Lipid Luminations: Novel Advancements in GLP-1 Receptor Agonist Treatment

Introduction

Obesity is a complex, chronic medical condition. Although defined by a BMI >30 kg/m², it is now understood to be much more than a BMI cutoff and modulated by neuroendocrine mechanisms with emerging therapeutic options.^1,2 Clinical guidelines recommend medical treatment for obese or overweight patients with at least one weight-related comorbidity.³ Glucagon-like peptide-1 (GLP-1), an incretin hormone secreted from gut endocrine cells, increases insulin production and decreases glucagon secretion, slowing digestion and decreasing appetite.^4,5 Initially, GLP-1 agonists were developed for diabetes management, but given promising effects on weight loss, two injectable GLP-1 receptor agonists, liraglutide (Saxenda) and semaglutide (Wegovy), are currently approved for obesity. Other semaglutide medications, such as Ozempic and Rybelsus, are not yet approved for obesity.

The most common side effects associated with GLP-1 receptor agonists are gastrointestinal, including nausea and vomiting, and are often dose-dependent and decrease over time.⁶ Contraindications to GLP-1 receptor agonists include history of pancreatitis, personal or family history of medullary thyroid cancer, pregnancy or breast feeding.⁶ Cost is a major limitation in prescribing GLP-1 receptor agonists; however, studies suggest lower inpatient and outpatient costs as a result of the drug, resulting in budget neutrality.⁷

In addition, GLP-1 receptor agonists have been shown to reduce major adverse cardiac events and heart failure hospitalizations⁸; ACC/AHA guidelines now recommend using GLP-1 receptor agonists in patients with diabetes at high risk of atherosclerotic cardiovascular disease, even if glucose is well controlled.^9,10 Given the promising weight loss and cardiovascular effects of GLP-1 receptor agonists, novel treatment options are currently being studied. This review discusses two emerging GLP-1 receptor treatment options currently under investigation. 

A New, Oral GLP-1 for Weight Loss 

There are currently no FDA approved oral GLP-1 receptor agonists for weight loss. Oral semaglutide (Rybelsus) is approved for diabetes treatment but not for obesity.¹¹ There is a need for oral GLP-1 receptor agonists to increase treatment options and adherence for patients with obesity given injectable medications are often viewed as a barrier for many patients.¹²

The GZGI trial, recently published in the New England Journal of Medicine in June of 2023, is a Phase 2, randomized, double-blind trial investigating an oral GLP-1 receptor agonist, orforglipron, for weight loss.¹³ The primary endpoint was percentage of body weight change from baseline to 26 weeks.

A total of 272 nondiabetic patients with obesity or those overweight with one weight-related condition were randomized to varying doses of orforglipron (12 - 45 mg once daily) or placebo for 36 weeks. At baseline, mean BMI was 37.9 kg/m², mean age 54.2 years, 59% of the patients were women, and 91% were white. By week 26, all orforglipron dose cohorts had a decrease in body weight from baseline, ranging from -8.6% to -12.6% depending on dose, compared to -2.0% in the placebo group. At 36 weeks, the effect continued with decrease in body weight from baseline ranging from -9.4% to -14.7%, compared to -2.3% in the placebo group. Additionally, there was improvement in systolic blood pressure, total cholesterol, LDL, VLDL, and triglycerides in patients receiving orforglipron. The most common side effects of orforglipron were gastrointestinal, such as nausea and vomiting, and mild to moderate in severity. Overall, the safety profile was similar to that of other GLP-1 receptor agonists.  

This trial suggests that orforglipron may be an effective oral GLP-1 receptor agonist treatment option for patients with obesity or overweight patients with complications, which would increase the availability of GLP-1 receptor agonists to those unwilling or unable to use injectable GLP-1 receptor agonists. Limitations of this study include the small sample size and that the population was predominantly white and female. A phase 3 trial (ATTAIN-1) estimated to have approximately 3,000 participants is currently in process. 

GLP-1 Combination Drugs for Additional Weight Loss Benefit 

The current GLP-1 receptor agonists approved for weight loss include liraglutide (Saxenda) and semaglutide (Wegovy). Recently, GLP-1 receptor agonists have been studied in combination with other hormone targets in the attempt to achieve greater weight loss than GLP-1 receptor agonism alone. Glucose-dependent insulinotropic peptide (GIP), another incretin hormone, is thought to enhance the efficacy of GLP-1 by promoting storage of dietary lipids and reducing appetite, as well as improving glucose control.¹⁴  SURMOUNT-1 was a phase 3, double-blind, randomized, controlled trial which investigated the weight loss effects of tirzepatide, a combination GLP-1 and GIP agonist, in patients without type 2 diabetes.¹⁵ Once weekly subcutaneous tirzepatide resulted in significant weight loss in obese or overweight patients with at least one weight related comorbidity compared to placebo alone over 72 weeks (mean weight change -15.0%, [95% CI, -20.4 to -18.5] versus -3.1% [95% CI, -4.3 to -1.9]). 

A novel, phase 2 trial was recently published examining the effects of retatrutide, a drug that not only targets GLP-1 and GIP, but also glucagon receptors.¹⁶ In this double-blind, randomized, controlled trial, 338 nondiabetic patients with obesity or those overweight with at least one weight-related comorbidity were randomized to retatrutide at varying doses (1 to 12 mg with varying starting doses) versus placebo. The primary endpoint was the percentage change in weight from baseline to 24 weeks.

At baseline, mean BMI was 37.3 kg/m², 52% of patients were men, and 88% were white. By week 24, participants in the retatrutide dose cohorts lost a substantial amount of weight (-7.2% to -17.9% depending on dose) versus -1.6% in the placebo group. By 48 weeks, the effect was even more pronounced with weight loss in the retatrutide dose cohorts ranging from -8.7% to -24.2%, compared to -2.1% in the placebo group. Retatrutide treatment was also associated with improved blood pressure, HbA1c, glucose, and lipid profiles. The most common adverse effects of the drug were gastrointestinal, and the discontinuation of retatrutide occurred in 6 - 16% of patients receiving the drug based on dose. 

This was the first trial to demonstrate nearly 25% body weight reduction (24.2% in the 12 mg dose group over 48 weeks) by agonism of incretin hormones, suggesting high efficacy with combination of receptor activity. Limitations of this study include a small sample size and predominantly white population. A phase 3 trial is currently undergoing to further investigate the effects of retatrutide. 
 
Conclusions

Obesity, which is now understood to be modulated by complex neuroendocrine mechanisms, has promising treatment options on the horizon, with novel therapeutics currently in investigation. GLP-1 receptor agonists have demonstrated efficacy in weight loss in patients with obesity or those overweight with at least one weight-related comorbidity, as well as offer cardiovascular benefits. Oral GLP-1 receptor agonists serve as an exciting treatment option for those unable or unwilling to take subcutaneous medications. In addition, combining GLP-1 with additional targets such as GIP and glucagon, demonstrates additional weight loss efficacy. Both oral GLP-1 receptor agonists and triple (GLP-1, GIP, and glucagon) agonists are currently in phase 3 trials and will hopefully be safe and effective medications for obesity available to patients over the next several years. Additionally, given the cardiovascular protection seen with GLP-1 receptor agonists, ideally, these novel drugs will not only result in weight loss, but also support a decrease in major adverse cardiovascular events. We look forward to future studies of the cardiovascular benefits of these novel therapeutics. 
 
Dr. Tobin has no financial relationships to disclose. Dr. Lundberg has no financial relationships to disclose. 

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