Introduction
Overweight and obesity have become significant public health concerns, with increasing prevalence rates globally. These conditions not only pose significant challenges to individual health but also impose substantial burdens on healthcare systems worldwide. The prevalence of overweight and obesity has reached alarming levels, affecting individuals across all age groups and socioeconomic strata. The multifaceted nature of overweight and obesity intertwines with various comorbidities, including cardiovascular diseases, type 2 diabetes mellitus (T2DM), musculoskeletal disorders, and certain cancers, thereby underscoring the imperative for effective management strategies. Current guidelines advocate for a multifaceted approach to weight management, integrating lifestyle modifications, dietary interventions, and pharmacotherapy. However, achieving sustainable weight loss remains a formidable challenge for many individuals. While behavioral modifications and dietary restrictions constitute cornerstone interventions, pharmacological agents play a pivotal role, particularly in cases where lifestyle interventions alone prove insufficient. Among the pharmacological agents, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have gained prominence for their efficacy in facilitating weight loss in individuals with overweight or obesity. GLP-1 RAs exert their therapeutic effects through multiple mechanisms, primarily by stimulating the GLP-1 receptor, which in turn enhances insulin secretion, suppresses glucagon release, delays gastric emptying, and promotes satiety. Consequently, these agents not only aid in glycemic control but also exhibit pronounced effects on body weight. Multiple glucagon-like peptide-1 (GLP-1) agonist medications, created for the treatment of type 2 diabetes mellitus, are now labeled for the treatment of obesity.
What are GLP-1 Agonists?
Glucagon-like peptide 1 (GLP-1) was first discovered through research demonstrating a sustained insulin release in response to oral glucose load when compared with the intravenous glucose load. GLPs' enhanced release of insulin in response to glucose ingestion became known as the ‘incretin effect'. Further, study showed that patients with type 2 diabetes (T2D) had an impaired incretin effect after glucose load. Subsequently, glucagon-like peptide 1 (GLP-1) was found to be specifically effective in stimulating insulin and reducing peak plasma glucose concentrations. GLP-1 is released from the distal bowel within minutes of a meal and does enhance glucose-dependent insulin production and secretion, decrease glucagon secretion, increase glucose uptake and glycogen synthesis in peripheral tissues, delay gastric emptying, and increase satiety, making it an ideal target for diabetes therapy. The first GLP-1 receptor agonist (GLP-1 RA) was exenatide, which was approved by the US Food and Drug Administration (FDA) in 2005 for the treatment of T2DM. Since then, several GLP-1 RAs have been recommended for treatment of diabetes as a second line therapy in view of their clinical efficacies including improved weight loss, low risk for hypoglycaemia, and reduction in glycated haemoglobin (HgA1c). GLP-1 RAs have its unique mechanism of action of simultaneously increasing insulin secretion and inhibiting glucagon only in response to increased glucose levels and can potentially be used in obese and nondiabetic individuals without the risk of hypoglycaemia.
Types of GLP-1 Receptor Agonists
A wide range of GLP-1 receptor agonists are currently approved or in clinical development for weight loss or glycemic control. These include short-acting agents (e.g., exenatide BID), long-acting formulations (e.g., liraglutide, semaglutide, dulaglutide), dual agonists such as tirzepatide (GIP/GLP-1 RA), and novel oral agents like orforglipron and danuglipron. Additionally, long-acting amylin analogues like cagrilintide are being investigated in combination with GLP-1 RAs for enhanced weight loss efficacy.
How GLP-1 Agonists Work for Weight Loss
GLP-1s can help you lose weight, but they aren’t a magic fix. GLP-1 RAs exert their therapeutic effects through multiple mechanisms, primarily by stimulating the GLP-1 receptor, which in turn enhances insulin secretion, suppresses glucagon release, delays gastric emptying, and promotes satiety. Consequently, these agents not only aid in glycemic control but also exhibit pronounced effects on body weight. One lesser-known side effect? “GLP-1s slow food moving through the intestines. It tells your brain it’s not hungry,” says Sara Fausett, a registered dietitian at Intermountain Health Cedar City Hospital.
Administration of GLP-1 Medications
GLP-1 medications are typically taken as a once-weekly injection. You use a small needle to inject the medication into fatty tissue - usually in your belly, thighs, arms, or upper buttocks.
Read also: Weight Loss Guide Andalusia, AL
Efficacy of GLP-1 Agonists in Non-Diabetic Individuals
Current research with GLP-1 RAs has provided significant evidence, especially liraglutide accounting for up to 56% of the global pharmacological approach to obesity management. Long-acting analogues of GLP-1 RAs showed good weight loss activity. Recent review has shown clear evidence of GLP-1 RAs to reduce body weight by 5.8-9.6% in obese adults with T2DM. Liraglutide has been shown to result in weight loss that is dose-dependent, up to 3.0 mg daily. A 56-week RCT of liraglutide 3.0 mg daily, used as an adjunct with a reduced calorie diet and increased physical activity in nondiabetic overweight or obese adults demonstrated a significant averaged weight reduction by −8.4 kg ± 7.3 kg, corresponded to an averaged reduced BMI of −3.0 ± 2.6 kg/m2. Another RCT comparing semaglutide with liraglutide and placebo in nondiabetic patients demonstrated a 7.8% weight loss in the liraglutide 3.0 mg group. Interestingly, however, the study found a higher average weight loss in the semaglutide group of 11-14% at doses of 0.2 mg daily or more. The average weight loss was found to be dose-dependent with reduction of both fat mass and lean mass at a rate of 3 : 1 on 1.0 mg daily. A review included three medications that have been approved by the US Food and Drug Administration for chronic weight management-semaglutide, liraglutide (Saxenda; Novo Nordisk), and tirzepatide (Zepbound; Eli Lilly), which is a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist. The review identified 26 randomized, placebo-controlled trials in otherwise healthy individuals with overweight or obesity but not diabetes or other conditions like cardiovascular disease, polycystic ovary syndrome, or chronic obstructive pulmonary disease. Active treatment induced weight loss relative to placebo across all trials, with varying effects.
Benefits Beyond Weight Loss
“These medications don’t just help people lose weight. They also improve overall health,” says Patrick Welch, PharmD, BCACP, an Advanced Clinical Pharmacist at Intermountain. The GLP-1 receptor agonists have shown “important cardiorenal protective effects,” they add, citing evidence from trials like SELECT, STEP-HFpEF, and STEP-HFpEF DM.
Safety and Side Effects
Despite their therapeutic benefits, GLP-1 RAs are associated with a spectrum of adverse events, with gastrointestinal disturbances being among the most commonly reported. Gastrointestinal adverse events represent a notable concern in individuals receiving GLP-1 RAs, potentially impacting treatment adherence and patient satisfaction. These adverse events encompass a range of symptoms, including nausea, vomiting, diarrhea, and abdominal discomfort, which may vary in severity and duration. While the exact mechanisms underlying these gastrointestinal disturbances remain incompletely elucidated, they are believed to stem from the actions of GLP-1 RAs on gastrointestinal motility and secretion. In terms of safety, overall adverse events generally occurred at a higher rate with active treatment (80-97%) than with placebo (63-100%).
Common Gastrointestinal Side Effects
A total of 29 trials were evaluated regarding the risk of nausea in patients receiving GLP-1 RAs. All evaluated GLP-1 RAs were associated with a significant increased risk of nausea, in the following order: cagrilinitide (RR 2.2983 [95% CI 1.6884, 3.1285; p-value < 0.0001]), exenatide (RR 2.6645 [95% CI 1.3956, 5.0870; p-value 0.0030]), tirzepatide (RR 2.8997 [95% CI 2.0048, 4.1939; p-value < 0.0001]), semaglutide (RR 2.9464 [95% CI 2.6138, 3.3213; p-value < 0.0001]), liraglutide (RR 3.0919 [95% CI 2.7271, 3.5056; p-value < 0.0001]), orforglipron (RR 4.7748 [95% CI 2.0161, 11.3085; p-value 0.0004]. A total of 23 trials were evaluated regarding the risk of vomiting in patients receiving GLP-1 RAs. Some of the evaluated GLP-1 RAs were associated with significant increased risk of vomiting, in the following order: liraglutide (RR 3.8722 [95% CI 3.1510, 4.7585; p-value < 0.0001]), orforglipron (RR 3.8722 [95% CI 1.4471, 13.5578; p-value 0.0091]), semaglutide (RR 4.2108 [95% CI 3.5822, 4.9497; p-value < 0.0001]), tirzepatide (RR 13.2265 [95% CI 4.8471, 36.0917; p-value < 0.0001]). On the contrary, the following GLP-1 RAs were not associated with a significant increased risk of vomiting: cagrilinitide (RR 1.3701 [95% CI 0.8106, 2.3158; p-value 0.2397]), exenatide (RR 4.5238 [95% CI 0.2472, 82.7745; p-value 0.3088]). A total of 24 trials were evaluated regarding the risk of diarrhea in patients receiving GLP-1 RAs. Some of the evaluated GLP-1 RAs were associated with significant increased risk of diarrhea, in the following order: semaglutide (RR 1.7714 [95% CI 1.4679, 2.1377; p-value < 0.0001]), liraglutide (RR 1.8231 [95% CI 1.4804, 2.2452; p-value < 0.0001]), tirzepatide (RR 3.3537 [95% CI 1.9216, 5.8533; p-value < 0.0001]). On the contrary, the following GLP-1 RAs were not associated with a significant increased risk of diarrhea: exenatide (RR 0.1756 [95% CI 0.0231, 1.3355; p-value 0.0929]), cagrilinitide (RR 1.1956 [95% CI 0.6819, 2.0961; p-value 0.5329]), orforglipron (RR 2.2973 [95% CI 0.8893, 5.9347; p-value 0.0859]). A total of 24 trials were evaluated regarding the risk of constipation in patients receiving GLP-1 RAs. Some of the evaluated GLP-1 RAs were associated with a significant increased risk of constipation, in the following order: semaglutide (RR 2.0979 [95% CI 1.6722, 2.6321; p-value < 0.0001]), liraglutide (RR 2.2368 [95% CI 1.7424, 2.8715; p-value < 0.0001]), tirzepatide (RR 3.3575 [95% CI 1.7007, 6.6282; p-value 0.0005]). On the contrary, the following GLP-1 RAs were not associated with significant increased risk of constipation: cagrilinitide (RR 1.2782 [95% CI 0.6950, 2.3508; p-value 0.4299]), exenatide (RR 5.0000 [95% CI 0.2379, 105.0709; p-value 0.3003]), orforglipron (RR 4.0541 [95% CI 1.1930, 13.7766; p-value 0.0249]). A total of 11 trials were evaluated regarding the risk of abdominal distention in patients receiving GLP-1 RAs. Only semaglutide (RR 1.4245 [95% CI 1.1320, 1.7925; p-value 0.0026] was associated with a significantly increased risk of abdominal distention, while liraglutide (RR 1.5656 [95% CI 0.8445, 2.9025; p-value 0.1547]), and exenatide (RR 6.5609 [95% CI 0.8253, 52.1544; p-value 0.0753]), were not associated with a significantly increased risk of abdominal distention.
Other Considerations
Many online services now offer quick prescriptions for GLP-1s. “Many direct-to-consumer brands don’t have full access to a patient’s medical history,” Welch explains. With Intermountain Health’s online program, you can easily start your weight loss journey from home. There is a potential to regain the lost weight, but those chances decrease when you work with a healthcare provider to transition off the medication safely. “All the clinical trials that showed these medications working also included education on eating and exercise,” explains Welch. Your doctor will also look at your full health history, including past and current medical conditions, family history, previous weight loss attempts, and medications.
Read also: Beef jerky: A high-protein option for shedding pounds?
FDA Concerns Regarding Compounded Versions
The agency has identified some areas of concern for compounded GLP-1 drugs. Improper storage during shipping may lead to quality issues. Injectable GLP-1 drugs require refrigeration as indicated in their package inserts. FDA has received complaints that certain compounded GLP-1 drugs have arrived warm or with inadequate ice packs to keep the drug at recommended storage temperatures. FDA is aware of one reported adverse event associated with a product labeled as compounded tirzepatide from a pharmacy that did not actually compound the product. The adverse event report included symptoms such as redness, site swelling, pain, and a red lump at the injection site. FDA received multiple reports of adverse events, some requiring hospitalization, that may be related to dosing errors associated with compounded injectable semaglutide products. These dosing errors resulted from patients measuring and self-administering incorrect doses of the drug, and in some cases, health care professionals miscalculating doses of the drug. Additionally, the agency has received adverse event reports that may be related to patients prescribed compounded semaglutide or tirzepatide products in doses beyond what is in the FDA-approved drug label. Some of the adverse events are serious and some patients reported seeking medical attention for their symptoms, including nausea, vomiting, diarrhea, abdominal pain and constipation. The agency also encourages patients to talk with their health care provider or compounder about how to measure and administer the intended dose of compounded semaglutide or tirzepatide. Salt forms should not be used to compound semaglutide . The agency is aware that some semaglutide products sold by compounders may be the salt forms. These salt forms, including semaglutide sodium and semaglutide acetate, are different active ingredients than are used in the approved drugs. The agency does not have information on whether these salts have the same chemical and pharmacologic properties as the active ingredient in the approved drug, and we are not aware of any lawful basis for their use in compounding.
GLP-1 RAs and Cardiovascular Outcomes in Non-Diabetic Individuals
Some of the interpretation with GLP-1 RA trials suggested the possible role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in primary prevention of cardiovascular diseases in nondiabetic individual, echoed by a recent editorial redefining the role of GLP-1 RAs being beyond glycaemic control. The focus of the review is on GLP-1 RAs' preventive roles in nondiabetic individuals with cardiovascular disease, chronic kidney diseases, obesity, dyslipidaemia, hypertension, nonalcoholic fatty liver diseases, polycystic ovarian syndrome (PCOS), and perioperative complications of bariatric surgery, albeit in small studies and subset analysis of clinical trials of diabetic patients. Further exploration of GLP-1 RAs in nondiabetic patients, a mild improvement of left ventricular function has recently been demonstrated in patients with ST-segment elevation myocardial infarction (STEMI) treated acutely with the GLP-1 analogue liraglutide for 7 days. Similar results were shown in patients with non-STEMI irrespective of diabetic status. It raised the possible preventive role of GLP-1 RAs on cardiovascular events in nondiabetic population that needs to be confirmed in future studies. Taking together, there is no convincing trial evidence with GLP-1 RA for prevention of cardiovascular events in nondiabetic population.
Effects on Blood Pressure and Lipid Profile
There are no direct clinical trial examining GLP-1 RA effects on cardiometabolic variables including blood pressure and dyslipidaemia. In the recent liraglutide trial with obese nondiabetic patients, both changes between baseline and week 56 of systolic and diastolic blood pressure were significantly different between the liraglutide group and the placebo group with a risk difference of -2.8 mmHg (95%Cl -3.56 to -2.09) and -0.9 (95%Cl -1.41 to -0.37), respectively ,Similarly, the reduction of total cholesterol from baseline to week 56 was significantly higher in the liraglutide group with a risk difference -2.3% (95%Cl -3.3 to -1.3) . In summary, there is no direct trial evidence of GLP-1 RAs' effects on prevention of CKD in nondiabetic population (Table 2). A dedicated trial should be carefully designed to examine cardiometabolic endpoints including blood pressure, lipid, and other metabolic variables with GLP-1 RAs in nondiabetic population.
GLP-1 Agonists and Surgical Outcomes
Glucagon-like peptide 1 (GLP-1) agonists are an effective medication for glycemic control and weight loss. These effects may reduce complications in diabetic patients undergoing total hip arthroplasty (THA). However, there remains a paucity of data on the impact of GLP-1 medications in nondiabetic patients using the medication solely for weight reduction. Patients who were on GLP-1 agonist medications were less likely to develop acute blood loss anemia (OR: 0.57; 95% confidence interval [CI]: 0.34 to 0.96) and require postoperative transfusion (OR: 0.53; 95% CI: 0.36 to 0.78) or visit the emergency department within 90 days of surgery (OR: 0.81; 95% CI: 0.69 to 0.92) when compared to patients who did not have GLP-1 therapy. Patients were at comparable risk of deep venous thrombosis, pulmonary embolism, mortality, stroke, myocardial infarction, acute kidney injury, and sepsis regardless of GLP-1 status (P > 0.05). Notably, the rate of aspiration pneumonia was similar between groups (OR: 1.17; 95% CI: 0.62 to 2.19).
Read also: Inspiring Health Transformation