What Are GLP-1 Receptor Agonists?
Sacred Leaves Research
Glucagon-like peptide-1 (GLP-1) is a hormone produced naturally in the gut in response to food intake. It signals the pancreas to release insulin, suppresses glucagon (which raises blood sugar), slows gastric emptying, and crucially — signals the brain's hypothalamus to reduce appetite and induce satiety. GLP-1 receptor agonists (GLP-1 RAs) are drugs engineered to mimic and amplify this hormone's effects, with dramatically longer half-lives than the natural hormone.
The two agents that have defined this class in the modern era are semaglutide
(Ozempic/Wegovy, Novo Nordisk) and tirzepatide (Mounjaro/Zepbound, Eli Lilly). While semaglutide is a pure GLP-1 agonist, tirzepatide is a dual agonist — targeting both GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) receptors, achieving synergistic metabolic effects through simultaneous activation of two hormonal pathways found in the
brain, fat cells, and pancreatic cells.
Weight Loss Efficacy: What the Data Shows
The clinical evidence for GLP-1 RAs in obesity is now among the most robust in pharmaceutical history:
Liraglutide (3mg daily): ~5% placebo-corrected weight loss · FDA approved 2014
Semaglutide 2.4mg (weekly): ~12% placebo-corrected weight loss · 50.5% of participants lost ≥15% of body weight
Tirzepatide 15mg (weekly): ~18% placebo-corrected weight loss · 56.7% lost ≥20% body weight · 36% lost ≥25%
A 2025 Cochrane systematic review — requested by the WHO to guide global obesity treatment recommendations — confirmed that all three agents produced clinically meaningful weight loss over 12–24 months. Tirzepatide produced approximately 16% body weight reduction at 12–18 months, while semaglutide achieved approximately 11% over 24–68 weeks.
In December 2025, the FDA approved an oral formulation of semaglutide, demonstrating approximately 13.7% average weight loss over 64 weeks — nearly equivalent to the injectable form. This marks a significant step toward wider patient access.
Beyond Weight Loss: The Expanding Evidence Base
The most scientifically compelling aspect of GLP-1 research in 2025 is the accumulating evidence for benefits extending far beyond glucose control and weight management:
Cardiovascular Protection
A 2025 landmark head-to-head study from Mass General Brigham, published in Nature Medicine and presented at the American Heart Association Scientific Sessions, compared cardiovascular outcomes in nearly one million adults. Semaglutide reduced risk of stroke and heart attack by 18% versus sitagliptin (a diabetes drug with neutral cardiovascular effects).
Tirzepatide lowered risk of stroke, heart attack, and death by 13%. In the EU, the EMA approved semaglutide in September 2025 as the first stroke management therapy, based on the phase 3 SOUL trial of nearly 10,000 patients.
Sleep Apnea
In a historic 2024–2025 milestone, the FDA approved tirzepatide (Zepbound) as the first medication approved for obstructive sleep apnea (OSA). Phase 3 trials demonstrated a reduction in the Apnea-Hypopnea Index by 23.8 events per hour compared to placebo, attributed to reductions in upper airway adiposity including tongue fat.
Liver Disease (MASH/NAFLD)
Both semaglutide and tirzepatide have shown significant reductions in hepatic steatosis and liver inflammation markers in patients with metabolic dysfunction-associated steatotic liver disease (MASLD/MASH) — a condition with very few effective pharmacologic treatments — making GLP-1 RAs promising candidates for this major unmet clinical need.
Neurological Conditions
Emerging research (2025) has identified GLP-1 receptors in the brain's reward circuits and explored GLP-1 RAs for depression, Parkinson's disease, and Alzheimer's disease. Trials including OxSENSE are investigating semaglutide's effects on cognition, reward processing, and neuroinflammation. GLP-1 agents are also being studied for idiopathic intracranial hypertension.
Important Considerations and Limitations
GLP-1 RAs are not without concerns that the research community is actively studying:
▸ Gastrointestinal side effects (nausea, diarrhea, vomiting, constipation) affect 20–40% of patients, typically mild-to-moderate and dose-dependent
▸ Lean mass loss: 25–45% of total weight lost may come from lean body mass, raising concerns about muscle preservation, particularly in older patients
▸ Weight regain: stopping treatment leads to significant weight regain. Real-world data shows that only 14% of patients remain on Wegovy after 3 years
▸ Rare risks: gallbladder disorders, rare cases of pancreatitis; safety in thyroid cancer- prone patients under monitoring
▸ A 2025 Nature study of 27,885 participants identified genetic variants in GLP1R and GIPR associated with both efficacy and side effects — pointing toward a precision medicine future where genetic profiling guides drug selection
The Future: Triple Agonists and Beyond
Research is already moving beyond dual agonism. Retatrutide, a triple agonist targeting GLP-1, GIP, and glucagon receptors, is showing even greater weight loss in early phase trials. A 2025 UAB presentation described a five-receptor agonist combining GLP-1, GIP, and PPAR nuclear hormone receptors — theoretically targeting multiple metabolic pathways
simultaneously. The GLP-1 revolution is accelerating.
References
[1] Krüger N et al. Cardiovascular outcomes of semaglutide and tirzepatide for patients with type 2 diabetes in clinical practice. Nature Medicine. 2025. doi:10.1038/s41591-025-04102-x
[2] Guo H et al. Comparative efficacy and safety of GLP-1 receptor agonists for weight reduction: a model-based meta-analysis. Obes Pillars. 2025;13:100162.
[3] Lincoff AM et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. NEJM.
2023;389:2221-2232. doi:10.1056/NEJMoa2307563
[4] Jastreboff AM et al. Tirzepatide Once Weekly for the Treatment of Obesity. NEJM. 2022;387:205-216.
doi:10.1056/NEJMoa2206038
[5] Rodriguez PJ et al. Semaglutide vs tirzepatide for weight loss in adults with overweight or obesity.
JAMA Internal Medicine. 2024;184:1056–1064.
[6] Rubino DM et al. Semaglutide 2.4 mg in Adults with Overweight or Obesity and Type 2 Diabetes.
JAMA. 2022;327(2):138-150. doi:10.1001/jama.2021.23619.
[7] Nature (2026). Genetic predictors of GLP1 receptor agonist weight loss and side effects.
doi:10.1038/s41586-026-10330-z
The State of Cancer Treatment in 2025
Sacred Leaves Research
Cancer research in 2025 has been defined by a convergence of three transformative forces:
the maturation of immunotherapy as a standard-of-care approach across multiple tumour
types; the explosion of antibody-drug conjugates (ADCs) that deliver chemotherapy directly
to cancer cells while sparing healthy tissue; and the deepening of precision medicine —
matching treatments to the specific molecular fingerprint of each patient's tumour.
The result is a treatment landscape that would have been unrecognisable a decade ago —
patients with cancers previously considered untreatable are achieving durable remissions,
and the concept of cancer as an invariably fatal disease is being fundamentally challenged.
Immunotherapy: Cementing Its Role Across Cancer Types
Immune checkpoint inhibitors — drugs that release the brakes on the immune system's
ability to recognise and destroy cancer cells — have become foundational in the treatment of
lung, kidney, bladder, head and neck, and melanoma cancers. In 2025, the evidence base
has deepened significantly:
For lung cancer, long-term follow-up data from KEYNOTE and CheckMate trials confirm
durable 5-year survival rates in 15–30% of patients with advanced NSCLC treated with
pembrolizumab — a milestone unimaginable with chemotherapy alone. For previously
untreatable oesophageal and gastric cancers, nivolumab and pembrolizumab combinations
with chemotherapy have become standard of care, reducing mortality risk by 22–38%.
Neoadjuvant immunotherapy — giving immunotherapy before surgery to shrink tumours and
train the immune system — emerged as a major clinical strategy in 2025. The approach has
shown complete pathological responses in 35–60% of patients across multiple solid tumour
types, suggesting that combining surgery with pre-operative immune activation may
dramatically improve long-term outcomes.
Antibody-Drug Conjugates (ADCs): Precision Chemotherapy
ADCs represent one of the most significant advances in oncology in a generation. These
engineered molecules consist of a monoclonal antibody that targets a specific protein on
cancer cells, linked to a potent chemotherapy payload. The antibody "delivers" the chemo
directly to cancer cells, dramatically reducing systemic toxicity. In 2025, ADCs expanded
across multiple cancer types:
▸ Trastuzumab deruxtecan (T-DXd / Enhertu) for HER2-positive breast, gastric, and lung
cancers demonstrated survival benefits across all three tumour types, making it one of the
most impactful oncology drugs of the decade
▸ Sacituzumab govitecan (Trodelvy) for triple-negative breast cancer (TNBC) combined
with pembrolizumab showed a 35% reduction in progression or death versus chemotherapy
plus pembrolizumab in the ASCENT-04 trial
▸ Datopotamab deruxtecan became the first ADC to demonstrate overall survival benefit in
first-line metastatic TNBC, marking a major milestone at ESMO 2025
Liquid Biopsies: Cancer Detection Revolutionised
Circulating tumour DNA (ctDNA) — fragments of DNA shed by cancer cells into the
bloodstream — is transforming oncology from diagnosis through treatment monitoring. In
2025, major cancer conferences unveiled ctDNA-guided treatment as a real-time precision
medicine tool: liquid biopsies are now enabling detection of treatment resistance weeks
before radiological progression, allowing oncologists to switch therapies before clinical
deterioration.
A January 2026 study showed that risk-stratified breast cancer screening — based on
genetics, health history, and lifestyle factors rather than age-based mammography —
reduced advanced-stage cancer diagnoses, pointing toward a personalised screening future.
CAR-T Cell Therapy: From Blood Cancers to Solid Tumours
Chimeric antigen receptor T-cell (CAR-T) therapies have been transformative in
haematological malignancies (leukaemia, lymphoma, myeloma), achieving complete
remissions in patients who had exhausted all other options. The frontier in 2025 is solid
tumours — notoriously difficult for CAR-T due to their immunosuppressive
microenvironment. Early clinical data from trials targeting mesothelin, GD2, HER2, and
PSMA in solid tumours is encouraging, with several phase 2 trials delivering early evidence
of activity in lung, ovarian, and brain cancers.
PARP Inhibitors: Targeted Therapy Expands
PARP inhibitors — drugs that exploit the inability of BRCA-mutated cancer cells to repair
DNA damage — have moved from ovarian and breast cancer into prostate and pancreatic
cancers. Olaparib combined with abiraterone reduced risk of progression or death by 76%
versus abiraterone alone in BRCA-mutated metastatic castration-resistant prostate cancer.
In 2025, expanded genetic testing is identifying more patients eligible for this class of drugs
across multiple cancer types.
What Patients Can Do: Evidence-Based Cancer Prevention
While treatments advance, prevention remains the most powerful tool. The evidence for
lifestyle-based risk reduction is unambiguous:
▸ Not smoking remains the single most impactful cancer prevention act — responsible for
85% of lung cancers and strongly linked to 15 other cancer types
▸ Maintaining healthy body weight: obesity is now recognised as a cause of 13 cancer
types, including breast, colon, oesophageal, kidney, and pancreatic
▸ Physical activity: 30+ minutes daily of moderate exercise reduces risk of colon, breast,
and endometrial cancers by 20–30%
▸ Limiting alcohol: alcohol is a Group 1 carcinogen linked to 7 cancer types — any
consumption increases risk
▸ Screening: regular mammography, colonoscopy, cervical smears, and PSA testing
dramatically reduce cancer mortality through early detection
▸ HPV and Hepatitis B vaccination: preventing the viral infections that cause cervical and
liver cancer respectively
References
[1] Cortés J et al. Pembrolizumab plus Chemotherapy in Triple-Negative Breast Cancer. NEJM.
2022;387:217-226. doi:10.1056/NEJMoa2202809
[2] Modi S et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. NEJM.
2022;386:610-621. doi:10.1056/NEJMoa2114035
[3] Schmid P et al. ASCENT-04: Sacituzumab govitecan plus pembrolizumab in advanced TNBC. ASCO
2025.
[4] Breast Cancer Research Foundation. 5 Breast Cancer Breakthroughs from 2025. bcrf.org, January
2026.
[5] Wild CP, Weiderpass E, Stewart BW (eds). World Cancer Report: Cancer Research for Cancer
Prevention. IARC Press, 2020. ISBN 9789283204299.
[6] Baptist Health. Breast Cancer Research Updates for 2025. physicianresources.baptisthealth.net,
October 2025.
The Global Burden of Viral Hepatitis
Viral hepatitis remains one of the leading causes of preventable death globally. Hepatitis B
virus (HBV) chronically infects more than 254 million people worldwide, causing nearly
900,000 deaths annually through cirrhosis and hepatocellular carcinoma (liver cancer).
Hepatitis C virus (HCV) infects approximately 58 million people globally, and was
responsible for 290,000 deaths in 2019.
The good news is that both diseases are now at pivotal treatment inflection points — HCV
has effectively been cured in the clinical sense, while HBV research in 2025 achieved
breakthroughs that bring a true functional cure closer than at any previous time in history.
Hepatitis C: A Virus We Can Now Cure
The development of direct-acting antivirals (DAAs) represents one of the greatest
achievements in the history of infectious disease medicine. In less than a decade, HCV
treatment moved from year-long, poorly tolerated interferon-based regimens (with 40–50%
cure rates and severe side effects) to 8–12 week oral tablet regimens achieving cure rates
exceeding 95%.
In June 2025, the FDA approved a label expansion for glecaprevir/pibrentasvir (Mavyret) —
making it the first and only DAA approved for acute HCV infection, treating patients in just 8
weeks with a 96% cure rate (M20-350 Phase 3 trial). This is a landmark because earlier
treatment of acute HCV prevents progression to chronic infection and liver damage.
The WHO has set a target of eliminating HCV as a public health threat by 2030 — an
ambitious goal that modelling studies suggest could prevent 15.1 million new infections and
1.5 million deaths. However, a 2025 Lancet trial and systematic review identified critical
barriers: HCV disproportionately affects high-risk populations (people who inject drugs,
incarcerated individuals) who face significant obstacles to testing and treatment access.
Reinfection after cure also remains a challenge when risk behaviours continue.
Canadian researchers in 2025 demonstrated that successful HCV treatment and cure
produces benefits far beyond liver health — cured patients showed significantly lower risk of
kidney disease, cardiovascular events, stroke, and neurocognitive decline, confirming that
HCV's damage extends systemically.
Hepatitis B: The Functional Cure Revolution
While HCV is now curable, HBV has been far more difficult to eliminate. Current standard-of-
care treatments — nucleos(t)ide analogues (NAs) such as tenofovir and entecavir —
effectively suppress viral replication and reduce the risk of cirrhosis and liver cancer, but
they do not eradicate the virus. This is because HBV establishes a stable reservoir of
covalently closed circular DNA (cccDNA) inside infected liver cells that persists indefinitely
and cannot be targeted by current NAs.
A functional cure — defined as sustained loss of hepatitis B surface antigen (HBsAg) and
undetectable HBV DNA 24 weeks after finite treatment — is now the clinical target. Current
NAs achieve functional cure in only about 1% of patients.
2025: Breakthrough Advances in Hepatitis B
Multiple new drug classes in advanced clinical trials are showing unprecedented HBsAg
reduction, bringing functional cure within reach:
RNA Interference (RNAi) Therapeutics
RNAi drugs silence HBV gene expression, dramatically reducing the viral antigen burden
that suppresses the immune system's ability to fight the virus. In Phase 2 trials, JNJ-3989
achieved over 1 log IU/mL HBsAg reduction in 98% of patients. AB-729 and VIR-2218
showed similarly potent HBsAg declines. These drugs are expected to be used in
combination strategies.
Bepirovirsen: GSK's Phase 3 Success
In January 2026, GSK announced positive results from the B-Well 1 and B-Well 2 Phase 3
trials of bepirovirsen — an antisense oligonucleotide that targets HBV RNA and reduces viral
antigen load. The trials met their primary endpoint, demonstrating a statistically significant
and clinically meaningful functional cure rate — significantly higher than standard of care
alone. Bepirovirsen has received Fast Track designation from the FDA, Breakthrough
Therapy designation in China, and SENKU designation in Japan.
Therapeutic Vaccines
The first patient was enrolled in June 2025 in the first clinical trial of TherVacB — a
therapeutic vaccine for chronic hepatitis B. Unlike preventive vaccines, therapeutic vaccines
aim to reactivate the patient's own immune response against HBV. A previous healthy
volunteer trial demonstrated a favourable safety profile and appropriate immune response.
BRII-179 (in combination with siRNA elebsiran) showed 40% of patients developing anti-HBs
antibodies — an extraordinary early result.
2025 EASL Guidelines: A New Treatment Paradigm
The 2025 European Association for the Study of the Liver (EASL) guidelines published in
August 2025 mark a significant shift toward biomarker-led, finite, personalised therapy for
chronic hepatitis B. Novel biomarkers including quantitative HBsAg (qHBsAg), HBcrAg, and
HBV RNA are now incorporated into treatment algorithms. Approximately 20–30% of
carefully selected non-cirrhotic HBeAg-negative patients may achieve sustained off-
treatment control after stopping NAs — a small but meaningful step toward functional cure
using existing drugs.
References
[1] Toma D, Anghel L, et al. Hepatitis C Virus: Epidemiological Challenges and Global Strategies for
Elimination. Viruses. 2025;17(8):1069. doi:10.3390/v17081069.
[2] HCPLive. Hepatitis in 2025: Year in Review. hcplive.com, December 2025.
[3] Marrapu S, Kumar R, et al. Hepatitis B functional cure: Current and future perspective. World J
Hepatol. 2025;17(10):110107. doi:10.4254/wjh.v17.i10.110107.
[4] GSK Press Release. B-Well 1 and B-Well 2 Phase III Trials for Bepirovirsen. gsk.com, January 2026.
[5] Liu T, Wang H, et al. Drug development for chronic hepatitis B functional cure: Recent progress.
World J Hepatol. 2025;17(4):105797. doi:10.4254/wjh.v17.i4.105797.
[6] Willner IR et al. Chronic hepatitis B in 2025: diagnosis, treatment and future directions.
PMC12681808. 2025.
[7] Roth D et al. Treatment options to support the elimination of hepatitis C. The Lancet. 2025.
doi:10.1016/S0140-6736(25)00097-2.
Alzheimer's in Numbers
Alzheimer's disease (AD) is the most common cause of dementia, accounting for 60–70% of
the 55 million people living with dementia worldwide. It is a progressive neurodegenerative
disease characterised by the accumulation of amyloid-beta (Aβ) plaques and tau
neurofibrillary tangles in the brain, leading to neuronal death, cognitive decline, and
eventually loss of independent function. AD affects an estimated 10% of people over age 65
and nearly 50% of those over age 85.
For over three decades, every attempt to develop disease-modifying therapy for Alzheimer's
— treatments that address the underlying biology rather than merely managing symptoms —
failed. That changed between 2023 and 2025, when the FDA approved the first-ever drugs
to actually slow the progression of Alzheimer's disease.
The Amyloid Hypothesis: Finally Validated
The dominant hypothesis in AD research has been the "amyloid cascade hypothesis" — the
idea that toxic accumulation of amyloid-beta protein in the brain initiates a cascade that
leads to tau tangle formation, neuroinflammation, and neuronal death. This hypothesis has
guided drug development but also been highly controversial after numerous failed clinical
trials.
The approvals of lecanemab and donanemab in 2023–2024 validated the amyloid
hypothesis in a fundamental way. Both drugs clear amyloid from the brain — and both slow
cognitive decline. The correlation between amyloid clearance and slowed decline is the
clinical proof that amyloid causally drives the disease.
Lecanemab (Leqembi): The First Approved Disease-Modifying Treatment
Lecanemab received traditional FDA approval in July 2023 and European Medicines Agency
approval in late 2024. It is a humanised monoclonal antibody that targets aggregated soluble
amyloid-beta protofibrils — the most neurotoxic form of amyloid.
The pivotal CLARITY-AD Phase 3 trial (18 months, double-blind, placebo-controlled)
demonstrated that lecanemab slowed cognitive decline by 27% as measured by the CDR-
SB (Clinical Dementia Rating Sum of Boxes) and achieved a 59-centiloid reduction in
amyloid burden on PET imaging. In simpler terms: patients on lecanemab had more than 5
months of additional time at a better cognitive level compared to those on placebo over 18
months.
Critically, 2025 brought major accessibility advances. The FDA approved monthly IV
maintenance dosing in January 2025, and — in a landmark August 2025 approval — weekly
subcutaneous (under-the-skin) self-injection maintenance dosing using an autoinjector,
allowing patients to manage their treatment at home rather than making frequent hospital
visits. Lecanemab has now been approved in 51 countries.
Donanemab (Kisunla): A Finite Course of Treatment
Donanemab received FDA approval in July 2024. It targets a specific modified form of amyloid-beta (pyroGlu-Aβ) found in mature plaques. The TRAILBLAZER-ALZ 2 Phase 3 trial (76 weeks) showed that donanemab slowed clinical progression by 29% compared to placebo across all cognitive and functional measures.
A unique and clinically important feature of donanemab is that treatment can be paused or discontinued once amyloid PET imaging confirms sufficient plaque clearance — effectively a finite course of therapy. Long-term extension data presented at AAIC 2025 confirmed that patients who began donanemab early continued to experience meaningful benefit for up to 3 years, with more than 75% achieving amyloid clearance within 76 weeks.
However, the European Medicines Agency rejected donanemab's marketing authorisation application in 2025 based on an unfavourable benefit-risk assessment — a difference from the FDA's decision that highlights ongoing regulatory and scientific debate about the magnitude of clinical benefit relative to safety risks.
Safety: The ARIA Challenge
Both lecanemab and donanemab carry a risk of Amyloid-Related Imaging Abnormalities (ARIA) — brain swelling (ARIA-E) and microhemorrhages (ARIA-H) — that occur in 21–37% of patients and are serious or symptomatic in 2–3%. These risks are higher in patients carrying the APOE-ε4 genetic variant (which also increases AD risk). Anti-amyloid therapies are contraindicated in patients taking anticoagulants. Regular MRI monitoring is required.
These safety requirements have prompted active research into less toxic delivery systems — Eli Lilly is developing a brain-shuttle technology for donanemab to reduce ARIA incidence.
What Is Coming Next
Both drugs slow, but do not stop, decline — slowing progression by 25–30% over 18 months, with uncertain long-term effects. The next frontier is targeting tau pathology in parallel with amyloid — researchers believe that combination therapy (anti-amyloid + anti-tau) may produce dramatically greater benefits than either approach alone. Tau-targeting drugs including etalanetug (E2814, Eisai) are currently in Phase 3 trials. Prevention trials (AHEAD study, TRAILBLAZER-ALZ 3) are now testing anti-amyloid drugs in cognitively normal people who have elevated amyloid — the hope being to prevent Alzheimer's before symptoms begin. In August 2025, the 18th CTAD Conference reported 138 drugs in 182 active global trials — the most robust pipeline in AD history.
References
[1] van Dyck CH et al. Lecanemab in Early Alzheimer's Disease (CLARITY-AD). NEJM. 2023;388:9-21.
doi:10.1056/NEJMoa2212948.
[2] Sims JR et al. Donanemab in Early Symptomatic Alzheimer Disease: TRAILBLAZER-ALZ 2. JAMA.
2023;330(6):512-527. doi:10.1001/jama.2023.13239.
[3] Wang H, Pan J et al. Re-evaluation of anti-Aβ monoclonal antibodies in early AD. Front Pharmacol.
2025;16:1599048. doi:10.3389/fphar.2025.1599048.
[4] Alzheimer's Association. Lecanemab (Leqembi). alz.org, August 2025.
[5] ALZ-NET. New results from TRAILBLAZER-ALZ 2 long-term extension. alz-net.org, August 2025.
[6] Alzheimer's Research UK. CTAD 2025: Six highlights from the latest clinical trials. December 2025.
[7] Loera-Valencia R et al. Anti-Amyloid Therapies for Alzheimer's: Progress, Pitfalls, and the Path
Ahead. PMC12524931. 2025.
