Peptide YY

1. Overview

Peptide YY (PYY) is a 36-amino acid gut hormone belonging to the neuropeptide Y (NPY) family, first isolated by Kazuhiko Tatemoto from porcine intestinal extracts in 1980 using a novel chemical method for detecting C-terminally amidated peptides [1]. The name "peptide YY" reflects the presence of tyrosine residues (single-letter code: Y) at both the N- and C-termini of the molecule [1][2].

PYY exists in two major circulating forms: PYY1-36 (the full-length peptide) and PYY3-36 (the N-terminally truncated form generated by dipeptidyl peptidase IV [DPP-IV] cleavage). PYY3-36 is the predominant circulating form, accounting for approximately 60-70% of total plasma PYY, and is the biologically relevant form for appetite suppression [4][12]. The truncation by DPP-IV dramatically alters receptor selectivity: while PYY1-36 activates all Y receptor subtypes (Y1, Y2, Y4, Y5), PYY3-36 is highly selective for the Y2 receptor, which is the critical mediator of PYY's anorexigenic (appetite-suppressing) effects [4][13].

PYY is produced by specialized enteroendocrine L-cells located primarily in the distal ileum, colon, and rectum, with the highest density in the rectum [3]. L-cells co-secrete PYY with glucagon-like peptide-1 (GLP-1), and both hormones are released in response to nutrient ingestion, particularly fat and protein [3][14]. Plasma PYY levels are low in the fasted state and rise within 15-30 minutes of eating, peaking at 1-2 hours and remaining elevated for several hours [3].

The landmark 2002 discovery by Rachel Batterham and colleagues at Imperial College London that peripheral PYY3-36 administration potently suppresses food intake in humans by acting on hypothalamic Y2 receptors established PYY as a key satiety signal and generated intense interest in its potential as an anti-obesity therapeutic [4].

Molecular Weight

4049.5 Da (PYY1-36); ~3787 Da (PYY3-36)

Sequence

YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY-NH2 (36 aa, C-terminal amide)

Active Form

PYY3-36 (DPP-IV cleaved, Y2-selective)

Gene

PYY (17q21.1)

Primary Receptor

Y2 receptor (Gi/o-coupled GPCR)

Source

Enteroendocrine L-cells (ileum, colon, rectum)

Discovery

Tatemoto & Mutt, 1980 (porcine intestinal extracts)

Half-life

~30 minutes (PYY3-36, IV)

FDA Status

Not approved. Research compound and drug development target.

2. Mechanism of Action

Y2 Receptor Signaling

PYY3-36 mediates its anorexigenic effects primarily through the Y2 receptor, a Gi/Go-coupled GPCR that functions as a presynaptic autoreceptor on NPY/AgRP neurons in the hypothalamic arcuate nucleus [4][13][17].

The signaling cascade proceeds as follows: PYY3-36 binds Y2 receptors on the terminals of orexigenic NPY/AgRP neurons in the arcuate nucleus, Y2 receptor activation (Gi/Go coupling) inhibits adenylyl cyclase and activates GIRK channels, resulting in reduced NPY and AgRP release (these are potent appetite-stimulating peptides), removal of tonic NPY/AgRP inhibition disinhibits neighboring anorexigenic POMC/CART neurons, and POMC neurons release alpha-MSH, which activates MC4R to suppress food intake [4][14][17].

This mechanism is distinct from leptin signaling (which directly activates POMC neurons) and complementary to GLP-1 signaling, providing a rationale for combination approaches [18].

The Ileal Brake

PYY is a key mediator of the "ileal brake," a feedback mechanism whereby the arrival of nutrients (particularly fat) in the distal small intestine and colon triggers a hormonal response that slows upper gastrointestinal function [10][19]. The ileal brake effects include slowed gastric emptying (increasing gastric distension and satiety), reduced small intestinal motility and transit, decreased pancreatic and biliary secretion, and reduced gastric acid output [10][19].

These effects optimize nutrient absorption by allowing more time for enzymatic digestion and mucosal uptake in the proximal gut when undigested nutrients are detected distally [10].

Central Nervous System Effects

Batterham et al. (2007) used functional MRI to demonstrate that PYY3-36 infusion modulates neuronal activity in the hypothalamus (arcuate nucleus), brainstem (area postrema, nucleus tractus solitarius), and corticolimbic regions involved in reward processing [6]. The brainstem effects suggest that PYY3-36 also acts on Y2 receptors in the area postrema (a circumventricular organ outside the blood-brain barrier) and vagal afferents, providing both humoral and neural routes for central appetite suppression [6][14].

3. Researched Applications

3.1 Obesity and Weight Management

Batterham et al. (2002) published the landmark study demonstrating that intravenous PYY3-36 (0.8 pmol/kg/min for 90 minutes) reduced caloric intake by 36% in lean subjects at a free-choice buffet meal served 2 hours after the infusion [4]. This was among the first demonstrations that a peripheral gut hormone could potently suppress food intake in humans.

Batterham et al. (2003) extended these findings to obese subjects, showing that PYY3-36 significantly reduced food intake in both obese and lean individuals. Critically, they also demonstrated that obese subjects had lower fasting and postprandial PYY levels compared to lean controls, suggesting a relative PYY deficiency in obesity [5].

le Roux et al. (2006) confirmed that postprandial PYY release is significantly blunted in obese compared to lean subjects, and this attenuation correlates with reduced meal-induced satiety. Importantly, weight loss partially restored PYY responses, suggesting the PYY deficit is a consequence rather than a primary cause of obesity [9].

Sloth et al. (2007) tested subcutaneous PYY3-36 in 17 obese men, showing dose-dependent reductions in 24-hour caloric intake of up to 16.5%. However, nausea occurred at the highest dose (0.8 mcg/kg), identifying a critical therapeutic limitation [8].

Gantz et al. (2007) conducted a Phase II trial of intranasal PYY3-36 in 134 obese adults (BMI 30-40), administered three times daily before meals for 12 weeks. The results showed modest weight loss compared to placebo with generally acceptable tolerability, though nausea remained the dose-limiting side effect [11].

3.2 Combination with GLP-1

Since PYY and GLP-1 are co-secreted by L-cells and act through complementary mechanisms, combination therapy has been explored. Neary et al. (2005) demonstrated that PYY3-36 and GLP-1(7-36) inhibit food intake additively when co-administered in humans, supporting the concept that targeting multiple satiety pathways may be more effective than either hormone alone [18]. This finding has relevance for understanding the mechanisms of bariatric surgery, which dramatically increases postprandial PYY and GLP-1 levels.

3.3 Post-Bariatric Surgery Physiology

Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy produce dramatic increases in postprandial PYY and GLP-1 release, which are thought to contribute substantially to the appetite-suppressive and metabolic effects of these procedures [14][15]. The exaggerated PYY response after bariatric surgery may be one of the key mechanisms underlying the sustained weight loss and appetite reduction that distinguishes surgical from dietary interventions.

4. Clinical Evidence Summary

5. Dosing in Published Research

6. Safety and Side Effects

The primary safety concern with exogenous PYY3-36 administration is dose-dependent nausea. In the subcutaneous study by Sloth et al. (2007), nausea occurred at the highest dose of 0.8 mcg/kg, limiting the usable dose range [8]. Degen et al. (2005) reported similar nausea at the higher end of IV infusion rates [7]. This nausea appears to be mediated through Y2 receptors in the area postrema and potentially through vagal afferents.

Other reported effects in clinical studies include transient discomfort at injection sites (subcutaneous), reduced gastrointestinal motility (physiological ileal brake effect), and no significant cardiovascular effects at therapeutic doses [7][8][11].

The intranasal formulation (Gantz et al., 2007) was generally well tolerated over 12 weeks, with nausea as the most common side effect but at a lower incidence than with parenteral administration [11].

No serious adverse events have been attributed to PYY3-36 in published clinical studies. The peptide's endogenous nature and relatively short half-life (~30 minutes) provide inherent safety margins.

7. PYY in the NPY Family

PYY belongs to the neuropeptide Y family, which includes three structurally related peptides with a characteristic "PP-fold" tertiary structure:

| Feature | PYY | NPY | Pancreatic Polypeptide (PP) | |---|---|---|---| | Length | 36 amino acids | 36 amino acids | 36 amino acids | | Source | Intestinal L-cells | CNS neurons | Pancreatic F-cells | | Primary receptor | Y2 (PYY3-36) | Y1, Y5 | Y4 | | Primary function | Satiety, ileal brake | Appetite stimulation, anxiolysis | Satiety, pancreatic secretion | | Metabolic effect | Anorexigenic | Orexigenic | Anorexigenic |

8. Historical Context

• 1980: Tatemoto isolates PYY from porcine intestinal extracts [1]
• 1982: Tatemoto characterizes PYY as an inhibitor of pancreatic exocrine secretion [2]
• 1985: Adrian et al. map human PYY distribution and postprandial release pattern [3]
• 1994: Grandt et al. identify PYY3-36 as the major circulating form [12]
• 2002: Batterham et al. demonstrate PYY3-36 suppresses appetite in humans via Y2 receptor (landmark Nature paper) [4]
• 2003: Batterham et al. show PYY deficiency in obesity and efficacy in obese subjects [5]
• 2005: Additive effects of PYY3-36 + GLP-1 demonstrated [18]; nausea identified as dose-limiting [7]
• 2006: Attenuated PYY release in obesity documented [9]
• 2007: Phase II intranasal PYY3-36 trial completed [11]; subcutaneous dose-response established [8]
• 2010s-present: Focus shifts to combination approaches and understanding PYY's role in bariatric surgery outcomes
• 2025: PYY1875, a long-acting PYY3-36 analogue developed by Novo Nordisk, showed modest but not clinically meaningful efficacy as add-on to semaglutide in a Phase 2 obesity trial, with poor tolerability at the 2.0 mg dose
• 2025: Roche terminated its PYY program (CT-173, acquired from Carmot Therapeutics) due to developability issues and lack of competitiveness
• 2025: Novo Nordisk published variant screening study in Science Translational Medicine identifying potent long-acting PYY analogs with superior Y2 receptor selectivity

9. Pharmacokinetics

Understanding the pharmacokinetic profile of PYY and its active form PYY3-36 is essential for designing effective obesity therapeutics and interpreting the dose-limiting nausea observed in clinical studies.

Endogenous PYY1-36. Full-length PYY1-36 is secreted by L-cells into the portal circulation and rapidly cleaved by dipeptidyl peptidase IV (DPP-IV) to generate PYY3-36. The conversion occurs primarily in the hepatic sinusoids and systemic capillary endothelium, with DPP-IV cleaving the N-terminal Tyr-Pro dipeptide. Approximately 60-70% of circulating PYY exists as PYY3-36, with the remainder as intact PYY1-36 [12]. Full-length PYY1-36 has a plasma half-life of approximately 10-15 minutes and activates all Y receptor subtypes non-selectively (Y1, Y2, Y4, Y5), including the orexigenic Y1 and Y5 receptors, which may partially counteract its anorexigenic Y2-mediated effects [13][14].

PYY3-36 intravenous pharmacokinetics. Following IV infusion at the standard research dose of 0.8 pmol/kg/min for 90 minutes (Batterham et al., 2002), PYY3-36 achieves steady-state plasma concentrations of approximately 40-60 pmol/L, which approximate the high-physiological postprandial range [4]. The terminal elimination half-life of IV PYY3-36 is approximately 20-30 minutes, with clearance primarily through renal filtration and enzymatic degradation by neutral endopeptidase (NEP 24.11), aminopeptidases, and further DPP-IV activity. Following cessation of IV infusion, plasma PYY3-36 levels decline to baseline within approximately 2-3 hours, though the appetite-suppressive effect persists for 4-6 hours beyond the infusion, suggesting sustained receptor occupancy or downstream signaling persistence [4][7].

Subcutaneous pharmacokinetics. Sloth et al. (2007) characterized the SC pharmacokinetics: following 0.2-0.8 mcg/kg SC injection, peak plasma concentrations (Cmax) are reached at approximately 30-60 minutes (Tmax). Bioavailability via the SC route is estimated at approximately 50-70% relative to IV administration. The absorption phase creates a more gradual rise in plasma levels compared to IV infusion, with peak concentrations of approximately 50-100 pmol/L at the 0.8 mcg/kg dose. The apparent half-life following SC administration is approximately 40-50 minutes, extended relative to IV due to the absorption phase. The duration of appetite suppression following a single SC dose extends to approximately 6-8 hours [8].

Intranasal pharmacokinetics. The intranasal formulation (Gantz et al., 2007) achieves rapid absorption through the nasal mucosa, with Tmax of approximately 15-30 minutes. Bioavailability is estimated at approximately 5-8% relative to IV, meaning that a 600 mcg intranasal dose delivers an effective systemic dose of approximately 30-50 mcg. Despite the low bioavailability, three-times-daily dosing before meals was sufficient to achieve measurable appetite suppression over 12 weeks. The intranasal route offers the advantage of non-invasive self-administration and avoidance of first-pass hepatic metabolism [11].

DPP-IV degradation and stability. PYY3-36 is itself subject to further proteolytic degradation. The primary cleavage sites are at the Pro5-Glu6 bond (by post-proline cleaving enzyme) and at multiple internal sites by neprilysin. Serum stability studies show that PYY3-36 retains approximately 70-80% integrity after 1 hour in human plasma at 37 degrees C, declining to approximately 40-50% at 4 hours. This relatively rapid degradation has motivated development of DPP-IV-resistant PYY analogs and sustained-release formulations [12][14].

Physiological PYY dynamics. Postprandial PYY release follows a biphasic pattern: an early phase (15-30 minutes, driven by neural signals before nutrients reach the distal gut) and a sustained phase (1-6 hours, driven by direct L-cell nutrient contact). Fasting PYY3-36 levels are approximately 8-15 pmol/L in lean subjects and 5-10 pmol/L in obese subjects. Postprandial peak levels reach approximately 30-50 pmol/L in lean subjects but only 15-30 pmol/L in obese subjects, representing the blunted PYY response described by le Roux et al. (2006) [9][14].

Post-bariatric surgery pharmacokinetics. Following Roux-en-Y gastric bypass, postprandial PYY3-36 levels increase dramatically to approximately 80-150 pmol/L (3-5 fold above preoperative levels), with faster time-to-peak (approximately 15-30 minutes vs 60-90 minutes preoperatively). This exaggerated PYY response is sustained years after surgery and is thought to contribute significantly to the durable appetite suppression and weight loss maintenance observed with bariatric surgery [14][15].

10. Dose-Response Relationships

PYY3-36's dose-response relationships across different routes of administration reveal both the therapeutic potential and the nausea-limited therapeutic window that has challenged clinical development.

Intravenous infusion dose-response. Degen et al. (2005) conducted the most systematic IV dose-response study in 12 healthy male volunteers [7]. PYY3-36 infused at 0.2 pmol/kg/min for 90 minutes produced no significant effect on food intake or nausea. At 0.4 pmol/kg/min, caloric intake at a subsequent meal was reduced by approximately 15-20%, with minimal nausea (1/12 subjects). At 0.8 pmol/kg/min (the standard Batterham dose), caloric intake was reduced by approximately 31% with moderate nausea in 4/12 subjects. At 1.2 pmol/kg/min (explored in other studies), nausea became the dominant effect, with emesis in some subjects, establishing that the effective dose range is narrow -- approximately a 2-3 fold window between threshold efficacy and dose-limiting nausea.

Subcutaneous dose-response. Sloth et al. (2007) tested SC PYY3-36 at 0.2, 0.4, and 0.8 mcg/kg in 17 obese men [8]. At 0.2 mcg/kg, 24-hour caloric intake was reduced by approximately 5-8% (not statistically significant). At 0.4 mcg/kg, reduction was approximately 11% (p=0.04). At 0.8 mcg/kg, reduction was approximately 16.5% (p=0.001), but nausea occurred in 5/17 subjects (29%). The dose-response for appetite suppression was approximately linear, but the nausea dose-response was steeper, creating a narrowing therapeutic index at higher doses.

Intranasal dose-response. Gantz et al. (2007) tested intranasal PYY3-36 at 200, 400, and 600 mcg three times daily for 12 weeks [11]. Weight loss was modestly dose-dependent: approximately 0.5 kg (200 mcg), 1.0 kg (400 mcg), and 1.5 kg (600 mcg) above placebo over 12 weeks. Nausea incidence was lower than with injectable formulations (approximately 8-12% vs 25-30%) but still dose-related. The modest weight loss likely reflects the low bioavailability of the intranasal route.

Lean vs. obese dose-response. Batterham et al. (2003) demonstrated that obese subjects retain sensitivity to exogenous PYY3-36, with comparable percent reductions in food intake (approximately 30%) at the 0.8 pmol/kg/min IV dose despite lower baseline PYY levels [5]. This preserved responsiveness distinguishes PYY3-36 from leptin, where obese subjects show marked resistance, and was a major factor driving commercial interest in PYY3-36 as an obesity therapy.

Additive effects with GLP-1. Neary et al. (2005) demonstrated that PYY3-36 (0.8 pmol/kg/min) and GLP-1(7-36) (1.2 pmol/kg/min) reduced food intake additively: PYY3-36 alone reduced intake by approximately 15%, GLP-1 alone by approximately 13%, and the combination by approximately 27% -- consistent with additive but not synergistic effects [18]. This finding supports the concept of combination gut hormone therapy.

11. Comparative Effectiveness

PYY3-36 vs. GLP-1 Receptor Agonists (Semaglutide)

The most clinically relevant comparison is between PYY3-36 and GLP-1 receptor agonists, which have become the dominant pharmacological approach to obesity treatment.

| Parameter | PYY3-36 (SC 0.8 mcg/kg) | Semaglutide 2.4 mg/wk (Wegovy) | Liraglutide 3.0 mg/day (Saxenda) | |---|---|---|---| | Mechanism | Y2 receptor (arcuate NPY/AgRP inhibition) | GLP-1R (arcuate POMC activation, brainstem satiety) | GLP-1R | | Weight loss (clinical data) | ~1.5-2.5 kg over 4 weeks (SC trial) | ~15% over 68 weeks (STEP 1) | ~8% over 56 weeks (SCALE) | | Nausea incidence | 25-30% at effective doses | 44% (mostly mild-moderate, decreasing) | 39% | | Half-life | ~20-30 min (requires multiple daily dosing) | ~7 days (once weekly) | ~13 hours (once daily) | | Cardiovascular benefit | Not demonstrated | 20% MACE reduction (SELECT trial) | 9% MACE reduction (LEADER) | | Development status | Failed Phase II (intranasal); no active program | FDA-approved (2021) | FDA-approved (2014) | | Route | SC injection or intranasal | SC injection | SC injection | | Additive with GLP-1 | Yes (complementary mechanism) | N/A (same pathway) | N/A |

Semaglutide is dramatically superior to PYY3-36 as a standalone obesity therapy, with 5-10 fold greater weight loss, once-weekly dosing convenience, demonstrated cardiovascular benefits, and regulatory approval. PYY3-36's clinical development failed primarily because of the narrow therapeutic window (nausea limits effective dosing), the short half-life requiring multiple daily injections, and modest weight loss that could not compete with GLP-1 RAs.

PYY3-36 vs. Tirzepatide

Tirzepatide (Mounjaro/Zepbound), a dual GIP/GLP-1 receptor agonist, achieves weight loss of up to 22.5% at the 15 mg dose over 72 weeks (SURMOUNT-1), further widening the gap with PYY3-36. Tirzepatide's dual incretin mechanism provides superior glycemic control and weight loss compared to GLP-1 RAs alone, making the standalone development case for PYY3-36 even less compelling.

PYY3-36 as a Combination Partner

Despite its failure as a standalone therapy, PYY3-36's additive effects with GLP-1 (Neary et al., 2005) and its distinct mechanism of action suggest it could still have value as part of a combination regimen [18]. Several investigational approaches have explored multi-gut-hormone combinations (PYY + GLP-1 + OXM), peptide cocktails that mimic the hormonal profile of bariatric surgery, and long-acting PYY analogs with improved pharmacokinetics for once-weekly or monthly dosing.

However, recent clinical data have tempered this optimism. In 2025, Novo Nordisk reported Phase 2 results for PYY1875, a novel long-acting PYY3-36 analogue tested as an add-on to semaglutide in participants with overweight or obesity. The results were disappointing: PYY1875 1.0 mg showed a modest but not clinically meaningful treatment effect versus placebo as add-on to semaglutide, and the 2.0 mg dose escalation regimen was not tolerated due to gastrointestinal adverse events. Separately, Roche terminated its PYY program (CT-173), acquired from Carmot Therapeutics, in July 2025 due to developability issues and lack of competitiveness. Boehringer Ingelheim also discontinued its PYY analogue BI 1,820,237 after a Phase 1 trial showed a half-life of approximately 120 hours but no significant weight reduction when combined with liraglutide. Boehringer Ingelheim continues to explore a tri-agonist peptide (BI 3,034,701), potentially combining GLP-1/GIP/PYY activity.

On the research side, a 2025 Novo Nordisk publication in Science Translational Medicine described a systematic variant screening of PYY3-36, identifying potent long-acting PYY analogs with superior Y2 receptor selectivity, which may inform the next generation of PYY-based therapeutics. Despite these setbacks, the rationale for engaging multiple satiety pathways remains sound, and PYY receptor targeting may yet find a role in multi-mechanism obesity regimens if tolerability challenges can be overcome.

PYY in Bariatric Surgery Context

Post-bariatric surgery PYY levels (80-150 pmol/L postprandially) are substantially higher than those achieved by exogenous PYY3-36 infusion (40-60 pmol/L), and the surgical setting provides simultaneous elevation of GLP-1, OXM, and other gut hormones. The superior and durable weight loss of bariatric surgery (25-35% at 5 years) compared to any single gut hormone therapy underscores the importance of multi-hormone engagement [14][15].

12. Enhanced Safety Profile

PYY3-36 has been administered to several hundred human subjects across multiple clinical studies, providing a reasonable safety database for an investigational peptide hormone.

Nausea and emesis (dose-limiting toxicity). Nausea is the primary safety concern and the dose-limiting adverse event for PYY3-36. The mechanism is thought to involve Y2 receptor activation in the area postrema (a circumventricular organ outside the blood-brain barrier that serves as the chemoreceptor trigger zone for emesis) and potentially vagal afferent activation [6][7][8]. Quantitative nausea data across studies: IV 0.8 pmol/kg/min -- 33% incidence (Degen et al., 2005) [7]; SC 0.8 mcg/kg -- 29% incidence (Sloth et al., 2007) [8]; intranasal 600 mcg TID -- 8-12% incidence (Gantz et al., 2007) [11]. Nausea typically occurs within 15-30 minutes of dosing and resolves within 1-2 hours. In the 12-week intranasal trial, nausea incidence decreased over time, suggesting partial tolerance development. Emesis is rare at standard research doses but has been reported at supratherapeutic infusion rates.

Gastrointestinal motility effects. PYY3-36's activation of the ileal brake produces physiological slowing of gastric emptying and intestinal transit [10][19]. Savage et al. (1987) showed that PYY infusion increased mouth-to-cecum transit time by approximately 40-60% and slowed gastric emptying rate by approximately 30-40% [19]. While this contributes to satiety (a therapeutic effect), excessive slowing could theoretically cause constipation, bloating, or gastroparesis symptoms with chronic high-dose use. In the 12-week Gantz trial, no clinically significant GI motility complaints were reported beyond nausea [11].

Cardiovascular safety. No significant cardiovascular effects have been observed in any PYY3-36 clinical study. Heart rate, blood pressure, and electrocardiographic parameters remain unchanged during PYY3-36 infusion at standard research doses. This favorable cardiovascular profile is expected given the absence of Y2 receptors in cardiac tissue and the lack of sympathomimetic effects [7][8][11].

Metabolic safety. PYY3-36 does not cause hypoglycemia. Plasma glucose levels remain stable during PYY3-36 infusion, and the peptide does not significantly affect insulin secretion at appetite-suppressing doses. This distinguishes PYY3-36 from insulin secretagogues and represents a safety advantage [7][8].

Injection site reactions. SC PYY3-36 causes mild, transient injection site reactions (erythema, mild pain) in approximately 5-10% of subjects, comparable to other SC peptide therapeutics [8].

Immunogenicity. No anti-PYY antibodies have been reported in clinical studies, consistent with the endogenous nature of the peptide. The 12-week intranasal trial did not detect immunogenic responses [11].

Long-term safety. No long-term (greater than 12 weeks) human safety data exist for exogenous PYY3-36 administration. Theoretical long-term concerns include sustained appetite suppression leading to excessive weight loss or nutritional deficiency (unlikely at the modest weight loss observed), chronic ileal brake activation potentially affecting nutrient absorption, and unknown effects of sustained Y2 receptor activation on hypothalamic circuitry. However, the endogenous nature of PYY and the physiological range of plasma levels achieved with exogenous dosing provide inherent safety reassurance [14][16].

Comparison with GLP-1 RA safety profile. GLP-1 receptor agonists have a more extensive and concerning safety profile than PYY3-36, including pancreatitis risk (rare), gallbladder events, potential thyroid C-cell tumor signal (rodents), and higher nausea rates at initiation. PYY3-36 has none of these signals but also lacks the large safety databases that have enabled characterization of rare GLP-1 RA adverse events [14].

13. Related Peptides

See also: Neuropeptide Y, Semaglutide, Tirzepatide, Oxyntomodulin, Amylin

14. References

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