Glucagon Like Peptide -1 Receptor Agonists for Weight Loss: A Primary Care Perspective

Abstract

In this article we review the glucagon like peptide −1 receptor agonist (GLP-1) medications and discuss how to approach using them for weight loss and management in non-diabetic patients.

Introduction

“Hey Doctor, I know this person who has been using a shot for weight loss, do you think that’s something I could try?”

This has become a daily conversation in primary care and for good reason. According to the World Health Organization (WHO), as of 2022 one out of eight people in the world were living with obesity; a rate that has more than doubled since 1990.¹ To say this another way, 43% of adults were overweight and 16% were obese. Obesity is now the most prevalent chronic disease worldwide.² Obesity is defined using a combination of a body mass index (BMI) of 30kg/m² or greater and overweight is defined as BMI 25kg/m² to 29.9kg/m², or increasing waist circumference in men: waist circumference > 40 inches (102 cm), in women: waist circumference > 35 inches (89 cm). According to the 2021 Behavioral Risk Factor Surveillance Survey, the rates in Missouri adults are even higher with prevalence of 37.2% being obese and 32% being overweight.³

Obesity results from an imbalance of energy intake and energy expenditure, but is also multifactorial due to environment, psychosocial factors, and genetics. Not only that, adipose tissue accumulates when a person is overweight or obese and functions as an organ. Adipose tissue uses energy, has vascular supply, and grows. It also secretes hormones, adipokines, and inflammatory cytokines.

Obesity is chronic, progressive, and relapsing with increased morbidity and mortality and reduced quality of life. Adults in their 20s with obesity are estimated to have a reduced lifespan from 5.6 to 10.3 years.⁴ The Global Burden of Disease study reported over 4.7 million deaths yearly due to obesity.⁵ The leading causes of death associated with obesity are cardiovascular disease, chronic kidney disease, type 2 diabetes, and cancer of various types.⁴ In addition, obesity is associated with hypertension, hyperlipidemia, obstructive sleep apnea, metabolic dysfunction associated with steatotic liver disease, and osteoarthritis. Patients with obesity are at higher risk of mental health disorders, physical and sexual dysfunction.⁴

Many of the effects of obesity can be halted, reversed, and prevented by losing weight. Traditionally, weight loss centered around discussions of reduced caloric intake and increased physical activity. This is difficult because weight loss activates central and peripheral compensatory mechanisms that counter weight loss and favor weight gain.⁴ When lifestyle intervention is the sole treatment, weight is typically regained even with continued compliance.⁶ Treatment requires a comprehensive approach that includes lifestyle interventions, pharmacotherapy and in some instances, bariatric surgery. If it were simple to overcome obesity, we would have already done it. Fortunately, through research we have a better understanding and way to approach treating obesity. Despite this there is still some hesitancy in using medication for weight loss which comes from a variety of reasons including, but not limited to, lack of recognition of obesity as a disease, lack of provider experience, biases, concerns about safety and efficacy, cost, and lack of reimbursement.

Medications

Up until recently, the medications used to treat obesity were not very effective and had many limiting side effects and contraindications. These included phentermine, orlistat, phentermine/topiramate (Qsymia) and bupropion/naltrexone (Contrave). To date, there are two GLP-1s approved for weight loss; liraglutide (Saxenda) and semaglutide (Wegovy), and one GLP-1 and gastric inhibitory polypeptide also know as glucose-dependent insulinotropic polypeptide receptor agonist (GIP), tirzepatide (Zepbound).

These medications work by mimicking the natural GLP-1 which is an incretin peptide released from cells in the bowel.⁵ It enhances insulin secretion in the hyperglycemic state, inhibits glucagon secretion, delays gastric emptying, regulates food preference, and reduces food intake by increasing satiety thru central appetite suppression. Some studies suggest the delayed gastric emptying is only in the first hour and overall gastric emptying did not seem to be affected.^7,8 GLP-1 is also expressed in the brainstem, endocrine pancreas, and immune system. Part of the GLP-1 action is to activate metabolism of brown fat and adipose redistribution with decreased visceral fat and relative increase in lower-body subcutaneous fat deposition.⁸ GIP is also an incretin hormone involved in energy and nutrient metabolism through cell surface receptor signaling in the brain and adipose tissue.²

Liraglutide was the first GLP-1 approved for weight loss and was studied in the Satiety and Clinical Adiposity-Liraglutide Evidence (SCALE) trials.⁹ The initial SCALE study evaluated the efficacy of liraglutide 3mg once daily in individuals with BMI greater than 27kg/m² with one or more comorbid conditions or BMI greater than 30kg/m². After 56 weeks, mean weight loss was 8.4kg in the liraglutide group and 2.8kg in the placebo group ( p value <0.001).¹⁰ In addition, 33.1% of trial participants lost greater than 10% of their body weight in the liraglutide group and 10.6% in the placebo group (p value <0.001).¹⁰ The SCALE obesity and prediabetes trial evaluated the effect of liraglutide 3mg daily versus placebo plus lifestyle intervention in individuals with BMI greater than 30kg/m² and prediabetes and showed fewer people were diagnosed with diabetes in the liraglutide arm (2% vs 6% liraglutide vs placebo, respectively).¹¹ The SCALE Intensive Behavioral Therapy (IBT) study compared participants receiving IBT to liraglutide 3mg versus placebo. Over 56% of participants achieved mean weight loss of 7.5% with liraglutide versus 4% with placebo. In addition, 30.5% vs 19.8% (p value = 0.0469) reported greater than 10% weight loss with liraglutide versus placebo, respectively.¹² More than 15% weight loss was seen in 18.1% in the liraglutide group and 8.9% in the placebo group (p value=0.0311). ¹²

The Semaglutide Treatment Effect in People with Obesity (STEP) trials evaluated the safety and efficacy of semaglutide for weight loss. The STEP 1 trial compared semaglutide to placebo over 68 weeks in individuals with BMI greater than or equal to 30 kg/m² or greater than or equal to 27 kg/m² with one or more weight-related comorbidity and showed that semaglutide was associated with a 14.9% weight loss whereas placebo was 2.4% ( p value <0.001).⁷ The STEP 3 trial, which looked at the effect of semaglutide versus placebo as an adjunct to IBT, showed that continued semaglutide at 2.4mg was associated with slightly more weight loss, up to 17.4%, whereas when switched to placebo there was weight gain and overall weight loss was only 5.9% with both groups continuing lifestyle interventions.⁷

Tirzepatide was studied in the SURMOUNT-1 trial and was shown to have average weight loss of 15% with the 5mg dose, 19.5% with 10mg and 20.9% with the 15mg dose, whereas the placebo group had 3.1% weight loss.² Similar to the STEP 1 trial, SURMOUNT-1 included individuals with BMI greater than or equal to 30 kg/m² or greater than or equal 27 kg/m² with one or more weight-related comorbidity, except diabetes, and patients were treated over 72 weeks. Participants also had improvement in waist circumference, systolic and diastolic blood pressure, fasting insulin level, lipid levels, and A1c with most of the participants who had prediabetes achieving normoglycemia.² This demonstrates a significantly decreased 10-year predicted atherosclerotic cardiovascular disease risk.¹³ Recently, semaglutide was approved for reducing risk of cardiovascular events in patients with cardiovascular disease who are obese or overweight. This approval was based on the SELECT trial which showed a 20% reduction in cardiovascular events in patients with BMI 27kg/m² or higher and preexisting cardiovascular disease without diabetes.¹⁴

Approach to Therapy

Medications are indicated when adult patients have failed non-pharmacologic methods such as diet modification, increased activity, and have a BMI of 30kg/m² or higher or BMI 27kg/m² or higher with an obesity related comorbidity such as hypertension, hyperlipidemia, heart disease, or obstructive sleep apnea. Semaglutide is indicated for weight loss in pediatric patients over the age of 12 with obesity.

The use of medications for weight loss needs to be an adjunct to diet and lifestyle changes to ensure the weight loss is sustainable. Ideally, this would be with a multidisciplinary team. Working with a dietician may help patients alter their food choices, but discussion of decreasing caloric intake is also helpful. Most international guidelines recommend at least a 500kcal daily energy deficit for weight loss.⁴ According to the American Heart Association and the Academy of Nutrition and Dietetics, as long as the diet is balanced and healthy the macronutrient composition is not significant.⁴ The recommended amount of exercise is 150 minutes per week of moderate intensity.⁴ This includes both endurance exercise and strength training. For long-term weight loss maintenance there would need to be an increase in weekly exercise to three hundred minutes, which is typically not sustainable.⁴ Additionally, individual or group sessions in a weight management program should be considered. Having patients track intake and physical activity has been shown to be helpful.

These medications are subcutaneous injections that patients do on their own. Liraglutide is daily, while semaglutide and tirzepatide are weekly. Liraglutide is a multiple use pen that requires a new needle with each injection and patients dial the pen to their dose, semaglutide and tirzepatide are single use pens.^15,16,17

Once patients decide to start medication, they should be counseled on side effects and how to take the medication. They can be injected into the abdomen (most common), fatty part of the thigh, or upper arm. The cost can be prohibitive, most insurances require prior authorization and making patients aware of this up front helps reduce frustration and phone calls/messages. At this time, Medicaid and Medicare will not cover them for weight loss. Each of the three medications has coupons on the manufacturer website patients can apply for, however, if they have government insurance, they are exempt from qualifying. It should be noted that the cost of future healthcare needed from consequences of obesity is likely to be more than that of the medication. There have also been ongoing shortages of some of the doses of the medications. Once started, the dose should be increased every four weeks (or weekly if using liraglutide) until maintenance dose is achieved (Table 1). If there are significant side effects a slower titration may be helpful but is usually limited by insurance.

Table 1.

Medication Dosage and Frequency,¹⁵,¹⁶,¹⁷

Medication	Liraglutide (Saxenda)	Semaglutide (Wegovy)	Tirzepatide (Zepbound)
Frequency	Daily injection with dose increased weekly	Weekly injection with dose increased every 4 weeks	Weekly injection with dose increased every 4 weeks
Starting dose	0.6mg	0.25mg	2.5mg
Dose increases	1.2mg	0.5mg	5mg*
	1.8mg	1mg	7.5mg
	2.4mg	1.7mg*	10mg*
	3.0mg*	2.4mg*	12.5mg
			15mg *

^*Denotes maintenance dose

Side-effects and Interactions

Most side effects are gastrointestinal and include nausea, vomiting, diarrhea, and constipation. These effects tend to be mild to moderate and are transient, mostly following dose increases.^5,7 Patients should be counseled on adequate water intake. Nausea can sometimes be alleviated by eating smaller amounts but more frequently, diarrhea and constipation can be mitigated with increased fiber intake.⁶ Other helpful changes include eating slowly, stopping eating when satiated, and avoiding high fat foods.⁷ Antiemetics may be considered if the smaller portions and diet changes are made but there are still significant side effects. Studies report that the discontinuation rate due to adverse effects were lower with semaglutide than liraglutide ( 3.2% vs 12.6% respectively).⁶ Despite these side effects, trials showed that nausea and vomiting did not really contribute to patients’ weight loss, it was the lower energy intake that has been thought to be responsible for the weight loss. Given that the gastrointestinal side effects are transient, and patients continue to lose weight it is likely not the side effects causing the weight loss.⁸

They are contraindicated in pregnancy, in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2.⁷ Some suggest that it not be used with patients with a history of pancreatitis as there have been rare cases reported. In the STEP trials there was no notable increase in the incidence of acute pancreatitis with the 2.4mg dose of semaglutide.⁶ Although rare, hypoglycemia, acute kidney injury, angioedema, and anaphylaxis have been reported. There has been an association with increased heart rate, usually one to four beats per minute, and so this should be monitored.⁷ Rapid weight loss is associated with increased risk of gallbladder disease and so patients need to be made aware of signs and symptoms to monitor for. Patients with renal and/or hepatic dysfunction may need closer monitoring as this may affect the pharmacokinetics and bioavailability.⁵ In January 2024 there was an alert from the Food and Drug Administration about concerns for suicidal thoughts and actions, this investigation is ongoing. Preliminary evaluation has not found evidence that use of these medications causes suicidal thoughts or actions.

There are some notable drug interactions. With the potential for delayed gastric emptying absorption of other medications should be considered.⁶ Most of the drug interactions are increased risk of hypoglycemia therefore education about symptoms is important. Other drug interactions are noted in Table 2.

Table 2.

Drug Interactions¹⁵,¹⁶,¹⁷

Medication	Effect	Next Steps
Medications with hypoglycemia as a side effect (ex. Antidiabetic agents, beta-blockers, etc)	Can increase risk of hypoglycemia	Educate patients on signs and symptoms of hypoglycemia and what to do in a hypoglycemic emergency
Furosemide	May increase serum concentration of furosemide	Educated patients on side effects Closer lab monitoring of electrolytes and renal function Dose adjustment of furosemide as indicated
Levothyroxine	May increase serum concentration of levothyroxine	Educated patients on signs and symptoms to monitor for Closer lab monitoring of thyroid function Dose adjustment of levothyroxine as needed
Oral hormonal contraceptives	May decrease serum concentration of contraceptive	Switch to an alternative contraceptive method or add a barrier method for four weeks after initiated and four weeks after dose escalation
Warfarin	Tirzepatide may increase serum concentration of warfarin	Educate patients on risk and effect of potentially elevated INR Closer lab monitoring of INR

Monitoring

Close follow-up is essential to success as well. Once started, follow-up within a few weeks allows discussion with patient on side effects and ongoing diet/lifestyle changes. It also allows continued documentation of weight to demonstrate success with the weight loss efforts. Notably, vital signs should be reviewed as there may need to be adjustments of other medications as the benefits of weight loss come through, especially blood pressure medications. It is important for patients to be aware of symptoms of low blood pressure.

Once a patient is on maintenance dose, follow-ups can be spread out, however, it may be beneficial to see patients more frequently if they continue to have weight loss or are not having the expected maintenance of weight. Since obesity is a chronic and relapsing disease, patients should be made aware that use of these medications is expected to be ongoing. Patients should know there is expected weight loss in the up titration but usually a plateau and then maximum weight loss after taking the maintenance dose for a year, then continued use of the medicine is meant for weight maintenance.^7,8 Providers and patients should be aware that metabolic adaption is likely the reason for the plateau and not a poor response or resistance to the medication.^7,8 That being said, if there is not at least 4–5% weight loss after 12 weeks on maintenance dose, the medication should be discontinued. If a dose is missed it can be made up as in Table 3. Of note as well, if a patient is undergoing a non-emergent surgery, newer anesthesia consensus-based guidance recommends holding GLP-1s up to a week in advance given possible gastroparesis leading to aspiration risk.¹⁸ If a patient is undergoing a surgery, it may be best to have anesthesia give guidance on their preference of preoperative GLP-1 management.

Table 3.

Missed Doses¹⁵,¹⁶,¹⁷

Medication	Administer dose as soon as possible)	Skip dose and give at next scheduled time	Other
Liraglutide (Saxenda)		Resume once-daily regimen with next scheduled dose if 1 or 2 days are missed	If ≥ 3 days missed, reinitiate at 0.6mg dose
Semaglutide (Wegovy)	If ≤ 5 days since last dose	If > 5 days since last dose
Tirzepatide (Zepbound)	If ≤4 days since last dose	If > 4 days since last dose

Conclusion

The recent advances in obesity medicine have led to many changes in the approach to patients with obesity and there is hope that this can be a manageable disease thus mitigating the consequences of it. With just 5% weight loss, there is noticeable improvement in health and reduced risk of complications. Weight loss would also be expected to reduce risk of cardiovascular disease, chronic kidney disease, metabolic dysfunction associated with steatotic liver disease, type 2 diabetes, and other diseases.³ With these medications most patients can achieve this 5% goal and as high as 20%. Some studies also suggest that GLP-1s may have a role to play in many other disease processes including Alzheimer’s, Parkinson’s, strokes, chronic pain, polycystic ovarian syndrome, and cancer.¹⁹