Premixed analog insulin: What is the tradeoff between convenience and achievement of target HbA1c?
Achievement of euglycemia requires regimens that control fasting and postprandial glucose.
The natural course of type 2 diabetes involves progressive loss of beta cell function and subsequent loss of glycemic control with oral antidiabetic drugs.
Options for initiating insulin include treatment with either an intermediate- or long-acting basal insulin as monotherapy or a combination of basal-bolus insulin available in various premixed insulin formulations. Although the Treat to Target study showed that patients could achieve the American Diabetes Association target of HbA1c <7% by adding basal insulin once daily, other researchers have asserted that addition of bolus insulin to a basal regimen can enable additional patients to achieve target blood glucose through improved control of postprandial glucose.
A physiologic regimen would require multiple daily injections, but patients are often reluctant to administer the three to four shots per day that would constitute an intensive insulin regimen. In addition, the risk of hypoglycemia with intensive regimens is increased. A common and patient-accepted approach is the use of twice daily injections of a premixed biphasic or dual-acting insulin. This offers the convenience of only twice daily insulin injection and avoids administration errors inherent in mixing separate insulins or giving two separate prandial injections.
Early premixed insulin formulations combined neutral protamine hagedorn with regular human insulin in a 70/30 proportion (70% neutral protamine hagedorn, 30% regular; Humulin 70/30). This is a stable combination and ensures that the regular insulin will not be affected by mixing with neutral protamine hagedorn. Although this provides the convenience of a basal-bolus regimen, it has the disadvantages of a prolonged time to peak (one to five hours) and long duration of action (six to 10 hours) of the regular component.
June Felice Johnson
Patients need to inject this at least 30 minutes before a meal, though some studies show that they often do not comply and administer this formulation either immediately before or even after meals. Due to the longer duration of action, patients also need to monitor themselves closely for hypoglycemia, making this a less-than-ideal prandial formulation.
The advent of the rapid-acting analogues allowed premixed insulins to be administered more conveniently, within 15 minutes of a meal, and to more closely match their peak onset to postprandial glucose excursions. The two premixed insulin analogue formulations are: insulin lispro 75/25 (75% lispro protamine suspension, 25% lispro; Humalog Mix) and biphasic insulin aspart 70/30 (70% neutral protamine aspart, 30% aspart; NovoLog Mix).
The question providers might ask is does the convenience and patient acceptability justify the glycemic control achieved with a less-than-physiologic premixed regimen?
Studies show support
Studies have shown that lispro 75/25 reduces peak glucose levels to a greater degree than either human insulin 70/30 or neutral protamine hagedorn insulin. Improved postprandial control with the lispro premix is attributed to its rapid absorption rate and faster appearance of insulin with the premix compared to human insulin 70/30 over the first 120 minutes after a meal. One study found that 42% of patients receiving lispro 75/25 achieved HbA1c <7% compared to only 18% of patients receiving glargine and metformin.
Researchers with one of the more important recent clinical trials, INITIATE, randomized 233 insulin-naive patients with type 2 diabetes who were on oral antidiabetic drugs to either glargine at bedtime or BIAsp (Novolog Mix) 70/30 twice daily for 28 weeks. Initial mean HbA1c was 9.5% and 8.9% in the BIAsp group and the glargine group, respectively. Mean age of the patients was 52.6 and 52.3 in the BIAsp group and the glargine group, respectively.
Sixty-six percent of patients in the BIAsp group achieved the HbA1c <7% compared to 40% of those in the glargine group. Fewer patients in both groups achieved ACE targets of < 6.5%, with 42% and 29% of the BIAsp group and the glargine group achieving target, respectively. HbA1c reduction was greater (-2.79%) in the BIAsp group compared to the glargine group (-2.36%), especially for subjects with baseline HbA1c >8.5%. Minor hypoglycemia was reported by 43% and 16%, respectively, in the BIAsp group compared to the glargine group. The researchers concluded that twice daily BIAsp 70/30 was superior to glargine in achieving target HbA1c in patients failing oral antidiabetic drugs, especially in those with baseline HbA1c >8.5%.
However, it is noteworthy that 34% of subjects did not meet their ADA targets with BIAsp and would need more intensive and physiologic insulin regimens, such as addition of pre-lunch bolus insulin or a switch to separate basal and prandial bolus insulin, for optimal glycemic control.
Achievement of euglycemia requires regimens that control both fasting and postprandial glucose. Monnier et al has determined that postprandial glucose is predominantly responsible for hyperglycemia in mild to moderate (HbA1c <7.3%) hyperglycemia while fasting glucose is predominantly responsible for more severe hyperglycemia (HbA1c > 8.4%). The studies with the best control of glycemia used a treat-to-target approach and dosing algorithms to make frequent adjustments.
The premixed analog insulins have the advantage of more rapid onset, faster time to reach postprandial insulin levels, and thus better coverage of postprandial excursions. The unique formulation of BIAsp results in 30% of the aspart remaining soluble and contributes to improved postprandial control, flexible dosing, and fewer occurrences of hypoglycemia compared with conventional human premix insulin. Postprandial glucose regulation is increasingly acknowledged as critical to overall glycemic control and may confer additional benefit in reducing atherosclerosis.
The use of premixed pens is viewed positively by patients who appreciate the convenience of carrying insulin pens, experience less embarrassment in administration of insulin in a social setting, are less at risk for administration errors compared with mixing separate vials of insulin, and have the potential for better adherence with their regimen.
The use of premixed analogue insulins is a reasonable initial choice in patients with type 2 diabetes with mild to moderate hyperglycemia. However, providers should be aware that a proportion of patients on twice dialy premix will not be able to achieve target HbA1c and will have to be switched to more physiologic regimens for improved glycemic control.
June Felice Johnson, PharmD, FASHP, CDM, is the Director of Faculty & Site Development and Associate Professor of Pharmacy Practice at Drake University College of Pharmacy & Health Sciences, Des Moines, Iowa.
For More Information:
- Garber AJ. Premixed insulin analogues for the treatment of diabetes mellitus. Drugs. 2006;66:31-49.
- Halimi S, Raskin P, Liebl A, et al. Efficacy of biphasic insulin aspart in patients with type 2 diabetes. Clinical Therapeutics. 2005;27(Supplement B):S57-S74.
- Malone JK, Bai S, Campaigne BN, et al. Twice-daily pre-mixed insulin rather than basal insulin therapy alone results in better overall glycemic control in patients with type 2 diabetes. Diabet Med. 2005;22:374-381.
- Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients. Diabetes Care. 2003:26:881-885.
- Raskin P, Allen E, Hollander P, et al. Initiating insulin therapy in type 2 diabetes. Diabetes Care. 2005;28:260-265.
- Riddle MC, Rosenstock J, Gerich J. Randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26:3080-3086.