TOPIC-COMPARISON BETWEEN LONG ACTING INSULINS

Insulin glargine
 Insulin glargine was the first long-acting insulin analogue produced by recombinant
DNA technology, approved for use by the US FDA in April 2000 and by the European
Agency for the Evaluation of Medicinal Products in June, 2000.
 It consists of two modifications to human insulin :
o Two arginine molecules are added to the C – terminus of the B chain shifting
the isoelectric point of the insulin from a pH of 5.4 to 6.7. This addition
makes the insulin more soluble at an acidic pH and insulin glargine is
formulated at a pH of 4.0.
o The second modification is at the A21 position, asparagine is replaced by
glycine.
o This substitution prevents deamination and dimerization that would occur
with acid – sensitive asparagine.

Structures of basal insulins

 When insulin glargine is injected into subcutaneous tissue , which is at physiologic

pH, the acidic solution is neutralized , leading to formation of micro precipitates from
which small amounts of insulin glargine are slowly released , resulting in a relatively
constant concentration / time profile over 24 hours with no pronounced peak which
allows once daily dosing .
 The biological action of insulin glargine is due to its absorption kinetics and not a
different pharmacodynamics activity (eg: stimulation of peripheral glucose uptake)
 Insulin glargine should not be mixed in the same syringe, with any another insulin or
solution because this will alter its pH and thus affect its absorption profile
 Re-suspension of the vial prior to administration is not required as insulin glargine is
a clear solution.
 Insulin glargine has been shown to have less nocturnal hypoglycaemia when used at
bedtime compared with NPH insulin
  Insulin glargine is indicated as a once daily subcutaneous injection to provide basal
glycaemic control in adults and children aged >2 years with T1DM (EMA) and in
adults with T2DM.

Time action profile of insulins

Insulin Detemir
 A long acting human insulin analogue clinically used to maintain the basal insulin
level.
 A fatty acid (myristic acid) is bound to the lysine amino acid at position B29
 After SC injection, quickly absorbed in to blood after which, it binds to albumin in the
blood through the fatty acid at position B29 and dissociates slowly over time.
 It has reduced HbA1c to target level of 7.0% in 70% of patients, similar to human
basal insulin NPH, but without the same hypoglycaemic risk and less weight gain.
 Limitations :
o Has to be administered twice daily for effective glycaemic control
o Has to be administered at higher doses than glargine for similar glycaemic
control.

Insulin Degludec
 A long acting insulin analogue , used as a basal insulin approved for use in
Europe in 2013
 Threonine in position B30 has been omitted, and a C16 fatty acid chain has
been attached to the amino acid B29 using a glutamic acid spacer.
 The pharmaceutical formulation of insulin degludec contains phenol. Once
the phenol in the pharmaceutical formulation has dispersed after
subcutaneous injection, the acyl side chain causes insulin degludec to self-
associate, forming large soluble multihexamers ; creating a subcutaneous
depot. These multihexamers slowly dissociate in to monomers and diffuse in
to the blood stream at a slow and steady rate. This provides a long duration
of action (~ 42 hours)
 Limitations :
o Very long duration of action may cause problems in dose titration
o Higher cost and Availability only in disposable pen