Humalog Mixes
Humalog Mix75/25 and Humalog Mix50/50 are mixtures of insulin lispro protamine, an intermediate-acting human insulin analog, and insulin lispro, a rapid-acting human insulin analog indicated to improve glycemic control in patients with diabetes mellitus.
The proportions of rapid-acting and intermediate-acting insulins in Humalog Mix75/25 and Humalog Mix50/50 are fixed and do not allow for basal versus prandial dose adjustments.
Select Important Safety Information
Humalog, Insulin Lispro Injection, Humalog Mix75/25, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, and Humalog Mix50/50 are contraindicated during episodes of hypoglycemia and in patients who are hypersensitive to these insulins or any of their excipients.


Efficacy of Humalog Mix75/25
In three studies of adult patients with type 2 diabetes:
Humalog Mix75/25 provided improved glucose control.1,2,3
When added to metformin, Humalog Mix75/25 improved A1C1,2
- Two open-label, randomized, crossover trials compared the glycemic response of Humalog Mix75/25 BID + metformin with that of glargine QD + metformin1,2
See PAIR-IN and PAIR-PI study design and methods below.
Humalog Mix75/25 improved fasting blood glucose (FBG) and postprandial glucose (PPG) control3
-
A randomized, double-blind study with 3-way crossover compared Human Insulin 70/30, Humalog Mix75/25, and Humalog
Mix50/50™ after a standardized breakfast meal3
See study design and methods below.
Select Important Safety Information
Never share a Humalog, Insulin Lispro Injection, Humalog Mix75/25, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, or Humalog Mix50/50 prefilled pen, cartridge, reusable pen compatible with Lilly 3 mL cartridges, or syringe between patients as it poses a risk for transmission of blood-borne pathogens.
PAIR-IN: Design and methods1
- Humalog Mix75/25 BID plus metformin versus glargine QD plus metformin
- Open-label, randomized, crossover trial, 16 weeks on each treatment
- 105 insulin-naive patients with type 2 diabetes
- Mean age 55 years
- All randomized patients included in safety analysis
- 67 patients included in efficacy analysis (29 patients excluded because they may have received expired study drug)
- Baseline A1C: 8.7%
Primary endpoint
- Change in A1C over 16 weeks
Note: PAIR-IN average (standard deviation) daily dose of insulin was 0.62 (0.37) U/kg for Humalog Mix75/25 vs 0.57 (0.37) U/kg for glargine (P<.001).
PAIR-PI: Design and methods2
- Humalog Mix75/25 BID plus metformin versus glargine QD plus metformin
- Inadequately controlled patients with type 2 diabetes on once- or twice-daily insulin alone or in combination with oral agents
- 97 patients
- Open-label, randomized, crossover trial
Note: PAIR-PI average (standard deviation) daily dose of insulin was 0.42 (0.20) U/kg for Humalog Mix75/25 vs 0.36 (0.18) U/kg for glargine (P<.001).
The bar graph in this image shows A1C change from baseline in the PAIR-IN study, comparing treatment group Humalog Mix75/25 plus metformin and treatment group glargine plus metformin. The Y-axis shows change in A1C ranging from 0 to negative 1.5 percent. On the X-axis, the Humalog Mix75/25 plus metformin group demonstrated an A1C change of negative 1.3 percent. Patients in the glargine plus metformin treatment group demonstrated an A1C reduction from baseline of negative 0.9 percent.
MET=metformin
The bar graph in this image shows A1C change from baseline in the PAIR-PI study, comparing treatment group Humalog Mix75/25 plus metformin with treatment group glargine plus metformin. The Y-axis shows change in A1C by percentage. The bars on the X-axis depict an A1C reduction of 1.0 percent from baseline in the Humalog Mix75/25 plus metformin group. The glargine plus metformin-treated group showed a 0.42 percent reduction in A1C from baseline.
The bar graph in this image shows the percentage of patients in the PAIR-IN study who reached an A1C of less than or equal to 7 percent. Treatment groups were Humalog Mix75/25 plus metformin and glargine plus metformin. The Y-axis shows the percentage of patients reaching that A1C level, with values ranging from 0 to 100 percent. On the X-axis, 42 percent of patients in the Humalog Mix75/25 plus metformin treatment group reached an A1C of less than or equal to 7 percent. Eighteen percent of patients in the glargine plus metformin treatment group reached an A1C of less than or equal to 7 percent.
The bar graph in this image shows the percentage of patients in the PAIR-PI study who reached an A1C of less than or equal to 7 percent in two treatment groups: Humalog Mix75/25 plus metformin and glargine plus metformin. The Y-axis shows the percentage of patients reaching an A1C of less than or equal to 7 percent, with values ranging from 0 to 100 percent. On the X-axis, 30 percent of patients in the Humalog Mix75/25 plus metformin treatment group reached an A1C of less than or equal to 7 percent. Twelve percent of patients in the glargine plus metformin treatment group reached an A1C of less than or equal to 7 percent.
The bar graph in this image shows end-of-therapy mean fasting blood glucose (FBG) in the PAIR-IN study in two treatment groups: Humalog Mix75/25 plus metformin and glargine plus metformin. The Y-axis shows fasting blood glucose, ranging from 0 to 150 milligrams per deciliter. On the X-axis, a bar for the Humalog Mix75/25 plus metformin treatment group showed a mean FBG of 139.3 milligrams per deciliter at the end of therapy. In the glargine plus metformin treatment group, mean FBG was 123.9 milligrams per deciliter at the end of therapy.
The bar graph in this image shows end-of-therapy mean fasting blood glucose (FBG) control in two treatment groups in the PAIR-PI study: Humalog Mix75/25 plus metformin and glargine plus metformin. The Y-axis shows mean fasting blood glucose, ranging from 0 to 150 milligrams per deciliter. On the X-axis, the Humalog Mix75/25 plus metformin treatment group reported a mean FBG of 142.2 milligrams per deciliter at the end of therapy. Glargine plus metformin-treated patients reported a mean FBG of 133.0 milligrams per deciliter at the end of therapy.
Select Important Safety Information
Changes in insulin regimen (e.g. insulin strength, manufacturer, type, injection site, or method of administration) may affect glycemic control and predispose patients to hypoglycemia and hyperglycemia. Make changes cautiously with increased frequency of blood glucose monitoring.
The bar graph in this image shows overall rates of hypoglycemia in the PAIR-IN study reported in two treatment groups: Humalog Mix75/25 plus metformin and glargine plus metformin. The Y-axis shows mean rate of hypoglycemia episodes per patient per 30 days, ranging from 0 to 1.5. The X-axis presents bars for both treatment groups. The Humalog Mix75/25 plus metformin treatment group reported a mean hypoglycemia rate of 0.68 episodes per patient per 30 days. Glargine plus metformin-treated patients reported a mean hypoglycemia rate of 0.39 episodes per patient per 30 days.
The bar graph in this image shows overall rates of hypoglycemia in the PAIR-PI study reported in two treatment groups: Humalog Mix75/25 plus metformin and glargine plus metformin. The Y-axis shows the mean rate of hypoglycemia episodes per patient per 30 days, ranging from 0 to 1.5. The X-axis presents bars for both treatment groups. The Humalog Mix75/25 plus metformin treatment group reported a mean hypoglycemia rate of 0.61 episodes per patient per 30 days. Glargine plus metformin-treated patients reported a mean hypoglycemia rate of 0.44 episodes per patient per 30 days.
The bar graph in this image shows rates of nocturnal hypoglycemia in the PAIR-IN study reported in two treatment groups: Humalog Mix75/25 plus metformin and glargine plus metformin. The Y-axis shows mean rate of nocturnal hypoglycemia episodes per patient per 30 days, ranging from 0 to 1.5. The X-axis presents bars for both treatment groups. The Humalog Mix75/25 plus metformin treatment group reported a mean nocturnal hypoglycemia rate of 0.14 episodes per patient per 30 days. Glargine plus metformin-treated patients reported a mean nocturnal hypoglycemia rate of 0.24 episodes per patient per 30 days.
The bar graph in this image shows rates of nocturnal hypoglycemia reported in the PAIR-PI study in two treatment groups: Humalog Mix75/25 plus metformin and glargine plus metformin. The Y-axis shows mean rate of nocturnal hypoglycemic episodes per patient per 30 days, ranging from 0 to 1.5. The X-axis presents bars for both treatment groups. The Humalog Mix75/25 plus metformin treatment group reported a mean nocturnal hypoglycemia rate of 0.14 episodes per patient per 30 days. Glargine plus metformin-treated patients reported a mean nocturnal hypoglycemia rate of 0.34 episodes per patient per 30 days.
See PAIR-IN: Study Design and Methods Above for Humalog Mix 75/25
See PAIR-PI: Study Design and Methods Above for Humalog Mix 75/25
Select Important Safety Information
Severe hypoglycemia may be life threatening and can cause seizures or death. Hypoglycemia is the most common adverse effect of Humalog, Insulin Lispro Injection, Humalog Mix75/25, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, and Humalog Mix50/50 therapy. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia.
Humalog Mix75/25 improved fasting3 and postprandial4 glucose control
Design and methods
- Comparison of insulin formulations: Human Insulin 70/30, Humalog Mix75/25, and Humalog Mix50/50 after a standardized breakfast meal
- Study was randomized and double-blind, with 3-way crossover of the premixed insulins in patients with type 2 diabetes. A control group of subjects without diabetes underwent the standardized test meal with no insulin treatment
- After the test breakfast, glucose was measured for 4 hours
- 22 patients received a single dose of Human Insulin 70/30 before breakfast; 22 received Humalog Mix75/25; and 23 received Humalog Mix50/50. Ten subjects without diabetes received no insulin. One patient who received Human Insulin 70/30 before the test meal, followed by the usual dose of insulin lispro before lunch, reported symptoms of hypoglycemia that resolved with oral carbohydrate
This line graph presents pre- and postprandial serum glucose concentrations over time for the four treatment groups: human insulin 70/30 mix (n equals 22); insulin lispro 75/25 mix (n equals 22); insulin lispro 50/50 mix (n equals 23); and a control group of healthy volunteers who received no insulin (n equals 10). The Y-axis shows mean serum glucose concentration ranging from 0 to 250 milligrams per deciliter. The X-axis shows time (in minutes) after meal administration, with values ranging from 20 minutes before meal administration to 240 minutes after meal administration. At 120 minutes, the postprandial mean glucose concentration was 212.6 milligrams per deciliter for human insulin 70/30, 198.0 milligrams per deciliter for insulin lispro 75/25, and 158.8 milligrams per deciliter for insulin lispro 50/50.
Note: Mean (SD) dose of insulin was 44.1 (18.2) U/day for Human Insulin 70/30; 44.1 (18.2) U/day for Humalog Mix75/25; and 43.8 (17.8) U/day for Humalog Mix50/50. Standard test breakfast: 500 kcal; 50% carbohydrate, 34% fat, 16% protein. Each regimen resulted in 2-hour postprandial glucose significantly different from all other regimens (pairwise comparison).
Select Important Safety Information
Instruct patients to always check the insulin label before each injection to avoid medication errors. Do NOT transfer Humalog U-200 from the Humalog KwikPen to a syringe as overdose and severe hypoglycemia can occur.
Efficacy of Humalog Mix50/50
Humalog Mix50/50 improved postprandial glucose control3,5,6
A randomized, double-blind study compared Human Insulin 70/30, Humalog Mix75/25, and Humalog Mix50/50 after a standardized breakfast meal in patients with type 2 diabetes.3 Humalog Mix50/50 improved postprandial glucose control.3,5,6
Design and methods3
Comparison of insulin formulations: Human Insulin 70/30, Humalog Mix75/25, and Humalog Mix50/50 after a standardized breakfast meal
Study was randomized and double-blind, with 3-way crossover of the premixed insulins in patients with type 2 diabetes. A control group of subjects without diabetes underwent the standardized test meal with no insulin treatment
All patients previously used insulin (excluding insulin glargine) for at least one month prior to the study
After the test breakfast, glucose was measured for 4 hours
22 patients received a single dose of Human Insulin 70/30 before breakfast; 22 received Humalog Mix75/25; and 23 received Humalog Mix50/50. Ten subjects without diabetes received no insulin. One patient who received Human Insulin 70/30 before the test meal, followed by the usual dose of insulin lispro before lunch, reported symptoms of hypoglycemia that resolved with oral carbohydrate
Humalog Mix50/50 provided improved postprandial control for patients after a standardized breakfast meal3
This bar graph presents 2-hour postprandial glucose concentrations for four treatment groups: human insulin 70/30 mix (n equals 22); Humalog insulin lispro 75/25 mix (n equals 22); Humalog insulin lispro 50/50 mix (n equals 23); and a control group of subjects without diabetes (n equals 10). The Y-axis shows 2-hour postprandial glucose concentration, with values ranging from 0 to 250 milligrams per deciliter. The X-axis presents a bar for each treatment group. The mean two-hour post postprandial blood glucose values for active treatment groups were (left to right on the bar graph): 212.6 milligrams per deciliter for human insulin 70/30; 198.0 milligrams per deciliter for insulin lispro 75/25; and 158.8 milligrams per deciliter for insulin lispro 50/50.
*Each regimen resulted in 2-hour postprandial glucose significantly different from all other regimens (pairwise comparison).
Note: Mean (SD) dose of insulin was 44.1 (18.2) U/day for Human Insulin 70/30; 44.1 (18.2) U/day for Humalog Mix75/25; and 43.8 (17.8) U/day for Humalog Mix50/50. Standard test breakfast: 500 kcal; 50% carbohydrate, 34% fat, 16% protein.
Select Important Safety Information
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with Humalog, Insulin Lispro Injection, Humalog Mix75/25, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, and Humalog Mix50/50. If hypersensitivity reactions occur, discontinue the insulin and treat per standard of care until signs and symptoms resolve.
Dosing for Humalog mixes
The following dosing options for patients with type 2 diabetes starting premixed insulin are based on Hirsch et al.7 Dosing guidelines should be individualized for each patient.
Recommended dose
- Start 10 units predinner
- Add subsequent prebreakfast dose based on patient's needs, or
- Start 10 units prebreakfast and predinner
Titration
- Prebreakfast dose: Adjust based on predinner/evening glucose values
- Predinner dose: Adjust based on prebreakfast/morning glucose values
- Do not increase dose if hypoglycemia (<70 mg/dL) or symptoms are present
Titration schedule for once-daily or twice-daily insulin regimens7
This two-column table presents a recommended titration schedule for people taking once-daily or twice-daily insulin regimens. The left column header says: If most values in the past 3 to 7 days fall in this range. The right column header says, Adjust dose by.
If most glucose values in the past 3 to 7 days fell below 80 milligrams per deciliter, the patient should reduce insulin dose by two units. If most glucose values in the past 3 to 7 days were between 80 and 109 milligrams per deciliter, the patient does not need to adjust insulin dose. If most glucose values in the past 3 to 7 days were between 110 and 139 milligrams per deciliter, the patient should increase their dose by two units. If most glucose values in the past 3 to 7 days were between 140 and 179 milligrams per deciliter, the patient should increase their dose by four units. If most glucose values in the past 3 to 7 days were above 180 milligrams per deciliter, the patient should increase their insulin dose by six units.
Some Important Dosing Information
Dosage regimens of insulin will vary among patients and should be determined by the healthcare provider familiar with the patient's metabolic needs, eating habits, and other lifestyle variables.
In addition, the dose must be individualized and adjusted for each patient, based on metabolic needs, blood glucose monitoring results and glycemic control goals.
References: 1. Malone JK, Kerr LF, Campaigne BN, Sachson RA, Holcombe JH; Lispro Mixture-Glargine Study Group. Combined therapy with insulin lispro Mix75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy [published correction appears in Clin Ther. 2005;27(7):1112]. Clin Ther. 2004;26(12):2034-2044. 2. Malone JK, Bai S, Campaigne BN, Reviriego J, Augendre-Ferrante B. Twice-daily pre-mixed insulin rather than basal insulin therapy alone results in better overall glycaemic control in patients with Type 2 diabetes. Diabet Med. 2005;22(4):374-381. 3. Schwartz S, Zagar AJ, Althouse SK, Pinaire JA, Holcombe JH. A single-center, randomized, double-blind, three-way crossover study examining postchallenge glucose responses to human insulin 70/30 and insulin lispro fixed mixtures 75/25 and 50/50 in patients with Type 2 diabetes mellitus. Clin Ther. 2006;28(10):1649-1657. 4. Koivisto VA, Tuominen JA, Ebeling P. Lispro Mix25 insulin as premeal therapy in type 2 diabetic patients. Diabetes Care. 1999;22(3):459-462. 5. Kazda C, Hülstrunk H, Helsberg K, Langer F, Forst T, Hanefeld M. Prandial insulin substitution with insulin lispro or insulin lispro mid mixture vs. basal therapy with insulin glargine: a randomized controlled trial in patients with type 2 diabetes beginning insulin therapy. J Diabetes Complications. 2006;20(3):145-152. 6. Roach P, Trautmann M, Arora V, Sun B, Anderson JH Jr. Improved postprandial blood glucose control and reduced nocturnal hypoglycemia during treatment with two novel insulin lispro-protamine formulations, insulin lispro mix25 and insulin lispro mix50. Clin Ther. 1999;23:523-534. 7. Hirsch IB, Bergenstal RM, Parkin CG, Wright E Jr, Buse JB. A real-world approach to insulin therapy in primary care practice. Clin Diabetes. 2005;23(2):78-86.
INDICATIONS
Humalog and Insulin Lispro Injection are rapid-acting insulin analogs indicated to improve glycemic control in adults and children with diabetes mellitus. Humalog Mix75/25 and Humalog Mix50/50, and Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 are mixtures of intermediate-acting and rapid-acting insulin analogs indicated to improve glycemic control in patients with diabetes mellitus.
Limitations of Use: The proportions of rapid-acting and intermediate-acting insulins in Humalog Mix75/25 and Humalog Mix50/50, and Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 are fixed and do not allow for basal versus prandial dose adjustments.