Insulin treatment and type 1 diabetes topics.

Insulin treatment Basal insulin. Malcolm Nattrass (Birmingham, U.K.) discussed basal insulin analogs, noting that the ideal approach will lead to “a flat profile that is reproducible.” The development of basal insulin began with protamine zinc insulin in 1936, followed by NPH insulin in 1946 and zinc insulins lente, semilente, and ultralente in 1951. All of these preparations have high variability, making them less than optimal for treatment. Natrass reviewed studies of persons given four injections of 0.4 units/kg NPH in the thigh, with measurement of the glucose infusion rate required to maintain euglycemia. Great variability in biologic activity was shown. Early strategies pursued with insulin analogs included changes in the isoelectric point leading to precipitation at pH 7.4 with NovoSol Basal (1) and strengthening hexamer formation with Co(III)-hexamer insulin. Neither strategy led to successful development of a commercial product. Subsequent research led to insulin glargine, which is stable and soluble in acidic solution, precipitating following injection into subcutaneous tissues. Compared with NPH, there is major improvement in variability comparable to that with continuous subcutaneous insulin infusion (CSII) and a considerably “flatter” action profile than seen with NPH. Another method involves acylation of the insulin molecule with hydrophobic residues. Insulin detemir has a myristic acid fatty acid side chain that strengthens self-association, leading to increased hexamer formation and to albumin binding at the injection site and in the circulation. The binding to albumin may buffer insulin action. Nattrass reviewed a number of studies of glargine and of detemir. In a study of 619 persons with type 1 diabetes, insulin glargine given at bedtime was associated with lower fasting glucose and with lower variability in fasting glucose level than NPH insulin given either once or twice daily (2). A similar 28-week study of 534 persons with type 1 diabetes showed reduction in HbA1c (A1C) from 7.7 to 7.5% for both insulin glargine and NPH, with greater fall in fasting glucose and with 40 vs. 49%, respectively, having nocturnal hypoglycemia with the agents (3). In a study of 394 type 1 diabetic persons receiving insulin glargine at bedtime or NPH insulin twice daily, fasting glucose again showed greater decrease with glargine, with 73 vs. 82% having at least one glucose 50 mg/dl and 36 vs. 46% having at least one glucose 36 mg/dl (4). In 756 type 2 diabetic persons, the “treat-to-target” approach was associated with similar lowering of fasting glucose to 120 mg/dl with both glargine and NPH, but again hypoglycemia was more frequent with NPH (5). Comparing NPH with detemir, mean glucose levels are similar but variability is less with the latter agent. Detemir also is associated with less weight gain and, in persons with type 1 diabetes, with weight loss, when compared with NPH. In a study of 54 persons with type 1 diabetes receiving four doses of NPH, glargine, or detemir, with 24-h glucose infusion, the coefficients of variation of glucose required to maintain euglycemia were 68, 48, and 27%, respectively, suggesting that the detemir may have the most predictable glucose-lowering effect. Nattrass commented that with regular insulin, “the tail of the conventional [regular] insulin lasted much longer and conceivably made a contribution to the basal insulin,” which is particularly a problem with long periods between meals, so that it may become difficult to “get away with a single injection” of basal insulin in persons receiving the shorter-acting insulin analogs, and many patients with type 1 diabetes require two basal doses. A number of studies of basal insulin analogs were presented at the ADA meeting. Hermansen and Tamer (abstract 271) analyzed results of treatment of 475 insulin-naı̈ve patients with type 2 diabetes with insulin detemir versus NPH twice daily, showing a BMI-related decrease in weight gain with detemir but not with NPH, with particular benefit of detemir in obese patients. Garber et al. (abstract 479) evaluated response to insulin detemir versus NPH among 418 and 890 persons aged 65 and 65 years, showing no difference in effect on A1C or fasting glucose but less weight gain and less variability of fasting glucose with insulin detemir. The likelihood of hypoglycemia was 40 and 23% lower with detemir than with NPH among the older and younger groups, respectively. Heller and Kim (abstract 487) and Kolendorf and Kim (abstract 489) compared hypoglycemia in 1,180 persons treated with detemir versus 810 receiving NPH insulin, showing that at every level of A1C, the frequency of hypoglycemia was lower with detemir versus NPH, 36 vs. 48% at A1C 7% and 26 vs. 34% at A1C 8%, with an overall reduction in risk of hypoglycemia of 39%. A number of studies addressed aspects of treatment with insulin glargine. Becker et al. (abstract 586) used the Biostator-supported euglycemic clamp in 24 nondiabetic men who were administered two preparations of 0.4 units/kg body wt glargine, finding that the coefficient of variation of the glucose infusion requirement was 18 and 32%. It would be interesting to see the degree of variability of detemir using this approach. Gerstein et al. (abstract 273) randomized 405 persons with type 2 diabetes and A1C 7.5% on up to two oral agents to either the addition of insulin glargine or to optimization of the oral regimen, showing more rapid and greater improvement in A1C and greater reduction in triglyceride and non-HDL cholesterol levels with glargine. Fiallo-Scharer et al. (abstract 1879) compared 45 children mixing insulin glargine with a rapid-acting insulin ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●