Indications

Glucagon-like peptide-1 receptor agonists (also known as GLP-1 receptor agonists, GLP-1DAs, incretin mimetics, or GLP-1 analogs)) are a class of medications utilized in the treatment of type 2 diabetes mellitus and obesity. Clinical trials show the superiority of GLP-1 RA to other antihyperglycemic drugs in improving glycemic efficacy, reducing weight and blood pressure, and having a cardioprotective effect, all without the risk of hypoglycemia. These drugs have transformed the guidelines for the management of patients with diabetes. 

There are currently seven GLP-1 receptor agonists that include exenatide twice-daily, exenatide extended-release (ER) once-weekly, lixisenatide once-daily, liraglutide once-daily, dulaglutide once-weekly, semaglutide once-weekly, and oral semaglutide once-daily. Albiglutide was discontinued in 2017 due to a decrease in sales. The FDA approved the first GLP-1 receptor agonist exenatide in 2005. The oral semaglutide tablet was approved by the FDA in 2019. Except for oral semaglutide, all the other drugs are subcutaneous injections. 

All GLP-1 receptor agonists are approved by the FDA to improve glycemic control in patients with type 2 diabetes mellitus as an adjunct to diet and exercise. All GLP-1 receptor agonists are not to be used in patients with type 1 diabetes mellitus (T1DM). The American Diabetes Association guidelines state metformin as the initial first-line therapy for patients diagnosed with type 2 diabetes mellitus. If a patient is intolerant to metformin or metformin is contraindicated, a GLP-1 receptor agonist should be introduced in their regimen. The addition of a GLP-1 analog should also be considered in those patients who are unable to reach their glycemic goal with other antidiabetic medications or if their HbA1c is 1.5% or greater above their target.

Subcutaneous semaglutide is FDA-approved to reduce the risk of major cardiovascular (CV) adverse events in patients with type 2 diabetes mellitus and established cardiovascular disease. Dulaglutide is FDA approved for improving HbA1c in patients with an increased risk of CV events. Lixisenatide can be used in combination with long-acting insulin. High-dose liraglutide has been FDA approved for chronic weight management in patients aged 12 or older with a BMI of 30 or greater. 

High-dose semaglutide at 2.4mg once-weekly injection has been studied for weight loss and shown efficacy and has also been approved by the FDA for chronic weight management as of 2021.[1] The other GLP-1 analogs have the favorable side effect of weight loss as well, although other than high dose liraglutide and semaglutide, they have not been FDA approved for this indication.

Mechanism of Action

Glucagon-like peptide 1 agonists are analogs of GLP-1, a gut-derived peptide hormone that exhibits a glucose-lowering effect via stimulation of insulin secretion from pancreatic islets in response to an oral glucose load, known as the incretin effect. Unlike the natural peptide hormone, synthetic GLP-1 is resistant to degradation by the dipeptidyl peptidase 4 (DPP-4) enzyme, and thus it has a longer half-life. The GLP-1 activity in patients with type 2 diabetes may be decreased.

GLP-1 also slows gastric emptying, suppresses appetite, improves satiety, decreases inappropriate glucagon secretion, and promotes beta-cell proliferation.[2] GLP-1 receptor agonists have also demonstrated the ability to restore insulin secretory functions, thereby contributing to improvements in glycemic control and body weight reduction in diabetic patients.[3]  

The short-acting formulations work by delaying gastric emptying, thus reducing postprandial glucose levels. The long-acting agents affect both fasting and postprandial glucose levels.[4]

Existing evidence suggests roles that GLP-1 analogs can play on receptors expressed throughout the human body, including reducing blood pressure, improvement in endothelial and myocardial function, recovery of failing and ischemic heart, arterial vasodilation, and increased diuresis and natriuresis.[5]

Comparison Of Different GLP-1 Agonists

Numerous clinical trials and studies have been conducted between the short-acting and long-acting GLP-1 analogs to gauge their efficacy, safety, and tolerability. In addition, the added benefit of weight loss and improved cardiovascular and renal outcomes was also assessed.Efficacy and Adverse Effects   

One meta-analysis showed that overall, once-weekly GLP-1 receptor agonists were more effective in reducing HbA1c levels and equally as effective in weight loss than exenatide twice-daily injection, but not better than liraglutide once-daily injection.[6] To further support this, a study showed that long-acting GLP-1 receptor agonists like dulaglutide, liraglutide, and once-weekly exenatide were superior to exenatide twice daily and lixisenatide at lowering fasting plasma glucose levels and HbA1c levels of patients.[7] 

Another meta-analysis demonstrated that liraglutide decreased HbA1c more than exenatide, and there was no difference in HbA1c reduction between liraglutide and dulaglutide. The adverse effects were mainly gastrointestinal, with less nausea seen in exenatide once-weekly injection, and most adverse effects were seen with short-acting agents.[8] The LEAD-6 trial compared liraglutide 1.8mg once a day with exenatide 10 mcg twice a day, and it showed a greater HbA1c reduction and fewer adverse effects with liraglutide including hypoglycemia.[9]  In DURATION-6, liraglutide once-daily was compared to exenatide once weekly, and liraglutide showed a significant reduction in both HbA1c and weight. However, there were more GI side effects associated with liraglutide use. Compared to exenatide once-weekly injection, exenatide twice-daily injection showed a greater reduction of HbA1c level; however, there were more injection site reactions.[10] 

In the AWARD-1 trial, dulaglutide was shown to be superior to exenatide twice-daily injection. This was followed up by further trials, and in the AWARD 6 trial, once-weekly dulaglutide was shown to be non-inferior to once weekly liraglutide. Liraglutide, however, had greater weight loss potential.[11]  In another trial, dulaglutide, when compared to liraglutide, had a greater HbA1c reduction.[12] When its initiation in patients was compared to exenatide once weekly as well as liraglutide, dulaglutide had a higher adherence rate and lower discontinuation rates within a 6 month period.[13]  A more recent randomized controlled trial called SUSTAIN-7 compared semaglutide once-weekly injection to dulaglutide at both low doses and high doses. Semaglutide showed superiority over dulaglutide to improve glycemic control and weight loss >5%, with both drugs having a similar safety profile.[14] 

Cardiovascular Outcomes Seven cardiovascular outcome trials have been done on the seven GLP-1 receptor agonists. The LEADER-6 trial showed that liraglutide had a cardiovascular benefit in high-risk patients. The SUSTAIN 6 trial demonstrated a statistically significant reduction in death from cardiovascular events with the use of subcutaneous semaglutide, but it also had the highest reduction in HbA1c, and so it was unsure whether the reduction of death from CV events was from the medication or the improved glycemic control.

Out of the seven trials, all have shown noninferiority, and liraglutide, subcutaneous semaglutide, and dulaglutide have shown significant reductions in cardiovascular outcomes.[15] 

According to a post hoc analysis done on the SUSTAIN and PIONEER trials, semaglutide has shown a reduced relative risk and absolute risk reduction for major adverse cardiovascular events versus its comparators.[16] 

Renal Outcomes

GLP-1 agonists have demonstrated the most renal benefit primarily by reducing new-onset severely increased albuminuria. The AWARD-7 trial comparing dulaglutide and insulin glargine was the only trial involving this class of medications to exclusively enroll patients with moderate-to-severe chronic kidney disease. Patients concurrently on an ACE inhibitor or angiotensin receptor blocker who received dulaglutide experienced significantly less eGFR decline than their counterparts who received insulin glargine. For this reason, patients with an eGFR as low as 15 mL/min per 1.73 m2 can safely be treated with dulaglutide per FDA labeling.[17] 

Use of injectable semaglutide in SUSTAIN-6 showed the largest albuminuria reduction (followed by liraglutide and dulaglutide in their respective cardiovascular outcomes trials) and included patients across the spectrum of renal dysfunction except for dialysis patients. PIONEER 6, which evaluated cardiovascular outcomes of oral semaglutide, did not assess the drug’s effect on albuminuria or loss of eGFR.[18] 

Weight Loss

Recently, weekly semaglutide 2.4 mg became the first approved drug for chronic weight management in overweight adults or those with general obesity with at least one weight-related comorbidity since the approval of high dose liraglutide in 2014. Compared to the SCALE trial comparing weight management in liraglutide versus placebo, the four randomized controlled trials comparing semaglutide to placebo showed greater mean weight loss and also resulted in a greater percentage of patients who lost at least 5% of their body weight.

Adherence to Therapy

The once-weekly injections were also compared to one another based on patient persistence and adherence. One retrospective observational study evaluated the adherence of dulaglutide versus liraglutide and exenatide once weekly. The patients taking dulaglutide were remarkably more persistent and adherent than those patients taking exenatide extended-release or liraglutide. Another observational study examined adherence between dulaglutide, semaglutide, and exenatide. At 6 months, more patients preferred to use dulaglutide as compared to exenatide and semaglutide.[19] Although the GLP-1 receptor agonists vary within their class, the efficacy and safety profile are comparable. Choosing which GLP-1 receptor agonist to use will depend on patient preferences, patient's comorbidities, reaction to adverse effects, convenience, and cost.

Administration

Initially, GLP-1 RA was manufactured as injectable medications due to their poor oral bioavailability. The once-daily injections are liraglutide and lixisenatide, while dulaglutide and semaglutide are once weekly. Exenatide has both a twice-daily formulation as well as an extended-release (ER) once-weekly injection. In 2019, an oral semaglutide tablet became available in dosages of 3 mg, 7 mg, and 14 mg.[20] Patient preference is mainly for less frequent dosing regimens and oral formulations over injectable medication. Patient adherence also depended upon the type of device and needle size, showing a preference for narrower needles.[21][22][13] GLP-1 receptor agonists can now be used in combination with insulin. This regimen has a synergistic effect, with insulin lowering fasting blood glucose levels and GLP-1 analogs lowering postprandial glucose levels. There is also a reduced risk of hypoglycemia, and the GLP-1 RA use will offset the weight gain that may be caused by insulin use.[23] The injectable medication should be administered in the patient’s thigh, abdomen, or upper arm. The patient should be instructed to change injection sites each time to reduce the risk of infection at the site. 

Missed dose instructions vary among the once-weekly formulations. Exenatide extended-release and dulaglutide can be taken as soon as the patient remembers as long as the next scheduled dose is at least three days later. Conversely, semaglutide can be taken as long as it is within five days of the missed dose. If outside these parameters, the patient should be instructed to skip the dose entirely and continue with the next regularly scheduled dosing day.

Short-acting exenatide and lixisenatide should be given within 60 minutes of meals, whereas all others can be given without regard to meals. The oral semaglutide tablet should be taken 30 minutes before any food, oral medication, or beverage, with 4 ounces of water. If taken with any other oral medication, it may alter the absorption of the oral semaglutide.[22]

Adverse Effects

Since GLP-1 receptor agonists mimic the action of a peptide produced in the GI tract, the majority of reported side effects are gastrointestinal (GI) in nature, which are nausea, vomiting, and diarrhea. The GI side effects are dose-dependent, and increasing the dosage should be done slowly.[8] Patients should be educated that as this drug slows down gastric emptying, there may be a feeling of early satiety. Nausea can occur if attempting to eat when already full. A 34 trial meta-analysis demonstrated that once-weekly exenatide had the lowest risk of vomiting when comparing the adverse effects.[7]

Although classified as low risk, GLP-1 receptor agonists can be associated with hypoglycemia with no clinically significant difference in incidence among the agents. This risk is potentiated by concomitant use with insulin or insulin secretagogues, such as sulfonylureas.[3] Injection site reactions and erythema have been reported to be more frequent with exenatide once weekly than with exenatide twice daily and more common with exenatide once-weekly compared to liraglutide once-daily. 

Exenatide also has a side effect of increasing the INR in patients taking warfarin. For semaglutide, rapid improvement of glycemic control has been associated with a temporary worsening of pre-existing diabetic retinopathy. The effects of long-term glycemic control on diabetic retinopathy complications have not been studied. In a trial for liraglutide, 3.1% of patients taking the medication versus 1.9% of patients on placebo reported an event of gallbladder disease. If cholelithiasis or cholecystitis is suspected, gallbladder studies and workup are indicated. 

Antibody formation was rare in patients treated with once-weekly injectables, while a greater percentage of patients developed antibodies to twice-daily exenatide and once-daily lixisenatide. The antibodies produced caused a smaller decrease in HbA1c and reduced glycemic efficacy in patients taking exenatide and lixisenatide. When these patients were switched to liraglutide, their new regimen was unaffected by the antibodies.[3] 

Dulaglutide is associated with cardiovascular conduction abnormalities such as sinus tachycardia, PR interval prolongation, and 1st degree AV block. It should be used cautiously in patients with preexisting arrhythmia.[24][25] In many phase III clinical trials, nasopharyngitis and upper respiratory infections (URIs) were reported. These symptoms were mostly noted in the PIONEER 9 and 10 trials. The mechanism of action of the URIs is unknown; however, its presence across trials qualifies it as an adverse effect to be studied further regarding GLP-1 receptor agonists. 

Contraindications

All GLP-1 receptor agonists are contraindicated in patients with hypersensitivity to the drug.

There is an increased risk of fatal hemorrhagic and necrotizing pancreatitis with the use of any GLP-1 analog. The mechanism of pancreatitis is currently unknown but has been demonstrated with postmarketing surveillance. If a patient has a previous history of pancreatitis or develops pancreatitis with this medication, its use should be discontinued.[26]

Semaglutide, dulaglutide, exenatide extended-release, and liraglutide are contraindicated in patients with a family history of medullary thyroid cancer or patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN2). Studies have shown that liraglutide causes C cell hyperplasia and increased calcitonin release in rodents. Further investigations on humans are necessary to make a more definitive statement.[27][28] 

Exenatide should not be used in patients with end-stage renal disease or CrCl less than 30 mL/min. There are also reports of drug-induced thrombocytopenia with exenatide, and it should be stopped once confirmed on a complete blood count panel.

GLP-1 receptor agonists should be avoided in patients with gastroparesis or inflammatory bowel disorders. They should also be used cautiously in pregnancy. In embryo-fetal studies done on animals, the use of these medications has shown evidence of pregnancy loss and adverse developmental outcomes when exposed to the maximum human recommended dosage. For other GLP-1 agonists, there is insufficient data to determine a drug-associated risk. Therefore, it should only be used when the benefit to the mother outweighs the risk to the fetus.

There is new evidence to support the use of high-dose liraglutide in pediatric patients for obesity. However, providers should still be vigilant about monitoring and dosage as more high-quality clinical studies are required to assess safety and tolerability.[29]

Monitoring

Similar to other medications for type 2 diabetes mellitus, HbA1c should be checked every 3 months to monitor glycemic control, and blood glucose levels should be checked regularly. Patients may opt for a continuous glucose monitoring (CGM) device to examine their glycemic patterns to help make dosage changes. There are reported cases of acute renal failure and renal insufficiency with the use of exenatide and lixisenatide.

Monitoring with renal function tests is recommended for patients taking these medications. Patients taking GLP-1 receptor agonists should be educated about the adverse effect profile and monitored for signs and symptoms of pancreatitis, gallbladder disease, and compressive symptoms of medullary thyroid cancer such as hoarseness or dysphagia. Currently, the FDA does not recommend monitoring calcitonin levels in patients taking GLP-1 analogs. It is exceedingly important for patients to receive yearly comprehensive eye exams as these agents, particularly semaglutide, may carry the risk of retinopathy associated with rapid glucose reduction.

If patients take GLP-1 receptor agonists along with sulfonylureas or insulin, there is an increased risk of hypoglycemia. Patients should be educated on signs and symptoms of hypoglycemia and monitored periodically by their clinician.[30]

Toxicity

GLP-1 analog overdoses are few and far between. When they do occur, the symptoms include nausea, vomiting, and diarrhea, which have led to acute kidney injury likely secondary to dehydration. Excessive belching and abdominal pain have been reported as well. Serious complications like pancreatitis have not been experienced. There have been rare episodes of hypoglycemia that were corrected without long-term complications.[31][32]

Several case reports have shown that an overdose of GLP-1 receptor agonists mainly causes GI symptoms but either no or minimal hypoglycemia. These patients are managed supportively according to their symptoms, with intravenous fluids to hydrate the patient and antiemetic medications to control nausea and vomiting.[33][34][35]

Enhancing Healthcare Team Outcomes

GLP-1 receptor agonists are an effective therapeutic choice for patients with type 2 diabetes mellitus and obesity. There is robust evidence from clinical trials and meta-analyses that show that GLP-1 receptor agonists reduce HbA1c levels, aid weight loss, and improve cardiovascular outcomes.[36][37][38] [Level 1]

An interprofessional team comprised of a primary care physician, an endocrinologist, a pharmacist, a diabetes educator, nursing staff, and a dietician should be utilized when treating T2DM and obese patients with a GLP-1 receptor agonist. Communication between these healthcare providers is the utmost priority. After reviewing the medication reconciliation and laboratory results, they should use a patient-centered holistic, interprofessional approach regarding who would benefit from a GLP-1 receptor agonist and work as a team in monitoring therapy to optimize patient outcomes. [Level 5]

The use of GLP-1 receptor agonists may be limited due to their gastrointestinal side effects, subcutaneous injection route of administration, and cost. Education should be provided by nurses and clinicians by demonstrating how to administer the drug properly and safely. This will help with compliance rates and adherence to the regimen and overall improve patient satisfaction. Pharmacists can contribute by counseling patients on adverse effects, monitoring parameters, appropriate usage, drug interactions, and therapy goals with GLP-1 analogs, and advising them to report any concerns to the office. Pharmacists can also assist in navigating insurance coverage and out-of-pocket costs to arrive at the optimal agent and means of access, which can be facilitated by working with patient assistance programs, especially for patients for whom medication cost is a major concern.

If a patient is experiencing gastrointestinal adverse effects following dose titration, the patient should be asked to verify the dose and the time of symptom onset.

Routine follow-ups should be instituted by the healthcare practice for monitoring weight, kidney function, complete blood count, and blood glucose levels. A diabetic educator and a dietician can stress the addition of diet and exercise while taking this medication for maximum treatment benefit. Dieticians also play a pivotal role by recommending smaller meals, eating more slowly, and avoiding fatty foods.Cost can be a major barrier as these medications are expensive. A discussion should be initiated between patient and physician to discuss cost-effectiveness and provide financial assistance if needed. A comprehensive interprofessional healthcare team can improve outcomes and quality of life for patients with type 2 diabetes. It can minimize adverse events, and it is important to support these patients to reach their personalized treatment goals to benefit their health. [Level 5]

The comparison of GLP-1 receptor agonists has demonstrated that all of them effectively reduce HbA1c levels in patients with type 2 diabetes mellitus. However, the agents vary within the class based on efficacy, safety, adverse effect profile, cardiovascular and renal effects, adherence, and persistence. When selecting a GLP-1 receptor agonist for a patient, a multidisciplinary healthcare team must consider all the clinical evidence available, as well as individual patient factors like preference, cost, accessibility, and convenience.

Regarding the greatest reduction of HbA1c, long-acting agents seem superior to short-acting agents, with semaglutide having the greatest reduction. The least reduction was with exenatide extended-release. However, it was still more effective at lowering the HbA1C than short-acting agents. For weight loss, the long-acting GLP-1 receptor agonists produced more significant weight loss than the short-acting formulations. Semaglutide was noted to cause the greatest weight reduction. The most gastrointestinal adverse effects were seen with short-acting agents and subcutaneous semaglutide, and the least side effects were seen with exenatide ER.

Patient satisfaction, adherence, and persistence were seen more with long-acting agents, likely due to their less frequent dosing of once-weekly injections compared to once-daily or twice-daily of the short-acting agents. All of these comparative factors should play an integral role in the healthcare provider’s decision to choose a GLP-1 receptor agonist.