The Future of Nutrient-Stimulating Hormone (NuSH) Therapies

The group of medications that clinicians, health systems, media, and the public currently call ‘GLP-1s’ will soon become antiquated and under-representative of the science. A new generation of nutrient-stimulating hormone (NuSH) therapies, (not just incretins [GLP-1 and GIP]) aims to combine complementary physiologic benefits for improving appetite and glucose regulation, energy expenditure, and other cardiometabolic outcomes.

Why change the language from ‘GLP-1s’ to ‘NuSH therapies’ now?

‘GLP-1s’ will soon under-describe the science: multi- and co-agonists are explicitly combining these hormones in various ways for increasing pharmacological efficacy via complementary mechanisms. Framing these agents as NuSH therapies clarifies this shift, prepares teams for combination pharmacology, and reduces confusion in clinical and payer communications.

The 5 NuSH Axes: A Brief Overview

GLP-1 (glucagon-like peptide-1)

Physiology: L-cells in the distal intestine secrete GLP-1 after nutrient ingestion. GLP-1 enhances glucose-dependent insulin secretion, suppresses glucagon release, delays gastric emptying, and reduces appetite, which results in early satiety, decreased portions, and less cravings.¹⁴

Pharmacology: GLP-1 receptor agonists (dulaglutide, liraglutide, semaglutide) mimic these effects. Clinical trials demonstrate meaningful weight loss and glycemic improvements with weekly and daily agents.²

GIP (glucose-dependent insulinotropic polypeptide)

Physiology: Secreted by K-cells in the proximal small intestine, GIP potentiates insulin secretion in a glucose-dependent manner. Its direct anorectic role is modest alone, but in combination with GLP-1 it appears to augment weight and metabolic effects.

Pharmacology: Dual GIP/GLP-1 receptor agonists (tirzepatide) exploit complementary insulinotropic and appetite-modifying activities. Trial data demonstrates increased mean weight reductions for dual agonists than GLP-1 monotherapy.³

Glucagon

Physiology: Pancreatic alpha (α) cells release glucagon to raise hepatic glucose output and mobilize substrates. Glucagon also increases energy expenditure.

Pharmacology: Glucagon co-agonism (glucagon + GLP-1) aims to raise resting energy expenditure and promote fat loss while GLP-1 counters hyperglycemia. This is an active area of early clinical development.

Amylin

Physiology: Co-secreted with insulin from pancreatic beta (β) cells, amylin slows gastric emptying and increases satiety, complementary to GLP-1’s effects.

Pharmacology: Amylin analogs (pramlintide historically with longer-acting analogs under development) reduce food portions and enhance satiety. Amylin-GLP-1 combinations (or tri-agonists that include amylin) are promising for amplifying weight loss while balancing tolerability.

PYY (peptide YY)

Physiology: Released from distal L-cells after meals (notably PYY3-36), PYY reduces appetite and slows gastric emptying.

Pharmacology: PYY analogs or agents that raise endogenous PYY are being studied as satiety-enhancing components in multi-agonist formulations.

Mechanistic takeaway: NuSH medications combine signals that reduce hunger, improve glucose regulation, and increase energy expenditure while reducing compensatory biology that limits mono-therapy weight management.¹,³

Summary of Clinical Implications

• Efficacy: Multi- and co-agonists are producing substantially increased mean weight loss than lifestyle interventions alone and often exceed outcomes with GLP-1 monotherapy. Professional summaries provide comparative ranges for currently approved agents and emerging candidates.
• Safety: GI adverse effects (nausea, heartburn/reflux, constipation, diarrhea) remain the most common. Rare concerns including gallbladder disease, pancreatitis, and thyroid C-cell findings in some models, require appropriate screening and timely monitoring. Lifestyle factors such as sufficient protein-kcal intake and consistent strength training remain essential for skeletal muscle maintenance and reducing risk of malnutrition, sarcopenia, and future weight cycling associated with worsening cardiometabolic outcomes in the long-term.⁴
• Behavioral effects: For some patients with binge-type or hunger-driven pathology, appetite-modulating NuSH therapies decrease pathological hunger and food preoccupation, potentially decreasing binge frequency when delivered with informed disordered eating care. However, initiation should include screening, informed consent, and plans for psychological support.⁴

NuSH Therapies Across the Socioecological Model of Health

1. Individual (Biology & Behavior):
   Benefits: Improved glycemia, reduced food preoccupation, and greater potential for sustainable cardiometabolic improvement and maintenance when pharmacotherapy implementation is indefinite.
   Risks: GI intolerance and loss of lean mass in the absence of implementing health-promoting behaviors. Clinicians must prescribe individualized lifestyle support interventions that address nutrition, progressive strength training, sleep, and stress management in conjunction with medication.
2. Interpersonal (Clinician-Patient, Patient-Family):
   Opportunities: Shift conversations from weight-centricity to body composition factors, function, biochemical markers, and patient-valued outcomes positively impacting their quality of life.
   Requirements: Clinician training in NuSH physiology, stigma-reducing language, and disordered eating risk assessment to individualize therapy safely.
3. Organizational (Clinical Programs & Workflows):
   New pathways for routine body composition and biochemical marker evaluation, medication initiation and titration, nutrition and exercise prescriptions, side effect management and prevention. Multidisciplinary staffing are necessities for optimal health outcomes in individuals and populations with the byproduct of positive financial and societal gain. EHR templates and documentation should capture non-scale outcomes and use non-stigmatizing ICD diagnostic codes and language.
4. Community (Access & Social Determinants of Health):
   Equity concerns: High-efficacy combinations risk widening disparities if coverage, clinic capacity, and delayed pharmacy access. Programs should plan for sliding scales, community partnerships, and culturally competent materials that avoid stigmatizing language.
5. Policy & Society:
   Action Needed: Payers and guideline developers should broaden outcome definitions beyond weight to include metabolic, functional, and patient-reported measures. Regulatory and surveillance systems must adapt to combination agents and long-term safety questions. Public messaging should use NuSH terminology to reflect biology and reduce oversimplified narratives with the anticipated byproduct of reducing societal weight bias, discrimination, and stigma.

Recommendations for Healthcare Leaders

Clinical Teams

• Adopt NuSH terminology in protocols and patient education to reflect mechanism and future combinations.
• Implement multidisciplinary pathways (physicians, advanced practice providers, registered dietitians, behavioral health, psychiatry, pharmacy, genetic counselors) with screening for disordered eating and automated safety checks.
• Make non-scale outcomes (improvement or remission of obesity-related comorbidities, strength, glycemic measures, sleep, patient-reported function) primary program metrics.

Administrators

• Fund workforce training (dietitians and behavioral health), digital coaching, and remote monitoring that scale nutrition and exercise support.
• Prioritize equitable access through value-based pilots, contracting models, and community engagement.
• Support real-world evidence generation (long-term safety, functional outcomes, and implementation economics).

Conclusion

GLP-1 receptor agonists led a major therapeutic advance. The coming wave of NuSH therapies extends that biology across GIP, glucagon, amylin, and PYY signals. Clinicians and healthcare systems that adapt by updating language, reorganizing around non-weight outcomes, integrating nutrition and behavioral safeguards, and investing in equitable delivery will be best positioned to translate pharmacologic promise into population and societal benefit.

Key Takeaways

• Move from the shorthand ‘GLP-1s’ to ‘NuSH therapies’ to reflect GLP-1, GIP, glucagon, amylin, and PYY-targeting drugs and upcoming multi-agonists.
• NuSH therapies combine complementary physiological benefits to produce greater efficacy than single-agent approaches.
• Expect higher % total weight reduction and metabolic effects but also common GI side effects and risk of lean mass loss. Integrate nutrition, progressive strength training, staged titration, disordered eating screening, and longitudinal behavioral support into initiation pathways.
• Reframe success beyond the scale. Prioritize metabolic, functional, and patient-reported outcomes by making them primary program metrics.
• Build multidisciplinary NuSH care pathways, hire and train teams in stigma-reducing language and risk assessment, and plan for equitable access (coverage, community partnerships, outcomes-based pilots) so high-efficacy combinations don’t widen disparities.