Glucagon-Like Peptide-1 Based Therapies Materials

PHARMACOLOGIC APPROACHES TO DIABETES MANAGEMENT GLUCAGON-LIKE PEPTIDE-1 BASED THERAPIES

Liz Fredrickson, PharmD, BCPS

Liz Fredrickson is an Associate Professor of Pharmacy Practice at the Northeast Ohio Medical University College of Pharmacy. She previously practiced as an Internal Medicine Clinical Pharmacy Specialist and is Board Certified in Pharmacotherapy.

Topic Overview

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 review glucagon-like peptide-1-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs. Dosing regimens, side effects, and monitoring parameters will be discussed. The role of GLP-1-based therapies within therapeutic regimens for patients with Type 2 diabetes mellitus will be discussed in the context of the updated American Diabetes Association Standards of Care in Diabetes 2023 guidelines.

Accreditation Statement:

RxCe.com LLC is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education.

Universal Activity Number (UAN): The ACPE Universal Activity Number assigned to this activity is 

Pharmacist  0669-0000-23-098-H01-P

Pharmacy Technician  0669-0000-23-099-H01-T

Credits: 1 hour of continuing education credit

Type of Activity: Knowledge

Media: Internet/Home study Fee Information: $4.99

Estimated time to complete activity: 1 hour, including Course Test and course evaluation

Release Date: June 24, 2023 Expiration Date: June 24, 2026

Target Audience: This educational activity is for pharmacists.

How to Earn Credit: From June 24, 2023, through June 24, 2026, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Study the section entitled “educational activity;” and

Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

Credit for this course will be uploaded to CPE Monitor®.

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Compare and contrast available glucagon-like peptide-1-based medications

Identify side effects and contraindications of glucagon-like peptide-1-based medications

Identify when to utilize glucagon-like peptide-1-based medications within a therapeutic regimen for patients with Type 2 diabetes

Recall patient counseling points related to the use of glucagon-like peptide-1-based medications

Disclosures

The following individuals were involved in the development of this activity: Liz Fredrickson, PharmD, BCPS and Pamela Sardo, PharmD, BS. Pamela Sardo, Pharm.D., B.S., was an employee of Rhythm Pharmaceuticals until March 2022 and has no conflicts of interest or relationships regarding the subject matter discussed. There are no financial relationships relevant to this activity to report or disclose by any of the individuals involved in the development of this activity.

© RxCe.com LLC 2023: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.

Introduction

While glucose control is paramount for patients with diabetes, the American Diabetes Association (ADA) Standards of Care 2023 Diabetes guidelines also emphasize the importance of managing comorbidities that can complicate diabetes management. Subsequently, the guidelines highlight the benefits of glucagon-like peptide 1-based therapies. This course will review glucagon-like peptide-1-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs. Dosing regimens, side effects, and monitoring parameters will be discussed. The role of GLP-1-based therapies within therapeutic regimens for patients with Type 2 diabetes will be discussed in the context of the updated Standards of Care in Diabetes 2023 guidelines.

Guidelines for Managing Diabetes and Comorbidities

The American Diabetes Association (ADA) Standards of Care 2023 Diabetes guidelines also emphasize the importance of managing comorbidities that can complicate diabetes management, including atherosclerotic cardiovascular disease (ASCVD), renal disease, and hypertension.1 These injectable medications have gained favor due to their beneficial effects on glycemic control and weight management and cardiorenal protective effects.1 Glucagon-Like Peptide-1 Receptor Agonists

GLP-1 and GIP are incretin hormones responsible for increasing insulin release and decreasing glucagon release, thereby lowering blood glucose levels.2,3 GLP-1 is made in the proglucagon gene within the L cells of the small intestine.3 It goes on to bind GLP-receptors, which are located in pancreatic beta cells, the kidney, heart, and lungs.3 The actions of GLP-1 include glucose- dependent stimulation of insulin secretion, reduction of gastric emptying, and reduction of the inappropriate secretion of glucagon during hyperglycemia.3 The physiological effects of GLP-1 RAs are summarized in Table 1.

Table 1. Physiological Effects of GLP-1 RAs3

There are currently several GLP-1 RAs available, including exenatide immediate-release, exenatide extended-release, liraglutide, dulaglutide, semaglutide, and lixisenatide. Exenatide and lixisenatide are short-acting agents with a main effect on post-prandial glucose levels.4 The long-acting agents (dulaglutide, liraglutide, exenatide XR, and semaglutide) can lower fasting and post-prandial blood glucose levels.5 Because of their long half- lives, they have more pronounced effects on fasting plasma glucose levels.4 These medications share the same mechanism of action but vary in their

pharmacokinetic profiles, efficacy rates, adverse effect rates, dosing schedules, and impact on blood glucose levels and weight loss.4 Below, each agent is described in detail.

Exenatide (Byetta, Bydureon, Bydureon BCise)

Exenatide is available in immediate-release (Byetta) and extended- release formulations (Bydureon and Bydureon BCise).5 Immediate-release exenatide is available as 5 mcg and 10 mcg dose pens, which should be stored in the refrigerator and protected from light.5 Pens should be discarded 30 days after the first use.5 The starting dose is 5 mcg SUBQ twice daily, within 60 minutes of the morning and evening meals (or at least 6 hours apart before two main meals).5 The dose can be increased to 10 mcg twice daily if needed.5 Dose reductions are not required for hepatic impairment.5 Exenatide immediate-release should be avoided in patients with a creatinine clearance of <30 mL/min or those with end-stage renal disease (ESRD).5 Patients with a CrCl of ≥ 30-50 mL/min should be monitored closely for hypovolemia.5

Bydureon is available as a 2 mg pen injector, and Bydureon BCise is available as a 2 mg/0.85 mL single-dose autoinjector.5 Bydureon and Bydureon BCise can be kept in the refrigerator for up to 4 weeks and protected from light.5 Extended-release exenatide is dosed as 2 mcg subcutaneously once weekly without regard to meals.5 If patients miss a dose and the next dose is not due for 3 or more days, the dose can be given at that time.5 If less than 3 days remain until the next dose, the patient should skip the current dose and take the next dose as scheduled.5 No dose adjustments are required for either hepatic impairment, and use is not recommended for an eGFR <30 mL/minute/1.73 m2.5 If a patient is being converted from immediate-release to extended-release exenatide, the extended-release formulation should be started the day after discontinuing the immediate-release form.5

Liraglutide (Victoza)

Liraglutide is available as 18 mg/3 mL multidose pen.6 Before the first use, it can be stored in the refrigerator and then kept at room temperature or

in the refrigerator. It should be discarded 30 days after its first use and protected from light and heat.6 Liraglutide is dosed initially at 0.6 mg SUBQ once daily.6 This initial dose is not therapeutic but is used to acclimate the patient to associated gastrointestinal (GI) symptoms, like nausea.6 After the first week, the dose is increased to 1.2 mg SUBQ once daily.6 The dose can be maximally increased to 1.8 mg, if needed, for glycemic control.6 Liraglutide can be dosed without regard to meals.6 If a dose is missed, the regimen can be resumed with the next scheduled dose.6 If the patient goes three days without a dose, they should resume dosing at 0.6 mg once daily and titrate appropriately. While dose adjustments are unnecessary for renal impairment, patients should be monitored closely when increasing the dose.6 Caution should be used if hepatic impairment is present.6

Insulin Degludec/Liraglutide (Xultophy 100/3.6)

Insulin degludec is available in combination with liraglutide as Xultophy.7 This multi-dose pen injector contains 100 units/mL of insulin degludec and 3.6 mg/mL of liraglutide.7 Pens must be stored in the refrigerator until first use, after which they can be kept at room temperature or in the refrigerator.7 Pens should not be stored with the needle attached.7 The dosing depends on if patients are naive to insulin and GLP-1 RA therapy.7

For patients naive to insulin and GLP-1 RA therapy, the starting dose is 10 units insulin degludec and 0.36 mg liraglutide once daily

For patients currently on basal insulin or GLP-1 agonist therapy, the starting dose is 16 units insulin degludec and 0.58 mg liraglutide once daily

Doses are adjusted by 2 units (2 units of insulin degludec and 0.072 mg of liraglutide) every three to four days (once or twice weekly) until glycemic goals are reached.7 The maximum dose is 50 units of insulin degludec and 1.8 mg of liraglutide.7 Like liraglutide monotherapy, if a dose is missed, it should be skipped, and the patient can resume the next dose.7 If the patient goes three days without a dose, they should resume dosing the starting dose to

minimize side effects.7 In patients with renal or hepatic impairment, monitoring for hypoglycemia should occur.7

Dulaglutide (Trulicity)

Dulaglutide is a once-weekly injection and comes as pens of numerous strengths, including 0.75 mg, 1.5 mg, 3 mg, and 4.5 mg.8 Pens should be stored in the refrigerator and not frozen.8 The starting dose is 0.75 mg SUBQ once weekly, which may be injected any time of day without regard to meals.8 If needed, the dose can be increased to 1.5 mg once weekly after 4-8 weeks.8 Further dose escalations to 3 mg (after more than 4 weeks on the 1.5 mg dose) and 4.5 mg (after more than 4 weeks on the 3 mg dose) can be done.8 If patients miss a dose and the next dose is not due for 3 or more days, the dose can be given at that time.8 If less than 3 days remain until the next dose, the patient should skip the current dose and take the next dose as scheduled.8 No dose adjustments are required for either hepatic or renal impairment, but caution is warranted.8

Lixisenatide (Adylxin)

Lixisendatide was discontinued within the US market in January of 2023.9

Insulin Glargine/Lixisenatide (Soliqua 100/33)

Insulin glargine is available in combination with lixisenatide as Soliqua.10 It is available as a pen that contains 100 units/mL of insulin glargine and 33 mcg/mL of lixisenatide.10 Pens can be stored in the refrigerator until the first use; afterward, they can be kept at room temperature for up to 28 days.10 The dosing of Soliqua is dependent on the current quantity of basal insulin the patient takes per day, with or without a GLP-1 RA.10

If the patient is naive to basal insulin or uncontrolled on <30 units/day of basal insulin (with or without a GLP-1 agonist), the starting dose is 15 units (15 units insulin glargine/5 mcg lixisenatide) once daily

If the patient is uncontrolled on 30 units to 60 units/day of basal insulin the starting dose is 30 units (30 units insulin glargine/10 mcg lixisenatide) once daily

Doses should be administered one hour before the first meal of the day.10 If a dose is missed, it should be skipped, and the next dose should be taken at the regularly scheduled time.10 The dose of Soliqua can be adjusted in increments of 2 to 4 units each week, up to a maximum dose of 60 units of insulin glargine and 20 mcg of lixisenatide per day.10 This combination is not recommended for patients with end-stage renal disease (ESRD), and patients with hepatic impairment should have increased blood glucose monitoring.10

Semaglutide (Ozempic)

Semaglutide injection, brand name Ozempic, is available in three strengths of multidose pens in various strengths.11 Pens should be stored in the refrigerator until the first use. After, they can be kept at room temperature or in the refrigerator for up to 56 days.11 They should be protected from heat and light.11

The starting dose of injectable semaglutide is 0.25 mg SUBQ once daily without regard to meals.11 This dose can be increased to 0.5 mg once weekly after four weeks and then to 1 mg once weekly after four additional weeks if needed.11 The max dose is 2 mg once weekly.11 If a dose is missed within 5 days of the scheduled dose, the patient may take that dose.11 If more than 5 days have passed, they should skip that dose and wait until the next scheduled dose.11 Doses need not be adjusted for renal or hepatic impairment.11

Semaglutide (Rybelsus)

Semaglutide is also available in an oral formulation, Rybelsus.12 This formulation is available as 3 mg, 7 mg, and 14 mg tablets.12 This initial dose is 3 mg once daily.12 If needed, the dose can be increased to 7 mg after 30 days and to 14 mg after an additional 30 days.12 Oral semaglutide should be taken with a maximum of 4 ounces of water 30 minutes before the first food,

drink, or medication of the day.12 Patients on the 14 mg dose can switch to injectable semaglutide at a dose of 0.5 mg once weekly, starting the day after the final oral dose.12 Conversely, patients on 0.5 mg SUBQ once weekly can switch to the oral formulation at either the 7 mg or 14 mg dose, starting one week after the last SUBQ dose.12 No dose adjustments are required for either hepatic or renal impairment.12

Side Effects and Monitoring

The most common side effects of GLP-1 RAs include nausea, vomiting, diarrhea, and injection site reactions. Side effects of specific GLP-1 RAs and their incidences are presented in Table 2.5-13 Nausea and other gastrointestinal (GI) side effects are often dose-dependent and more likely during the initiation and dose escalation of these medications.13 Fortunately, they are typically transient and mild to moderate in their severity.13 In clinical trials, GI side effects led to a discontinuation rate of 5-10%.13 To mitigate GI side effects such as nausea, a patient-centered approach should be used. Experts suggest using the “three Es” method, which includes Education and explanation, Escalation to an appropriate dose, and Effective management of GI side effects.13 First, patients should be educated on the potential for GI side effects, and that these are typically mild and transient.13 Second, gradual dose escalation can assist in reducing GI effects.13 Finally, the management of side effects that do occur includes decreasing the volume of food intake at meals, increasing fiber and water intake, and moderating consumption of alcohol and fizzy drinks.13 Due to a lack of evidence, GLP-1 RAs are not recommended in patients with gastroparesis.13

Injection site reactions are also common but have transient side effects.13 Potential signs and symptoms of injection site reactions include discomfort at the site of the injection, erythema, swelling, discoloration, pain, warmth, and pruritus.13 These side effects typically resolve with continued use of the medication.13 Exenatide XR may cause injection site nodules as a result of its formulation.4 Hypoglycemia is a rare side effect of GLP-1 RAs when used as monotherapy, but it may occur when used in combination with other glucose-lowering medications, such as insulin or sulfonylureas.13 Other

potential side effects of GLP-1 RAs include pancreatitis, thyroid tumors, and acute renal failure.13 However, the incidence of these adverse events is rare.13 Patients should be counseled on the signs and symptoms of pancreatitis, which include persistent, severe abdominal pain.1,13 Patients should also be advised on the risk of dehydration that may occur with these medications and be counseled to maintain an adequate intake of fluids.1,13

A progression of reinopathy was noted with semaglutide use in clinical trials.3 While the underlying etiology of this is uncertain, it is recommended to slowly titrate semaglutide in patients with a history of diabetic retinopathy and complete retinal screenings every 6 months.3

Table 2. Common Side Effects of GLP-1 RAs5-13

Contraindications

GLP-1 RAs are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or patients with multiple endocrine neoplasia syndrome type 2.4,5-12 They should also be used cautiously in patients with a history of pancreatitis.4,5-12 In post-marketing reviews of these drugs, cases of both hemorrhagic and nonhemorrhagic pancreatitis have been noted.4,5-12 If pancreatitis occurs, the drug should be discontinued and not restarted.4,5-12

GIP/GLP-1 RAs

In addition to the beneficial effects of GLP-1 RAs, recent evidence has found that the coadministration of a glucose-dependent insulinotropic polypeptide (GIP) with a GLP-1 RA has a synergistic effect on insulin and glucagon responses. GIP acts at the pancreas, GI tract, kidney, heart, and brain and is more predominant in its effects on releasing insulin as a response to glucose intake.15,16

Tirzepatide is a novel GIP/GLP-1 RA approved in 2022 that has been found to have significant effects on both glucose-lowering and weight loss.15 Five phase three clinical trials have supported the use of tirzepatide in the treatment of T2DM.15 The trials compared tirzepatide to either placebo, insulin, or semaglutide, with a primary endpoint of change in hemoglobin A1C (A1C).15 In SURPASS-1, which compared tirzepatide to placebo, 92% of patients achieved an A1C level of <7% compared to placebo.16 SURPASS-2 compared tirzepatide to once-weekly semaglutide and found more patients were able to achieve A1c levels less than 7%, 6.5%, and 5.7% compared to semaglutide.17 Tirzepatide also led to significantly greater weight loss. SURPASS-3 compared the addition of tirzepatide to metformin (with or without an SGLT2-i) and compared this to insulin degludec. A greater percentage of patients achieved an A1C <7% in the tirzepatide group compared to the insulin group.18

Pharmacokinetics

Tirzepatide is metabolized via proteolytic cleavage of the peptide backbone, beta-oxidation of the C-20 fatty diacid moiety, and through amide hydrolysis.19 Its half-life elimination is five days and it has a time to peak of 8 to 72 hours.19

Dosing

Tirpazetide is available as a 0.5 mL prefilled, auto injector pen.19 The pen should be stored in the refrigerator and left at room temperature for up to 21 days.19 Pens should be protected from light.19 The initial dose is 2.5 mg subcutaneously once weekly.19 After four weeks, the dose can be increased by 2.5 mg.19 The dose can be subsequently increased every four weeks to a maximum dose of 15 mg SUBQ once weekly to achieve glycemic goals.19 Dose adjustments are not necessary for either renal or hepatic impairment.19

Side Effects

The side effect profile of tirzepatide is similar to the GLP-1 RAs, with gastrointestinal adverse reactions common.19 These include nausea, diarrhea, vomiting, and a decrease in appetite.19 GI effects are dose-dependent and transient.13,19 To mitigate these side effects, patients should be started on the lowest dose, with gradual dose escalation.13,19 Less common side effects noted in the trials included hypoglycemia, injection site reactions, hypersensitivity reactions, and pancreatitis.19

Contraindications and Warnings

Tirzepatide is contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple neoplasia endocrine syndrome 2.19 Patients should be cautioned of the potential for acute pancreatitis and gallbladder disease.19 Like the GLP-1 RAs, tirzepatide can result in dehydration which can subsequently lead to acute kidney injury.19 Patients should be counseled to maintain adequate fluid intake.19

If tirzepatide is combined with sulfonylureas, meglitinides, or insulin, the doses of these antiglycemic agents may need to be lowered to avoid the risk of hypoglycemia.19 Tirzepatide should not be used in combination with a GLP-1 RA.19

Choice of Glucose-Lowering Therapy Type 2 Diabetes Mellitus

Current ADA guidelines highlight the importance of approaching the management of diabetes with a holistic, multi-factorial person-centered approach.1 With regard to the pharmacologic treatment of Type 2 Diabetes Mellitus (T2DM), many person-specific factors must be considered when determining the approach treatment regimen.1 These include glycemic goals, weight-loss goals, risk of hypoglycemia, cardiorenal protection, medication side effects, the complexity of the medication regimen, and access to and affordability of the chosen regimen.1 Unless contraindications are present, the guidelines recommend starting pharmacotherapy at the time of diagnosis.1

Cardiovascular and Renal Protection

The choice of glucose-lowering therapy is broadly divided between agents that provide cardiorenal protection and those that achieve and maintain glycemic and weight loss goals.1 The use of GLP-1 RAs is promoted for the achievement of both goals.1 For patients with ASCVD or high-risk indicators of ASCVD, GLP-1 RAs with a proven cardiovascular disease (CVD) benefit–dulaglutide, semaglutide, and liraglutide–are recommended, as they have demonstrated reductions in myocardial infarctions, and stroke.1,4 Lixisenatide and exenatide have demonstrated cardiovascular safety but not a reduction in major cardiovascular (CV) adverse events.4 GLP-1 RAs with CVD benefits are also recommended for patients with chronic kidney disease (CKD) who cannot tolerate or have a contraindication to an SGLT2 inhibitor.1

Short-Acting vs. Long-Acting Agents

In trials comparing long-acting GLP-1 RAs (exenatide or dulaglutide once weekly or liraglutide once daily) compared with short-acting GLP-1 RAs (exenatide twice daily), long-acting agents were found to have a greater effect on A1c reduction.3 Generally, long-acting GLP-1 RAs are preferred over short- acting GLP-1 RAs in patients without ASCVD, given their convenience and better efficacy with regard to blood glucose control.3

Glycemic Control

GLP-1 RAs can be used at many points during the course of treating T2DM and also may be combined with various other agents, including metformin and insulin.4 They should not be used with DPP-4 inhibitors due to similar mechanisms of action.4 A meta-analysis of 57 trials found GLP-1 RAs to be effective in lowering glucose levels in patients with T2DM while avoiding the hypoglycemia risks associated with the use of insulin and sulfonylureas.20 A second meta-analysis found dulaglutide and extended-release exenatide reduced A1C levels more than basal insulin.21

Table 3. Average A1C reduction for GLP-1 based therapies22-31

Regarding glycemic and weight control, high-dose dulaglutide, semaglutide, and tirzepatide are recommended first-line within the ADA guidelines due to their very high efficacy in lowering glucose levels.1 While glycemic control is similar among the agents, tirzepatide was found to be more efficacious compared to semaglutide 1 mg SUBQ; liraglutide and weekly semaglutide over weekly exenatide, and SUBQ semaglutide over dulaglutide or liraglutide.1,3 Average A1C reduction levels associated with GLP-1-based therapies are presented in Table 3 above.

Weight Loss

GLP-1 RAs and tirzepatide are well-associated with weight loss, which provides secondary benefits to patients with T2DM.1 Semaglutide and tirzepatide also have very high efficacy for weight loss, and dulaglutide and liraglutide have high weight loss efficacy.1

Table 4. Average weight loss with GLP-1 Based Therapies22,25-31,32,33

Combination Therapy

GLP-1 RAs are also helpful as combination therapy. These agents have been studied in combination with metformin, with or without a sulfonylurea.2 If these agents are used with a sulfonylurea, the dose of the sulfonylurea should be decreased to avoid hypoglycemia.2 They should not be used in combination with DPP4 inhibitors.2 Exenatide, liraglutide, dulaglutide, and semaglutide have been studied in combination with pioglitazone, and no dose reduction of pioglitazone is required.2 Extended-release exenatide and dulaglutide have been studied in combination with SGLT2 inhibitors. When added to SGLT2 therapy, patients see heightened cardiorenal protective effects while also receiving complementary benefits from each class of medication.2

Various trials have compared adding an injectable GLP-1 RA to insulin for patients requiring further glucose lowering.1,2 In these studies, findings suggest the glycemic efficacy of injectable GLP-1 RA was similar to or greater than that of basal insulin.1 GLP-1 RAs also had the benefit of causing less hypoglycemia than insulin while promoting weight loss rather than weight gain.1 Adding a GLP-1 RA to an insulin regimen is sometimes preferred over intensifying insulin therapy due to these beneficial effects.1 However, when GLP-1 RA to therapy, the cost, and tolerability of the medication should be considered.1,2 Additionally, the dose of basal insulin should typically be lowered to combat hypoglycemia risk.1,2 There is no specific dose reduction recommendation, but clinicians could begin with a 20% dose reduction of basal insulin when starting a GLP-1 RA.1,2

There is less data available to support using GLP-1 RAs in combination with prandial insulin.1 One study reviewed the addition of dulaglutide to insulin lispro in patients with T2DM who did not meet glycemic targets utilizing a basal-bolus insulin regimen.1 The dulaglutide combination decreased HbA1c levels significantly compared to the basal-bolus regimen.1

Renal and Hepatic Disease

Liraglutide, semaglutide, and dulaglutide are not renally excreted and do not require dose reductions due to renal impairment.3 These agents may be used in patients with stage 4 kidney disease, but close monitoring is required.3 More caution is warranted with the use of short-acting agents in the presence of decreased kidney function. It is recommended that serum creatinine levels are monitored within four weeks of initiating therapy and 2- 3 months following a dose increase.3

Patient Counseling Points

Despite their benefits, the use of GLP-1 RAs or tirzepatide adds complexity to patients’ diabetic regimens, given that most of these agents are injectables.2 Clinicians should be knowledgeable regarding the use and administration of these agents and prepared to counsel patients in a patient- centered manner.2 The following are pertinent patient counseling points.

Use and Administration

Table 5. Administration of GLP-1 Ras2

Table 5 above details pertinent information regarding the mode of administration of the GLP-1 RAs.2

Injection Technique

Proper injection technique is a crucial aspect of administering GLP-1 RAs and GIP-RAs to ensure effective treatment and patient safety.2 Each agent is associated with specific administration instructions.5 Proper injection techniques can minimize the risk of injection site reactions, increase medication absorption, and improve patient compliance.2,4

Storage

GLP-1 RAs and GIP-RAs are injectable diabetes medications that have specific storage requirements to ensure their effectiveness and safety. Storage recommendations for these medications vary by the type and brand, but generally, they should be stored in the refrigerator between 36°F and 46°F (2°C and 8°C) until their expiration date.5-12 Once opened, GLP-1 RAs and tirzepatide can be kept at room temperature (68°F to 77°F or 20°C to 25°C) for a specified period of time.5-12

Patients should be advised to check the expiration date before using their medication and to discard any expired medication. Additionally, they should be instructed to protect their medication from light, heat, and freezing temperatures.5-12

Summary

GLP-1 RAs are injectable medications that stimulate the GLP-1 receptor, leading to increased insulin secretion, decreased glucagon secretion, and delayed gastric emptying. They also have additional cardiovascular and weight loss benefits. There are many different types of GLP-1 RAs, including short- acting and long-acting formulations, which vary with regard to dosing and administration. Clinicians should be knowledgeable regarding the use and administration of these agents and prepared to counsel patients in a patient- centered manner.

Course Test

Which of the following GLP-1 RAs must be taken before a meal?

Exenatide immediate-release

Exenatide extended-release

Dulaglutide

Semaglutide

Which of the following GLP-1 RAs may lead to reductions in cardiovascular events such as strokes?

Lixisenatide

Exenatide

Semaglutide

Tirzepatide

Which of the following GLP-1 RAs is noted in the ADA guidelines as having high efficacy for weight loss?

Semaglutide

Lixisenatide

Dulaglutide

Liraglutide

Which of the following side effects of GLP-1 RAs can be mitigated by slowly titrating up doses of these medications?

Heachache

Nausea

Dizziness

Injection site reactions

Which of the following is a contraindication to GLP-1 RA therapy?

Colon cancer

Family history of heart disease

Multiple endocrine neoplasia syndrome

Adrenal hypoplasia

Per the ADA guidelines, which of the following medications would be recommended first-line for a patient with weight loss as a major goal of therapy?

Tirzepatide

Low dose dulaglutide

Liraglutide

Lixisenatide

Per the ADA guidelines, GLP-1 RAs can be combined with other antihyperglycemic agents. Which of the following agents should GLP-1 RAs not be combined with?

Metformin

Insulin

DPP-4 inhibitors

SGLT2-inhibitors

Patients should be counseled on reconstitution methods if they are taking which of the following agents?

Liraglutide

Dulaglutide

Extended-release exenatide

Immediate-release exenatide

Which of the following is an appropriate counseling point regarding the storage of GLP-1 RAs?

GLP-1 RAs can be stored in the freezer to prolong their shelf life

GLP-1 RAs do not require protection from light

GLP-1 RAs can be kept at room temperature for a specific period of time after the first use

GLP-1 RAs can be used for one year after their expiration date

Which of the following GLP-1 RAs can be dosed orally or subcutaneously?

Semaglutide

Dulaglutide

Liraglutide

Lixisenatide

References

Standards of Care in Diabetes 2023. American Diabetes Association. Diabetes Care. 2023; 46(1).

Romera I, Cebrián-Cuenca A, Álvarez-Guisasola F, Gomez-Peralta F, Reviriego J. A Review of Practical Issues on the Use of Glucagon-Like Peptide-1 Receptor Agonists for the Management of Type 2 Diabetes. Diabetes Ther. 2019;10(1):5-19. doi:10.1007/s13300-018-0535-9

Dugan K and DeSantis A. Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus. Uptodate. May 4, 2023. Accessed May 2023.

Trujillo J, Haines S. Diabetes Mellitus. In: DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey L. eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw Hill; 2023. Accessed May 30, 2023.

Lexicomp Online, Exenatide. Waltham, MA: UpToDate, Inc.; May 6, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Liraglutide. Waltham, MA: UpToDate, Inc.; June 2, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Xultophy. Waltham, MA: UpToDate, Inc.; June 1, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Dulaglutide. Waltham, MA: UpToDate, Inc.; June 2, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Lixisenatide. Waltham, MA: UpToDate, Inc.; May 5, 2023. https://online.lexi.com. Accessed May 30, 2023.

Lexicomp Online, Soliqua. Waltham, MA: UpToDate, Inc.; May 6, 2023. https://online.lexi.com. Accessed May 2023.

Lexicomp Online, Ozempic. Waltham, MA: UpToDate, Inc.; May 31, 2023. https://online.lexi.com. Accessed May 30, 2023.

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The information provided in this course is general in nature, and it is solely designed to provide participants with continuing education credit(s). This course and materials are not meant to substitute for the independent, professional judgment of any participant regarding that participant’s professional practice, including but not limited to patient assessment, diagnosis, treatment, and/or health management. Medical and pharmacy practices, rules, and laws vary from state to state, and this course does not cover the laws of each state; therefore, participants must consult the laws of their state as they relate to their professional practice.

Healthcare professionals, including pharmacists and pharmacy technicians, must consult with their employer, healthcare facility, hospital, or other organization, for guidelines, protocols, and procedures they are to follow. The information provided in this course does not replace those guidelines, protocols, and procedures but is for academic purposes only, and this course’s limited purpose is for the completion of continuing education credits.

Participants are advised and acknowledge that information related to medications, their administration, dosing, contraindications, adverse reactions, interactions, warnings, precautions, or accepted uses are constantly changing, and any person taking this course understands that such person must make an independent review of medication information prior to any patient assessment, diagnosis, treatment and/or health management. Any discussion of off-label use of any medication, device, or procedure is informational only, and such uses are not endorsed hereby.

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