Triple G Agonists — A Home Run for Obesity?
Among these therapies, the triple–hormone-receptor agonist retatrutide — the subject of a phase 2 trial by Jastreboff et al., the results of which are published in this issue of the Journal1 — showed unprecedented efficacy in treating obesity, with 24% weight loss over 48 weeks.
Hormonal responses to nutrient intake are key regulators of metabolism. The best known is insulin secretion in response to postprandial increases in levels of glucose or amino acids, promoting nutrient storage and maintaining normoglycemia. In addition, intestinal hormonal responses to food intake further magnify insulin secretion (e.g., the “incretin effect” mediated by glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) and modulate satiety, food intake, and other aspects of prandial metabolism (mediated by, e.g., GLP-1, GIP, peptide tyrosine tyrosine [PYY], and amylin). Incretin-mimetic GLP-1 agonists have already gained widespread acceptance for the management of type 2 diabetes and obesity. The addition of GIP receptor agonism, as with the dual GLP-1–GIP agonist tirzepatide, further enhances weight loss.
What is the new “triple G” hormone receptor agonist? Retatrutide is a single peptide that activates three G-protein–coupled receptors — GLP-1, GIP, and glucagon (GCG) receptors.2,3 Engaging the GCG receptor might seem counterintuitive; GCG is best recognized as a counterregulatory hormone released from pancreatic α cells during hypoglycemia, increasing blood glucose. However, GCG also has potent catabolic effects, in that it stimulates adipose lipolysis, reduces food intake, slows gastric emptying, and increases energy expenditure.4 Thus, incorporating GCG receptor agonism may further enhance weight loss, while simultaneous incretin-mimetic action of GLP-1–GIP signaling can balance the potential adverse glycemic effects of GCG. Preclinical studies showed that triple G agonists were superior to single or dual agonists for achieving weight loss, reducing hepatic steatosis, and normalizing glucose levels.2
Jastreboff et al. performed a double-blind, randomized trial of weekly subcutaneous retatrutide as compared with placebo in 338 adults without diabetes who had either class 1 obesity (a body-mass index [BMI, the weight in kilograms divided by the square of the height in meters] of ≥30) or overweight (a BMI of 27 to <30) with associated coexisting conditions. Doses of retatrutide ranged from 1 to 12 mg. All the participants received dietary counseling.
Among the participants treated with retatrutide per protocol, the mean weight loss at the highest dose was 18% at 24 weeks and 24% at 48 weeks, as compared with approximately 2% at both time points among the participants who received placebo. At the highest dose, 26% of the participants had weight loss of 30% or more at 48 weeks. Weight reductions occurred across the BMI spectrum but were greater among the participants with a BMI of at least 35. In this relatively short-term trial, the effect of retatrutide on cardiovascular events could not be determined, but several measures of cardiometabolic risk improved, including blood pressure and levels of glycated hemoglobin, fasting glucose, insulin, total and low-density lipoprotein cholesterol, and triglycerides. Modest increases in heart rate occurred, similar to findings in previous studies of incretin analogues.
As with GLP-1–GIP agonists, the side effects of retatrutide were dose-dependent and predominantly gastrointestinal, with nausea occurring in 45 to 60% of the participants at higher doses, mostly during early dose escalation. Adverse events led to drug discontinuation in 16% of the participants at the highest dose, but serious adverse events were few.
The trial included only participants without diabetes. Although weight loss is typically lower in persons with type 2 diabetes, another recently published study of retatrutide involving patients with type 2 diabetes5 reported 17% weight loss at 36 weeks, with a 2% decrease in the glycated hemoglobin level. Likewise, the benefits of triple agonism extended to treatment of nonalcoholic fatty liver disease; in a subgroup of 98 persons in the trial who had nonalcoholic fatty liver disease,6 fat content normalized in 90% of participants at the highest doses of retatrutide.
Together, these data offer further optimism about the idea that effective pharmacologic management of obesity and related disorders is possible. However, larger and longer-term studies are needed to expand the generalizability of the results, to confirm lasting safety and health outcomes, and to determine the protocols for clinical care. For example, it will be essential to identify the magnitude and rate of weight loss and the lifestyle and dietary interventions that will ensure adequate nutrition and minimize the loss of lean body mass. In addition, we will need to know the best options for the prevention of weight regain should the medication be discontinued because of side effects or as a result of changes in insurance coverage or drug availability.
The advent of highly effective therapy for obesity raises many questions both for clinicians and for public policy decision makers. Because obesity is a chronic disease (analogous to hypertension), it is necessary to manage it with long-term therapy. Clinicians and patients alike will need to carefully consider the available options for obesity; potential treatments include dietary and lifestyle interventions and long-term pharmacologic therapy, as well as bariatric metabolic surgery, which leads to an even greater magnitude of sustained weight loss and metabolic control than retatrutide.7-9 Triple G agonists could provide a bridge to more permanent surgical weight loss or potentially augment surgical efficacy. Given the estimated 42% prevalence of obesity among adults in the United States,10 the substantial costs of achieving successful obesity care with triple G agonists and other agents need to be balanced against anticipated cost savings that would be realized by preventing obesity-related complications.
Finally, a key challenge and societal imperative will be to ensure affordability and equitable access to effective antiobesity therapies, especially in underserved populations that carry the highest burden of disease. Only then will obesity management truly hit a home run.
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