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Clinical studies have shown that these properties lead to less prominent peaks of glucose after meals and less late postprandial hypoglycemia (74-91). However, rapid waning of the effects of mealtime analogue insulin leads to greater dependency on adequate basal insulin levels between meals and overnight.

The intermediate-acting insulins, NPH and lente, have gradual onset and the peak effects is usually between 4 and 8h, with a total duration of 10 to 16 h. Human ultralente insulin is somewhat longer acting, but still usually falls short of a 24-h effect. NPH and lente, have pronounced peaks of action and ultralente is thought to have substantial day-to-day variation with erratic peaks. These limitations cause variations of glucose levels and unpredictable hypoglycemia which are the leading factors limiting glycemic control at the present time. Indeed the lack of reproducibility in glucose-lowering effects of conventional basal insulin preparations, including NPH and ultralente, has been a major limitation for most insulin regimens.

There has been a growing need for reliable long-acting basal insulin that would mimic normal pancreatic basal insulin secretion to control hepatic glucose production in the postabsorptive state. Clinical use of the rapid acting insulin analogues (lispro, aspart or glulisine) has directed attention to the properties of extended-release human insulins that have been used to provide basal insulin replacement. Human NPH, lente, and ultralente insulin all have mean durations of action of less than 24 h, precluding them from providing adequate basal insulin replacement for many patients. All three, but especially NPH and lente, have pronounced peaks of action. Ultralente is thought to have substantial day-to-day variation of action. These limitations cause variations of glucose levels and unpredictable hypoglycemia, which are the leading factors limiting glycemic control at the present time. Indeed the lack of reproducibility in glucose-lowering effects of conventional basal insulin preparations, including NPH and ultralente, has been a major limitation for most insulin regimens.

The first insulin analogue with a prolonged duration of action that approaches 24 h, thus possibly dosed once daily, that became available for clinical use is insulin glargine (65). Insulin glargine results from two modifications of human insulin: a substitution of glycine at position A21 and the addition of two positive charges (two arginine molecules) at the C terminal of the B chain. Changes in amino acid content shift the isoelectric point, reducing the aqueous solubility of insulin glargine at physiologic pH and stabilizing the hexamer, delaying its dissociation into monomers. It is released gradually from the injection site and because of the delay in absorption its action is prolonged, allowing a relatively constant basal insulin supply. However, because insulin glargine is formulated as a clear acidic solution, it cannot be mixed with insulin formulated at a neutral pH, such as regular insulin. Studies have demonstrated no variation in absorption rates at various injection sites (arm, leg, abdomen) (92).

Glucose-insulin clamp studies have compared the actions of insulin glargine with those of NPH and ultralente (93-96). These studies have found that insulin glargine, compared with the other insulins provides an essentially flat profile with a longer duration for about 15 to 24 h (Fig. 4). The duration of action of insulin glargine is a function of the dose delivered. When used as a basal insulin in treating type 1 diabetes, because of the low doses required, insulin glargine may not have a long enough duration of action and thus may need to be given in a twice daily regimen (97-99). Clinical trials have shown improvements in glycemic control similar to NPH, with a slightly lower frequency of nocturnal hypoglycemia (100-106). Use of the flat or peakless insulin glargine profile now allows for a more vigorous titration regimen and more patients can reach target A1c levels with considerable less risk of nocturnal hypoglycemia (5).

Insulin Detemir is another long acting analogue that is available for clinical use (65). The principle for the longer duration of acting is based on covalent acylation of the epsilon amino group of Lys B29. This modification promotes reversible binding of insulin to albumin thereby delaying its resorption from subcutaneous tissue and also, possibly because of size, reducing the rate of transendothelial transport (107). The myristoyl fatty acid side chain at the C terminus of the B-chain does not alter aggregation properties of the molecule. NN304 has a slower disappearance rate from subcutaneous tissue and a much flatter time-action profile than NPH (108). The time action profile is very similar to that found with insulin glargine. When used as basal insulin in treating type 1 diabetes, because of the low doses required, insulin detemir may need to be given in a twice daily regimen. However, in the treatment of type 2 diabetes, the doses of basal insulin are typically high enough that both glargine and detemir can usually be dosed once daily.

In a 6-week crossover study, 59 patients with type 1 diabetes who were given NPH once daily before bedtime plus pre-meal soluble human insuli, titrated to achieve equivalent glycemic control, required a two-fold to three-fold higher dose than those given NPH in the same way (109). However, while some studies observe a need for higher doses of "basal" insulin with the use of insulin detemir, it has not been a consistent finding (110-112). In a long-term safety study, where insulin detemir or NPH were used as part of basal-bolus therapy for 252 patients with type 1 diabetes, they found similar improvement in A1cs with comparable rates of hypoglycemia but no weight gain in the group that received detemir (113).

Comparison of the use of twice daily insulin detemir with once daily glargine in 320 subjects with Type 1 diabetes showed that after 26 weeks, the two groups had similar glycemic control with similar weight gain (Fig. 5). The overall risk of hypoglycemia was comparable, whereas the risks of both severe and nocturnal hypoglycemia were significantly lower with insulin detemir (114). Studies in subjects with type 2 diabetes have shown similar decreases in A1c with the addition of insulin detemir or NPH insulin however, with insulin detemir more people achieved an A1c < 7.0%, the risk for all hypoglycemia was lower and mean weight gain was lower (110).

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