INDICATIONS

• Type 1 diabetes mellitus (T12DM)
• Type 2 diabetes mellitus (T2DM)
• NPH/regular pre-mixed insulin: Gestational diabetes mellitus (GDM)

MECHANISM

• Pre-mixed insulins combine, in the vial, a short-acting insulin (Regular) or fast-acting analog, with an intermediate acting insulin (NPH) or long-acting insulin analog.
• Insulin promotes glucose uptake into muscle and fat, and protein synthesis. Reduces hepatic glucose output. Inhibits lipolysis and protein breakdown.
• Pre-mixed insulin covers the increasing glucose after a meal as well as a longer between-meal insulin coverage.
• NPH and Regular insulin mix physically combines the NPH with Regular insulin; the analog mixes combine the fast-acting preparation with a protomine-modified longer acting insulin.

USUAL ADULT DOSING

• TDD = total daily dose; U = units of insulin; SQ = subcutaneously
• For NovoLog Mix 70/30, Humalog Mix 75/25, and Humalog Mix 50/50: initiate treatment with one injection SQ every 24 hrs, given 0-15 minutes before the biggest meal of the day. Then increase to two injections per day, the first one 0-15 minutes before breakfast, and the second 0-15 minutes before dinner.
• For NPH/regular pre-mixed insulin: administer 30 mins before breakfast and 30 minutes before dinner.
• T1DM: typical initial TDD is 0.2 U/kg/day. Maintenance TDD typically ranges from 0.2-0.5 U/kg/day, or more. Most patients are maintained on at least two injections per day.
• Type 2 Diabetes: typical initial TDD is either 10 U or 0.2 U/kg/day. Maintenance TDD typically exceeds  1 U/kg/day or more, depending on the degree of insulin resistance. Most patients are maintained on at least two injections per day.
• Weight-based dosing will require further adjustment based on the patient's glycemic response.
• If two daily injections do not provide adequate glycemic control, consider adding a rapid acting insulin analog (e.g. aspart, lispro, or glulisine) 0-15 mins before lunch.

FORMS

*Costs (rounded to the nearest dollar) are based on usual adult dosing per day, are representative of "Average Wholesale Price" (AWP), and are current within the prior three months.

^Dosage is indicated in mg unless otherwise noted.

DOSING IN SPECIAL POPULATIONS

• Dose reductions may be needed since insulin is excreted by the kidneys, and may have a longer half life in patients with renal impairment.

• Dose reductions may be needed since insulin is metabolized by the liver and patients with liver disease may have impaired gluconeogenesis. 

• NPH/regular (Novolin 70/30 and Humulin 70/30): FDA category B. However, this is the only pre-mixed insulin preparation that has received FDA approval for use in treating GDM.
• NovoLog Mix 70/30: FDA category C
• Humalog Mix 75/25 and Humalog Mix 50/50: FDA category B

• Maternal insulin requirements may decrease during breastfeeding due to effective increased caloric expenditure.
• NPH/regular (Novolin 70/30 and Humulin 70/30): unknown
• NovoLog Mix 70/30: infant risk cannot be ruled out (Thomson Lactation Ratings)
• Humalog Mix 75/25 and Humalog Mix 50/50: infant risk cannot be ruled out (Thomson Lactation Ratings)

ADVERSE DRUG REACTIONS

• Hypoglycemia, especially if meals are skipped or activity is increased
• Weight gain

• Local injection site reactions (redness, itching, swelling)
• Lipodystrophy at injection site (to avoid, rotate sites frequently)

• Immune hypersensitivity reactions
• Hypokalemia

DRUG INTERACTIONS

• Any drug which also lowers blood glucose (e.g. sulfonylureas), when used in a patient on insulin, could result in additive hypoglycemia.

PHARMACOKINETIC

Tables/Images

COMMENTS

• The pre-mixed insulin analogs (NovoLog Mix and Humalog Mix) have a similar action profile to NPH/regular pre-mixed insulin EXCEPT with a more rapid onset of action and higher peak insulin levels. Thus, the pre-mixed insulin analogs are more effective at controlling post-prandial blood glucose spikes than pre-mixed NPH/regular insulin.
• Adding protamine to the rapid acting insulin analogs (aspart and lispro) prolongs their action, and the resulting protaminated insulins (aspart protamine insulin and lispro protamine insulin) take on a pharmacokinetic insulin profile similar to NPH insulin.
• Given the rapid onset of the analog pre-mixed insulin, it should be given shortly before a meal is ingested, and not at bedtime.
• Given the longer-action of the protaminated component, the pre-supper insulin may cause overnight lows, in which case fast-acting insulin only at suppertime and longer acting insulin at bedtime is necessary.
• Pre-mixed insulin regimens (which typically require 2 injections per day) are best suited for patients who decline to use the more physiologic basal-bolus insulin regimens (which require up to 4 injections per day).
• Patients who choose to use the pre-mixed insulin preparations should have fairly routine lifestyles (eat regular meals consistently around the same times each day, and do not skip meals).
• Patients with highly variable or unpredictable lifestyles (skipping meals, exercising at different times, large variations in meal types and quantities) may be better treated using basal-bolus insulin regimens
• Patients may prefer using insulin pens (disposable, reusable, and with replaceable insulin cartridges) but  insulin pen needles must be prescribed and purchased separately, as they do not come packaged with the insulin pens. Refer to the "FORMS" table above to see which pre-mixed insulin preparations are available in pen form.
• Evidence  is inconsistent in randomized trials as to whether basal alone, prandial alone or premixed insulins are more effective (Holman) (Lasserson). 

References

1. Holman RR, Farmer AJ, Davies MJ, et al.; Three-year efficacy of complex insulin regimens in type 2 diabetes.; N Engl J Med; 2009; Vol. 361; pp. 1736-47;
   ISSN: 1533-4406;
   PUBMED: 19850703
   Comments:In this open-label, multicenter trial, 708 patients who had suboptimal HbA1c levels while taking metformin and sulfonylurea therapy were randomly assigned to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). After 3 years, the median HbA1c level was 6.9% (no statistical difference between the groups). However, fewer patients had a HbA1c < 6.5% in the biphasic group (31.9%) than in the prandial group (44.7%, P=0.006) or in the basal group (43.2%, P=0.03). Thus, more patients who added a basal or prandial insulin-based regimen to oral therapy were able to achieve HbA1c < 6.5% than those who added a biphasic insulin-based regimen.
   
   
2. Lasserson DS, Glasziou P, Perera R, et al.; Optimal insulin regimens in type 2 diabetes mellitus: systematic review and meta-analyses.; Diabetologia; 2009; Vol. 52; pp. 1990-2000;
   ISSN: 1432-0428;
   PUBMED: 19644668
   Comments:Found significantly greater reduction in HbA1c in patients with type 2 diabetes when insulin treatment was initiated using a biphasic or prandial insulin rather than basal insulin alone.
   
   
3. Garber AJ; Premixed insulin analogues for the treatment of diabetes mellitus.; Drugs; 2006; Vol. 66; pp. 31-49;
   ISSN: 0012-6667;
   PUBMED: 16398567
   Comments:Thorough review of the premixed insulin analogs, including their development, pharmacokinetics, efficacy, dosing regimen considerations, and comparison to more traditional insulins.
   
   
4. Rolla AR, Rakel RE; Practical approaches to insulin therapy for type 2 diabetes mellitus with premixed insulin analogues.; Clin Ther; 2005; Vol. 27; pp. 1113-25;
   ISSN: 0149-2918;
   PUBMED: 16199240
   Comments:Suggestions for initial dosing regimens and subsequent dosage titrations, including titration parameters, when using premixed insulin analogs.
   
   
5. Rubin RR, Peyrot M; Quality of life, treatment satisfaction, and treatment preference associated with use of a pen device delivering a premixed 70/30 insulin aspart suspension (aspart protamine suspension/soluble aspart) versus alternative treatment strategies.; Diabetes Care; 2004; Vol. 27; pp. 2495-7;
   ISSN: 0149-5992;
   PUBMED: 15451924
   Comments:In this study of the delivery device used with a premixed insulin analog (NovoLog 70/30), insulin pens were overwhelmingly preferred over conventional insulin syringes with vials; patients reported significant improvements in their quality of life with the pens, citing convenience and flexibility.
   
   

RELATED MODULES

• Introduction to Diabetes
• Type 2 Diabetes: Sequencing Therapies