The rise of glucagon-like peptide-1 (GLP-1) receptor agonists like Ozempic, Wegovy, and tirzepatide has revolutionized the treatment of type 2 diabetes and obesity. These medications have demonstrated significant weight loss outcomes and are becoming increasingly popular among the anti-obesity medication (AOM) treatment options. However, alongside their benefits, it's essential to consider the potential risks and side effects associated with these drugs.
GLP-1 Agonists: What are They?
GLP-1 agonists are medications that mimic the effects of the naturally occurring hormone GLP-1 in the body. GLP-1 is released in the gut after eating and has several effects that help regulate blood sugar and appetite. These medications have inspired a lot of hope but also intense debate. The drugs work by mimicking a hormone called glucagon-like peptide-1 (GLP-1), which curbs hunger. GLP-1 also slows down the movement of food from the stomach to the small intestine - hence a feeling of fullness - and increases insulin production, lowering blood sugar. The gist? GLP-1 drugs make you eat less.
The Food and Drug Administration (FDA) approved for the treatment of overweight and obesity the GLP-1 RA liraglutide in 2014 and semaglutide in 2021, and the dual GLP-1/GIP RA tirzepatide in 2023.
Benefits of GLP-1 Agonists
Weight Loss
GLP-1 agonists have demonstrated remarkable weight loss outcomes in clinical trials and real-world studies. In the Satiety and Clinical Adiposity Liraglutide Evidence (SCALE) clinical trial, liraglutide resulted in up to 8.0 ± 6.7 % (8.4 ± 7.3 kg) of body weight loss at 56 weeks compared to a mean of 2.6 ± 5.7 % (2.8 ± 6.5 kg) in the placebo group with a placebo corrected weight reduction of approximately 5 %. In the Semaglutide Treatment Effect in People with Obesity (STEP) trial in adults without diabetes, semaglutide 2.4 mg showed superior weight loss outcomes of 14.9 % compared to 2.4 % with the placebo group with a placebo corrected weight loss of around 12 %. As for tirzepatide 15 mg, the SURMOUNT-1 trial presented a mean weight loss of 20.9 % while the placebo group had 3.1 % of weight loss, reflecting a placebo-corrected weight loss of 18 %, approximately. In fact, all three tirzepatide doses (5, 10, and 15 mg) were superior to placebo.
A greater proportion of participants lost ≥5 %, ≥10 %, ≥15 % and ≥20 % of body weight with tirzepatide and semaglutide compared to liraglutide. In the pivotal RCTs of these AOMs, liraglutide 3 mg daily, semaglutide 2.4 mg weekly, and tirzepatide 15 mg weekly in adults without diabetes, 63.2 % vs 86.4 % vs 91 % of participants lost ≥5 % of body weight, respectively; 33.1 % vs 69.1 % vs 83.5 % of participants lost ≥10 % of body weight, respectively; and 14.4 % vs 50.5 % vs 70.6 % of participants lost ≥15 % of body weight. A greater proportion of participants lost ≥20 % of body weight with tirzepatide 15 mg (56.7 %) compared to semaglutide 2.4 mg (32.0 %). Importantly, in the tirzepatide trial, 36 % of participants achieved a body weight loss of ≥25 % at week 72 after starting the AOM.
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Cardiometabolic Benefits
Despite the different weight loss achieved by these AOMs, all trials have demonstrated improvement in glycemic control and cardiometabolic variables. There was a significantly greater reduction in glycated hemoglobin, fasting glucose, systolic and diastolic blood pressure with the three GLP-1RA as compared to the placebo groups. In fact, in the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial, major cardiovascular events (i.e., nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes nonfatal myocardial infarction or nonfatal stroke) occurred in 6.5 % of participants in the semaglutide group compared to 8.0 % of participants in the placebo group (hazard ratio, 0.80; 95 % confidence interval [CI], 0.72 to 0.90; P < 0.001).
The Food and Drug Administration has approved semaglutide to reduce the risk of cardiovascular death, heart attack and stroke in adults with heart disease and obesity.
Potential Neurological Benefits
Beyond glucose control and weight loss, benefits like a reduction in the risk of stroke, heart attacks, major cardiac events and kidney disease were expected, since some GLP-1 medicines have already been shown to be beneficial in reducing the incidence of these disorders in people with type 2 diabetes in clinical trials. “There’s very clearly some neurotropic aspect to GLP-1, in the sense the drugs actually reduce risk of quite a number of neurologic conditions,” the researcher says.
The study found mild reductions in the risk for dementia (8%) and Alzheimer’s (12%)-not overwhelming, but still noteworthy. Preclinical studies have highlighted the potential brain-protective effects of these drugs and the role they may have in treating various neurodegenerative diseases. Studies have shown that a GLP-1 drug, exenatide, sufficiently crosses the blood-brain barrier in rodent models of Parkinson’s disease, leading to improvements in motor performance, behavior, learning and memory.
Other Potential Benefits
GLP-1s also reduced the risk of respiratory failure, sepsis, chronic obstructive pulmonary disease and pneumonia in Al-Aly’s Nature Medicine study. The Food and Drug Administration has approved semaglutide to reduce the risk of cardiovascular death, heart attack and stroke in adults with heart disease and obesity.
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Risks and Side Effects
While GLP-1 agonists offer numerous benefits, it's crucial to be aware of the potential risks and side effects associated with their use.
Gastrointestinal Issues
A significant portion of participants have experienced side effects in the RCTs and real-world studies. In clinical trials, adverse and serious adverse events are presented by their preferred terms from the Medical Dictionary for Regulatory Activities.
In the liraglutide pivotal trial, 80.3 % of participants taking liraglutide experienced adverse events compared to 63.3 % of participants on placebo. However, it is important to note that adverse events reported in clinical trials do not indicate causality. Most of the experienced adverse events (94 %) were labeled as mild or moderate in severity. The majority of side effects were gastrointestinal-related, including nausea (40.2 %), diarrhea (20.9 %), constipation (20.0 %), and vomiting (16.3 %). In fact, gastrointestinal adverse events led to medication discontinuation in 6.4 % of participants compared to 0.7 % in the placebo group only. Most participants experienced nausea in the first 4-8 weeks, and this percentage progressively decreased with time.
For semaglutide, the incidence of side effects was a similar among participants in the treatment (89.7 %) and placebo groups (86.4 %) experienced side effects, irrespective of causality. Similar to liraglutide, gastrointestinal adverse events (e.g., nausea, diarrhea, vomiting, and constipation) were most commonly reported (74.2 % of participants taking semaglutide). Importantly, the majority of these side effects were considered mild-moderate and transient and did not require discontinuation.
With tirzepatide, compared to placebo, 78.9-81.8 % of participants on tirzepatide reported at least one adverse event compared (vs. 72.0 %), which is also irrespective of causality. The majority of adverse events were also gastrointestinal. In addition, most side effects were transient, mild to moderate in severity, and were experienced primarily during the dose-escalation period of tirzepatide. Most side effects occurred within the first 8-16 weeks of starting the medication.
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Serious Adverse Events
In RCTs, serious adverse events were statistically higher in the liraglutide group (6.2 %) compared to the placebo group (5.0 %). Similarly, participants taking semaglutide experienced a higher number of serious adverse events (9.8 %) compared to participants taking placebo (6.4 %). In fact, this difference was mainly attributed to gastrointestinal side effects (1.4 % vs 0 %) and hepatobiliary disorders (1.3 % vs 0.2 %). Consequently, the group taking semaglutide had a higher discontinuation percentage of the medication (7.0 % vs 3.1 %).
Gallbladder Problems
In participants taking liraglutide, the majority of documented severe adverse events were gallbladder-related (cholelithiasis, 0.8 % and acute cholecystitis, 0.5 %). The reported weight loss was greater in participants who experienced gallbladder related events as compared to the total population. A recent meta-analysis concludes that GLP-1 RAs were linked to a higher risk of gallbladder or biliary diseases, particularly when used at higher doses, for extended periods, and specifically for weight loss. Most participants (78 %) in the liraglutide group who reported cholelithiasis or cholecystitis underwent an elective cholecystectomy. Out of these individuals, 84 % continued their assigned course after recovery without encountering further complications.
In participants taking semaglutide, more gallbladder-related disorders were reported compared to participants taking placebo (2.6 % vs 1.2 %, respectively). The majority of these events were due to cholelithiasis. The incidence of cholelithiasis was similar among the three doses groups of tirzepatide and placebo groups (1.1 % in 5 mg, 1.4 % in 10 mg, 0.6 % in 15 mg, and 0.9 % in placebo groups). However, acute cholecystitis was more frequently demonstrated in the tirzepatide groups than in the placebo group (0.2-0.6 % vs 0 %). Importantly, the incidence of cholecystitis was relatively low (≤0.6 % of participants on tirzepatide).
Pancreatitis
Overall, ten participants taking liraglutide experienced pancreatitis compared to one in the placebo group. Out of these ten individuals, 9 were graded as mild and 5 had gallstone-related pancreatitis. With semaglutide, mild pancreatitis was reported in three participants taking semaglutide and all recovered during the trial period. In these participants, all had a personal medical history of acute pancreatitis and/or gallstones. As for tirzepatide, there were four reported cases evenly distributed across treatment groups, including the placebo group (1 case in each of 5 mg, 10 mg, 15 mg, and placebo group). Multiple recent systematic reviews and meta-analyses show that although there is a statistically significant increased risk of elevation of pancreatic enzymes associated with GLP-1-based agents, there is no significance difference in development of acute pancreatitis or pancreatic cancer between individuals on GLP-1 RAs compared to placebo.
Cardiac Arrhythmias
In the participants taking liraglutide, cardiac arrhythmias were similar compared to placebo despite tachycardia being higher in liraglutide group (0.6 events per 100 patient-years of exposure vs. 0.1 events per 100 patient-years of exposure). However, the majority of these cases were considered non-serious.
Mental Health
There was no clinically significant difference in terms of mental health assessments (e.g., psychiatric disorders, depression, or suicidal behavior) in participants taking liraglutide, semaglutide, or tirzepatide compared to participants on placebo. In fact, some studies show improvement in mental health in patients using GLP-1 RA. On the other hand, there has been also some cases of reported deterioration in mood with GLP1-RA.
Hypoglycemia
Spontaneous hypoglycemia was reported by 1.3 % vs 1.0 %, 0.6 % vs 0.8 %, and 1.6 % vs 0.2 % in the liraglutide, semaglutide and tirzepatide (15 mg) groups compared to their respective placebo groups. None of these events were considered to be serious. However, hypoglycemia remains a possible risk that should be taken into account when prescribing this medication in patients treated with insulin secretagogues or insulin, as shown in previous studies.
Neoplasms
There was no difference in the incidence of benign and malignant neoplasms in liraglutide, semaglutide, or tirzepatide groups compared to placebo. Importantly, there were no reports of medullary thyroid carcinoma or C-cell hyperplasia in individuals randomized to liraglutide, semaglutide, or tirzepatide group and there was no clinically significant increase in serum calcitonin concentrations associated with the use of these medications. Interestingly, more female participants in the liraglutide group compared to placebo (9 vs 3) had a diagnosis of malignant and premalignant breast neoplasms. Most of these women had above-average weight loss reported.
Mortality
Overall, there has not been an association between the use of GLP-1RA and death. In fact, multiple studies have been demonstrating the survival benefit of these medications. In one meta-analysis, the risk of all-cause mortality was decreased by 11 % in patients using GLP1-RA (RR 0.89, 95 % CI 0.81-0.99).
Other Risks and Considerations
- Cost: According to a KFF analysis, the list price for GLP-1 drugs can range between $936 and $1,349 before insurance, manufacturer coupons or rebates.
- Rebound Weight Gain: One thing researchers cannot yet answer is what would happen to patients who stopped taking a GLP-1. “One thing we know is that for people who discontinue GLP-1s, their weight gain rebounds. We know that very, very clearly,” says Al-Aly.
- Counterfeit Medications: Fake Ozempic and Wegovy are flooding the market.
- Use During Pregnancy and Breastfeeding: Semaglutide should not be used during pregnancy and there may be potential risks to an unborn baby from exposure to semaglutide during pregnancy. You should stop using semaglutide for at least 2 months before you plan to become pregnant. It is not known if semaglutide passes into your breast milk.
- Potential Thyroid Tumors: Semaglutide may cause serious side effects, including possible thyroid tumors, including cancer.
Important Safety Information
It is important to refer to the important safety details for information on intended use, potential side effects and risks, considerations for specific groups, and possible drug interactions linked to the prescription treatments mentioned. Amble encourages users to promptly report any side effects or adverse reactions to a licensed healthcare provider and the pharmacy that dispensed the medication.
Before starting semaglutide, tell your healthcare provider if you have any other medical conditions, including if you:
- Have or have had problems with your pancreas or kidneys.
- Have type 2 diabetes and a history of diabetic retinopathy.
- Have or have had depression, suicidal thoughts, or mental health issues.
Conclusion
GLP-1 and dual GLP-1/GIPRAs have been proven to be effective for the treatment of overweight and obesity. As with all pharmacologic agents, side effects can occur. Most side effects of GLP-1 and GLP-1/GIP RAs involve gastrointestinal symptoms, are mild-to-moderate, and improve with time. While concerns exist regarding the safety profile, tolerability, and health risks associated with these medications, the benefits often outweigh the risks for individuals struggling with obesity and related health conditions. However, it is essential to have a thorough discussion with a healthcare provider to assess individual risks and benefits before starting treatment with GLP-1 agonists.
The decision to use GLP-1 agonists for weight loss should be made in consultation with a healthcare professional, considering individual health status, potential risks, and lifestyle factors. Continuous research and vigilant monitoring are essential to optimize their safe use.