In another recent multicenter trial, 695 patients were randomized to 24 weeks of treatment with glimepiride plus 1 of 3 insulin regimens: morning insulin glargine, bedtime insulin glargine, or bedtime NPH insulin.36 Mean A1C levels decreased by 1.24% with morning glargine, 0.96% with bedtime glargine, and 0.84% with bedtime NPH. The percentage of patients achieving an A1C of ≤7.5% was 43% with morning glargine, 33% with bedtime glargine (P=.021 vs morning glargine), and 32% with bedtime NPH (P=.017 vs morning glargine). The percentage of patients who experienced nocturnal hypoglycemia was 17% with morning glargine, 23% with bedtime glargine, and 38% with bedtime NPH (P=.001 vs both glargine regimens). Finally, the percentage of patients who experienced symptomatic hypoglycemia was 56% with morning glargine (P=.004 vs bedtime glargine), 43% with bedtime glargine, and 58% with bedtime NPH (P=.001 vs bedtime glargine).
FIGURE 3 Treat-to-Target Trial: Rapid achievement of A1C goal
Practical aspects
Most commonly, insulin (Table 2) is introduced when single- or multipleagent oral therapy has failed to maintain glycemic control. Insulin may be added to existing oral therapy or, less typically, used as monotherapy. Of the 3 available insulins that have been used for basal therapy (NPH insulin, insulin glargine, and ultralente [insulin zinc extended]), ultralente may not be ideal since considerable variation has been noted in its pharmacokinetic and pharmacodynamic effects.37 Either NPH or glargine can be started at a dose of 10 U, at bedtime, while oral agents are continued at previous dosages. To provide 24-hour coverage, NPH may be needed twice daily whereas a single dose of glargine usually provides 24-hour coverage when administered at the same time each day.38 Patients usually need a total daily basal insulin dose of 0.5 to 0.6 U/kg (typically about 45 U daily for a 100-kg person).39 The dose may be adjusted weekly according to the patient’s FPG level.
Cost is a consideration in insulin therapy. Although more expensive than NPH, basal glargine is associated with 25% fewer episodes of nocturnal hypoglycemia, improved postdinner control, and slightly less weight gain.31,40 A retrospective review of medical and pharmacy claims demonstrated that considerable direct costs result from treatment of hypoglycemia associated with antidiabetic therapy, suggesting that therapies with less potential for inducing hypoglycemia would likely reduce these costs.41
The intensive insulin titration schedule used in the Treat-to-Target Trial is shown in Table 3. In clinical practice, a somewhat less intensive approach may work well. For example, the dose may be increased weekly by 4 U if the FPG level is >140 mg/dL on 3 consecutive occasions, or by 2 U if the FPG level is 120 to 140 mg/dL on 3 consecutive occasions.
Insulin glargine should not be mixed in the same syringe with other insulins as the pharmacokinetic profile may be altered. In the case of NPH, careful rolling or turning of the vial prior to injection to fully resuspend the crystals is advisable to minimize the variability of effect that may otherwise occur. Glargine, as with the regular and rapid-acting insulin analogues lispro and aspart, is a clear solution that does not need to be resuspended before administration. The addition of rapid-acting insulin analogues prandially to a regimen of basal insulin or basal-bolus therapy can be used to more closely mimic physiologic insulin secretion and may be needed when basal insulin replacement alone is insufficient to reach target levels of glycemic control.4
TABLE 2
Insulin formulations
| Insulin* | Onset | Peak | Effective duration (h) |
|---|---|---|---|
| Rapid-acting | |||
| Lispro | 5–15 min | 30–90 min | 5 |
| Aspart | 5–15 min | 30–90 min | 5 |
| Short-acting | |||
| Regular U100 | 30–60 min | 2–3 h | 5–8 |
| Regular U500 | 30–60 min | 2–3 h | 5–8 |
| Intermediate-acting | |||
| Isophane insulin (NPH) | 2–4 h | 4–10 h | 10–16 |
| Insulin zinc | 2–4 h | 4–12 h | 12–18 |
| Long-acting | |||
| Insulin zinc extended | 6–10 h | 10–16 h | 18–24 |
| Insulin glargine | 2–4 h† | No pronounced peak | 20–24 |
| Premixed | |||
| 70% NPH/30% regular | 30–60 min | Dual | 10–16 |
| 50% NPH/50% regular | 30–60 min | Dual | 10–16 |
| 75% NPL/25% lispro | 5–15 min | Dual | 10–16 |
| 70% NP/30% aspart | 5–15 min | Dual | 10–16 |
| *Assuming 0.1–0.2 U/kg per injection; onset and duration may vary by injection site (except for insulin glargine). | |||
| †Time to steady state. | |||
| NPH = neutral protamine Hagedorn; NPL = neutral protamine lispro; NP = neutral protamine. | |||
| Adapted from DeWitt and Hirsch.4 | |||
TABLE 3
Basal insulin: Initiation and dosage adjustment
| Forced titration schedule | |||
|---|---|---|---|
| |||
| Self-monitored FPG (mg/dL) | Dosage increase (IU/day) in Treat-to-Target Trial | ||
| ≥180 | 8 | ||
| ≥140 – <180 | 6 | ||
| ≥120 – <140 | 4 | ||
| >100 – <120 | 2 | ||
| *No increase if plasma glucose is <72 mg/dL in the preceding week; decrease dosage (2–4 IU/day) if plasma glucose is <56 mg/dL or severe hypoglycemia (requiring assistance) occurred within the preceding week. | |||
| FPG = fasting plasma glucose. | |||
| Adapted from Riddle et al.32 | |||
Summary
New evidence and methods continue to alter management of patients with type 2 diabetes. Appropriate screening and earlier intervention may help reduce the incidence and progression of microvascular and macrovascular complications. A multifactorial approach that addresses such risk factors as blood pressure, lipids, and glycemia has demonstrated reduced morbidity and mortality. While glycemic targets are getting lower, they can be efficiently attained with combined basal insulin and oral antidiabetic therapy. Insulin, too often considered a therapy of last resort, is an important intervention that can be used safely and effectively earlier in the course of type 2 diabetes.