The 'Triple G' Agonist for Obesity Management: 5 Things to Know

Beverly G. Tchang, MD


September 25, 2023

The complex pathophysiology of obesity requires a multidisciplinary approach that includes lifestyle and medical interventions for successful management. Anti-obesity medications (AOMs) have emerged as a powerful and life-changing tool for many individuals with obesity who are unable to sustain long-term weight loss through lifestyle changes alone. As with other chronic diseases such as hypertension and hyperlipidemia, the goal of decades of research has been to develop anti-obesity medications with long-term efficacy and safety. Recent groundbreaking findings from a phase 2 trial show immense potential for a new AOM.

Here are five things to know about the role of agonists in the management of obesity.

1. Gut hormone physiology informs the development of AOMs.

The three hormones associated with obesity or diabetes are glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon. GLP-1, a peptide released from the intestines in response to food ingestion, increases insulin production, reduces gut motility, and suppresses appetite. GIP is also an intestinal hormone that increases meal-stimulated insulin production and additionally facilitates lipolysis. Glucagon is known to increase hepatic glucose output but will also increase insulin secretion in the setting of hyperglycemia. Glucagon also promotes lipolysis.

Though these hormones are more commonly thought of as incretins, gut hormones that stimulate postprandial insulin secretion, their role in energy physiology is more diverse. Due to multiple mechanisms of action, incretins are increasingly referred to as nutrient-stimulated hormones (NuSH), a term which encompasses other peptides with therapeutic potential (eg, amylin, oxyntomodulin, peptide tyrosine tyrosine).

2. Studies have shown that NuSH therapies are highly effective AOMs.

In 2021 the US Food and Drug Administration approved subcutaneous semaglutide 2.4 mg, a GLP-1 receptor agonist, for the treatment of obesity. Clinical trials demonstrating an average weight loss of 15% in patients taking semaglutide ushered in a new era of AOMs associated with significant weight loss that not only improves disease activity but also has the potential to achieve diabetes remission. Recent findings from the OASIS I trial demonstrated an average weight loss of 15.1% from baseline in patients treated with oral semaglutide for 68 weeks. Medical societies, including the American Diabetes Association and the American Association for the Study of Liver Diseases, recommend 10%-15% weight loss to fully treat weight-related comorbidities like type 2 diabetes and nonalcoholic fatty liver disease. In 2022, tirzepatide, a dual GLP-1 and GIP receptor agonist, demonstrated an average weight loss of 22.5% in phase 3 of the SURMOUNT-1 trial for obesity — a weight loss approaching that of some bariatric surgeries.

3. Clinical trial data show that the novel triple agonist retatrutide induces significant weight loss.

Preclinical studies on the newest NuSH therapy, triple GLP-1–GIP–glucagon receptor agonist retatrutide showed predominant activity at the GIP receptor, with less GLP-1– and glucagon-receptor agonism than that of endogenous GLP-1 and GIP. Results from a phase 2 trial published in June 2023 showed a weight loss of 24% at 48 weeks in adults with obesity treated with retatrutide, which is the greatest weight loss reported in an obesity trial so far. Moreover, for the first time in obesity pharmacotherapy research, 100% of participants achieved clinically significant weight loss (defined as ≥ 5% of baseline weight).

4. Retatrutide may improve lipid metabolism.

In the phase 2 trial, retatrutide reduced low-density lipoprotein cholesterol (LDL-C) levels by approximately 20%. This degree of reduced plasma LDL-C is dramatic in weight loss studies. Typically, weight loss significantly reduces triglyceride levels, increases high-density lipoprotein cholesterol levels, and has a modest effect on LDL-C reduction of about 5%.

A 20% reduction in LDL-C with retatrutide is hypothesis-generating. Preclinical studies have shown glucagon to be an important regulator of proprotein convertase subtilisin/kexin type 9degradation, with the lack of glucagon resulting in increased PCSK9 levels, decreased LDL receptors, and increased plasma LDL; conversely, treatment with glucagon decreased plasma LDL.

5. The long-term safety of retatrutide still needs to be determined.

In the 48-week phase 2 trial, retatrutide was observed to have a side effect profile largely similar to other NuSH therapies (eg, semaglutide 2.4 mg, tirzepatide), with a predominance of gastrointestinal symptoms including nausea, diarrhea, vomiting, and constipation. However, side effects potentially unique to retatrutide also emerged. Cutaneous hyperesthesia and skin sensitivity were reported in 7% of participants in the retatrutide group vs 1% in the placebo group; none of these effects were associated with physical skin findings. Of note, 17 out of 198 (9%) participants in the retatrutide group developed cardiac arrhythmia vs two out of 70 (3%) in the placebo group. There was no consistent pattern of arrhythmia type (eg, supraventricular, ventricular) observed, and some of these events were reported as "palpitations" or "increased heart rate" without further detail. Phase 3 clinical trial data will provide further insight into the long-term safety of retatrutide.

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