The revolution is just starting - Inflacretins and their effects on humanity

Antibiotics, and contraceptive drugs are major, recent, radical influences on humanity and human evolution. Inflacretins are the next revolution.

GLP-1 receptor agonists, GIP receptor agonists, Tirzepatide, Mounjaro, Exenatide, Liraglutide, Dulaglutide, Semaglutide, Lixisenatide, Retatrutide,, Zepbound, Cagrilintide, Orforglipron, are the new wonder-drugs that will change the nature of humanity fundamentally.

GLP-1 and GIP receptor agonists (GLP-1RAs and dual agonists) demonstrate remarkable pleiotropic effects  ( in the sense of ‘: "Multi-system effects mediated through ubiquitous GLP-1 receptors and shared inflammatory pathways”’) across multiple organ systems, extending far beyond their original indication for type 2 diabetes and obesity. These medications work through tissue-specific GLP-1 receptors and shared anti-inflammatory pathways, with many benefits occurring independently of weight loss and glycaemic control.

Yes, they are mainly seen as fat-busters, slimming drugs, and secondarily, as drugs against obesity, but this only scratches the surface of how fundamentally, they are going to affect humanity, in the long term.

Essentially, though these drugs do enable radical, sustainable weight loss, and the remission of diabetes, thay are more far-reaching than that.

This is because they affect the brain directly, and also affect inflammation directly. Already these far-reaching effects are becoming apparent, though a lot more research is needed to understand exactly how they work (after all, they were developed from the venom of the Gila Monster, a venemous lizard that spends most of it time underground, and used the particular chemical, Exendin-4, to cause a spike in insulin in their victimes, and, thus, a  hypoglycaemic coma in their victims. The same effect famous in whodunit stories that arises from a massive injection of insulin.

Of course, almost everybody knows them as slimming drugs, fat-busters, that reduce users from being overweight to being a shadow of their former selves. That, though, is only the very tip of the huge iceberg.

The also are wll known for putting diabetes into remission - they don't cure it, because, if you stop taking them, the diabetes, and weight, return within a year.

What's much more amazing, and important to their future use, is the long-term consequences, mainly positive, that they offer.

This is because they are anti-inflammatory drugs. Inflammation seems a very general term, we have inflamed  wounds after an injury, we have auto-immune deseases that are inflammatory, and so forth. What they affect include - in decreasing levels of evidence, at the moment:

Type 2 Diabetes

Chronic Kidney Disease

NAFLD/MASLD

NASH

COPD

Sleep Apnoea/EDS

Liver Cirrhosis (compensated)

Cognitive Decline

Peripheral Neuropathy

Rheumatoid Arthritis

Hypertension

PCOS

IBD (Crohn's/UC)

Brain/Vascular Inflammation

Osteoarthritis

Type 1 Diabetes

Alcohol Use Disorder

Nicotine/Tobacco Use

DVT Sequelae

Gut Microbiome

Other Addictions

Vascular Eczema

Atopic Eczema

If you go through this list, it is truly amazing. Addictions, auto-immune disorders, heart problems, mental problems, and so much more!

I'm not trying to open floodgates for the treatment of all these conditions - the floodgates are already open on weight loss along. The drugs are in short supply and very expensive.

This has to change. Not that everybody with eczema should take these drugs, just for that, but, rather, if there is a primary condition, overweight, diabetes, or hypertension, these drugs make sense, as seriously effective for conditions previously thought chronic and only partly improved by various specific drugs.

Instead, I'm proposing that the current guidelines that make either diabetic, or weight control the only criteria for using these drugs ought to be widened to include treatment of all these potential comorbitities. Often people with diabetes and / or overweight, suffer from a number of these as well.

There needs to be an integrated pathway to treatment that weighs up the effect of all these comorbitities on a particular person and adapts the dose appropriately - rather than deciding that once, say, diabetes is in remission, the dose should be only a maintenance does.

To give a wider picture:

GLP-1 and GIP Receptor Agonists: Comprehensive Review of Comorbidities Ameliorated Beyond Diabetes

Core Mechanisms

GLP-1RAs achieve therapeutic effects through multiple pathways:

Anti-Inflammatory Actions:

• Inhibition of NF-κB activation
• Reduction of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β)
• AMP-activated protein kinase phosphorylation
• Decreased oxidative stress via NADPH oxidase 4 (NOX4) suppression

Direct Receptor-Mediated Effects:

• GLP-1 receptors present in brain, peripheral nerves, liver, kidneys, joints, lungs, and other tissues
• Local tissue-specific signalling independent of systemic metabolic effects

Metabolic Improvements:

• Enhanced insulin sensitivity
• Improved glucose homeostasis
• Beneficial lipid profile changes
• Weight reduction (amplifies but not always required for benefit)

I. CARDIOMETABOLIC AND ORGAN PROTECTION (Strongest Evidence)

Type 2 Diabetes

Evidence Quality: Very Strong | Mechanism Understanding: Very Well-Characterised | Status: Licensed Indication

Evidence: Foundational indication with decades of evidence demonstrating HbA1c reductions of 1-2% and cardiovascular outcome benefits.

Mechanisms:

• Enhanced glucose-dependent insulin secretion
• Suppressed glucagon release
• Delayed gastric emptying
• Improved insulin sensitivity
• Reduced hepatic glucose output

Pathway: Multiple metabolic effects → Improved glycaemic control + cardiovascular protection

Chronic Kidney Disease (CKD)

Evidence Quality: Very Strong | Mechanism Understanding: Very Well-Characterised | Status: FDA-Approved (semaglutide, December 2024)

Evidence: FLOW trial and multiple 2024 meta-analyses show dramatic renoprotection. In CKD patients with T2DM:

• 15% reduction in composite kidney outcomes
• 22% reduction in >30% eGFR decline
• 28% reduction in >50% eGFR decline
• 71% reduction in dialysis-requiring ESKD (HR 0.29)
• 72% reduction in renal death (HR 0.28)

Benefits extend to CKD patients with overweight/obesity even without T2DM. Estimated lifetime benefit when combined with RASi, SGLT2i, and finerenone: 5.5 additional event-free years.

Mechanisms:

• Direct GLP-1 receptor activation in kidney tissue
• Beneficial glomerular haemodynamic effects
• Reduced inflammatory burden and oxidative stress in kidneys
• Improved endothelial function
• BP control (mediates ~48% of benefit)
• Glycaemic control (mediates ~48% of benefit)
• Weight loss reducing "fatty kidney" and renal sinus fat deposition
• Reduced albuminuria and proteinuria

Pathway: Direct renal GLP-1R effects + improved haemodynamics + reduced inflammation + BP/glucose control + weight loss → Slowed eGFR decline + reduced albuminuria + delayed progression to ESKD

Note: Now considered the "fourth pillar" of kidney protection alongside RASi, SGLT2i, and finerenone.

Non-Alcoholic Fatty Liver Disease (NAFLD/MASLD) and NASH

Evidence Quality: Very Strong | Mechanism Understanding: Well-Characterised | Status: Off-Label (Phase 3 trials ongoing for NASH)

Evidence:

• NASH Resolution: Semaglutide 0.4mg/day achieved NASH resolution without fibrosis progression in 59% versus 17% placebo at 72 weeks
• Tirzepatide SYNERGY-NASH (Phase II): 73.3% on highest dose achieved absence of NASH without fibrosis worsening versus 13.2% placebo at 52 weeks
• Fibrosis: Liraglutide showed fibrosis progression in only 9% versus 36% placebo (p=0.04)
• Progression Prevention: Large cohort (16,058 patients) showed significant reduction in progression to cirrhosis and complications
• Meta-analysis of 16 trials (2,178 patients) demonstrated significant histological improvement

Mechanisms:

• Autophagy-dependent lipid degradation in hepatocytes
• Improved lysosomal function
• Reduction in hepatic triglyceride accumulation
• Direct GLP-1R stimulation in liver tissue
• Weight loss as major contributor
• Improved insulin signalling
• Reduction in systemic and hepatic inflammation (CRP, IL-6, TNF-α)
• Enhanced tissue repair pathways
• Modulation of protease/anti-protease balance
• Reduced hepatic stellate cell activation

Pathway: Direct hepatocyte effects + weight loss + improved insulin sensitivity + anti-inflammatory action → Reduced steatosis + NASH resolution + slowed fibrosis progression

Liver Cirrhosis (Compensated)

Evidence Quality: Strong | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: 2024 Taiwanese study (467 matched pairs) showed GLP-1RA users had:

• Significantly lower mortality (27.46 vs 55.90 per 1000 person-years)
• Reduced decompensation risk
• Lower hepatic encephalopathy
• Decreased acute-on-chronic liver failure
• Longer cumulative duration associated with better outcomes

US studies showed lower rates of hepatic decompensation versus sulfonylureas and DPP-4 inhibitors.

Important Note: Safety data limited to compensated cirrhosis. Not studied in decompensated cirrhosis.

Mechanisms:

• Prevention of disease progression through NASH/fibrosis effects
• Cardiovascular protection (cirrhotic diabetics have higher CV risk)
• Reduced systemic inflammation
• Metabolic improvements

Pathway: Multiple protective mechanisms → Reduced decompensation + lower mortality + decreased liver failure progression

Obstructive Sleep Apnoea (OSA) and Excessive Daytime Sleepiness

Evidence Quality: Strong | Mechanism Understanding: Well-Characterised | Status: FDA-Approved for OSA (tirzepatide, December 2024)

Evidence:

• First medication approved for OSA
• Clinical trials showed 20-25.8 event/hour reductions in apnoea-hypopnoea index (AHI)
• Greater AHI improvements than mandibular advancement devices
• Exenatide reduced Epworth Sleepiness Scale scores from 12.3 to 5.7 (p=0.003) in 22 weeks

Mechanisms:

• Weight loss reducing upper airway fat deposition
• Decreased rostral-to-caudal fluid shifts during sleep
• Direct effects via GLP-1 receptors in hypothalamic nuclei regulating sleep/wakefulness
• Normalisation of neurogenesis and synaptic plasticity
• Protection against neuronal apoptosis
• Suppression of oxidative stress
• Reduction in systemic inflammation (hs-CRP)

Pathway: Weight loss + reduced airway obstruction + direct CNS effects on sleep regulation + anti-inflammatory effects → Reduced AHI + improved sleep quality + decreased daytime sleepiness

Hypertension

Evidence Quality: Strong | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: Trials consistently show reductions in systolic blood pressure alongside other metabolic improvements. Tirzepatide trials demonstrated significant BP reductions.

Mechanisms:

• Reduced sympathetic nervous system activation
• Improved endothelial function
• Decreased vascular inflammation
• Weight loss effects
• Improved insulin sensitivity

Pathway: Reduced inflammation + improved endothelial function + weight loss → Lower blood pressure

II. PULMONARY CONDITIONS (Strong Evidence)

Chronic Obstructive Pulmonary Disease (COPD)

Evidence Quality: Very Strong | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: Multiple 2023-2024 studies in patients with COPD and T2DM showed GLP-1RA use associated with:

• 48% reduction in all-cause mortality (far exceeding the 12% in general diabetic population)
• 88% lower risk of COPD exacerbations
• 77% reduced oxygen dependence
• 78% lower pulmonary hypertension risk
• 80% reduced pneumonia risk
• 77% lower pulmonary oedema risk
• 64% reduced intubation risk

Mechanisms:

• Reduction of airway inflammation
• Decreased oxidative stress through inhibition of inflammatory factors
• Improved protease/anti-protease balance
• Enhanced airway mucus homeostasis
• Reduced airway remodelling
• Direct GLP-1R activation in lung tissue
• Possible surfactant protein enhancement

Pathway: Multi-level pulmonary anti-inflammatory effects + improved airway function + weight reduction → Reduced exacerbations + improved lung function + dramatic mortality reduction

Note: The 48% mortality reduction far exceeds cardiovascular benefits alone, suggesting lung-specific protective mechanisms.

III. NEUROLOGICAL CONDITIONS (Strong to Moderate Evidence)

Cognitive Decline and Early Dementia

Evidence Quality: Strong (Phase 2b/3 Ongoing) | Mechanism Understanding: Well-Characterised | Status: Off-Label, Trials Ongoing

Evidence:

• Phase 2b ELAD trial (2024): Liraglutide reduced cognitive decline by 18% over 12 months in mild Alzheimer's disease
• Brain volume loss (frontal, temporal, parietal lobes, total grey matter) reduced by nearly 50%
• Dulaglutide study (8,828 participants) showed significant cognitive benefit

Important Note: Not effective against established Alzheimer's disease pathology (does not directly affect amyloid-β or tau), but protective against progression of early cognitive impairment.

Mechanisms:

• Enhanced brain insulin signalling (reduces insulin resistance in hippocampus)
• Neuroprotection through reduced neuroinflammation
• Normalisation of cerebral glucose metabolism
• Prevention of expected decline in blood-brain glucose transfer
• Support for synaptic plasticity and neuronal survival
• Reduction in oxidative stress

Pathway: Improved brain insulin sensitivity + reduced neuroinflammation + enhanced glucose metabolism → Slowed cognitive decline and reduced brain atrophy

Peripheral Neuropathy

Evidence Quality: Strong | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: Prospective studies in 24 participants with diabetic peripheral neuropathy showed:

• Improvements in clinical neuropathy scores (baseline 3.7, post-treatment 2.3, p=0.005)
• Improved nerve conduction studies and axonal excitability
• Nerve morphology improved in 86% at one month, with 32% returning to normal
• Effects occur independently of glycaemic control

Mechanisms:

• Improved Na⁺/K⁺-ATPase pump function in peripheral nerves
• ERK1/2 signalling activation in sciatic nerve
• Reduced pro-inflammatory cytokines in peripheral serum and nerve tissue
• Enhanced expression of neuritin and nerve growth factor
• Preservation of intraepidermal nerve fibre density
• Direct GLP-1 receptor activation in dorsal root ganglia, neurons, and Schwann cells

Pathway: GLP-1R activation in peripheral nerves → ERK signalling + improved Na⁺/K⁺-ATPase → Preserved nerve structure and function + reduced neuropathic symptoms

IV. RHEUMATOLOGICAL CONDITIONS (Strong to Moderate Evidence)

Rheumatoid Arthritis

Evidence Quality: Strong, Expanding | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: Multiple 2024-2025 studies demonstrate significant improvements:

• Retrospective study of 173 RA patients on GLP-1RAs (2018-2024) showed reduced disease activity and improved cardiovascular risk markers
• ACR Convergence 2025 abstracts: RA patients on DMARDs plus GLP-1 agonists had fewer disease flares
• Semaglutide use associated with improved joint outcomes

Mechanisms:

• Direct NF-κB pathway inhibition in synovial tissue (weight-independent)
• Reduction in synovial inflammation and pro-inflammatory cytokine production
• Decreased oxidative stress via NOX4 suppression
• p38 MAPK pathway modulation

Pathway: Anti-inflammatory → Reduced synovial inflammation → Decreased joint damage and improved mobility

Osteoarthritis

Evidence Quality: Moderate | Mechanism Understanding: Emerging | Status: Off-Label

Evidence: ACR Convergence 2025 data showed GLP-1RAs delivered greater improvements in pain and physical function compared with SGLT2 inhibitors in OA patients. The effect extends beyond weight loss.

Mechanisms:

• Direct impact on articular chondrocytes and joint tissues
• Improved cartilage health through reduced inflammation
• Lower systemic inflammatory burden
• Reduced mechanical stress from weight loss

Pathway: Reduced inflammation + weight loss → Decreased cartilage damage + improved joint function

V. GASTROINTESTINAL CONDITIONS (Strong Evidence)

Inflammatory Bowel Disease (Crohn's Disease and Ulcerative Colitis)

Evidence Quality: Strong, Expanding Rapidly | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: Multiple 2024-2025 studies show promising results:

• Israeli nationwide cohort: GLP-1 use associated with reduced composite poor disease outcomes (steroid dependence, advanced therapy initiation, hospitalisation, surgery)
• US studies: Reduced rates of colectomy in UC (aHR: 0.37) and IBD-related surgery in CD (aHR: 0.55)
• CRP levels significantly reduced (p=0.04)
• New $3 million Helmsley Charitable Trust study (2024) investigating GLP-1RAs for promoting intestinal healing in severe Crohn's disease

Paradigm Shift: Moving from purely suppressing inflammation to actively promoting tissue repair.

Mechanisms:

• Direct anti-inflammatory effects on intestinal epithelium
• Modulation of intestinal microbiota and group 3 innate lymphoid cells
• Induction of barrier-protective expression in Brunner's glands
• Reduction in systemic inflammation
• Enhancement of tissue repair and healing pathways
• Improved gut permeability

Pathway: Anti-inflammatory effects + microbiome modulation + tissue repair enhancement → Reduced disease activity + fewer flares + decreased need for surgery

Gut Microbiome Dysbiosis

Evidence Quality: Preliminary | Mechanism Understanding: Emerging | Status: Off-Label

Evidence: Emerging research suggests beneficial effects on gut microbiome composition.

Mechanisms:

• Direct effects on gut epithelium
• Modified gastrointestinal transit time
• Anti-inflammatory effects in gut tissue
• Potential prebiotic-like effects

Pathway: GI effects + anti-inflammatory action → Improved microbiome diversity and composition

VI. ENDOCRINE AND REPRODUCTIVE CONDITIONS (Strong Evidence)

Polycystic Ovary Syndrome (PCOS)

Evidence Quality: Strong | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: Multiple studies and meta-analyses (2024) demonstrate:

• GLP-1RAs reduce BMI more effectively than metformin (SMD −1.02)
• Improve insulin sensitivity (SMD −0.40)
• Enhance ovulation rates
• Semaglutide 2.4mg shows highest efficacy
• 62% of liraglutide-treated women achieved normal menstrual bleeding ratio

Mechanisms:

• Weight reduction as primary mechanism
• Direct effects on insulin resistance (independent of weight)
• Improvement in glucose homeostasis
• Reduction in hyperandrogenism
• Enhancement of ovulation through multiple pathways

Pathway: Weight loss + improved insulin sensitivity + reduced inflammation → Improved menstrual cyclicity + enhanced fertility + metabolic improvement

Important Note: Requires effective contraception during therapy and washout period before pregnancy attempts.

Type 1 Diabetes (Adjunct Therapy)

Evidence Quality: Moderate | Mechanism Understanding: Emerging | Status: Off-Label

Evidence: Emerging evidence for Type 1 diabetes as adjunct therapy to insulin.

Mechanisms:

• Suppressed glucagon release
• Delayed gastric emptying
• Improved insulin sensitivity
• Weight management
• Reduced glycaemic variability

Pathway: Multiple metabolic effects → Improved glycaemic control with reduced insulin requirements

VII. ADDICTION AND BEHAVIOURAL CONDITIONS (Moderate to Preliminary Evidence)

Alcohol Use Disorder (AUD)

Evidence Quality: Moderate (Promising) | Mechanism Understanding: Emerging | Status: Off-Label, Trials Ongoing

Evidence:

• Preclinical studies show consistent reductions in alcohol consumption
• Clinical trials show mixed but encouraging results
• Largest pharmacoepidemiological studies show lower alcohol-related events with GLP-1RA use
• Subgroup analysis suggests strongest effects in patients with comorbid obesity (BMI >30)

Mechanisms:

• Modulation of mesolimbic dopamine reward pathways
• Reduced alcohol-induced dopamine release
• Decreased reward salience through central GLP-1 receptors
• Modification of stress response systems
• Effects on brain areas regulating addiction (nucleus tractus solitarius, septal area)

Pathway: GLP-1R activation in reward centres → Reduced dopamine signalling + decreased reward response → Lower alcohol craving and consumption

Nicotine/Tobacco Use

Evidence Quality: Preliminary | Mechanism Understanding: Emerging | Status: Off-Label, Trials Ongoing

Evidence:

• Preclinical data show GLP-1RAs reduce nicotine self-administration and reinstatement of nicotine seeking
• Early clinical trials suggest potential to reduce cigarettes per day and prevent post-cessation weight gain

Mechanisms: Similar dopamine pathway modulation as with alcohol.

Pathway: Reduced reward from nicotine + prevention of weight gain → Improved smoking cessation outcomes

Opioids and Stimulants

Evidence Quality: Preliminary (Preclinical) | Mechanism Understanding: Emerging | Status: Research Phase

Evidence: Preliminary preclinical evidence for reduced use of opioids, cocaine, and methamphetamine. Human data very limited.

Note: This is an emerging area requiring substantial further research. Most evidence is preclinical, and clinical trials are ongoing.

VIII. VASCULAR AND CARDIOVASCULAR CONDITIONS (Moderate to Preliminary Evidence)

Vascular and Brain Inflammation

Evidence Quality: Strong | Mechanism Understanding: Well-Characterised | Status: Off-Label

Evidence: Multiple studies demonstrate reductions in inflammatory markers (CRP, TNF-α, IL-6, IL-1β) both systemically and in specific tissues.

Mechanisms:

• NF-κB pathway inhibition
• Direct anti-inflammatory signalling
• Reduced oxidative stress
• Improved microvascular function

Pathway: Multi-level anti-inflammatory action → Reduced vascular and brain inflammation → Improved organ function

Sequelae of Deep Vein Thrombosis

Evidence Quality: Preliminary | Mechanism Understanding: Theoretical | Status: Off-Label

Evidence: Emerging evidence for vascular protective effects through anti-inflammatory mechanisms.

Mechanisms:

• Reduced systemic inflammation
• Improved endothelial function
• Enhanced vascular health through multiple pathways

Pathway: Anti-inflammatory effects + improved endothelial function → Reduced post-thrombotic complications

IX. DERMATOLOGICAL CONDITIONS (Anecdotal Evidence)

Vascular Eczema and Atopic Eczema

Evidence Quality: Anecdotal | Mechanism Understanding: Theoretical | Status: Off-Label

Evidence: Anecdotal evidence emerging; formal studies needed. Mechanism plausible given anti-inflammatory properties.

Mechanisms (Proposed):

• Systemic anti-inflammatory effects
• Improved microvascular function
• Reduced oxidative stress
• Potential direct effects on skin immune cells

Pathway: Systemic anti-inflammatory effects + improved microvascular health → Reduced eczema severity

Note: Requires formal clinical investigation to establish efficacy.

Summary Table: Evidence Quality and Clinical Status

Condition Evidence Quality Mechanism Understanding Clinical Availability

TIER 1: STRONGEST EVIDENCE

Type 2 Diabetes Very strong Very well-characterised Licensed indication

Chronic Kidney Disease Very strong Very well-characterised FDA-approved (semaglutide)

NAFLD/MASLD Very strong Well-characterised Off-label

NASH Very strong Well-characterised Off-label, Phase 3 trials ongoing

COPD Very strong Well-characterised Off-label

TIER 2: STRONG EVIDENCE

Sleep Apnoea/EDS Strong Well-characterised FDA-approved (tirzepatide)

Liver Cirrhosis (compensated) Strong Well-characterised Off-label

Cognitive Decline Strong (Phase 2b/3 ongoing) Well-characterised Off-label, trials ongoing

Peripheral Neuropathy Strong Well-characterised Off-label

Rheumatoid Arthritis Strong, expanding Well-characterised Off-label

Hypertension Strong Well-characterised Off-label

PCOS Strong Well-characterised Off-label

IBD (Crohn's/UC) Strong, expanding rapidly Well-characterised Off-label

Brain/Vascular Inflammation Strong Well-characterised Off-label

TIER 3: MODERATE EVIDENCE

Osteoarthritis Moderate Emerging Off-label

Type 1 Diabetes Moderate Emerging Off-label

Alcohol Use Disorder Moderate (promising) Emerging Off-label, trials ongoing

TIER 4: PRELIMINARY/EMERGING

Nicotine/Tobacco Use Preliminary Emerging Off-label, trials ongoing

DVT Sequelae Preliminary Theoretical Off-label

Gut Microbiome Preliminary Emerging Off-label

Other Addictions Preliminary (preclinical) Emerging Research phase

TIER 5: ANECDOTAL

Vascular Eczema Anecdotal Theoretical Off-label

Atopic Eczema Anecdotal Theoretical Off-label

Key Insights

1. Pleiotropic Drug Class: GLP-1RAs demonstrate effects across virtually every organ system, transitioning from diabetes/obesity medications to broad metabolic-inflammatory disease modifiers with organ-protective properties.
2. Weight-Independent Mechanisms: Many benefits occur independently of weight loss through direct anti-inflammatory, neuroprotective, and tissue-protective mechanisms mediated by local GLP-1 receptors.
3. Shared Pathways: NF-κB inhibition, reduced pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), improved cellular signalling, and decreased oxidative stress are common mechanisms across diverse conditions.
4. Tissue-Specific Receptors: GLP-1 receptors are present in brain, peripheral nerves, liver, kidneys, joints, lungs, gut, and other tissues, enabling direct local effects beyond systemic metabolic improvements.
5. Organ Protection Beyond Metabolic Control: Dramatic reductions in hard outcomes:
• 71% reduction in dialysis-requiring ESKD
• 48% reduction in COPD mortality
• 50% reduction in cirrhosis mortality
• 63% reduction in IBD surgery
• These effects exceed what would be expected from glycaemic control and weight loss alone
6. Combination Therapy Synergy: GLP-1RAs work synergistically with other disease-modifying drugs:
• With RASi, SGLT2i, and finerenone for CKD (5.5 additional event-free years)
• With DMARDs for rheumatoid arthritis
• Potential for multi-drug approaches to inflammatory conditions
7. Emerging Addiction Treatment: Modulation of mesolimbic dopamine reward pathways suggests potential for treating substance use disorders, with strongest evidence for alcohol use disorder in patients with comorbid obesity.
8. Paradigm Shift in IBD Treatment: Moving from purely immunosuppressive approaches to promoting active tissue repair and intestinal healing.
9. Neuroprotection: Direct effects on brain insulin signalling, neuroinflammation, and glucose metabolism offer potential for neurodegenerative disease modification, though not curative for established pathology.
10. Safety Profile Supports Broad Use: Generally well-tolerated across diverse patient populations, though specific contraindications exist (e.g., decompensated cirrhosis not studied, pregnancy contraindicated).

Research Priorities

High Priority (Strong Mechanistic Rationale, Preliminary Human Evidence):

• Long-term outcomes for rheumatological conditions
• Optimal dosing protocols for non-metabolic indications
• Comparative effectiveness of different GLP-1RAs for specific conditions
• Addiction treatment protocols and patient selection criteria
• Mechanisms of pulmonary benefits beyond weight loss
• Long-term IBD healing and remission rates

Medium Priority (Plausible Mechanisms, Need Human Data):

• Dermatological effects require formal clinical trials
• Post-thrombotic syndrome prevention and treatment
• Gut microbiome effects need mechanistic clarification

Emerging Areas (Preclinical Promise):

• Other substance use disorders (opioids, stimulants)
• Additional neurodegenerative conditions
• Cancer prevention (emerging epidemiological signals)

Patient Selection:

• Identification of patient subgroups most likely to benefit from specific indications
• Biomarkers predicting response
• Optimal timing of intervention for different conditions

Clinical Implications

GLP-1 and GIP receptor agonists represent a new class of pleiotropic medications with far-reaching effects beyond their original metabolic indications. The breadth of conditions affected, combined with generally favourable safety profiles and the availability of both weight-neutral (liraglutide, dulaglutide) and weight-reducing (semaglutide, tirzepatide) formulations, positions these medications as potential disease-modifying treatments across multiple specialities.

Healthcare providers should consider these broader benefits when prescribing for approved indications and remain alert to emerging evidence for off-label uses. Patients with multiple comorbidities may experience compounding benefits across several conditions simultaneously.

The transition from viewing these as "diabetes drugs" to recognising them as "metabolic-inflammatory disease modifiers with organ-protective properties" represents a fundamental shift in therapeutic thinking.