Insulin Analogs or Premixed Insulin Analogs in Combination With Oral Agents for Treatment of Type 2 Diabetes

Philip Levy, MD, FACE

Disclosures

April 16, 2007

Insulin Formulations: Human Insulins vs Insulin Analogs

The aim of insulin administration in patients with diabetes is to mimic normal physiologic secretion of insulin to control both FPG and PPG.[34] Human insulin formulations have been used extensively for the treatment of type 1 or 2 diabetes, but their utility for achievement of tight glycemic control is limited; that is, their pharmacokinetic/pharmacodynamic profiles do not mimic the physiologic profile of insulin secretion found in individuals without diabetes. Regular human insulin (RHI), for example, is used to control PPG, but it is slowly absorbed, necessitating dosing 30-45 minutes before meals. RHI is also cleared slowly from the circulation, which increases risk of hypoglycemia between meals. For basal insulin replacement, the intermediate-acting neutral protamine Hagedorn (NPH) is often used. NPH is a human insulin that has a distinct peak in action that increases the risk of hypoglycemia. Two or more injections of NPH are required for adequate basal 24-hour coverage. In addition, both RHI and NPH exhibit considerable variability in absorption. This variability is apparent between patients, but more importantly, variation also occurs within the same individual.[35,36,37] This variation means that, when giving identical doses of subcutaneous insulin injections -- even at the same dose, site of injection, time of day, with controlled dietary intake and physical activity -- different and unpredictable glycemic effects can result.[37] The time-action profiles of human insulin formulations can therefore result in insulin effects that do not match the glucose demand or the patient's needs.[38]

New insulin analogs and premixed insulin analogs have overcome some limitations of human insulins. Three rapid-acting analogs (insulin lispro, aspart, and glulisine), 2 long-acting insulin analogs (insulin glargine and insulin detemir), and 3 premixed insulin analogs (biphasic insulin aspart 70/30, insulin lispro 75/25, and insulin lispro 50/50) are currently available in the United States ( Table 3 ).[39]

Compared with RHI, rapid-acting insulin analogs show faster absorption, more rapid onset of activity, and a shorter duration of action.[39,40] These pharmacokinetic and pharmacodynamic improvements result in superior PPG control and decreased risk of hypoglycemia. In contrast to RHI, which must be administered at least 30 minutes before a meal, rapid-acting insulin analogs can be administered within 15 minutes before eating or even after a meal, thereby synchronizing insulin administration with food absorption and the associated increase in blood glucose.[41,42] They are also more convenient for patients with unpredictable meal times.

Long-acting insulin analogs are designed to provide up to 24-hour basal insulin levels with once- or twice-daily administration. Compared with previous intermediate- or long-acting human insulins, long-acting insulin analogs have relatively flat time-action profiles, and they also decrease the risk of nocturnal hypoglycemia.[39,41,42]

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