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.