acting insulin taken with food to reduce the effect of prandially derived glucose. It is fasting glucose elevation which more significantly affects HbA_1c and thus determines the progression of the long-term complications of diabetes mellitus.

File:Glargine 02a.jpg

glargine vs. NPH insulin

Benefit

The peakless profile of Lantus also enables the dose to be relatively higher than standard NPH insulin. Because standard NPH is normally administered at night, its peak of action tends to coincide with the lower serum glucose levels associated with nocturnal metabolism. This can induce nocturnal hypoglycaemia. Lantus offers the benefit of a more consistent pharmacological dynamic without nocturnal hypoglycaemia. The result of this is a patient who feels more confident and more comfortable with a lower pre-bed and pre-breakfast capillary glucose level.

Pharmacological specifications

Mechanism of action (pharmacodynamics)

Insulin glargine have substitution of glycine for asparagine at A21 and two arginines added to the carboxy terminal of B chain. This allows insulin glargine to form a precipitate (hexamer) when injected subcutaneously into the patient. It can achieve a peakless level for at least 24 hours.

Acceptance and repartition in the body (pharmacokinetic)

Lantus is formulated at an acidic pH 4, where it is completely water soluble. After subcutaneous injection of the acidic solute ( which can cause discomfort and a stinging sensation and can be mitigated with the use of the I-port ), the body, at pH 7, slowly neutralizes the solution, causing insulin microcrystals to gradually precipitate from the insulin glargine solution, which then release insulin in biologically active form. This gradual process ensures that small amounts of Lantus are released into the body continuously, giving an almost peakless profile.

Usage

Mixing with other insulin preparations

Unlike some other longer-acting insulins, Lantus must not be diluted or mixed with other insulin or solution in the same syringe.

Other information

Development

The development of Lantus was conducted at Sanofi-Aventis's biotechnology competence center in Frankfurt-Höchst. Sanofi supplies the product to over 100 countries and more than 3,5 million patients worldwide. This makes Lantus Germany´s largest and most important export pharmaceutical product. Sanofi-Aventis increased its turn-over with Lantus around 28 % to 2,45 Billion €, therefrom 130 Million € in Germany, where approx. 1,8 Mio. diabetics applied this preparation. In 2007 Lantus ranked place 15 on top-selling pharmaceutical products in Germany.

The investment in the production of Lantus and insulin-pen-manufacturing at the location Frankfurt-Höchst lied at 700 Mio. €. In 2008 a new manufacturing plant was established for further insulin-pen with an investment sum of 150 Mio. €. At Sanofi-Aventis the production of Lantus created 3000 jobs in Berlin and Frankfurt-Höchst.

On June 9th, 2000 the European Commission approbated Sanofi-Aventis Germany Ltd. the launching of Lantus® in the entire European Union. The admission was prolonged on June 9th, 2005.

Studies and discourse

International clinical studies confirmed advantage of insulin glargine in the treatment of heavy hypoglycaemia compared to standard NPH insulin. Lantus reduced the risk of nocturnal severe hypoglycaemia. Extensive clinical studies (ACCORD) have confirmed the higher risk of mortality under higher incidence of severe hypoglycaemia.

On June 13, 2009, Diabetologia, the journal of European Association for the Study of Diabetes EASD, published the 5-year-long-term-study 4016, a randomised, open-label study. During the study no other safety issues, such as unexpected adverse events for either insulin emerged. However, NPH insulin treatment was associated with a higher incidence of severe hypoglycaemia compared with insulin glargine.

Other systematic reviews corroborate the results of benefit of insulin glargine regarding lower incidence of severe hypoglycaemia.

On June 26, 2009, Diabetologia published four registry studies from Scotland, Sweden, UK and Germany. Especially, the German study of around 127,000 insulin-treated patients from an insurance database, supposed a possible link between insulin glargine (Lantus) and increased cancer risk. But in the conclusion the authors stress that their analyses are inconclusive and the German study “relies on a statistical correction for insulin dose”.

The results of the four registry studies are not comparable with the results of the randomised, open-label 5-year-long-term-study 4016 (above mentioned) because of different level of used methods. Randomised, clinical studies based on a high ranked level of studies, the so called "methodical gold standard", which is accepted as a higher scientifically evidence value: patient groups are comparable. The authors are careful to point out the limitations of the studies, and state categorically that "Lantus and other insulins do not cause cancer".

The European Association for the Study of Diabetes (EASD) stated the four studies “far from conclusive, but they do indicate the need for further investigation of this issue.” EASD makes an urgent call for more research into a possible link between use of insulin glargine and increased risk of cancer. EASD does not recommended patients “stop taking insulin glargine (Lantus) on the evidence presented here”

The European Medicines Agency (EMEA) stated on June 29, 2009 that the results of the four studies were found to be inconsistent, and that a relationship between insulin glargine and cancer can neither be confirmed nor excluded. The Agency’s Committee for Medicinal Products for Human Use (CHMP) is to perform a detailed assessment of the studies’ results and any other relevant information. The review will also address issues like dose-response effects or influence of other factors on the risk of cancer (e.g. age, body mass index (BMI), menopausal status, parity, socioeconomic status). Patients being treated with insulin glargine (Lantus) are advised to continue their treatment as normal. On July, 23, 2009 the European Medicines Agency (EMEA) “concluded that the available data does not provide a cause for concern and that changes to the prescribing advice are therefore not necessary.”

The American Diabetes Association (ADA) and the French health regulatory agency (AFSSAPS) stated that the findings of the four published registry studies are “conflicting and confusing” and “inconclusive”. ADA and AFSSAPS has advised patients in USA and France not to stop taking Lantus and has warned against over-reaction.

On Wed Jul 15, 2009, a multidisciplinary board of 14 international independent experts signed a statement, following their independent, rigorous and thorough review of the published data about Lantus. Professor Matthew Riddle, Professor of Medicine, Diabetes Section Head, Division of Endocrinology/Diabetes/Clinical Nutrition, Oregon Health Sciences University, Portland, OR, USA state: “Regarding the merits of the published data, we agreed that all four published manuscripts have significant methodological limitations and shortcomings. The nature of these limitations and their potential magnitude are such that, individually or in aggregate, these studies provide inconsistent and inconclusive results which do not justify new clinical recommendations to patients”.

External links

• Insulin glargine - MedlinePlus
• Lantus website (Sanofi-Aventis)