PHARMACOLOGIC APPROACHES TO DIABETES MANAGEMENT: GLUCAGON-LIKE PEPTIDE-1 BASED THERAPIES
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 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 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: JA4008424-0000-26-045-H01-P
Pharmacy Technicians: JA4008424-0000-26-045-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
Type 2 diabetes management is evolving to more frequently include treatment to improve glycemic control and simultaneously address weight and cardiorenal risk. Available glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs differ in dosing, duration of action, efficacy, adverse effects, contraindications, and place in therapy. Healthcare professionals must be able to counsel patients accurately to support the safe use of these treatments and to promote treatment adherence. Challenges persist when patients presenting with type 2 diabetes mellitus also present with obesity, cardiovascular risk, or kidney disease. Treatment intensification may include GLP-1-based therapies, which require assessment of clinical goals and tolerability. Careful selection and counseling are required in the consideration of gastrointestinal side effects and injection techniques. This activity aims to address safety challenges, compare the treatments, and improve education, with the ultimate goal of optimizing patient outcomes.
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 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
Clinical trials, particularly the SUSTAIN-6 study, identified a higher incidence of diabetic retinopathy complications (such as vitreous hemorrhage or blindness) in patients using semaglutide. It is recommended that patients with a history of diabetic retinopathy should
avoid or discontinue using semaglutide.
titrate semaglutide and complete retinal screenings every 6 months.
alternate between different oral semaglutide brands to see which one performs best.
be counseled to reduce fluid intake to mitigate the progression of retinopathy.
Which of the following side effects of GLP-1 RAs can be mitigated by slowly titrating up doses of these medications?
Headaches
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 type 2
Adrenal hypoplasia
Educational Activity
Pharmacologic Approaches to Diabetes Management: Glucagon-Like Peptide-1 Based Therapies
Introduction
While glucose control is paramount for patients with diabetes, the American Diabetes Association (ADA) 2023 Standards of Care also emphasize 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 in therapeutic regimens for patients with Type 2 diabetes will be discussed in the context of the updated 2023 Standards of Care in Diabetes 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 that increase insulin release and decrease 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 β-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
| Location | Increased | Decreased |
| Brain | Neuroprotection (preclinical) | Appetite |
| Cardiovascular system | Regional and global LV function | Blood pressure |
| Heart rate (Clinical) | Endothelial dysfunction (Preclinical) | |
| – | Ischemia-induced myocardial damage | |
| Muscle | Glucose uptake | – |
| Adipose tissue | Glucose uptake | – |
| Lipolysis | – | |
| Liver | – | Glucose production |
| Lipid profile | ||
| Stomach | – | Gastric emptying (Clinical) |
| Kidney | Natriuresis | – |
| Pancreas | Glucose-dependent insulin secretion (Clinical) | Glucose-dependent glucagon secretion (Clinical) |
| β-cell proliferation | β-cell apoptosis |
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 Lixisenatide as monotherapy has been discontinued but remains available in a combination product. 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 an 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 in renal impairment, patients should be monitored closely when the dose is increased.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 whether 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 of insulin degludec and 0.36 mg of liraglutide once daily
For patients currently on basal insulin or GLP-1 agonist therapy, the starting dose is 16 units of insulin degludec and 0.58 mg of 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 at 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 at 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
Insulin Glargine/Lixisenatide (Soliqua 100/33)
Insulin glargine is available in combination with lixisenatide as Soliqua.9 It is available as a pen that contains 100 units/mL of insulin glargine and 33 mcg/mL of lixisenatide.9 Pens can be stored in the refrigerator until the first use; afterward, they can be kept at room temperature for up to 28 days.9 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.9
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 of insulin glargine/10 mcg lixisenatide) once daily
Doses should be administered one hour before the first meal of the day.9 If a dose is missed, it should be skipped, and the next dose should be taken at the regularly scheduled time.9 The dose of insulin glargine/lixisenatide 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.9 This combination is not recommended for patients with end-stage renal disease (ESRD), and patients with hepatic impairment should have increased blood glucose monitoring.9
Semaglutide (Ozempic)
Semaglutide injection, brand name Ozempic, is available in multidose pens in three strengths.10 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.10 They should be protected from heat and light.10
The starting dose of injectable semaglutide is 0.25 mg SUBQ once daily, regardless of meals.10 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.10 The max dose is 2 mg once weekly.10 If a dose is missed within 5 days of the scheduled dose, the patient may take that dose.10 If more than 5 days have passed, they should skip that dose and wait until the next scheduled dose.10 Doses need not be adjusted for renal or hepatic impairment.10 The Ozempic brand of oral semaglutide tablets is available in 1.5 mg, 4 mg, and 9 mg tablets.10
Semaglutide (Rybelsus)
Semaglutide is also available in an oral formulation, Rybelsus.11 This formulation is available as 3 mg, 7 mg, and 14 mg tablets.11 This initial dose is 3 mg once daily.11 The dose can be increased to 7 mg after 30 days and to 14 mg after an additional 30 days.11 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.11 Patients on the 14 mg dose can switch to injectable semaglutide at 0.5 mg once weekly, starting the day after the final oral dose.11 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.11 No dose adjustments are required for either hepatic or renal impairment.11
The two oral semaglutide brands are not substitutable on a mg-per-mg basis.10,11 The prescribing information indicates that the lowest doses are ineffective for glycemic control. It should not be taken with any liquid other than water. Dose escalation should occur slowly to achieve and maintain glycemic control and to minimize side effects.
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 2.5-11 Nausea and other gastrointestinal (GI) side effects are often dose-dependent and more likely during the initiation and dose escalation of these medications.12 Fortunately, they are typically transient and mild to moderate in their severity.12 In clinical trials, GI side effects led to a discontinuation rate of 5-10%.12 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.12 First, patients should be educated on the potential for GI side effects and that these are typically mild and transient.12 Second, gradual dose escalation can help reduce GI effects.12 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.12 Due to a lack of evidence, GLP-1 RAs are not recommended in patients with gastroparesis.12
Injection site reactions are also common but have transient side effects.12 Potential signs and symptoms of injection site reactions include discomfort at the site of the injection, erythema, swelling, discoloration, pain, warmth, and pruritus.12 These side effects typically resolve with continued use of the medication.12 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.12 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.1,12 Patients should also be advised of the risk of dehydration associated with these medications and counseled to maintain adequate fluid intake.1,12
Clinical trials, particularly the SUSTAIN-6 study, identified a higher incidence of diabetic retinopathy complications (such as vitreous hemorrhage or blindness) in patients using semaglutide, notably among those with pre-existing eye disease.13 While the underlying etiology of this is uncertain, it is recommended to titrate semaglutide slowly in patients with a history of diabetic retinopathy and complete retinal screenings every 6 months.13
Table 2
Common Side Effects of GLP-1 RAs5-11
| Medication | Side Effects (Incidence) |
| Dulaglutide | Nausea, dose-dependent (11-20%) Skin rash (4%) |
| Exenatide (immediate-release) | Nausea (8-11%) |
Exenatide (extended-release) | Nausea (8-11%) |
| Liraglutide | Nausea (39-42%) Injection site reactions (1-14%) |
| Insulin degludec/liraglutide | Nausea (8%) Injection site reactions (3%) |
| Insulin glargine/lixisenatide | Nausea (10%) Injection site reactions (2%) |
| Semaglutide (injection) | Nausea (16-44%) Skin rash (3%) |
Semaglutide (oral) | Nausea (11-20%) |
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 2.4,5-11 They should also be used cautiously in patients with a history of pancreatitis.4,5-11 In post-marketing reviews of these drugs, cases of both hemorrhagic and nonhemorrhagic pancreatitis have been noted.4,5-11 If pancreatitis occurs, the drug should be discontinued and not restarted.4,5-11
GIP/GLP-1 RAs
In addition to the beneficial effects of GLP-1 RAs, recent evidence indicates that coadministration of glucose-dependent insulinotropic polypeptide (GIP) with a GLP-1 RA has a synergistic effect on insulin and glucagon responses. GIP acts on the pancreas, GI tract, kidney, heart, and brain, and is more prominent in its effects on insulin release in response to glucose intake.14,15
Tirzepatide is a novel GIP/GLP-1 RA approved in 2022 that has been shown to have significant effects on both glucose lowering and weight loss.14 Five phase three clinical trials have supported the use of tirzepatide in the treatment of T2DM.14 The trials compared tirzepatide to either placebo, insulin, or semaglutide, with a primary endpoint of change in hemoglobin A1C (A1C).14 In SURPASS-1, which compared tirzepatide to placebo, 92% of patients achieved an A1C level of <7% compared to placebo.15
SURPASS-2 compared tirzepatide to once-weekly semaglutide and found that more patients achieved A1c levels of less than 7%, 6.5%, and 5.7% than with semaglutide.16 Tirzepatide also led to significantly greater weight loss.16
SURPASS-3 compared the addition of tirzepatide to metformin (with or without an SGLT2-i) versus insulin degludec. A higher percentage of patients achieved an A1C <7% in the tirzepatide group than in the insulin group.17
Pharmacokinetics
Tirzepatide is metabolized via proteolytic cleavage of the peptide backbone, beta-oxidation of the C-20 fatty diacid moiety, and through amide hydrolysis.18 Its half-life is 5 days, and its time to peak is 8 to 72 hours.18
Dosing
Tirpazetide is available as a 0.5 mL prefilled, auto-injector pen.18 The pen should be stored in the refrigerator and left at room temperature for up to 21 days.18 Pens should be protected from light.18 The initial dose is 2.5 mg subcutaneously once weekly.18 After four weeks, the dose can be increased by 2.5 mg.18 The dose can be subsequently increased every four weeks to a maximum dose of 15 mg SUBQ once weekly to achieve glycemic goals.18 Dose adjustments are not necessary for either renal or hepatic impairment.18
Side Effects
The side effect profile of tirzepatide is similar to that of the GLP-1 RAs, with gastrointestinal adverse reactions common.18 These include nausea, diarrhea, vomiting, and a decrease in appetite.18 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.12,18 Less common side effects noted in the trials included hypoglycemia, injection site reactions, hypersensitivity reactions, and pancreatitis.18
Contraindications and Warnings
Tirzepatide is contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome 2.18 Patients should be cautioned of the potential for acute pancreatitis and gallbladder disease.18 Like the GLP-1 RAs, tirzepatide can result in dehydration, which can subsequently lead to acute kidney injury.18 Patients should be counseled to maintain adequate fluid intake.18
If tirzepatide is combined with sulfonylureas, meglitinides, or insulin, the doses of these antiglycemic agents may need to be reduced to avoid the risk of hypoglycemia.18 Tirzepatide should not be used in combination with a GLP-1 RA.18
Choice of Glucose-Lowering Therapy
Type 2 Diabetes Mellitus
Current ADA guidelines highlight the importance of managing diabetes with a holistic, multifactorial, 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 to 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 control 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 multiple points in the course of treating T2DM and may also be combined with 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.19 A second meta-analysis found dulaglutide and extended-release exenatide reduced A1C levels more than basal insulin.20
For glycemic and weight control, high-dose dulaglutide, semaglutide, and tirzepatide are recommended as first-line options in 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 below.
Table 3
Average A1C reduction for GLP-1 based therapies5-11,18,21
| Medication | Average A1C reduction |
| Dulaglutide (at max dose) | 1.5-1.8% |
| Exenatide (immediate-release) | 1% |
Exenatide (extended-release) | 1.4% |
| Liraglutide | 1-1.5% |
| Insulin degludec/liraglutide | 1.5% |
| Insulin glargine/lixisenatide | 1.5% |
| Semglutide (injection) | 1.4-1.6% |
| Semaglutide (oral) | 1.3% |
| Tirzepatide | 2% |
Weight Loss
GLP-1 RAs and tirzepatide are well-associated with weight loss, which provides secondary benefits to patients with T2DM.1,22 Semaglutide and tirzepatide also have very high efficacy for weight loss, and dulaglutide and liraglutide have high efficacy for weight loss.1,22
Table 4 below presents an overview of the average weight loss reported with GLP-1-based therapies.
Table 4
Average weight loss with GLP-1 Based Therapies5-11,18,21
| Medication | Average Weight Loss |
| Dulaglutide (at max dose) | 3-4.5 kg |
| Exenatide (immediate-release) | 2 kg |
Exenatide (extended-release) | 2.5 kg |
| Liraglutide | 2.8 kg |
| Insulin degludec/liraglutide | 2.2 kg |
| Insulin glargine/lixisenatide | 0.7 kg |
| Semaglutide (injection) | 4 kg |
| Semaglutide (oral) | 3 kg |
| Tirzepatide | 8 kg |
Patient Case
Sally T is a 55-year-old female with type 2 diabetes mellitus. She takes metformin 1000 mg twice a day and empagliflozin 25 mg daily. Her most recent HbA1c is 7.9%, and her BMI is 32 kg/m2. She has gained 11 pounds in the past year. Her father had a myocardial infarction at age 60.
What additional questions could be asked of the patient?
She was asked about a history of pancreatitis, gallbladder disease, and thyroid cancer. She has no known personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2.
What are examples of labs to consider in this patient?
The patient’s renal function is mildly reduced but stable. She has an estimated glomerular filtration rate of 59 ml/min/1.73m2.
She expresses that her personal goal is to lose weight and control her diabetes. She states that she wishes she only had to take medicine once a week
What is a possible next step to achieve a personalized approach to this patient?
The physician discusses glucagon-like peptide-1-based treatment as an option. The differences between treatments are discussed with the patient, including daily and weekly options and possible gastrointestinal side effects. The patient is also counseled to slowly escalate the dose and what to do if a dose is missed, and when to contact the clinic for symptoms such as abdominal pain or nausea.
This patient is prescribed semaglutide 0.25 mg subcutaneously once weekly with dose escalation after 4 weeks to reduce gastrointestinal side effects.
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 experience enhanced cardiorenal protective effects and 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 is used in 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 the use of 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 be 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 (proper injection technique), and storage of these agents. Counselling should be done in a patient-centered manner.2
Administration
Table 5 above details pertinent information regarding the mode of administration of the GLP-1 RAs.2
Table 5
Administration of GLP-1 RAs2,5-11,18,21
| Drug | Reconstitution or mixing required | Automatic dose administration | Need to prime the device before use | Needle attachment required | Dose selection required | Single use |
| Daily | ||||||
| Exenatide | No | No | Yes | Yes. Needles are not included | Yes | No |
| Liraglutide | No | No | Yes | Yes. Needles are not included | Yes | No |
| Semaglutide oral | N/A | N/A | N/A | N/A | Yes | N/A |
| Once-weekly | ||||||
| Exenatide | Yes | No | No | Yes. Needles are included | No | Yes |
| Exenatide BCISE (pre-filled pen) | Yes | Yes | No | No. Pre-attached hidden needle | No | Yes |
| Dulaglutide | No | Yes | No | No. Pre-attached hidden needle | No | Yes |
| Semaglutide | No | No | Yes | Yes. Needles are included | Yes | No |
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.5-11,18,21 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.5-11,18,21
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.5-11,18,21
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 offer additional cardiovascular and weight-loss benefits. There are many types of GLP-1 RAs, including short-acting and long-acting formulations, which vary in 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.
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
Liu QK. Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists. Front Endocrinol (Lausanne). 2024;15:1431292. Published 2024 Jul 24. doi:10.3389/fendo.2024.1431292
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.
EXENATIDE injection. Prescribing Information. Amneal Pharmaceuticals LLC. Updated December 31, 2025. Accessed April 1, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e6cb5c8f-e97f-4a6a-95a4-939fd2393949
LIRAGLUTIDE injection. Prescribing Information. Hikma Pharmaceuticals USA Inc. Updated March 30, 2026. Accessed April 1, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2100ec49-57b2-4330-ab5f-057ce9b7e4d0
XULTOPHY 100/3.6- insulin degludec and liraglutide injection, solution. Prescribing Information. Novo Nordisk. Updated October 14, 2025. Accessed April 1, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=21335fe4-d395-4501-ac2a-2f20d7520da9
TRULICITY- dulaglutide injection, solution. Prescribing Information. Eli Lilly and Company. Updated March 12, 2026. Accessed April 1, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=463050bd-2b1c-40f5-b3c3-0a04bb433309
SOLIQUA 100/33- insulin glargine and lixisenatide injection, solution. Prescribing Information. Sanofi-Aventis U.S. LLC. Updated March 18, 2026. Accessed April 1, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4bba538b-cf7c-4310-ae8f-cb711ed21bcc
OZEMPIC- semaglutide injection. Prescribing Information. Novo Nordisk. Updated October 14, 2025. Accessed April 2, 2026. solution. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79
OZEMPIC- oral semaglutide tablet RYBELSUS- oral semaglutide tablet. Prescribing Information. Novo Nordisk. Updated January 30, 2026. Accessed April 1, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=27f15fac-7d98-4114-a2ec-92494a91da98
Wharton S, Davies M, Dicker D, et al. Managing the gastrointestinal side effects of GLP-1 receptor agonists in obesity: recommendations for clinical practice. Postgrad Med. 2022;134(1):14-19. doi:10.1080/00325481.2021.2002616
Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141
Min T, Bain SC. The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials. Diabetes Ther. 2021;12(1):143-157. doi:10.1007/s13300-020-00981-0
Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143-155.
Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6):503-5.
Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 2021;398(10300):583-598.
MOUNJARO- tirzepatide injection, solution MOUNJARO KWIKPEN- tirzepatide injection, solution. Prescribing Information. Eli Lilly and Company. Updated January 21, 2026. Accessed April 2, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0
Wu JH, Foote C, Blomster J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis [published correction appears in Lancet Diabetes Endocrinol. 2016 Sep;4(9):e9]. Lancet Diabetes Endocrinol. 2016;4(5):411-419. doi:10.1016/S2213-8587(16)00052-8
Zhang L, Zhang M, Zhang Y, Tong N. Efficacy and safety of dulaglutide in patients with type 2 diabetes: a meta-analysis and systematic review. Sci Rep. 2016;6:18904. Published 2016 Jan 8. doi:10.1038/srep18904
BYDUREON BCISE® (exenatide) extended-release injectable suspension. Prescribing Information. AstraZeneca Pharmaceuticals LP. Revised: 03/2024. Accessed April 2, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/209210s025lbl.pdf
Haddad F, Dokmak G, Bader M, Karaman R. A Comprehensive Review on Weight Loss Associated with Anti-Diabetic Medications. Life (Basel). 2023;13(4):1012. Published 2023 Apr 14. doi:10.3390/life13041012
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