Medications> Glucose-lowering>

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

*Prices represent cost per unit specified and are representative of "Average Wholesale Price" (AWP). AWP Prices were obtained and gathered by Lakshmi Vasist Pharm D using the Red Book, manufacturer's information, and the McKesson database.

^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

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

RELATED MODULES

• Introduction to Diabetes
• Type 2 Diabetes: Sequencing Therapies