Open questions
What the research has not yet answered, why not, and which studies come closest. A question stays open until evidence capable of answering it exists.
Are the anti-inflammatory effects of GLP-1 receptor agonists independent of weight loss, and do they occur in people without excess adiposity?
Domains: inflammation. Best current evidence is biomarker-level in obesity (SELECT hs-CRP; liraglutide vs diet). No normal-weight data.
Closest evidence so far
- Effect of Semaglutide on the Inflammatory Biomarker High-Sensitivity CRP in Patients With Established Cardiovascular Disease and Overweight or Obesity in SELECT: A Prespecified Secondary AnalysisPrespecified secondary (sub-study) analysis of a randomized, double-blind, placebo-controlled, parallel-group phase 3 trial (select) · 2026 · Study tier 2 · Different population · Benefit · Industry funded
hs-CRP fell before major weight loss in SELECT.
- Effects of GLP-1 Receptor Agonists and Dual GIP/GLP-1 Receptor Agonists on Inflammatory and Metabolic Biomarkers in Type 2 Diabetes: A Systematic Review and Meta-AnalysisMeta-analysis · 2026 · Study tier 3 · Different population · Benefit
Biomarker meta-analysis in T2D.
- Comparative effects of weight loss and incretin-based therapies on vascular endothelial function, fibrinolysis and inflammation in individuals with obesity and prediabetes: A randomized controlled trialRandomized, parallel-group, quadruple-blind (drug arms), placebo-controlled trial; 3 arms (liraglutide, hypocaloric diet, sitagliptin) in 2:1:1 ratio; 14 weeks; measurements at baseline, 2 weeks (pre-weight-loss), and 14 weeks. · 2023 · Study tier 3 · Different population · Mixed
MCP-1 lowered by liraglutide but not diet at similar weight loss.
Is chronic GLP-1 receptor agonist use beneficial, neutral or harmful in metabolically healthy people?
Domains: core_question, metabolic, aging. No trial exists. Harms documented in treated populations (GI, gallbladder, lean mass) would apply.
Closest evidence so far
- Cardiovascular Outcomes of GLP-1-Based Medicines Among People With Overweight and Obesity: An Umbrella Review of Meta-Analyses of Randomized Controlled TrialsUmbrella review · 2026 · Study tier 2 · Different population · Mixed
No CV benefit signal without baseline CVD.
What is the risk-benefit balance in normal-weight adults aged 55-75?
Domains: core_question, adverse_effects, lean_mass, bone. Unanswerable with current evidence; this observatory tracks whether any direct evidence appears.
Closest evidence so far
- Semaglutide and Cardiovascular Outcomes in Obesity without DiabetesRandomized trial · 2023 · Study tier 1 · Different population · Benefit · Industry funded
Closest large trial still required BMI >= 27 and CVD.
Are the cardiovascular effects independent of obesity?
Domains: cardiovascular. Within obesity, benefit is largely independent of weight loss (SELECT analyses). Outside obesity, untested.
Closest evidence so far
- Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trialRandomized trial · 2025 · Study tier 2 · Different population · Benefit · Industry funded
Benefit independent of baseline adiposity and weight loss within SELECT.
- Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 DiabetesRandomized trial · 2025 · Study tier 1 · Different population · Mixed · Industry funded
Greater weight loss with tirzepatide did not yield superiority over dulaglutide.
Do GLP-1 receptor agonists affect biological aging in humans?
Domains: aging. Mechanistic reviews only; no human trial with an aging endpoint.
Closest evidence so far
- The GLP-1-Mitochondria Axis in Metabolic AgingMechanistic review · 2026 · Not rated · Not human evidence · Unclear
Review; no prespecified mitochondrial or aging endpoint in any trial.
Is there clinically meaningful neuroprotection (dementia, Parkinson's) in humans?
Domains: dementia, alzheimers, parkinsons, neuroinflammation. Phase 3 trials in established AD and PD were negative; observational prevention signals remain untested by RCT.
Closest evidence so far
- Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trialsRandomized trial · 2026 · Study tier 1 · Partial match · Null · Industry funded
evoke/evoke+ negative.
- Exenatide once a week versus placebo as a potential disease-modifying treatment for people with Parkinson's disease in the UK: a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trialRandomized trial · 2025 · Study tier 1 · Partial match · Null
Exenatide-PD3 negative.
- GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related DementiasRetrospective cohort · 2025 · Study tier 3 · Different population · Benefit
Observational ADRD reduction in T2D.
What happens to lean mass and muscle function in normal-weight users?
Domains: lean_mass, muscle, bone. No data in normal-weight users; lean mass falls with weight loss in every studied population.
Closest evidence so far
- Effects of Semaglutide on Body Composition and GFR: A Prespecified Analysis of the SMART TrialRandomized trial · 2026 · Study tier 3 · Different population · Mixed · Industry funded
Lean mass reduced with semaglutide in CKD with overweight/obesity.
- Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trialRandomized trial · 2026 · Study tier 3 · Different population · Mixed · Industry funded
Lean-mass loss with tirzepatide partially preserved by myostatin inhibition.
Is there an effective dose for non-weight indications below weight-loss doses?
Domains: metabolic, addiction, cardiovascular. FLOW used 1.0 mg semaglutide; the AUD trial used 0.5-1.0 mg; CVOTs in T2D used lower doses than obesity trials. No dose-ranging data for non-weight endpoints in non-obese people.
Closest evidence so far
- Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical TrialRandomized trial · 2025 · Study tier 3 · Partial match · Benefit
Low-dose semaglutide reduced drinking measures.
- Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 DiabetesRandomized trial · 2024 · Study tier 1 · Different population · Benefit · Industry funded
1.0 mg weekly kidney benefit in T2D.
What happens with use measured in decades rather than years?
Domains: adverse_effects, cancer, endocrine, bone. Longest follow-up in RCTs is about 5 years (REWIND). Thyroid cancer and other slow outcomes remain uncertain.
Closest evidence so far
- Glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer: Scandinavian cohort studyRetrospective cohort · 2024 · Study tier 3 · Different population · Null · Partly industry funded
Mean 3.9-year follow-up; thyroid cancer not increased so far.
- Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trialRandomized trial · 2019 · Study tier 1 · Different population · Benefit · Industry funded
Median 5.4-year follow-up; longest CVOT.
How large are rare irreversible harms (NAION, pancreatitis, obstruction) and are they dose-related?
Domains: ophthalmologic, gastrointestinal, adverse_effects.
Closest evidence so far
- Semaglutide-associated risk of nonarteritic anterior ischemic optic neuropathy in patients with type 2 diabetes: A systematic review and meta-analysis of observational studiesMeta-analysis · 2026 · Study tier 3 · Different population · Harm direction
NAION ~1 extra case per 7,000 treated per year in T2D (observational).
- Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical TrialsMeta-analysis · 2022 · Study tier 1 · Different population · Harm direction
Biliary events higher with higher doses and longer use.