Continuing Education Activity

Insulin glargine is a synthetic version of human insulin that is FDA approved to treat adults and children with type 1 diabetes and adults with type 2 diabetes to improve and maintain glycemic control. Insulin glargine is a long-acting insulin injected once daily and provided a basal insulin level throughout the day. Regimens often combine it with rapid-acting insulin to obtain optimal glycemic control. The insulin should not be used to treat diabetic ketoacidosis, as short-acting insulin is preferred. This activity will cover the indications, mechanism of action, adverse effects, contraindications, monitoring, and toxicity of insulin glargine pertinent for healthcare professionals.

Objectives:

• Identify the mechanism of action of insulin glargine.
• Describe the contraindications of insulin glargine.
• Review the appropriate monitoring for insulin glargine.
• Explain some interprofessional team strategies for improving care coordination and communication to advance treatment with insulin glargine and improve outcomes.

Indications

Insulin glargine is a synthetic version of human insulin that is FDA approved to treat adults and children with type 1 diabetes and adults with type 2 diabetes to improve and maintain glycemic control. Insulin glargine is a long-acting insulin injected once daily and provides a basal insulin level throughout the day. Regimens often combine it with rapid-acting insulin to obtain optimal glycemic control. The insulin should not be used to treat diabetic ketoacidosis, as short-acting insulin is preferred. 

In type 1 diabetes, both long-acting and short-acting insulins are often necessary at the onset of the disease. In type 1 diabetes, the body lacks the ability to produce insulin from the pancreas due to autoimmune-mediated beta cell destruction, with a resulting rapid loss of regulation of blood glucose levels. Insulin glargine functions as basal glycemic control due to its 24-hour duration of action, while rapid-acting insulin works as coverage of elevated blood glucose and carbohydrate intake due to its quick onset and short duration of action. 

In adults with type 2 diabetes, insulin glargine, or another long-acting insulin, should be initiated for glycemic control after 2 or 3 oral antidiabetic medications have failed to attain glycemic control or in patients with a hemoglobin A1c value higher than 9% who are experiencing symptoms. Insulin glargine may be used alone in individual patients or with rapid-acting insulin and/or oral medication(s) for diabetes management. Insulin glargine does not have approval for children with type 2 diabetes.[1]  

Insulin glargine is not FDA-approved in pregnancy, although studies have not shown contraindications to its use or adverse fetal outcomes. It is considered a first-line treatment for gestational diabetes after lifestyle modifications have proven insufficient.[2][3]

Mechanism of Action

Insulin glargine is a recombinant human insulin analog that binds to insulin receptors (IR). Insulin is necessary to regulate lipid, glucose, and energy homeostasis. It acts mainly on the skeletal muscle, adipose tissue, and liver. The IR is a tyrosine kinase receptor with two extracellular alpha domains and two intracellular catalytic beta domains. Upon insulin binding, a conformational change occurs to the beta catalytic domains that activate the tyrosine kinase domains, causing them to auto-phosphorylate the beta subunits. Once activated, the beta subunits can bind docking proteins, which leads to the activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3k) and an intracellular signaling cascade, eventually activating protein kinase B (also known as Akt). Akt regulates the activity of the glucose transporter type 4 (GLUT4) receptor, protein kinase C (PKC), and the mitogen-activated protein kinase (MAPK or MAP kinase) pathway.[4]

Insulin glargine has an onset of action of 1.5 to 2 hours. It has a long duration of action of up to 24 hours due to modifications of amino acids, including Asn to Gly at position 21 of the A chain and the addition of two Arg residues and positions 31 and 32 of the B chain. This arrangement allows the insulin to remain soluble at a pH of 4.0, which is the pH of the solution in which it is administered, and then become insoluble at physiologic pH. Once insulin glargine is injected into the body and introduced to the higher pH, the insoluble precipitate that forms slowly releases soluble protein over 24 hours.[5]

Administration

Insulin glargine comes either in 100 ml vials or dosing pens containing 3 ml cartridges of medication and is administered via subcutaneous injection only. The drug is available at a concentration of 100 units per ml. Its administration includes a diluent with a pH of 4.0 to maintain the solubility of the drug before use. The medication is administered once daily at the same time of day by the patient. Decisions of when to administer insulin glargine depend on the patient's schedule and the resultant effects that the insulin has on the patient's blood glucose levels. Patients should rotate injection sites to avoid lipodystrophy; these include the top of the thighs, back of the upper arms, buttocks, or abdomen. 

The estimated starting dose of insulin therapy is usually 0.4 to 0.5 units/kg per day of total insulin. However, differing amounts might be necessary for patients undergoing puberty or those with obesity. The current consensus regarding basal insulin dosing is that it should make up 50% of the total daily insulin requirement. Although it is worth noting that recent studies have suggested that a basal dose closer to 40% of total daily insulin may result in more optimal glycemic control.[6]

Adverse Effects

The most common adverse effect of insulin glargine is hypoglycemia. Special attention is necessary for insulin usage in fasting patients who have recently changed their diets or have had recent activity changes, such as beginning a workout program. Hypoglycemia characteristically demonstrates autonomic symptoms, including diaphoresis, nausea, palpitations, tremors, anxiety, lethargy, and decreased concentration, among others. With severe hypoglycemia, unconsciousness, seizures, coma, and death may occur. Adverse effects may also include allergic reactions to the diluent, site injection reactions or infection, and lipodystrophy at the injection site. Insulin glargine may also cause pain upon injection at the site due to the acidity of the diluent.[7]

It is also essential to be aware of medications administered concurrently with insulin glargine. Certain medications can increase the risk of hypoglycemia when given concomitantly with insulin. Certain medications may also diminish the effectiveness of insulin glargine, causing hyperglycemia or masking symptoms of hypoglycemia. The risk of hypoglycemia may increase with the coadministration of antidiabetic drugs, other insulins, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, sulfonamide antibiotics, and somatostatin analogs. The effectiveness of insulin glargine may diminish when administered with atypical antipsychotics, corticosteroids, danazol, diuretics, estrogens, isoniazid, niacin, phenothiazines protease inhibitors, somatotropin, sympathomimetic agents, and thyroid hormone replacements.[8]

Another concern regarding drug interactions includes the possibility of medications such as beta-blockers, clonidine, guanethidine, and reserpine, masking symptoms of hypoglycemia. Lastly, thiazolidinediones have an increased risk of causing dose-related fluid retention when administered with insulin.

Contraindications

Insulin glargine is contraindicated in patients with a documented hypersensitivity to the drug or one of its components. It also should not be administered during a hypoglycemic episode. However, patients can restart the medication once the episode has resolved. Caution is advisable in current infection, hypokalemia, kidney dysfunction, and liver disease.[9]

Insulin glargine is considered safe during pregnancy, and there are no known risks of infant harm if using the medication during lactation. However, the FDA lists insulin glargine as category C in pregnancy, stating that the patient should only use it if the benefits outweigh the risk.[10][2][10][2]

Monitoring

There is no specific safe range for insulin glargine as the dose is adjusted individually and depends on factors specific to the individual, including responsiveness to the insulin, diet, and daily routine. Other contributing factors that merit consideration during dosing include the type of diabetes, body weight, compliance, and rate of medication elimination. Safety issues that can arise include confusing insulin glargine with another insulin that the patient is taking concurrently. If an individual takes an inappropriate insulin dose, they are at high risk of suffering severe hypoglycemia.

The effects of insulin glargine are monitored on an outpatient basis utilizing a glucometer or continuous glucose monitor to follow blood glucose trends. The dosing of insulin depends on those findings. Continuous glucose monitors are becoming a more popular means to monitor blood glucose levels and the efficacy of an insulin regimen.[11]

Toxicity

Overdose of insulin glargine leads to hypoglycemia, which can be severe and persistent due to the long-acting nature of this insulin. In the case of mild hypoglycemia, carbohydrate intake is typically sufficient to restore euglycemia. The patient should ingest 15 grams of carbohydrates, wait 15 minutes, and recheck their blood glucose level. If it remains hypoglycemic, the procedure is repeated. In the case of severe hypoglycemia or if there is a reason that oral intake is not possible, then injectable glucagon is an option. Another option typically reserved for severe hypoglycemia in the hospital or EMS setting is intravenous dextrose. From published reports, dextrose infusion alone was sufficient to correct hypoglycemia. The long-acting nature of the insulin must also merit consideration; dextrose infusions may need to be repeated beyond the predicted 24-hour lifetime of the medication.[12][13][14]

Enhancing Healthcare Team Outcomes

The increasing rates of type 2 diabetes and the relative paucity of endocrinologists mean that initiating glucose control in uncomplicated type 2 diabetes should be part of the routine practice of interprofessional healthcare teams. Ideally, these teams would be composed of clinicians (MDs, DOs, NPs, PAs), practice nurses, pharmacists, and certified diabetes educators. Some obstacles to implementing such care within a primary interprofessional team include ambiguity of roles, uncertainty of competency, and poor communication. For example, there is some ambiguity in the role of the primary care versus specialist clinician in the initiation of insulin and determining which patients do or do not meet the criteria of 'complicated.' Furthermore, there are misunderstandings as to the ability to administer, educate, and adjust insulin between clinicians, practice nurses, and diabetes nurse educators.

Finally,  poor communication between professional categories can lead to inadequate care, such that physicians communicate better with other physicians than with practice nurses, etc. Overcoming the obstacles listed above can lead to better patient outcomes and improved safety. [Level 4-5] This study has some limitations due to its use of a convenience sample of providers. Also, the study focused on provider factors alone that affect patient outcomes and did not consider any patient factors that may have impacted patient outcomes.[15] But all of these factors point towards interprofessional team management of diabetes in general and the use of insulin glargine specifically, driving better patient outcomes.