Insulin glargine (Lantus) was the first available long-acting human insulin analogue . Glargine is a clear solution and there is no need to thoroughly mix it before injection. Insulin glargine (21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin) differs from native insulin in that the 21 amino acid residue aspargine on the A chain has been substituted with a glycerine residue and 2 arginine residues have been added to the C terminus of the B chain, making glargine soluble in the acidic environment at pH of 4 . Glargine precipitates in the neutral pH of subcutaneous tissue, which prolongs its absorption to the blood. The addition of zinc as a hexamer-stabilising agent further prolongs the duration of action. Insulin glargine must not be mixed with other insulins .
Clamp studies in normal subjects and type 1 diabetic patients have confirmed that the duration of glargine is longer than NPH insulin and the action profile is flatter. Median duration of action is 23 h for glargine versus 14 h for NPH insulin, and during the first 12 h intra-individual variability of the absorption rate is lower with glargine . The pharmacokinetic suggests that glargine is more suitable than NPH human insulin to mimic the normal pattern of physiological basal insulin secretion.
Insulin glargine has been compared with NPH in type 2 patients. In theory, basal insulin supplementation with glargine offers the advantage of a simple once-daily injection regimen, which is easy to add to current oral glucose-lowering drugs.
In the "treat-to-target" studies glargine was administered once daily at bedtime and NPH was given once daily at bedtime or twice daily at bedtime and in the morning in combination with sulfonylurea (glimepiride)[14-19]. The overall conclusions from the studies are that the reduction in HbA1c was similar in the glargine and NPH groups and that the number of patients reaching the target of HbA1c <7.0% was not different. The fasting blood glucose was lower in the glargine groups than in the NPH groups. Except for one of the studies, comparing either bedtime or morning glargine versus bedtime NPH insulin, significantly more patients reached an HbA1c <7.5% with morning glargine than with bedtime glargine and bedtime NPH insulin . In another study there was no difference in the reduction in HbA1c between morning and bedtime administration of glargine and similar proportion of patients achieved HbAlc <7.0 at the end of the study period .
In a recent 36-weeks study glargine or NPH insulin were combined with metformin . HbAlc decreased similar values in the two groups, but the incidence of hypoglycaemia was lower in the glargine group the first 12 weeks of treatment. Thereafter, no difference was observed between the two treatments.
Treatment with glargine has also been compared with biphasic premix insulin. Once-daily morning glargine added to OADs induced a greater reduction in HbAlc and fasting blood glucose than twice-daily biphasic human premix (30% regular and 70% NPH) alone . In three other studies, which are discussed later in detail, glargine once daily compared with twice-daily biphasic premix lispro (Mix 25) or biphasic premix aspart (BIAsp 30). The reduction in HbAlc was greater in the premix groups [23-25].
In 518 type 2 patients on basal-bolus regimen with glargine at bedtime plus a rapid acting analogue before meals or NPH once or twice daily in combination with fast-acting human insulin before meals , a similar HbAlc level was achieved in the two groups, and the decrease in fasting blood glucose and the number of hypogly-caemic episodes were the same.
The glargine studies (treat-to-target) are very important landmark studies. The studies illustrate for the first time the importance of using a forced titration algorithm to optimise glycaemic control. The treat-to-target studies have shown that it is possible to obtain HbAlc below 7.0% in approximately 50% of subjects with type 2 diabetes using one injection and one blood glucose measurement per day.
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