Insulin glargine

Insulin glargine is the most frequently used basal insulin analogue today. It was made by Novo Nordisk, but because they deemed it unpromising and decided to pursue acylated insulins instead, the analogue was sold to Hoechst (now part of sanofi). Originally designated HOE901, it was taken through a clinical development program which led to its launch in 2003. Heralded as the first insulin with a peakless action profile and a duration of action beyond 24 hours, it soon became a marketing success, even though it was subsequently shown that it does have a peak action and that its duration of action will vary between individuals. Moreover, the clinical benefits over conventional NPH insulin are actually limited to a slight reduction in hypoglycaemia rates.

Insulin glargine Figure 1. The amino acid composition of insulin glargine.
Figure 1. The amino acid composition of insulin glargine.
(21A-Gly-30Ba-L-Arg-30Bb-L-Arg human insulin or di-arginyl insulin) derives its prolonged action from an altered amino-acid composition, i.e. the replacement of asparagine (Asn) by glycine (Gly) at the end of the alfa-chain and the addition of two arginine (Arg) amino acids at the end of the beta-chain (Figure 1). These amino-acids increase the iso-electric point[a] of the insulin to a pH of approximately 7. The clinical formulation of insulin glargine is dissolved in a fluid with pH =4. When injected subcutaneously, the pH rises and this leads Figure 2. Mode of prolonged action of insulin glargine (see text for full explanation)
Figure 2. Mode of prolonged action of insulin glargine (see text for full explanation)
to crystallization and micro-precipitation of the insulin; subsequently, insulin glargine is slowly released into the circulation from this depot (Figure 2).

Pharmacokinetics

Insulin glargine is not registered for i.v. use. After subcutaneous injection, plasma insulin levels rise slowly to a peak after 8 to 10 hours, with a duration of action of about 20 up to 30 hours. As usual, at higher doses duration of action tends to be longer than at lower doses. Compared to NPH insulin, peak plasma levels of insulin are about halved. In the plasma, insulin glargine is partly degraded to two active metabolites by stepwise removal of the C-terminal arginine residues. Insulin glargine is equipotent to human insulin for its action on the insulin receptor, but the altered amino-acid sequence leads to a six-fold higher affinity of insulin glargine for the IGF-1 receptor compared to human insulin. However, this affinity is still very low compared to the affinity of IGF-1 itself.

Clinical Efficacy of insulin glargine

Remarkably few large scale trials have tested the clinical efficacy of insulin glargine compared to NPH insulin in multiple injection regimens in type 1 diabetes. Available data suggest that the use of insulin glargine or NPH insulin leads to similar HbA1c. And while some studies reported a decrease of 20-30% in hypoglycaemia rates, others found no difference.

Figure 3. A Cochrane meta-analysis by Horvath and colleagues comparing insulin glargine and NPH insulin in patients with type 2 diabetes found no difference in HbA1c and a slight decrease in hypoglycaemia risk  with insulin glargine.
Figure 3. A Cochrane meta-analysis by Horvath and colleagues comparing insulin glargine and NPH insulin in patients with type 2 diabetes found no difference in HbA1c and a slight decrease in hypoglycaemia risk with insulin glargine.
In type 2 diabetes several trials have compared the use insulin glargine as a once-daily basal insulin with NPH insulin, both in combination with oral glucose-lowering drugs. A Cochrane meta-analysis found that the use of insulin glargine was associated with the same HbA1c and (based on only 3 studies) a reduction of hypoglycaemia rates by 16% (figure 3). Company-sponsored meta-analyses tend to find somewhat greater benefits, with glargine reducing the number of hypoglycaemic episodes by about 30%, from approximately 1.5 episodes/patient/year to 1 episode/patient/year. Considering the absolute numbers, this is of relatively minor importance for most patients (in fact, up to 70% of users of NPH insulin will not experience any hypoglycaemia at all), but in some individuals hypoglycaemia rates may be considerably higher and use of the more expensive insulin glargine could be warranted.

In the ORIGIN trial, the use of glargine as first-line treatment for (early) type 2 diabetes was compared to standard treatment with oral glucose-lowering drugs (metformin and/or sulfonylurea derivative) in over 12.000 patients to determine whether early insulin use would reduce hard endpoints such as (cardiovascular) mortality. After 6.2 years of follow-up, glycaemic control in both groups was slightly better in the glargine treated group (6.2% =44 mmol/mol with glargine versus 6.5% =46 mmol/mol in the standard group) but this was associated with a 3 fold higher risk of overall hypoglycaemia (9.8 vs. 2.7 episodes/patient/year) and severe hypoglycaemia (1 vs 0,3 episodes per 100 patients/year) and (cardiovascular) mortality was exactly the same in both groups. Of note, 43% and 75% of patients in the glargine and standard group had no hypoglycaemic episodes during the whole follow-up, again highlighting the necessity to tailor the use of this more expensive insulin to those who demonstrably have frequent hypoglycaemic episodes.

Glargine and cancer risk

In 2009 a series of studies in the journal Diabetologia drew attention to a possible risk of (breast) cancer associated with the use of insulin glargine. This has led to a torrent of observational studies investigating this matter, with some supporting but others finding no evidence for such an association. However, the only large randomized trials looking at hard endpoints, most notably the aforementioned ORIGIN trial, found no evidence of an increased cancer risk. A detailed analysis of the data can be found in our page on Insulin glargine and cancer.

Conclusion

The clinical benefits of glargine are probably limited to a slight reduction in hypoglycaemia rates and the fact that (unlike NPH insulin) it does not have to be resuspended before injection. These benefits have to be weighed against the higher cost of insulin glargine and the fact that many patients will not suffer from hypoglycaemia when using NPH insulin. Side-effects other than slight irritation at the injection site as a result of the acidity of the solution have not been conclusively demonstrated.

Footnotes

  1. ^ The iso-electric point is the acidity at which a protein has the lowest net charge and thus is least soluble in water.

Comments

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    Jothydev Kesavadev added a compliment on 25 June 2016 at 12:34PM
    Though all of us know that glargine is a Novo Nordisk innovation, this is the only document I could obtain from the internet. Well done.
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