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Glucagon-Like Peptide-1 Receptor Agonists
Indications
FDA-Approved Indications
GLP-1 agonists (also known as GLP-1 receptor agonists, incretin mimetics, or GLP-1 analogs) represent a class of medications used to treat T2DM and, in some cases, obesity. Examples of drugs in this class include Exenatide, Liraglutide, Dulaglutide, and Semaglutide. According to the American Diabetes Association (ADA), metformin remains the preferred first-line therapy for treating T2DM. However, the addition of a GLP-1 analog should be considered in patients with a contraindication or intolerance to metformin, in patients with a hemoglobin A1c greater than 1.5% over target, or in patients who do not reach their target A1c in 3 months, particularly in patients with atherosclerosis, heart failure, or chronic kidney disease.[1][2][3][4] Furthermore, Semaglutide and high-dose Liraglutide are FDA-approved as pharmacologic treatments for obesity or can be prescribed to overweight patients with comorbidities. The utilization of GLP-1 analogs is an area of research with favorable hemoglobin A1c results and weight loss results in patients with type-1 diabetes mellitus (T1DM). Of note, higher costs, as well as tolerability, remain significant barriers to prescribing these medications.[5][6][7][8]
As per the 2023 ADA guidelines, GLP-1 receptor agonists are recommended for mitigating cardiovascular risk. These agents not only lower the chances of cardiovascular events and hypoglycemia but also demonstrate potential in potentially decreasing the progression of chronic kidney disease (CKD). GLP-1 agonists are recommended for individuals with a history of clinical ASCVD (eg, prior myocardial infarction, stroke.[9][10] GLP-1 agonists, with proven cardiovascular benefits, include Liraglutide, subcutaneous Semaglutide, and Dulaglutide.[11]
Structurally, these agents fall into 2 broad categories: human GLP-1 backbone agents and exendin-4 backbone agents. Below are FDA-approved GLP-1 agonists.
Human GLP-1 backbone:
- Dulaglutide
- Albiglutide - discontinued
- Liraglutide
- Semaglutide
Exendin-4 backbone:
- Exenatide (2 formulations)
- Lixisenatide - discontinued
- Tirzepatide is a GIP analog that activates both the GLP-1 and GIP receptors.
Liraglutide/insulin-degludec has obtained FDA approval, affirming their effectiveness and safety in diabetes management.[12][13] Because of safety concerns, research on another agent, taspoglutide, has been halted in phase III trials.[14] Recently, Orforglipron, a nonpeptide oral GLP-1 receptor agonist, has demonstrated promising results in phase 2 clinical trials.[15]
Mechanism of Action
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Mechanism of Action
GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), both incretin hormones inactivated by dipeptidyl peptidase-4 (DPP-4), stimulate insulin secretion after an oral glucose load via the incretin effect.[16][17] In T2DM, this process can become blunted or absent; however, pharmacological levels of GLP-1 can revive insulin excretion. The benefits of this therapy to treat T2DM include delayed gastric emptying and inhibiting glucagon production from pancreatic α-cells if blood sugar levels are high. Furthermore, GLP-1 receptor agonists can decrease pancreatic β-cell apoptosis while promoting their proliferation.[18][19][20]
This class of medications promotes an average weight loss of 2.9 kg compared to placebo, in addition to lowering both systolic and diastolic blood pressure and total cholesterol. Regarding cardiovascular effects, GLP-1 agonists can improve left ventricular ejection fraction, myocardial contractility, coronary blood flow, cardiac output, and endothelial function while reducing infarction size and overall risks for a cardiovascular event.[21][22] Other functions of GLP-1 include increased glucose uptake in the muscles, decreased glucose production in the liver, neuroprotection, and increased satiety due to direct actions on the hypothalamus. GLP-1 analogs have also exhibited lower all-cause mortality and a hemoglobin A1c reduction of about 1% compared to control groups in patients with T2DM.[23][8] As per the ADA, strategies with higher efficacy are more likely to attain glycemic targets successfully. Specifically, the interventions regarded as highly effective for lowering glucose levels are high-dose Dulaglutide and Semaglutide, as well as Tripeptide, a combination of gastric inhibitory peptide (GIP) and GLP-1 receptor agonist, insulin therapy, oral combination therapy, and injectable combination therapy.[10]
Pharmacokinetics
Absorption: GLP-1 Receptor Agonists (RAs) like Exenatide, Liraglutide, and Semaglutide are administered subcutaneously, ensuring rapid absorption and achieving peak concentrations within hours. The novel oral formulation of Semaglutide is tailored for gastrointestinal (GI) absorption, with consideration for bioavailability. Factors such as first-pass metabolism and potential interactions with food and other medications bear relevance in determining effective dosing regimens for oral Semaglutide.
Distribution: Post-absorption, GLP-1 RAs (eg, Exenatide, Liraglutide, and Semaglutide) exhibit a low volume of distribution, predominantly remaining in the bloodstream. These agents selectively target GLP-1 receptors in various tissues involved in glucose regulation, with specific affinity for pancreatic cells and other metabolic control sites.
Metabolism: Exenatide undergoes primary metabolism in the kidneys and liver through hydrolysis, yielding smaller, inactive peptides subsequently excreted renally. Liraglutide follows a similar pathway involving proteolytic cleavage in various tissues, akin to the metabolism of large proteins. Enzymes like Dipeptidyl Peptidase-4 (DPP-4) and Neutral Endopeptidase (NEP) are likely involved, resulting in smaller, biologically inactive fragments subsequently eliminated. Semaglutide, a polypeptide, undergoes metabolic breakdown into individual amino acids facilitated by serum and tissue proteases.[24][25]
Excretion: Renal elimination primarily governs the clearance of GLP-1 RAs, including Exenatide, Liraglutide, and Semaglutide. The kidneys play a pivotal role in removing these compounds from the body. The rate of renal excretion impacts the duration of action and dosing frequency. Semaglutide, with its extended-release (ER) profile, exhibits a significantly prolonged half-life compared to short-acting formulations.
Administration
Available Dosage Forms, Strengths, and Adult Dosage
Many formulations of GLP-1 agonists were historically injectable. GLP-1 agonists are generally administered subcutaneously due to poor oral bioavailability. Liraglutide is dosed daily. Dulaglutide and semaglutide dosing is weekly, and exenatide can be dosed twice daily or once weekly. Recently, the FDA approved an oral formulation of Semaglutide. Researchers have suspended trials investigating taspoglutide as a novel GLP-1 analog due to GI side effects and hypersensitivity reactions.[26][27][14]
Summary of dosing frequency for some commonly prescribed GLP-1 receptor agonists:
- Dulaglutide - weekly
- Liraglutide - daily
- Semaglutide - weekly subcutaneously, daily orally
- Exenatide BID - twice daily
- Exenatide QW - weekly
- Tirzepatide - weekly
- Albiglutide - weekly (withdrawn from the market)[28]
Depending on the drug prescribed, the medication may be available as a single- or multi-dose pen, and patients may need a separate prescription for needles with various needle gauge requirements. Patients have shown improved satisfaction with weekly exenatide compared to a twice-daily regimen, and studies have demonstrated their preferences for narrow needles. However, concerns regarding compliance with a weekly, as opposed to a daily regimen, have also been raised. GLP-1 analogs and long-acting insulin in a single injection have also been introduced to the pharmaceutical market.[29][8] This regimen potentially synergizes with insulin-lowering fasting, post-absorptive blood sugars, and GLP-1 agonists targeting postprandial blood sugars. This strategy may lower the risk of hypoglycemia due to less reliance on bolus and basal insulin and may offset potential weight gain experienced with insulin.[30][31] GLP-1 analogs are primarily excreted via renal pathways, and no dosage modifications are required for patients with mild renal or hepatic impairment. However, dose adjustment according to the product monograph should be considered, especially in older patients.[11] No recommendations are stated for specific populations, with limited data available for breastfeeding or pediatric patients. Moreover, use is contraindicated in patients who are pregnant.
Adverse Effects
The most frequently exhibited side effects from GLP-1 agonists include nausea, vomiting, and diarrhea that could lead to an acute kidney injury due to volume contraction. Dizziness, mild tachycardia, infections, headaches, and dyspepsia may also occur. Patients should receive counseling that this class of drugs increases satiety, and transient, mild nausea may occur if they attempt to eat while feeling full. Increasing the dosage of these medications should occur slowly if nausea is present. Injection-site pruritus and erythema are also common, most notably with the longer-acting medications in this class.[16][32][18]
A low risk of minor episodes of hypoglycemia is evident; however, research has not described any major hypoglycemic episodes at this time. Patients can form antibodies to particular GLP-1 analogs that could affect the efficacy of these medications, particularly with exenatide. This immunogenicity could lead to injection site reactions and potential anaphylaxis. Studies have shown that these adverse effects typically lead to a low discontinuation rate of around 10%.[14][33][34] Anti-drug antibodies were more common, and titers were higher with the weekly dosed formulation of exenatide than with the twice-daily formulation of exenatide.[35] A meta-analysis revealed an association between the utilization of GLP-1 receptor agonists and an elevated likelihood of gallbladder or biliary disorders. This correlation was particularly notable in cases involving higher dosage and prolonged usage.[36]
Combination therapy with GLP-1 agonists and dipeptidyl peptidase-4 inhibitors is not a current recommendation due to statistically insignificant glycemic improvement and enhanced hypoglycemic effects. Depending on the glycemic control, adjust the insulin dosage by approximately 25% or reduce the sulfonylurea dosage to mitigate the risk of hypoglycemia.[8][37][11]
Contraindications
Boxed Warnings
Contraindications to utilizing GLP-1 agonists include hypersensitivity and pregnancy as prohibitions to prescribing this class of medications. Some formulations of contraception are recommended with GLP-1 agonists in women of childbearing age. Patients with severe GI diseases such as gastroparesis and inflammatory bowel disease should also avoid GLP-1 analogs. Concern for long-term consequences on the thyroid gland using GLP-1 agonists has been a topic of investigation. Liraglutide stimulated calcitonin release in rodent models, leading to thyroid gland C-cell and tumor hyperplasia. The effects on humans remain unclear, with further investigations being necessary. Consequently, GLP-1 agonists are not recommended in patients with a personal or family history significant for multiple endocrine neoplasia 2A (MEN 2A), multiple endocrine neoplasia 2B (MEN 2B), or medullary thyroid cancer.[38][39][14][40]
While the mechanism remains largely unknown, acute pancreatitis, including potentially fatal hemorrhagic and necrotizing types, has been noted in users of GLP-1 analogs. Whether a causal relationship exists between GLP-1 analogs and pancreatitis or pancreatic cancer is still unknown. Nonetheless, GLP-1 agonists should not be prescribed in patients with a history of pancreatitis and should be discontinued in those who develop pancreatitis when taking this medication.[33][41][42]
Warnings and Precautions
The FDA has recently issued a cautionary statement regarding the compounding of Semaglutide formulations. Compounding involves customizing medications to individual patient needs by blending, altering, or combining various ingredients, including multiple drugs. It is critical to highlight the reported adverse events associated with compounded Semaglutide. Patients should be educated not to purchase compounded products, as the FDA does not assess compounded versions for safety, efficacy, or quality. Additionally, adverse effects are associated with cases where compounders salts of Semaglutide, such as Semaglutide sodium and Semaglutide acetate. In 3 recent cases, patients experienced adverse effects due to the incorrect administration of Semaglutide for weight loss. These incidents occurred after obtaining the medication from compounding pharmacies and an aesthetic spa. In 2 instances, patients self-administered doses 10 times higher than prescribed. All individuals reported experiencing significant symptoms such as nausea, vomiting, and prolonged abdominal discomfort lasting several days. Additionally, one patient mentioned experiencing a headache, reduced appetite, weakness, and fatigue. Notably, one patient sought medical evaluation and showed improvement after receiving antiemetic and intravenous fluids. Another patient, who obtained their medication from a compounding pharmacy, reported receiving a vial with syringes for self-administration but noted a lack of counseling on proper administration by the pharmacist. Compounded Semaglutide lacks the safety features in prefilled pens, potentially leading to dangerous overdoses. Using incorrect syringes adds to dosing variability and patient confusion. Stringent labeling, dispensing, and counseling practices are crucial to mitigate these risks. Healthcare professionals should actively advocate for the proper use and dispensing of compounded Semaglutide. These measures hold the potential to significantly decrease the risk of severe adverse events and unnecessary hospitalizations due to dosing errors.[43]
Monitoring
GLP-1 analogs are principally renally eliminated. Dosing adjustments of GLP-1 agonists are unnecessary due to hepatic or mild renal impairment. Moderate renally impaired patients, on the other hand, should avoid weekly exenatide, and dosing escalations should be considered carefully in patients on twice-daily exenatide. Dosing increases of twice-daily exenatide for patients aged 70 years and older merit evaluation of the potential risks and benefits.
Patients with severe renal dysfunction should not take GLP-1 agonists. If a GLP-1 agonist is added to a regimen already consisting of a Sulfonylurea or long-acting insulin, patients require monitoring for hypoglycemia. A decrease in the insulin dose may become necessary, depending on the GLP-1 analog selected. Patients taking GLP-1 analogs should periodically have their hemoglobin A1c measured and their glycemic patterns examined. The clinician should follow the international normalized ratio (INR) in patients prescribed warfarin, as a GLP-1 agonist may alter the absorption of this medication by delaying gastric emptying. Clinicians should also monitor patients taking GLP-1 agonists for signs and symptoms consistent with pancreatitis. The FDA recommends not monitoring calcitonin levels for medullary thyroid cancer.[8][33][40]
Concerns have been raised about the potential for GLP-1 agonists to delay gastric emptying. This raises the risk of regurgitation and aspiration.[44] As a precaution for elective procedures, it is suggested that GLP-1 agonists be discontinued temporarily. This recommendation applies regardless of the indication for which the medication is prescribed. In cases where prolonged discontinuation of GLP-1 agonists may be necessary, consulting an endocrinologist for guidance on bridging antidiabetic therapy is advisable to prevent hyperglycemia. On the day of the procedure, if patients experience severe GI symptoms such as nausea, vomiting, retching, abdominal bloating, or abdominal pain, it may be prudent to consider postponing the elective procedure after discussing potential risks with the surgeon and the patient. In the absence of such symptoms and with appropriate suspension of GLP-1 agonists, the procedure can proceed as planned. However, if patients have not adhered to the recommended suspension of GLP-1 agonists, proceeding with caution or evaluating gastric volume through ultrasound, if possible, is recommended. If this is not feasible, considering a delay or proceeding with 'full stomach' precautions is advised, again after discussing potential risks with the surgeon and the patient. While no definitive fasting duration is established for patients on GLP-1 agonists, adhering to current American Society of Anesthesiologists (ASA) fasting guidelines is recommended until further evidence is available.[45][46][47]
Toxicity
Research into GLP-1 analog overdoses remains limited. Reports exist of symptoms such as nausea, vomiting, diarrhea, excessive belching, and abdominal pain due to toxic ingestion of medication within this class; however, no serious complications, such as pancreatitis or hypoglycemia, have been noted in case studies.[48] Treatment consists of supportive care, including antiemetics, to control excessive nausea and vomiting.[34][49]
Enhancing Healthcare Team Outcomes
Treating T2DM and obesity should involve an interprofessional team, including a primary care provider (MD, DO, NP, or PA), diabetes educator (nurse or pharmacist), pharmacist, and possibly an endocrinologist. Providers and pharmacists collaborate on the decision to select a GLP-1 agonist and include a complete medication reconciliation in their decision. The interprofessional approach will maximize positive outcomes and minimize adverse events.
Healthcare professionals like MDs, DOs, NPs, and PAs play a role in prescribing GLP-1 agonists. Clinicians, pharmacists, dieticians, and nurses should educate patients on potential side effects and drug interactions. Regular follow-up appointments with primary care clinicians are necessary to monitor blood glucose levels, weight, and kidney function. Nursing involves monitoring and reporting concerns to the prescriber and pharmacist. A registered dietitian nutritionist should guide food choices. Consult with a gastroenterologist for acute pancreatitis. Endocrinologists offer valuable guidance as well when managing T1DM or T1DM. A cohesive team approach maximizes glycemic control and weight loss while minimizing adverse reactions from GLP-1 agonists.
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