Insulin detemir

The first of the long-acting insulin analogues marketed by Novo Nordisk, insulin detemir has some peculiar properties. First, insulin detemir has a reduced biological effect as compared with human insulin, which is compensated for by increasing its molar strength in the clinical product. Even so, slightly higher doses are needed to achieve the same effect. Second, for not entirely explained reasons, its use is associated with slightly less weight gain than other insulins. Third, it has a duration of action that falls short of 24 hours, particularly at lower doses where the duration of action is in fact similar to NPH insulin. As a result, it has been registered for once or twice daily use, and objective clinical advantages as a basal insulin for type 2 diabetes have been limited. Nonetheless, insulin detemir has been a marketing success.

Originally coded NN304, insulin detemir derives its prolonged action from the attachment of a fatty acid (myristic acid) tail to the 29th position of the B-chain through a glutamic acid linking molecule, after removal of Threonine at the B30 position (Figure 1). This fatty acid tail leads to a high binding affinity of the insulin for albumin in the subcutaneous compartment and in the plasma, with > 98% of insulin detemir being protein-bound. Figure 1. Structure of insulin detemir. The B-chain is truncated at the B29 position and a myristic acid is attached to the insulin molecule.
Figure 1. Structure of insulin detemir. The B-chain is truncated at the B29 position and a myristic acid is attached to the insulin molecule.
The protein-bound insulin forms a depot from which insulin molecules are released more slowly. In clinical reality however, the duration of action of insulin detemir is dose-dependent, and ranges from 8 hours at doses of 0.1 IU/kg up to about 20-24 hours at higher doses (above 0.4IU/kg), which is not that much longer than the duration of action of NPH insulin. Insulin detemir has a peak action after 6 to 8 hours.

The affinity of detemir for the insulin receptor is about 1/5th of the affinity of human insulin and its metabolic potency is about 1/4th. In an attempt to overcome this, the clinical formulation of insulin detemir contains a 4 times higher molar dose than all other insulins (insulin detemir 2400 nmol/ml versus all other insulins 600 nmol/ml).

Clinical efficacy

Insulin detemir compared to NPH insulin

As stated, insulin detemir does not exactly meet the standards of a true long-acting basal insulin analogue, with a duration of action that in many patients will not reach 24 hours. This is reflected in its registration for once or twice-daily use. Thus, it is not really surprising that a Cochrane analysis[1] of its effects in type 2 diabetes concluded that it was associated with a reduction of 18% in hypoglycaemia compared to NPH insulin while HbA1c was actually worse with insulin detemir. It must be noted that this meta-analysis included only two trials. However, the same pattern was found in another meta-analysis by Monami et al[2], and also transpires when looking at the (unpublished) trials reported to the European Medicines Agency: detemir may reduce hypoglycaemia and severe hypoglycaemia but is inferior to NPH insulin in lowering HbA1c in type 2 diabetes. In type 1 diabetes this pattern is a bit better, with equal or slightly (0,1%) improved HbA1c levels, a 40% reduction in nocturnal and a 25% reduction in severe hypoglycaemia rates but no difference in total hypoglycaemia.

A consistent finding in trials comparing detemir to either NPH insulin or insulin glargine is that the use of insulin detemir is associated with slightly less weight gain (by 0.3 to 0.8 kg). This effect has not been fully explained but it has been attributed to reduced food intake in relation to (direct or indirect) effects of insulin detemir on the satiety centre in the brain.

The variability in absorption profiles of insulin detemir is theoretically better than NPH, but has not resulted in less clinical variability as measured by variation in fasting plasma glucose. Likewise, claims that insulin detemir might be more hepatospecific (i.e. have a greater efficacy on the liver compared to other tissues) are more likely related to the lower overall plasma insulin levels than to a true effect of insulin detemir itself.

Insulin detemir compared to insulin glargine

Another Cochrane review comparing insulin detemir and insulin glargine in type 2 diabetes[3] concluded that “to achieve the same glycaemic control insulin detemir was often injected twice-daily in a higher dose but with less weight gain, while insulin glargine was injected once-daily, with somewhat fewer injection site reactions”. This meta-analysis was hampered by the fact that insulin detemir was used either once or twice daily. A later trial directly comparing once daily detemir and once daily glargine in type 2 diabetes (of note: sponsored by the manufacturer of detemir, Novo Nordisk) found that glargine improved HbA1c more (by 0.3% = 3 mmol/mol) whereas the relatively uncommon occurrence of hypoglycaemia was reduced by 27% with detemir.

Conclusion

Taking all the data comparing insulin detemir, insulin glargine and NPH insulin into account, the main lesson to be learned is that the long-acting analogues do not improve HbA1c compared to NPH insulin, but may reduce (nocturnal) hypoglycaemia rates. The latter is more relevant in patients with type 1 diabetes, who have frequent hypoglycaemia, than in most patients with type 2 diabetes. Glargine seems to be slightly more efficacious with respect to HbA1c, while detemir is associated with slightly less weight gain.

References

  1. ^ Horvath K, Jeitler K, Berghold A, Ebrahim SH, Gratzer TW, Plank J, Kaiser T, Pieber TR, Siebenhofer A. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD005613

  2. ^ Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues versus NPH human insulin in type 2 a meta-analysis. Diabetes Res Clin Pract. 2008;81(2):184-9.

  3. ^ Swinnen SG, Simon AC, Holleman F, Hoekstra JB, Devries JH. Insulin detemir versus insulin glargine for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011 Jul 6;(7):CD006383. doi:10.1002/14651858.CD006383.pub2.

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