PHARMACOLOGIC APPROACHES TO DIABETES MANAGEMENT: INSULIN
Faculty:
L. Austin Fredrickson, MD, FACP
L. Austin Fredrickson is an Associate Professor of Internal Medicine at Northeast Ohio Medical University, where he serves as core faculty and teaches diagnostics, therapeutics, clinical skills, and health humanities. He is board-certified in general internal medicine and practices rural primary care.
Liz Fredrickson, PharmD, BCPS
Liz Fredrickson, PharmD, BCPS, is an Associate Professor of Pharmacy Practice and Pharmaceutical Sciences at the Northeast Ohio Medical University (NEOMED) College of Pharmacy, where she is course director of the Parenteral Products and Basic Pharmaceutics Lab courses.
Pamela Sardo, PharmD, BS
Pamela Sardo, PharmD, BS, is a freelance medical writer and licensed pharmacist. She is the founder and principal at Sardo Solutions in Texas. Pam received her BS from the University of Connecticut and her PharmD from the University of Rhode Island. Pam’s career spans many years in retail, clinics, hospitals, long-term care, Veterans Affairs, and managed health care responsibilities across a broad range of therapeutic classes and disease states.
Abstract
Diabetes mellitus remains a significant public health problem as a leading cause of death and micro- and macrovascular morbidity. The management of diabetes continues to evolve as new research, technology, and treatments allow for enhanced patient care. It is vital for health care providers, including physicians, nurses, and pharmacists, to be current with diabetes care guidelines, including the pharmacologic management of diabetes mellitus. This course will compare available insulin preparations and review dosing regimens, pharmacokinetics, side effects, and monitoring parameters. The role of insulin within therapeutic regimens for patients with Type 1 and Type 2 diabetes will be discussed in the context of the updated American Diabetes Association Standards of Care in Diabetes 2023 guidelines.
Accreditation Statements
In support of improving patient care, RxCe.com LLC is jointly accredited by the Accreditation CouncilTM for Continuing Medical Education (ACCME®), the Accreditation Council for Pharmacy Education (ACPE®), and the American Nurses Credentialing Center (ANCC®), to provide continuing education for the healthcare team.
This activity was planned by and for the healthcare team, and learners will receive 2 Interprofessional Continuing Education (IPCE) credits for learning and change.
Joint Universal Activity Number: The Joint Accreditation Universal Activity Numbers assigned to this activity are as follows:
Pharmacists: JA4008424-0000-26-046-H01-P
Pharmacy Technicians: JA4008424-0000-26-046-H01-T
Credits: 2 contact hour(s) (0.2 CEU(s)) of continuing education credit.
Credit Types:
IPCE Credits - 2 Credits
AAPA Category 1 Credit™️ - 2 Credits
AMA PRA Category 1 Credit™️ - 2 Credits
Pharmacy - 2 Credits
Type of Activity: Application
Media: Computer-Based Training (i.e., online courses)
Estimated time to complete activity: 2 contact hour(s) (0.2 CEU(s)), including Activity Pre-Test, Post-Test, and Activity Evaluation.
Release Date: April 3, 2026 Expiration Date: April 3, 2029
Target Audience: This educational activity is for Physicians, Physician Assistants, Pharmacists, and Pharmacy Technicians
How to Earn Credit: From April 3, 2026, through April 3, 2029, participants must:
Read the “learning objectives” and “author and planning team disclosures;”
Take the “Educational Activity Pre-Test;”
Study the section entitled “Educational Activity;” and
Complete the Educational Activity Post-Test and Activity Evaluation. The Educational Activity Post-Test will be graded automatically. Following successful completion of the Educational Activity Post-Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)
CME Credit: Credit for this course will be uploaded to CPE Monitor® for pharmacists. Physicians may receive AMA PRA Category 1 Credit™️ and use these credits toward Maintenance of Certification (MOC) requirements. Physician Assistants may earn AAPA Category 1 CME credit, reportable through PA Portfolio. All learners shall verify their individual licensing board’s specific requirements and eligibility criteria.
Statement of Need
Diabetes management often requires treatment with insulin, but the wide range of insulin formulations, concentrations, and delivery devices can make regimen selection and dosing options challenging. Healthcare professionals must be able to compare available preparations and recognize when insulin should be initiated or intensified in patients presenting with type 1 or type 2 diabetes. Challenges remain with adjusting doses to meet glycemic control while minimizing hypoglycemia. Practical counseling strategies are needed to support correct administration, storage, timing, and safe injection technique. This activity aims to improve knowledge, competence, and confidence regarding insulin treatment options in clinical practice.
Learning Objectives: Upon completion of this educational activity, participants should be able to:
Compare and contrast available insulin preparations
Identify insulin dosing strategies for Type 1 and Type 2 diabetes
Identify when to utilize insulin within a therapeutic regimen for patients with Type 1 and Type 2 diabetes
Recall patient counseling points related to the use of insulin
Disclosures
The following individuals were involved in planning, developing, and/or authoring this activity: L. Austin Fredrickson, MD, FACP; Liz Fredrickson, PharmD, BCPS; and Pamela Sardo, PharmD, BS. None of the individuals involved in developing this activity has a conflict of interest or financial relationships related to the subject matter. There are no financial relationships or commercial or financial support relevant to this activity to report or disclose by RxCe.com or any of the individuals involved in the development of this activity.
© RxCe.com LLC 2026: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.
Educational Activity Pre-Test
Which of the following insulin preparations has no peak?
Insulin aspart
Insulin lispro
Insulin glargine
Insulin NPH
Which of the following is true regarding the use of insulin in a patient with Type 2 diabetes (T2DM)?
All newly diagnosed patients with T2DM should be started on insulin therapy
Insulin is preferred over other injectable medications (GLP-1 RAs) in patients with T2DM
Early insulin initiation should be considered in patients with weight loss, symptoms of hyperglycemia, A1C > 10%, or elevated blood glucose levels (>/300 mg/dL)
Prandial insulin should be initiated before basal insulin is added
Which of the following combinations of insulin can be safely mixed together?
NPH and regular insulin
Insulin glargine and insulin lispro
Insulin glargine and NPH
Regular insulin and insulin aspart
Educational Activity
Pharmacologic Approaches to Diabetes Management: Insulin
Introduction
The use of insulin offers patients with diabetes several benefits, including the ability to achieve a variety of glucose targets and individually titrate doses. However, its use puts patients at risk of hypoglycemia, weight gain, and the burden of using daily injectable medications. Given the variety of available insulin preparations, it is crucial for clinicians to understand how to utilize these safely and effectively. This course will compare available insulin preparations and review dosing regimens, pharmacokinetics, side effects, and monitoring parameters. The role of insulin within therapeutic regimens for patients with Type 1 and Type 2 diabetes will be discussed in the context of the updated American Diabetes Association Standards of Care in Diabetes 2023 guidelines.
Pause and Ponder Before selecting an insulin regimen, what patient-specific factors should be assessed to balance glycemic control with safety? |
|---|
Types of Insulin
Insulin is a hormone that plays key roles in glucose homeostasis and metabolism.1 Proinsulin peptide in pancreatic β-cells is cleaved to insulin and inactive C-peptide.1 The biosynthesis and secretion of insulin are influenced by glucose levels in the blood.2 The intake of food triggers the increased production of insulin via β-cells.2 Once secreted, insulin circulates and prompts glucose storage in hepatocytes, skeletal muscle cells, and adipocytes, thereby decreasing blood glucose levels.2 In individuals with Type 1 diabetes mellitus (T1DM), the pancreatic β-cells are destroyed by an autoimmune response, leading to a complete absence of insulin production.2 In Type 2 diabetes mellitus (T2DM), insulin-sensitive tissues become resistant to the effects of insulin, and pancreatic β-cells are no longer able to produce enough insulin to maintain blood glucose levels within a healthy range.2 Insulin therapy is necessary for the treatment of T1DM, and approximately 30% of patients with T2DM use insulin.3
All manufactured insulin is produced using recombinant DNA technology and contains only the active insulin peptide.1 Two types of insulin preparations are available: human insulins, which are recombinant DNA-derived human insulin, and insulin analogs, which are formulated via substituting amino acids within the insulin molecule.1 These substitutions have effects on the pharmacokinetics (onset and duration) of the preparation.1 All insulin is administered subcutaneously, except for inhaled insulin.1 Available concentrations include 100 units/mL (U-100), 200 units/mL (U-200), 300 units/mL (U-300), and 500 units/mL (U-500), with U-100 the most common.1 By using more concentrated preparations, patients can take larger doses without increasing the volume of the injection.1
Key pharmacokinetic properties of insulin preparations include the onset, peak, and duration of action.1 The absorption of insulin varies depending on many factors. Insulin-related factors include the source of insulin, its concentration, and potential additives (such as zinc).1 Physiologic factors include the injection site and blood flow to the injection site, which can be increased via rubbing the area and exercise.1
Insulin regimens for patients with diabetes consist of basal (background) and bolus insulin.1,4 Basal insulin acts to keep glucose levels steady over the course of the day, keeping blood glucose levels within the normal range throughout the fasting state.1,4 Types of basal insulin include long-acting insulin preparations, NPH insulin, and the continuous delivery of rapid-acting insulin via an insulin pump.1,4 Bolus insulin provides quick-acting coverage that assists in countering the effects of meals on blood glucose (prandial insulin).1,4 Prandial insulins include short- and rapid-acting insulin preparations.1,4 Correctional insulin is supplemental bolus insulin used to bring a high blood glucose level within the desired range, often around meal times.1,4 Rapid- or short-acting insulin can be used as correctional insulin.1,4
Rapid-acting insulin
Rapid-acting insulin is designed to reach peak activity quickly. It can be used in various situations, including before meals, to control postprandial glucose levels and as a correction dose for high blood glucose levels.1 For patients with T1DM, rapid-acting insulin must be used as part of a multiple daily injection regimen in conjunction with an intermediate- or long-acting insulin.1 For patients with T2DM, rapid-acting insulin is an option when glycemic targets have not been met despite an adequately titrated basal insulin regimen.1
Formulations
Rapid-acting insulin is available in several different formulations, including insulin lispro.5 Conventional formulations of insulin lispro include Ademlog and Humalog.5 Lyumjev is an ultra-rapid-acting formulation with a different onset of action.6 Insulin aspart is available as Novolog and the ultra-rapid acting Fiasp; these are not interchangeable.7
A meta-analysis comparing ultra-rapid-acting insulin use in T1DM and T2DM found that treatment with these formulations had a similar effect on HbA1c to rapid-acting insulins.8 A third rapid-acting formulation is insulin glulisine, under the brand name Apidra®.9 Table 1 details available rapid-acting insulin formulations.
Table 1
Rapid-acting insulin formulations5-9
| Product | Dosage Form | Product, Concentration (Volume) |
|---|---|---|
| Insulin aspart | Solution, Injection | Novolog ReliOn, 100 units/mL (10 mL) |
| Solution Catridge, Subcutaneous | Fiasp PenFill, 100 units/mL (3 mL) | |
| Solution Pen-injector, Subcutaneous | Fiasp FlexTouch, 100 units/mL (3 mL) | |
| Insulin glulisine | Solution, Injection | Apidra, 100 units/mL (10 mL) |
| Solution Pen-injector, Subcutaneous | Apidra SoloStar, 100 units/mL (3 mL) | |
| Insulin lispro | Solution, Injection | Admelog, 100 units/mL (3 mL, 10 mL) HumaLOG, 100 units/mL (3 mL, 10 mL) Lyumjev, Insulin lispro-aabc 100 unit/mL (10 mL) Generic, 100 units/mL (10 mL) |
| Solution, Subcutaneous | Humalog, 100 units/mL (3 mL) | |
| Solution Pen-injector, Subcutaneous | Admelog SoloStar: 100 units/mL (3 mL) HumaLOG Junior KwikPen: 100 units/mL (3 mL) HumaLOG KwikPen: 100 units/mL (3 mL); 200 units/mL (3 mL) HumaLOG Tempo Pen: 100 units/mL (3 mL) Lyumjev KwikPen: Insulin lispro-aabc 100 unit/mL (3 mL); Insulin lispro-aabc 200 unit/mL (3 mL) Lyumjev Tempo Pen: Insulin lispro-aabc 100 units/mL (3 mL) Generic: 100 units/mL (3 mL) |
Pharmacokinetics
Available rapid-acting insulin formulations differ slightly in properties but generally have similar onset, peak, and duration of action. The onset of action of rapid-acting insulin is typically 15 to 30 minutes, with a peak effect occurring 1 to 3 hours after injection.5-9 Depending on the formulation, the duration of action may range from 3 to 7 hours, underscoring the importance of appropriately timing meals and physical activity to avoid hypoglycemia.5-9 Table 2 details the pharmacokinetics of rapid-acting insulin formulations.
Table 2
Pharmacokinetic properties of
rapid-acting insulin formulations5-9
| Name | Onset | Peak Effect | Duration | Half-life |
|---|---|---|---|---|
| Insulin aspart | ||||
| Fiasp | 16.1 mins (T1DM) 22.4 mins (T2DM) | 1.5 to 2.2 hours (T1DM) 2.5 hours (T2DM) | 5 to 7 hours (T1DM) | 63 mins (T1DM) 70 mins (T2DM) |
| Novolog | 12 to 18 minutes | 1-3 hours | 3-7 hours | 40-50 mins |
| Insulin glulisine | ||||
| Apidra and Apidra SoloStar | 15 to 30 minutes | 1.6 to 2.8 hours | 3-4 hours | 42 mins |
| Insulin lispro | ||||
| Admelog | 30 mins | 2.1 hours | 6.9 hours (T1DM) | 50-60 mins |
| Humalog | 30 mins | 2.4-2.8 hours | 5.7-6.6 (T1DM) 6.7 hrs (T2DM) | 50-60 mins |
| Lyumjev | 15-17 mins | Lyumjev: 2-3 hours | 4.6-7.3 hrs | 30-90 mins |
Dosing
The dosing of rapid-acting insulins varies depending on the type of diabetes and also the use of concomitant antihyperglycemic medications.1 For patients with T1DM, rapid-acting insulin is included within the total daily dose (TDD) of insulin, which considers all insulin formulations combined and is dosed in units/kg/day.5-9 The initial TDD is 0.4 to 0.5 units/kg/day, with a recommended maintenance range of 0.4 to 1 unit/kg/day.5-9 During the honeymoon phase, the dose may be lower, at 0.1 to 0.4 units/kg/day, and during acute illness or stress, higher doses may be required.1 Prandial insulin accounts for 50-60% of the TDD, and this total dose is divided into three doses.5–9
For patients with T2DM on maximally titrated basal insulin, if the goal A1C is not achieved, prandial insulin should be considered.1 Similar to basal insulin, a stepwise approach can be used to target glucose goals while minimizing hypoglycemia.1 Patients can be started on one pre-meal injection prior to the largest meal of the day, with a second or third mealtime injection added as needed.1 The recommended initial dose of prandial insulin is 4 or 6 units OR 10% of the patient's basal insulin dose.5-9 For patients with an HbA1c of less than 8%, it is recommended to reduce the basal insulin daily dose by 4 units/day or by 10% when adding prandial insulin.5-9
Rapid-acting insulin should be administered at mealtimes or immediately prior.5-9 Doses can be titrated up or down to reach glycemic goals while avoiding hypoglycemia.5-9 For patients with T1DM or T2DM, dose adjustments must be made on a patient-specific basis, considering glucose levels and daily carbohydrate intake.5-9 If a patient has persistently elevated glucose levels, the prandial insulin dose can be increased by 1 or 2 units or by 10-15% every day until glycemic targets are achieved.5-9 Patients should be closely monitored for hypoglycemia during this titration period.5-9 For patients taking more than 20 units of rapid-acting insulin daily, a more aggressive titration of 5 or more units may be warranted.5-9 If mild-to-moderate hypoglycemia occurs, clinicians may consider decreasing the dose by 10-20%.5-9 A 20-50% reduction may be needed if blood glucose levels fall below 40 mg/dL.5-9 Insulin doses may need to be decreased for patients with renal or hepatic impairment.5-9 Blood glucose levels should be monitored closely in these patients.5-9
Side Effects and Monitoring
The most common and potentially most severe adverse reaction associated with rapid-acting insulin is hypoglycemia.5-9 The prevalence of severe hypoglycemia is 1-17% for patients with T1DM and 3-10% for patients with T2DM.5-9 Other side effects include weight gain, the development of antibodies, nasopharyngitis, chest pain, hypersensitivity reactions, injection site reactions (redness, swelling, itching), and lipoatrophy at the injection site.5-9
Monitoring parameters for rapid-acting insulin include blood glucose levels, the frequency of which is dependent on the treatment regimen, the patient’s hypoglycemic risk, and other patient-specific factors.5-9 Hemoglobin A1C levels should be measured at least twice a year for patients with stable glycemic control and at least four times a year for those not meeting glycemic goals.5-9 Other monitoring parameters include body weight, electrolytes, renal function, and hepatic function.5-9 The use of insulin concomitantly with other glucose-lowering medications can potentially exacerbate hypoglycemia.5-9 Insulin may also enhance the hypoglycemic effects of the following agents: beta-1-selective blockers, direct-acting antiviral agents, salicylates, and selective serotonin reuptake inhibitors.5-9
Short-acting insulin
Short-acting insulin can be used in various situations, including before meals, to control postprandial glucose levels and as correctional insulin.9 For patients with T1DM, short-acting insulin is used as part of a multiple daily injection regimen in conjunction with an intermediate- or long-acting insulin.1,9 However, it is not preferred over rapid-acting analogs.1,9 For patients with T2DM, it may be an option when glycemic targets have not been met despite an adequately titrated basal insulin regimen.9
Formulations
Short-acting insulin is a clear product available in U-100 (100 units/mL) and U-500 (500 units/mL) concentrations.9 Available formulations are detailed in Table 3.9
Table 3
Short-acting insulin formulations9
| Dosage Form | Product, Concentration (Volume) |
|---|---|
| Solution, Injection | Humulin R: 100 units/mL (3 mL, 10 mL) Novolin R: 100 units/mL (10 mL) Novolin R ReliOn: 100 units/mL (10 mL) |
| Solution, Intravenous | Myxredlin, 100 units/100 mL in NaCl (0.9%) (100 mL) |
| Solution, Subcutaneous | Humulin R U-500, 500 units/mL (20 mL) |
| Solution, Pen-injector, Injection | Novolin R FlexPen, 100 units/mL (3 mL) Novolin R FlexPen ReliOn, 100 units/mL (3 mL) |
| Solution, Pen-injection, Subcutaneous | Humulin R U-500 KwikPen: 500 units/mL (3 mL) |
Pharmacokinetics
The onset of action of short-acting insulin is typically 30 minutes to 1 hour, with peak effect varying by concentration.9 Table 4 details the pharmacokinetic properties of regular insulin.9
Table 4
Pharmacokinetic properties of regular insulin9
| Concentration | Onset | Peak Effect | Duration | Half-life |
|---|---|---|---|---|
| U-100 | 30 mins | 1.5-3.5 hours | 8 hours | 1.5 hours |
| U-500 | <15 mins | 4-8 hours | 13-24 hours | 4 hours |
Dosing
The dosing of short-acting insulin varies depending on the type of diabetes.9 For patients with T1DM, short-acting insulin is included within the total daily dose (TDD) of insulin, which considers all insulin formulations combined and is dosed in units/kg/day.9 The initial TDD is 0.4 to 0.5 units/kg/day, with a recommended maintenance range of 0.4 to 1 unit/kg/day.9 Prandial insulin accounts for 50-60% of the TDD, and this total dose is divided into three doses.9 Short-acting insulin should be administered 30 minutes before mealtimes.9 Doses can be titrated to reach glycemic goals while avoiding hypoglycemia.9
For patients with T2DM, regular insulin (U-100) can be initiated when fasting glycemic targets have not been met or if the patient is taking more than 0.7-1.0 units/kg/day of basal insulin.9 Short-acting insulin should be initiated as a single daily injection before the largest meal at a dose of 4-6 units or 10% of the basal insulin dose.9 For patients with an A1c level less than 8%, it is recommended to reduce the basal insulin daily dose by 4 units/day or by 10% when adding prandial insulin.9
Further dose adjustments of short-acting insulin mimic those of rapid-acting insulin.9 If a patient takes more than 200 units/day of insulin, the use of U-500 (500 units/mL) may be considered.9 Before starting U-500 insulin, all other insulin products must be discontinued.9 It is essential that patients utilize U-500 only under the care of a clinician who has experience with U-500, given the safety risks.9 The initial dose of U-500 depends on how close the patient is to their glycemic goals.9 One strategy is to administer U-500 as the current total daily insulin dose, rounded down to the nearest 5 units.9 This dose should be divided into two doses, with 60% of the TDD given before the morning meal and 40% given before the evening meal.9 Alternatively, the division could be 50%/50%.9
The following dose reductions are recommended for patients with altered kidney function.9
CrCl >50 mL/minute: No dosage adjustment is necessary
CrCl 10 to 50 mL/minute: Administer 75% of the normal dose and monitor glucose closely
CrCl <10 mL/minute: Administer 50% of the normal dose and monitor glucose closely
Hemodialysis: Because of a large molecular weight (6,000 Daltons), insulin is not significantly removed by hemodialysis; a supplemental dose is not necessary
Peritoneal dialysis: Because of a large molecular weight (6,000 Daltons), insulin is not significantly removed by peritoneal dialysis; a supplemental dose is not necessary
Continuous renal replacement therapy: Administer 75% of the normal dose and monitor glucose closely; supplemental dose is not necessary
Patients with hepatic impairment should be monitored more closely, and dose reductions may be required.9
Side Effects and Monitoring
The side effects and monitoring parameters of short-acting insulin mirror those of rapid-acting insulin.9
Intermediate-acting insulin
Intermediate-acting insulin, also known as NPH (neutral protamine Hagedorn), is designed to last longer than short-acting or rapid-acting insulin.10 It is utilized in T1DM as the basal component of a multiple injection regimen, though it is not preferred to long-acting insulin preparations due to its duration and occurrence of a peak.1,10 Its duration of action is less than 24 hours and often must be dosed twice daily.1 NPH may be used to manage T2DM in addition to oral medications or as part of a basal-bolus regimen.1 NPH may be preferred over long-acting formulations for financial reasons.1
Formulations
Notably, the appearance of NPH is cloudy.10 NPH formulations are detailed in Table 5.10
Table 5
NPH formulations10
| Dosage Form | Product, Concentration (Volume) |
|---|---|
| Suspension | Humulin N: 100 units/mL (3 mL) |
| Novolin N: 100 units/mL (3mL) | |
| Novolin N ReliOn: 100 units/mL (10 mL) | |
| Suspension Pen-injector | Humulin N KwikPen: 100 units/mL (3 mL) |
| Novolin N FlexPen: 100 units/mL (3mL) | |
| Novolin N FlexPen ReliOn: 100 units/mL (3 mL) |
Pharmacokinetics
The onset of action of NPH insulin is typically 1 to 2 hours, with a peak effect occurring four to 12 hours after injection.10 The duration of action is 14-24 hours, with a time to peak in plasma of 6 to 10 hours.10
Dosing
The dosing regimen of insulin NPH differs depending on the type of diabetes being treated.10 For the treatment of T1DM, insulin NPH is used with rapid or short-acting insulin as a part of a multiple daily injection regimen, with a TDD of 0.4-0.5 units/kg/day initially.10 The maintenance TDD is 0.4 to 1 unit/kg/day in divided doses.10 In general, insulin NPH will account for 40 to 50% of the TDD.10 Insulin NPH is administered in two divided doses, either split equally or as 2/3 of the dose before the morning meal and 1/3 of the dose before the evening meal.10 The dose of NPH should be titrated to maximize glucose control and avoid hypoglycemia.10
For the treatment of T2DM, insulin NPH is dosed as 10 units/day or 0.1 to 0.2 units/kg/day as a single dose, most commonly administered at bedtime.10 NPH can also be split into two daily doses.1 The dose can be increased to 0.2-0.3 units/kg/day for patients with an HbA1c >8% or a fasting glucose > 250 mg/dL.10 The typical recommended range is 10-20 units/day. For patients with persistently elevated blood glucose levels, the daily dose can be increased by 2-4 units or by 10-20% every 2-3 days to achieve goal fasting glucose targets while also avoiding hypoglycemia.10 If patients experience hypoglycemia, the daily dose should be reduced by 10-20%.10
Side Effects and Monitoring
Common adverse reactions associated with NPH insulin include hypoglycemia, weight gain, injection site reactions, atrophy at the injection site, lipodystrophy, and hypersensitivity reactions.10 Patients should be monitored by checking blood glucose levels, renal function, hepatic function, and weight gain, and should also be monitored for signs and symptoms of hypoglycemia.10 An HbA1c level should be monitored twice yearly in patients meeting treatment goals and quarterly in those who have not met their goals.10
Long-acting insulin
Long-acting insulin is a type of insulin with a slow onset and prolonged duration of action.11 It is created by changing the amino acids in insulin to produce a formulation that mimics normal insulin secretion independent of food intake.11 It is typically administered once a day to provide basal insulin coverage.1 For patients with T1DM, these preparations are the preferred basal component of a multiple-injection regimen.1 Long-acting insulin may be used to manage T2DM in addition to oral or injectable medications or as part of a basal-bolus regimen.1
Formulations
Formulations of long-acting insulin include insulin glargine (Lantus®) and insulin detemir (Levemir®).12,13 Insulin detemir and several other nonbranded insulin formulations are slowly being discontinued by the manufacturer for business reasons, not quality or safety reasons. Insulin glargine is also available in a formulation with lixisenatide (Soliqua®).14 Semglee® (insulin glargine-yfgn) and Rezvoglar® (insulin glargine-aglr) are available as interchangeable biosimilars for Lantus.15 Insulin glargine-yfgn is slowly being discontinued. Table 6 details available preparations.12,13
Table 6
Long-acting insulin formulations12,13
| Product | Dosage form | Product, Concentration (Volume) |
|---|---|---|
| Insulin glargine | Solution, Subcutaneous | Lantus: 100 units/mL (10 mL) Semglee: 100 units/mL (10 mL) Generic: 100 units/mL (10 mL) |
| Solution Pen-injector, Subcutaneous | Basaglar KwikPen: 100 units/mL (3 mL) Basaglar Tempo Pen: 100 units/mL (3 mL) Lantus SoloStar: 100 units/mL (3 mL) Rezvoglar KwikPen: Insulin glargine-aglr 100 units/mL (3 mL) Semglee: 100 units/mL (3 mL [DSC]) Toujeo Max SoloStar: 300 units/mL (3 mL) Toujeo SoloStar: 300 units/mL (1.5 mL) Generic: 100 units/mL (3 mL) |
Pharmacokinetics
The pharmacokinetic properties of long-acting insulin formulations are detailed in Table 7.12,13
Table 7
Pharmacokinetic properties of
long-acting insulin preparations12,13
| Name | Onset | Peak | Duration |
|---|---|---|---|
| Insulin glargine | 3-4 hours | Flat | 10.8-24 hours |
| Insulin levemir | 3-4 hours | Flat | 6-23 hours (dose-dependent) |
Dosing
For patients with T1DM, long-acting insulin is used as the basal component of a multiple-injection regimen. Basal insulin typically comprises 40-50% of the TDD, with insulin glargine administered once daily and insulin detemir given once or twice daily.12,13 Basal insulin should be administered regardless of food intake.12 If once-daily dosing does not adequately cover the basal insulin needs of a patient, the daily dose can be given in two divided doses.12,13
The ADA warns clinicians against the “overbasalization” of insulin therapy in patients with T2DM.16 This may occur when the basal dose is more than 0.5 units/kg/day, when there is a high bedtime-morning or post-preprandial glucose differential, when hypoglycemia occurs, or when high glycemic variability occurs.16
For patients with T2DM, insulin glargine or detemir can be started at a once-daily dose of 10 units in the morning or 0.1-0.2 units/kg/day.12,13 This dose can be increased to 0.2-0.3 units/kg/day initially for those with inadequate blood glucose control.12,13 Insulin glargine has a preferable pharmacokinetic profile and is given once daily in most cases.1 A common basal insulin titration method is the 3-0-3 method.1 The patient checks their fasting glucose levels daily for 3 days and determines an average level.1 If the average blood glucose level is greater than 130 mg/dL, the dose of basal insulin is increased by 3 units.1 This titration scheme is continued until the target level or a basal insulin dose of 0.7-1.0 units/kg/day is reached.1 The dose can be decreased by 3 units if unexplained hypoglycemia occurs.1
In patients with an eGFR between 10 and 50 mL/min/1.73 m², the dose of insulin glargine should be reduced by 25%.12 For those with an eGFR of 10 or less, the dose should be reduced by 50%.12
Converting Insulin Preparations
If a patient is converted from once-daily NPH to insulin glargine, glargine may be substituted on an equivalent, unit-for-unit basis.12 If a patient is converted from twice-daily NPH to insulin glargine, 80% of the total NPH dose should be given as glargine once daily.12 If a patient is converted from once- or twice-daily insulin detemir to glargine U-100, 80-90% of the total insulin detemir dose should be given as insulin glargine once daily.12 Insulin glargine U-100 can be converted to U-300 on a unit-per-unit basis, but often a higher daily dose of U-300 will be needed to maintain glycemic control.12 Conversely, transitioning from U-300 to U-100 insulin glargine requires a 20% dose reduction.12
Side Effects and Monitoring
The most common side effects of long-acting insulin formulations are hypoglycemia, weight gain, hypertension, peripheral edema, infections, pain at the injection site, and injection site reactions.12,13 Patients using basal insulin should check blood glucose levels at least once a day, if not more, depending on the insulin regimen and blood glucose control.12,13 Electrolytes, renal function, hepatic function, and body weight should be monitored.12,13
Ultra-long-acting insulin
Ultra-long-acting insulin (ULA-I) is a type of insulin developed recently to provide extended blood sugar control for patients with diabetes.17 ULA-I has a prolonged duration of action, typically lasting over 24 hours, which can improve glycemic control and potentially reduce the treatment burden of frequent injections required by patients.17
Formulations
Current options include insulin degludec (Tresiba®),17 insulin glargine U-300, and the newer once-weekly insulin icodec-abae (Awiqli®).18 The extended duration of action allows for once-daily or even every-other-day dosing with insulin degludec,17 depending on the patient’s individual needs. Insulin glargine U-300 is a more concentrated form of insulin glargine U-300, allowing for a smaller injection volume.12 Insulin icodec-abae is approved for adults with type 2 diabetes and is supplied in a U-700 solution in a single-patient-use pen.18 It is also approved and available in Europe and Canada. It is administered subcutaneously once weekly on the same day each week.18 Because of its prolonged half-life and extended glucose-lowering effect, icodec-abae should be individualized based on glycemic response and only used with close blood glucose monitoring. Table 8 details ULA-I formulations.12,17,18
Table 8
ULA-I Formulations
| Product | Dosage form | Product, Concentration (Volume) |
|---|---|---|
| Insulin glargine | Suspension pen-injector | Toujeo Max SoloStar: 300 units/mL (3 mL) Toujeo SoloStar: 300 units/mL (1.5 mL) |
| Insulin degludec | Solution | Treisiba: 100 units/mL (10 mL) |
| Solution Pen-injector | Treisiba FlexTouch: 100 units/mL (3 mL) | |
| Insulin icodec-abae | Solution Prefilled pen | Awiqli FlexTouch: 2,100 units (3 ml) Awiqli FlexTouch: 1,050 units (1.5 ml) Awiqli FlexTouch: 700 units (1 ml) |
Pharmacokinetics
The pharmacokinetics of ULA-I are detailed in Table 9.12,17,19
Table 9
Pharmacokinetic properties of ultra-long acting insulin12,17,19
| Formulation | Onset | Time to Peak | Duration |
|---|---|---|---|
| Insulin glargine (Toujeo) | 6 hours | Peakless | >24 hours |
| Insulin degludec | 1 hour | Peakless | At least 42 hours |
| Insulin icodec-abae | 15-18 hours | 2nd-4th day | 1 week |
Dosing
Dosing strategies are the same as for long-acting insulin formulations.12,17 The insulin glargine and insulin degludec formulations are peakless, with durations longer than those of glargine and detemir, and thus can be dosed once daily.1 Patients may need to be converted from insulin glargine or insulin detemir to insulin degludec.17 In these cases, insulin degludec can be substituted on an equivalent unit-per-unit basis.17 If the patient takes twice daily basal insulin (NPH or detemir), a dose reduction of 10-20% can be considered when switching to degludec.17 When converting a patient from insulin detemir to U-300 glargine, the initial dose can be substituted on an equivalent unit-for-unit basis.12
Due to the long half-life of insulin icodec-abae, dose adjustment is not advised during acute illness or when short-term changes in physical activity or diet occur.18 The recommended weekly starting dose in insulin-naive patients is 70 units subcutaneously weekly.18 When switching from daily basal insulin, administer the first dose of insulin icodec-abae on the day after the last dose.18 The recommended starting dose is 1.5 times the total daily basal dose multiplied by 7, and rounded to the nearest 10 units.18
Combination Insulin
Combination insulins, or insulin mixes, are formulations that contain a mixture of rapid- or short-acting and intermediate-acting insulin in the same vial or pen.1 These insulins are commonly used to simplify insulin regimens and reduce the number of injections required per day, particularly for patients who have difficulty managing multiple daily injections.1,4 However, they may not provide as much flexibility in dosing as separate vials or pens of rapid or short-acting and intermediate-acting insulin.1,4 In addition, it can be difficult to titrate the dose of mixed insulin to meet individual patient needs, as the ratio of short-acting to intermediate-acting insulin is fixed.1,4 Due to a lack of flexibility, they are not preferred for use in T1DM.1,4
Formulations
Combination insulin preparations are cloudy formulations that come in different ratios of rapid- or short-acting and intermediate-acting insulin, such as 70/30, 75/25, and 50/50.4 The first number represents the percentage of intermediate-acting insulin, while the second represents the percentage of rapid or short-acting insulin. For example, 70/30 insulin contains 70% intermediate-acting and 30% rapid-acting insulin.4
Some insulin aspart formulations are being slowly discontinued. The following insulin combinations are available: insulin aspart protamine and insulin aspart, insulin lispro protamine and insulin lispro, and insulin NPH and regular insulin.20-22 These are detailed in Table 10.21-27
Table 10
Combination insulin formulations
| Formulation | Product |
|---|---|
| Injection, suspension | Novolog Mix 70/30:23 insulin aspart protamine suspension 70% and insulin aspart solution 30% (100 units/mL), 10 mL |
| Novolog Mix 70/30 FlexPen®:24 Insulin aspart protamine suspension 70% [intermediate acting] and insulin aspart solution 30% [rapid acting]: 100 units/mL (3 mL) | |
| Suspension, SQ | Humalog Mix 50/50:25 Insulin lispro protamine suspension 50% [intermediate acting] and insulin lispro solution 50% [rapid acting]: 100 units/mL (10 mL) Humalog Mix 75/25:26 Insulin lispro protamine suspension 75% [intermediate acting] and insulin lispro solution 25% [rapid acting]: 100 units/mL (10 mL) |
| Suspension, Pen-injector, SQ | Humalog Mix 50/50 KwikPen:25 Insulin lispro protamine suspension 50% [intermediate acting] and insulin lispro solution 50% [rapid acting]: 100 units/mL (3 mL) Humalog Mix 75/25 KwikPen:21 Insulin lispro protamine suspension 75% [intermediate acting] and insulin lispro solution 25% [rapid acting]: 100 units/mL (3 mL) |
| Injection, suspension | Humulin 70/30:22 Insulin NPH suspension 70% [intermediate acting] and insulin regular solution 30% [short acting]: 100 units/mL (3 mL, 10 mL) Humulin 70/30 KwikPen:22 Insulin NPH suspension 70% [intermediate acting] and insulin regular solution 30% [short acting]: 100 units/mL (3 mL) Novolin 70/30:27 Insulin NPH suspension 70% [intermediate acting] and insulin regular solution 30% [short acting]: 100 units/mL (10 mL) Novolin 70/30 FlexPen:27 Insulin NPH suspension 70% [intermediate acting] and insulin regular solution 30% [short acting]: 100 units/mL (3 mL) Novolin 70/30 FlexPen ReliOn:27 Insulin NPH suspension 70% [intermediate acting] and insulin regular solution 30% [short acting]: 100 units/mL (3 mL) |
Pharmacokinetics
The pharmacokinetic properties of mixed insulin formulations are detailed in Table 11.18,19,20
Table 11
Combination Insulin Pharmacokinetics18,19,20
| Product | Onset | Peak | Duration |
|---|---|---|---|
| Insulin aspart protamine and insulin aspart | 10-20 mins | 1-4 hours | 18-24 hours |
| Insulin lispro protamine and insulin lispro | 0.25-5 hours | 0.8-4.8 hrs (50/50 mix) 1-6.5 hrs (75/25 mix) | 14-24 hours |
| Insulin regular and NPH | 0.5 hours | 2-12 hours | 18-24 hours |
Dosing
Mixed insulin preparations are normally administered twice a day, before breakfast and dinner.18,19,20 70% insulin aspart protamine suspension/30% insulin aspart solution, 75% insulin lispro protamine suspension/25% insulin lispro solution, and 50% insulin lispro protamine suspension, 50% insulin lispro solution should be administered 15 minutes before the meal.18,19,20 70% NPH/30% regular should be administered 30 minutes before the meal.18,19,20
Side Effects and Monitoring
The side effects and monitoring of mixed insulin preparations are similar to those of rapid- and short-acting formulations.18,19,20
Inhaled Insulin
Inhaled regular insulin (brand name Afrezza®) is a rapid-acting, human insulin formulation uniquely delivered via the pulmonary route.28 Affrezza takes advantage of novel Technosphere technology, which enables delivery of insulin via the pulmonary route.28,29 After administration, insulin rapidly dissolves in the lung tissue and is absorbed into the systemic circulation.28 One of the main advantages of inhaled insulin is its convenience to patients who struggle with injections.28,29
Affrezza is FDA-approved for treating both type 1 and type 2 diabetes mellitus.28 It must be used in combination with long-acting insulin to treat T1DM.28,29 Inhaled regular insulin has an onset of action of 12 minutes and a peak effect of 35-55 minutes.28 The duration is 90-270 minutes (proportional to the dose), and the half-life is 120-206 minutes.28 It is available as a powder for inhalation as a 4-unit, 8-unit, or 12-unit preparation.28 For patients with T1DM or T2DM, Afrezza is dosed at 4 units at each meal in patients who are insulin naïve.28 If patients have previously been on prandial insulin, the following scale can be used.28
≤4 units SUBQ dose per meal: Inhalation: 4 units at each meal
5 to 8 units SUBQ dose per meal: Inhalation: 8 units at each meal
9 to 12 units SUBQ dose per meal: Inhalation: 12 units at each meal
13 to 16 units SUBQ dose per meal: Inhalation: 16 units at each meal
17 to 20 units SUBQ dose per meal: Inhalation: 20 units at each meal
21 to 24 units SUBQ dose per meal: Inhalation: 24 units at each meal
If patients were previously on mixed insulin, the new daily basal insulin dose could be calculated as half of the total daily mixed dose.28 For patients replacing the prandial insulin component with inhaled insulin, half of the total daily dose of mixed insulin should be divided equally among three meals.28 Then, each estimated prandial dose should be converted to prandial inhalation using the following scale.28
Estimated ≤4 units SUBQ dose per meal: Inhalation: 4 units at each meal
Estimated 5 to 8 units SUBQ dose per meal: Inhalation: 8 units at each meal
Estimated 9 to 12 units SUBQ dose per meal: Inhalation: 12 units at each meal
Estimated 13 to 16 units SUBQ dose per meal: Inhalation: 16 units at each meal
Estimated 17 to 20 units SUBQ dose per meal: Inhalation: 20 units at each meal
Estimated 21 to 24 units SUBQ dose per meal: Inhalation: 24 units at each meal
The dose can be adjusted in 4-unit increments to achieve blood glucose targets while avoiding hypoglycemia.28 If hypoglycemia does occur, the dose can be reduced by 10-20%.28
Side Effects and Monitoring
As with all insulin formulations, the most common side effect of Afrezza is hypoglycemia.28 Affrezza may also cause a decrease in pulmonary function. Other side effects include cough, throat pain, and headache.28,29 Additionally, because it is administered via the pulmonary route, subsequent pulmonary adverse effects may occur.28,29 Patients must be assessed to determine whether inhaled insulin is appropriate; such testing includes obtaining an FEV1 (forced expiratory volume at 1 second).28,29 A black box warning for acute bronchospasm in patients with chronic lung disease is included within Afrezza packaging, and this product is contraindicated in patients with asthma or chronic obstructive pulmonary disease.28,29
Choosing Glucose-Lowering Therapy
It is critical for clinicians to review the pharmacokinetic properties of insulin formulations when determining an appropriate regimen.1,16 In general, all basal insulin preparations result in similar reductions in A1c levels when used and dosed appropriately.1 However, long-acting preparations are beneficial in terms of hypoglycemic risk and often result in less variability in glucose levels.1 Unfortunately, these formulations are often more expensive, and these pros and cons should be weighed.1,16 In a similar manner, the rapid- and ultra-rapid-acting insulin analogs offer advantages over human insulin in terms of their onset and duration of action.1 This is especially important for patients with T1DM as these preparations more closely mimic pancreatic insulin release.1
Type 1 Diabetes Mellitus
Insulin therapy is critical for patients with T1DM.1,16 While there are many approaches to insulin management for T1DM, some form of insulin should be used in a plan that is customized to the patient's specific needs, prevents hypoglycemia, and achieves glycemic targets.1,16
According to the 2023 Standards of Care Diabetes guidelines, the treatment of T1DM for most patients should involve a multiple daily injection (MDI) regimen of prandial and basal insulin or the use of a continuous subcutaneous insulin infusion (CSII) via a pump.1,16 An example of an MDI regimen is one basal injection and three rapid-acting insulin injections with meals.1 With pump therapy, rapid-acting insulin is infused to cover basal and bolus needs.1 A basal rate of insulin is infused throughout the day, and the patient gives themselves bolus doses based on calculations that take into account glucose levels, carbohydrate intake, and the current amount of insulin being infused.1 While this approach requires more patient education, it allows for a tailored approach to insulin dosing.1
Intensive insulin regimens are meant to mimic normal physiologic insulin secretion.1,16 Recent evidence suggests this approach provides greater efficacy and safety than a once- or twice-daily injection regimen.16 The Diabetes Control and Complications Trial (DCCT) found that intensive insulin therapy reduced A1C and improved long-term outcomes, such as microvascular complications, compared to conventional treatment.30 However, intensive therapy was associated with a greater risk of hypoglycemia.30
Preferably, patients with T1DM should learn carbohydrate counting to better dose their prandial insulin based on carbohydrate intake.1 This can be done using carbohydrate-to-insulin ratios (C:I ratios) and correction factors (CF).1 Carbohydrate-to-insulin ratio estimates the grams of carbohydrates each unit of rapid-acting insulin covers, with a typical ratio being 15:1, wherein 1 unit of insulin covers 15 grams of carbohydrates.1 A starting C:I ratio can be determined by dividing 550 by the TDD of insulin.1 A correction factor is the decrease in BG executed from one unit of insulin and is useful to lower high blood glucose levels before a meal.1 An initial CF can be calculated by dividing 1650 by the TDD of insulin.1
The chosen regimen will be most successful when doses are adjusted based on the patient’s diet, glucose levels, and stress levels, and account for exercise reigmens.1 Intensive regimens are more complex, given the greater number of injections and enhanced monitoring requirements.1
Table 12 provides example insulin regimens for T1DM.16
Table 12
Examples of Insulin Regimens16
| Regimen | Timing and distribution | Advantages | Disadvantages | Adjusting doses |
|---|---|---|---|---|
| Regimens that more closely mimic normal insulin secretion | ||||
Insulin pump therapy (hybrid closed-loop, low-glucose suspend, CGM- augmented open-loop, BGM- augmented open-loop) | Basal delivery of URAA or RAA; generally, 40–60% of TDD. Mealtime and correction: URAA or RAA by bolus based on ICR and/or ISF and target glucose, with pre-meal insulin ∼15 min before eating. | Can adjust basal rates for varying insulin sensitivity by the time of day, for exercise, and for sick days. Flexibility in meal timing and content. The pump can deliver insulin in increments of fractions of units. Potential for integration with CGM for low-glucose suspend or hybrid closed-loop systems. TIR% is the highest, and TBR% is the lowest with: hybrid closed-loop low-glucose suspend CGM- augmented open-loop BGM- augmented open-loop. | Most expensive regimen. Must continuously wear one or more devices. Risk of rapid development of ketosis or DKA with interruption of insulin delivery. Potential reactions to adhesives and site infections. Most technically complex approach (harder for people with lower numeracy or literacy skills). | Mealtime insulin: if carbohydrate counting is accurate, change ICR if glucose after meal consistently out of target. Correction insulin: adjust ISF and/or target glucose if correction does not consistently bring glucose into range. Basal rates: adjust based on overnight, fasting, or daytime glucose outside of the activity of URAA/RAA bolus. |
| MDI: LAA + flexible doses of URAA or RAA at meals | LAA once daily (insulin detemir or insulin glargine may require twice-daily dosing); generally, 50% of TDD. Mealtime and correction: URAA or RAA based on ICR and/or ISF and target glucose. | Can use pens for all components. Flexibility in meal timing and content. Insulin analogs cause less hypoglycemia than human insulins. | At least four daily injections. Most costly insulins. Smallest increment of insulin is 1 unit (0.5 unit with some pens). LAAs may not cover strong dawn phenomenon (rise in glucose in early morning hours) as well as pump therapy. | Mealtime insulin: if carbohydrate counting is accurate, change ICR if glucose after meal consistently out of target. Correction insulin: adjust ISF and/or target glucose if correction does not consistently bring glucose into range. LAA: based on overnight or fasting glucose or daytime glucose outside of activity time course, or URAA or RAA injections. |
| MDI regimens with less flexibility | ||||
| Four injections daily with fixed doses of N and RAA | Pre-breakfast: RAA ∼20% of TDD. Pre-lunch: RAA ∼10% of TDD. Pre-dinner: RAA ∼10% of TDD. Bedtime: N ∼50% of TDD. | May be feasible if unable to carbohydrate count. All meals have RAA coverage. N is less expensive than LAAs. | Shorter duration RAA may lead to basal deficit during day; may need twice-daily N. Greater risk of nocturnal hypoglycemia with N. Requires relatively consistent mealtimes and carbohydrate intake. | Pre-breakfast RAA: based on BGM after breakfast or before lunch. Pre-lunch RAA: based on BGM after lunch or before dinner. Pre-dinner RAA: based on BGM after dinner or at bedtime. Evening N: based on fasting or overnight BGM. |
| Four injections daily with fixed doses of N and R | Pre-breakfast: R ∼20% of TDD. Pre-lunch: R ∼10% of TDD. Pre-dinner: R ∼10% of TDD. Bedtime: N ∼50% of TDD. | May be feasible if unable to carbohydrate count. R can be dosed based on ICR and correction. All meals have R coverage. Least expensive insulins. | Greater risk of nocturnal hypoglycemia with N. Greater risk of delayed post-meal hypoglycemia with R. Requires relatively consistent mealtimes and carbohydrate intake. R must be injected at least 30 min before meal for better effect. | Pre-breakfast R: based on BGM after breakfast or before lunch. Pre-lunch R: based on BGM after lunch or before dinner. Pre-dinner R: based on BGM after dinner or at bedtime. Evening N: based on fasting or overnight BGM. |
| Regimens with fewer daily injections |
|---|
| Three injections daily: N+R or N+RAA | Pre-breakfast: ∼40% N + ∼15% R or RAA. Pre-dinner: ∼15% R or RAA. Bedtime: 30% N. | Morning insulins can be mixed in one syringe. May be appropriate for those who cannot take injection in middle of day. Morning N covers lunch to some extent. Same advantages of RAAs over R. Least (N+R) or less expensive insulins than MDI with analogs. | Greater risk of nocturnal hypoglycemia with N than LAAs. Greater risk of delayed post-meal hypoglycemia with R than RAAs. Requires relatively consistent mealtimes and carbohydrate intake. Coverage of post-lunch glucose often suboptimal. R must be injected at least 30 min before meal for better effect. | Morning N: based on pre-dinner BGM. Morning R: based on pre-lunch BGM. Morning RAA: based on post-breakfast or pre-lunch BGM. Pre-dinner R: based on bedtime BGM. Pre-dinner RAA: based on post-dinner or bedtime BGM. Evening N: based on fasting BGM. |
|---|---|---|---|---|
| Twice-daily “split-mixed”: N+R or N+RAA | Pre-breakfast: ∼40% N + ∼15% R or RAA. Pre-dinner: ∼30% N + ∼15% R or RAA. | Least number of injections for people with strong preference for this. Insulins can be mixed in one syringe. Least (N+R) or less (N+RAA) expensive insulins vs analogs. Eliminates need for doses during the day. | Risk of hypoglycemia in afternoon or middle of night from N. Fixed mealtimes and meal content. Coverage of post-lunch glucose often suboptimal. Difficult to reach targets for blood glucose without hypoglycemia | Morning N: based on pre-dinner BGM. Morning R: based on pre-lunch BGM. Morning RAA: based on post-breakfast or pre-lunch BGM. Evening R: based on bedtime BGM. Evening RAA: based on post-dinner or bedtime BGM. Evening N: based on fasting BGM. |
Type 2 Diabetes Mellitus
Experts recommend that the management of T2DM center on a holistic, multifactorial person-centered approach.16 For many patients, initiation of insulin therapy may be a part of this process. If insulin is started, oral medications may need to be discontinued or dose-reduced, including pioglitazone and sulfonylureas.1 Metformin should be continued. SGLT2 inhibitors and DPP-4 inhibitors can be continued.1
According to ADA guidelines, early initiation of insulin is warranted if any of the following are present: weight loss, symptoms of hyperglycemia, A1C > 10%, or elevated blood glucose levels (> 300 mg/dL).16 If not, GLP-1 RAs are preferred as the first injectable agent.1 Basal insulin can be added to a GLP-1 RA if glycemic targets are not achieved.1 Combining insulin with a glucagon-like peptide receptor agonist provides greater efficacy, durability of the treatment effects, and benefits related to weight and hypoglycemia.16 Fasting glucose can be controlled by adding NPH or a long-acting insulin analog.16 Studies have found long-acting basal analogs reduce the risk of hypoglycemia compared to NPH insulin.16
Given the rising cost of insulin, a patient's ability to afford this treatment should be factored into the decision to add insulin to a regimen.16 Patients with more lenient A1c goals and lower rates of hypoglycemia may benefit from the use of NPH or regular insulin, as these are significantly less expensive.16
Patients with T2DM may also require prandial insulin before meals.16 The guidelines recommend the initiation of a GLP-1 RA prior to adding prandial insulin, given the benefits related to hypoglycemia risk and weight gain. There are no significant differences between regular human insulin and rapid-acting insulin use in T2DM.16
Patient Case
A 59-year-old man with type 2 diabetes returns for follow-up after three months of persistent hyperglycemia despite metformin, semaglutide, and maximally tolerated insulin glargine at 28 units nightly. His HbA1c is 8.4%. His postprandial readings are often above 220 mg/dl. He admits to missing doses when traveling as a commercial truck driver. He requests medication that is easy to remember.
Pause and Ponder What is a possible next step for this patient? |
|---|
The physician discusses differences among insulin preparations and reviews the role of basal, prandial, and ultra-long-acting options.
Insulin icodec-abae is a personalized option for him, a long-distance truck driver, as it is a once-weekly basal insulin. The patient agrees. He is counseled to begin treatment at a dose of 70 units subcutaneously on the same day each week.
An interprofessional clinic team reviews the case together. The pharmacist confirms the appropriate insulin selection and dose, and monitors for any drug interactions. The diabetes educator reinforces injection technique, educates on optimal diet and nutrition options, and lifestyle changes. The primary care team coordinates follow-up monitoring and adherence support.
Pause and Ponder What are some important counseling points to be emphasized when initiating insulin to help a patient use it safely and confidently? |
|---|
Patient Counseling
Counseling that is comprehensive and presented in a patient-friendly, inclusive manner is critical to ensure patients are comfortable with and appropriately utilize their insulin therapies.1,16 Insulin regimens are most effective when used appropriately; thus, not only is the selection of insulin preparations important, but patient counseling is crucial.1 The following are areas of counseling that the healthcare team should address.
Dosing Schedules
Insulin dosing schedules can be complex and require careful monitoring to ensure optimal glycemic control.1 When counseling patients, it is important for clinicians to review individual dosing schedules and emphasize the importance of adherence.1 Patients should be counseled on the appropriate timing of injections as well.1
Storage and Use
The various insulin preparations are associated with different delivery devices. Insulin may come in a vial, disposable pen device, or pen cartridge.1 Further, each pen device differs in terms of its quantity, injection dose, and storage requirements.1 Before use, NPH insulin and suspension-based insulins should be gently rolled or inverted 20 times to ensure the preparation is fully suspended.1 This should be done before each use.1 All insulin pens should be primed with 2 units of insulin prior to each injection, with the exception of the Xultophy pen (patients select a priming symbol), the Humulin R U-500 Kwikpen (should be primed with 5 units), and the Toujeo SoloStar (should be primed with 4 units).
Patients should also be counseled on the appropriate storage of their insulin preparations. This is critical to ensure the medication remains safe and effective. Insulin should be kept refrigerated at 2°C to 8°C (36°F to 46°F) and never frozen.4 Additionally, patients should avoid exposing their insulin to extreme temperatures, such as leaving it in direct sunlight or a car on a hot day.4 Recommendations for the use of coolers can be made for patients who travel frequently. Basal insulin should be stored separately from prandial insulin, if possible, to avoid mixups.4 Patients can use colored stickers on their products to help identify them.4
Patients should be counseled to inspect their insulin before each use and should not use it if the clear formulation appears cloudy, is discolored, or contains floating particles.4 If insulin appears abnormal, it should be disposed of, and a new vial should be used.4 Insulin vials should not be shaken; instead, gently rotate them between the palms to mix the solution.4
Patients should be counseled not to mix insulin preparations unless their clinician has specifically instructed them to do so.4 Insulin glargine, detemir, and degludec should never be mixed in a syringe.4 NPH and regular can be mixed and administered together.4 Patients should be instructed to draw up the clear (regular) insulin first, then the cloudy (NPH) insulin to ensure accurate dosing.4
Potential Side Effects
Insulin therapy can elicit many side effects, including hypoglycemia, weight gain, and injection site reactions. When counseling patients, it is important to provide information on how to recognize and manage these side effects. Hypoglycemia is common with all insulin regimens, but is more likely for patients on an intensive regimen.1 In the DCCT study, the risk of severe hypoglycemia was increased threefold in the intensive glycemic control group versus the conventional therapy group.1,23 Patients should be educated on the signs and symptoms of hypoglycemia and how to treat it, including carrying a fast-acting carbohydrate source with them at all times.1 The primary treatment for hypoglycemia is the consumption of fast-acting carbohydrates, such as glucose tablets, fruit juice, or regular soda.16 Patients should consume 15-20 grams of carbohydrates, wait 15 minutes, and then recheck their blood glucose levels.1 If their blood glucose levels have not returned to normal, they should repeat the treatment.1 If a patient is unconscious or unable to swallow, they may require an injection of glucagon or emergency medical attention.1
Weight gain is also a common side effect of insulin, with most gain occurring in truncal fat.1 Clinicians should also review strategies for managing weight gain, such as following a healthy diet and increasing physical activity. Weight gain can also be offset by combining insulin with other antidiabetic medications that cause weight loss.1
Injection site reactions are common. Signs include redness, itching, edema, and inflammation.1 Lipohypertrophy, a condition characterized by the buildup of fat tissue at the injection site, is also possible.16 This can impair insulin absorption and lead to potential hypoglycemia.16 When lipodystrophy occurs, soft, smooth, raised areas will be noted at the injection site.1 Patients should be instructed to inject insulin into a different site within the same general area rather than repeatedly injecting at the same site.16 Lipoatrophy is caused by insulin antibodies destroying the fat at the injection site and results in skin depression.1 If this occurs, the injection site should be avoided.1
Insulin Injection Technique
Several insulin injection devices are available, including syringes, insulin pens, and insulin pumps.1 Each device has unique features that may be more suitable for some patients than others.1 For example, insulin pens may be more convenient and discreet, while insulin pumps may be more precise and adjustable.1,16 Patients should be instructed in the proper use of their chosen device and given an opportunity to practice under a pharmacist's supervision. Clinicians should directly observe their patients’ injection techniques and offer corrective feedback as needed.1
Components of the insulin injection technique include injecting into the appropriate body areas, rotating the site of injection, appropriately caring for the site(s) of injection to avoid complications, and avoiding intramuscular insulin delivery.16
Insulin injection sites
Insulin must be injected subcutaneously.16 The most common injection sites for insulin are the abdomen, thighs, buttocks, and upper arms.16 If insulin is injected via an intramuscular (IM) route, this can lead to variable absorption and effects on blood glucose levels.16 Ideally, a shorter (4-mm) pen needle should be used.16
Injection technique
Patients should be instructed to first wash their hands and disinfect the site before administering insulin. The following techniques should be used for insulin injections:
Pinch the skin: Patients should be instructed to pinch the skin at the injection site to form a slight fold, creating a space for the needle to enter.1
Needle insertion: The needle should be inserted at a 45 or 90-degree angle, depending on age, skin thickness, and manufacturer recommendations. The needle should be inserted quickly and smoothly, without any hesitation or movement.1
Injection speed: Insulin should be injected slowly over 5-10 seconds to prevent pain and ensure proper absorption.1
Needle withdrawal: The needle should be withdrawn quickly and smoothly to prevent insulin leakage and minimize bleeding.1
Disposal: Used needles and syringes should be disposed of in a sharps container to prevent needlestick injuries.1
Summary
Insulin therapy is a cornerstone of management for many patients with diabetes. The selection of insulin therapy depends on various factors, including the patient's age, weight, lifestyle, comorbidities, and the severity of their diabetes. Each type of insulin has its own onset, duration, and peak of action, making it suitable for different clinical situations. The goal of insulin therapy is to provide tight glycemic control while minimizing the risk of hypoglycemia. Patients with diabetes should work closely with their healthcare provider to develop an individualized insulin regimen that meets their specific needs and lifestyle.
References
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Rahman MS, Hossain KS, Das S, et al. Role of Insulin in Health and Disease: An Update. Int J Mol Sci. 2021;22(12):6403. Published 2021 Jun 15. doi:10.3390/ijms22126403
Trief PM, Cibula D, Rodriguez E, Akel B, Weinstock RS. Incorrect Insulin Administration: A Problem That Warrants Attention. Clin Diabetes. 2016;34(1):25-33. doi:10.2337/diaclin.34.1.25
Donnor T, Sarkar S. Insulin- Pharmacology, Therapeutic Regimens and Principles of Intensive Insulin Therapy. [Updated 2023 Feb 15]. In: Feingold KR, Adler RA, Ahmed SF, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Accessed April 2, 2026. https://www.ncbi.nlm.nih.gov/books/NBK278938/
Wong EY, Kroon L. Ultra-Rapid-Acting Insulins: How Fast Is Really Needed?. Clin Diabetes. 2021;39(4):415-423. doi:10.2337/cd20-0119
LYUMJEV- insulin lispro-aabc injection, solution. Prescribing Information. A-S Medication Solutions. Updated November 6, 2024. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=616daea1-0b79-4970-a141-6f99f2072f02
Alexanian SM, Cheney MC, Spartano NL, et al. Comparing Postprandial Glycemic Control Using Fiasp vs Insulin Aspart in Hospitalized Patients With Type 2 Diabetes. Endocr Pract. 2025;31(3):306-314. doi:10.1016/j.eprac.2024.11.015
Avgerinos I, Papanastasiou G, Karagiannis T, et al. Ultra-rapid-acting insulins for adults with diabetes: A systematic review and meta-analysis. Diabetes Obes Metab. 2021;23(10):2395-2401. doi:10.1111/dom.14461
Hirsch IB, Juneja R, Beals JM, Antalis CJ, Wright EE. The Evolution of Insulin and How it Informs Therapy and Treatment Choices. Endocr Rev. 2020;41(5):733-755. doi:10.1210/endrev/bnaa015
HUMULIN N- insulin human injection, suspension. Prescribing Information. Eli Lilly and Company. Updated December 19, 2025. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6edd793-440b-40c2-96b5-c16133b7a921
Gururaj Setty S, Crasto W, Jarvis J, Khunti K, Davies MJ. New insulins and newer insulin regimens: a review of their role in improving glycaemic control in patients with diabetes. Postgrad Med J. 2016;92(1085):152-164. doi:10.1136/postgradmedj-2015-133716
LANTUS- insulin glargine injection, solution. Prescribing Information. A-S Medication Solutions. Updated February 4, 2023. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ae27bb66-5dbe-4f01-a89e-f4fa7cb09c99
LEVEMIR- insulin detemir injection, solution. Prescribing Information. Novo Nordisk. Updated December 8, 2022. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d38d65c1-25bf-401d-9c7e-a2c3222da8af
SOLIQUA 100/33- insulin glargine and lixisenatide injection, solution. Prescribing Information. Sanofi-Aventis U.S. LLC. Updated March 18, 2026. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4bba538b-cf7c-4310-ae8f-cb711ed21bcc
Matli MC, Wilson AB, Rappsilber LM, Sheffield FP, Farlow ML, Johnson JL. The First Interchangeable Biosimilar Insulin: Insulin Glargine-yfgn. J Diabetes Sci Technol. 2023;17(2):490-494. doi:10.1177/19322968211067511
Standards of Care in Diabetes 2023. American Diabetes Association. Diabetes Care. 2023; 46(1).
TRESIBA- insulin degludec injection, solution. Prescribing Information. Novo Nordisk. Updated July 1, 2022. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=456c5e87-3dfd-46fa-8ac0-c6128d4c97c6
Awiqli. Prescribing Information. Novo Nordisk Inc. March 2026. Accessed April 2, 2026. https://www.novo-pi.com/awiqli.pdf
Diabetes Toolbox. Diabetes Quebec. 2024. Accessed April 2, 2026. https://www.diabetestoolbox.ca/insulines.html#:~:text=Onset%20of%20action:%2015%20min,at%20room%20temperature:%2028%20days
INSULIN ASPART PROTAMINE AND INSULIN ASPART MIX 70/30- insulin aspart injection, suspension. Prescribing Information. Novo Nordisk Pharma, Inc. Updated February 28, 2023. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fc94baa4-3606-48bc-a781-9617ab6960ef
INSULIN LISPRO PROTAMINE AND INSULIN LISPRO INJECTABLE SUSPENSION MIX75/25 KWIKPEN- insulin lispro injection, suspension. Prescribing Information. Eli Lilly and Company. Updated August 6, 2024. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e49f701d-c19f-4cb2-b63f-01a917b33abc
HUMULIN 70/30- insulin human injection, suspension HUMULIN 70/30 KWIKPEN- insulin human injection, suspension. Prescribing Information. Eli Lilly and Company. Updated December 10, 2024. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e245e0c5-b2d6-418b-baa4-1c3324292885
NOVOLOG MIX 70/30- insulin aspart injection, suspension. Prescribing Information. Novo Nordisk. Updated February 28, 2023. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=Novolog+Mix+70%2F30&pagesize=100&page=1
NOVOLOG MIX 70/30 - insulin aspart injection, suspension. Novo Nordisk. Revised 11/2010. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=973a9333-fec7-46dd-8eb5-25738f06ee54&type=display
HUMALOG MIX50/50- insulin lispro injection, suspension HUMALOG MIX50/50 KWIKPEN- insulin lispro injection, suspension. Prescribing Information. Eli Lilly and Company. Updated November 13, 2024. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b34cd3ff-d0af-4852-b4ef-2a8b4a93aeae
HUMALOG MIX75/25- insulin lispro injection, suspension. Prescribing Information. Physicians Total Care, Inc. Updated December 20, 2011. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fbc1ff07-701e-4b7f-93a3-f4309e238e5a
NOVOLIN 70/30- human insulin injection, suspension. Prescribing Information. Novo Nordisk. Updated November 23, 2022. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=508a2763-3cb7-4be5-9e53-544e84cd9b1f#:~:text=NOVOLIN%2070/30%20should%20be%20administered%20subcutaneously:%20*,or%20syringe%20between%20patients%20*%20Medication%20errors
AFREZZA- insulin human powder, metered AFREZZA- insulin human kit AFREZZA- insulin human kit. Prescribing Information. Mannkind Corporation. Updated February 3, 2026. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=29f4637b-e204-425b-b89c-7238008d8c10
Inhaled Insulin: controlling A1c without a needle. US Pharm. 2015;40(10)(Diabetes suppl):3-7.
Diabetes Control and Complications Trial (DCCT): results of feasibility study. The DCCT Research Group. Diabetes Care. 1987;10(1):1-19. doi:10.2337/diacare.10.1.1
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