This is the first prospective randomized trial to compare the use of insulin analogs and human insulins both during acute intravenous treatment and during the transition to subcutaneous insulin in patients with DKA. During the initial treatment phase, we observed no differences in the mean duration of treatment or in the amount of intravenous insulin administration until resolution of DKA between regular and glulisine insulin. After resolution of ketoacidosis, the transition to subcutaneous glargine and glulisine insulin resulted in glycemic control similar to that for NPH and regular insulin; however, treatment with glargine and glulisine insulin is safer and is associated with a significantly lower rate of hypoglycemia. A total of 14 patients (41%) treated with NPH and regular insulin and 5 patients (15%) in the glargine and glulisine group had one or more episodes of hypoglycemia (P < 0.03).
The comparable response to intravenous glulisine and regular insulin during the acute resolution of DKA in this study is in line with previous reports of generally equal efficacy and in vivo potency of intravenous rapid-acting insulin analogs (glulisine, aspart, and lispro) and regular insulin in animal and human studies (15
). Pharmacokinetics and pharmacodynamic studies comparing the intravenous administration of glulisine and regular insulin have shown a similar onset of action within 20 min, a similar distribution and elimination profile, and equivalent glucose utilization and disposal on a molar, unit-per-unit basis (16
). The present study confirms these observations and provides evidence of the equal efficacy and in vivo potency of intravenous rapid-acting insulin analogs and regular insulin in patients with severe hyperglycemia and ketoacidosis. Their comparable in vivo potency is attributable to their similar receptor binding affinity and receptor-mediated clearance (18
). Our study and these previous reports indicate that treatments with intravenous glulisine and regular insulin are equally safe and efficacious in the acute management of patients with DKA. However, intravenous regular insulin is more cost-effective and should be preferred over rapid-acting insulin analogs during the acute intravenous treatment phase of DKA.
Previous randomized studies in patients with DKA have focused on the amount and route of insulin administration during the acute resolution phase of ketoacidosis (2
). Few studies, however, have focused on the transition period to subcutaneous insulin after the resolution of DKA. Accordingly, in this study we aimed to compare differences between treatment with basal bolus insulin analogs and NPH and regular insulin after resolution of DKA. We found no differences in the daily glucose concentration between treatment groups; however, patients treated with NPH and regular insulin had higher rates of hypoglycemia (41%) than subjects treated with basal bolus (15%) insulin (P
< 0.03). The rate of hypoglycemic events in this study is similar to the rate reported previously with the use of NPH and regular insulin after discontinuation of intravenous therapy (3
The higher rate of hypoglycemia with human insulins is explained by the pharmacological features and peak duration of action of NPH and regular insulin (10
) as well as the high day-to-day variability in absorption (11
). NPH has an onset of action ranging between 2 and 4 h, a peak concentration of ~6–8 h, and a duration of action up to 20 h (19
). Regular human insulin has an onset of action in 30 min, peaks at 2–3 h when given subcutaneously, and has a duration of action of 6–8 h (19
). The combination of basal and rapid-acting insulin analogs represents a more physiological approach to glucose control in the hospital. Glargine is a peakless, long-acting basal insulin with an onset of action of ~2 h, a plateau of biological action at 4–6 h, and duration of action up to 24 h (20
). Glulisine has a faster onset of action and a shorter duration of action after subcutaneous injection compared with regular insulin (21
). In agreement with these results, we recently reported that a basal bolus algorithm with glargine and glulisine is an effective intervention for glucose control with a low rate of hypoglycemic events (3%) in hospitalized patients with type 2 diabetes (14
). More recently, we reported that 38% of hospitalized patients treated with a combination of NPH and regular insulin experienced one or more episodes of blood glucose <70 mg/dl during the hospital stay (23
). Minimizing the rate of hypoglycemia events is of major importance in hospitalized patients because it may represent an independent risk factor of poor clinical outcome (24
We acknowledge several limitations in our study, including a relatively small number of patients and the fact that the large majority of patients were African Americans with poor adherence to therapy as the primary precipitating cause of DKA. We also excluded patients with hypovolemic shock, patients in a comatose state, and patients who had acute myocardial ischemia, congestive heart failure, end-stage renal or hepatic failure, or pregnancy. A large prospective, randomized clinical trial of strict glycemic control is certainly needed to address these important issues.
In summary, our study indicates that intravenous treatments with regular insulin and glulisine insulin are equally effective with no differences in the mean duration of treatment or in the amount of insulin infusion until resolution of DKA. After resolution of DKA, transition to subcutaneous glargine once daily and glulisine before meals resulted in similar glycemic control but in a lower rate of hypoglycemic events than treatment with NPH and regular insulin twice daily. These findings indicate that a basal bolus insulin regimen with glargine and glulisine is safer and should be preferred over NPH and regular insulin after the resolution of DKA.