Why GLP-1s make sense beyond weight loss
GLP-1–based therapies (GLP-1 receptor agonists like semaglutide, liraglutide, dulaglutide; and dual GIP/GLP-1 agents like tirzepatide) may help beyond weight loss—what conditions they can treat today, where evidence is emerging, and what to expect long-term.
GLP-1 receptors live not just in the pancreas but also in the brain, heart, kidneys, liver, and vasculature. Activating them can improve insulin secretion (glucose-dependent), slow gastric emptying, reduce inflammation, improve endothelial function, and modify neurohormonal signaling that drives appetite, autonomic tone, and even reward pathways. Those pleiotropic effects help explain the benefits below.
Conditions with established or strong evidenceType 2 diabetes and cardiovascular disease (CVD).
Multiple large outcomes trials show GLP-1 RAs lower major adverse cardiovascular events (MACE) in people with T2D at high CV risk—e.g., liraglutide (LEADER), semaglutide (SUSTAIN-6), and dulaglutide (REWIND). Benefits include fewer CV deaths, nonfatal MI/stroke, with signal toward stroke reduction in particular. New England Journal of Medicine+1The Lancet
Cardiovascular prevention in people with obesity without diabetes.
SELECT showed once-weekly semaglutide reduced MACE in adults with established CVD and overweight/obesity, even when diabetes was absent, expanding GLP-1 use as a CV prevention drug. The FDA also added a Wegovy® indication to reduce risk of CV death, MI, and stroke. New England Journal of MedicineU.S. Food and Drug Administration
Chronic kidney disease (CKD).
The 2024 FLOW trial found semaglutide slowed eGFR decline and reduced a composite of kidney outcomes and CV death in patients with T2D and CKD, suggesting direct kidney protection beyond glycemia/weight. New England Journal of Medicinemediacenteratypon.nejmgroup-production.org
Heart failure with preserved EF (HFpEF) in obesity.
In STEP-HFpEF, semaglutide 2.4 mg improved symptoms, physical limitations, and exercise capacity over 1 year vs placebo—likely via weight loss plus anti-inflammatory and decongestive effects. New England Journal of Medicine+1
Obstructive sleep apnea (OSA) in adults with obesity.
Two phase 3 SURMOUNT-OSA trials showed tirzepatide reduced apnea–hypopnea index, hypoxic burden, hs-CRP, and BP; in Dec 2024 the FDA approved tirzepatide (Zepbound®) as the first drug for moderate–severe OSA in adults with obesity. mediacenteratypon.nejmgroup-production.orgU.S. Food and Drug Administration
Metabolic dysfunction–associated steatotic liver disease (MASLD/MASH, formerly NAFLD/NASH).
Semaglutide improved MASH resolution in a phase 2 biopsy-proven NASH trial (though fibrosis improvement was not significant), and tirzepatide (SYNERGY-NASH, 2024) achieved higher rates of MASH resolution and clinically meaningful fibrosis responses at 52 weeks. Larger/longer studies are ongoing. New England Journal of Medicine+1
Conditions with emerging or investigational evidence:
Addiction biology (alcohol, nicotine).
A 2025 randomized trial in adults with alcohol use disorder found weekly semaglutide reduced drinking and craving over 9 weeks; prior mechanistic work and small RCTs with related incretins show dampened reward-cue reactivity. Promising, but early and off-label. JAMA NetworkPMC
Cognitive outcomes/dementia risk.
Recent observational syntheses suggest GLP-1 RAs may be associated with lower dementia risk in people with diabetes/obesity; causality is unproven and RCTs are needed. Treat as hypothesis-generating for now. PMCJAMA Network
Polycystic ovary syndrome (PCOS).
Meta-analyses indicate GLP-1 RAs (often added to metformin/lifestyle) improve weight and insulin resistance and may aid menstrual/metabolic parameters in PCOS; long-term reproductive outcomes remain under study. BioMed CentralNature
Durable cardiometabolic risk reduction.
CV benefits are now shown across diabetes and obesity populations; kidney protection is supported by FLOW. These effects likely reflect both weight loss and direct organ-level actions. New England Journal of Medicine+1The Lancet
Renal trajectory slowing.
Expect a modestly slower eGFR decline and fewer kidney events with semaglutide in T2D+CKD. New England Journal of Medicine
Symptom and function gains in obesity-related HFpEF and OSA.
Improvements track with weight loss but include reductions in inflammation and congestion/sleep-disordered breathing burden. New England Journal of Medicinemediacenteratypon.nejmgroup-production.org
Liver histology improvement is plausible but not yet “proven” to reverse fibrosis broadly.
Semaglutide resolves steatohepatitis more than placebo; tirzepatide shows stronger biopsy responses at 1 year—confirmation with longer outcomes is in progress. New England Journal of Medicine+1
Safety, monitoring, and who should avoid them
Common adverse effects are GI (nausea, fullness, constipation/diarrhea). Class-wide, there’s a small but real increase in gallbladder/biliary disease risk—higher with larger doses, longer duration, and rapid weight loss—so monitor biliary symptoms. JAMA Network
Eyes: In SUSTAIN-6, semaglutide had a signal for early worsening of diabetic retinopathy (likely from rapid A1c drops), so people with pre-existing DR should get baseline and follow-up eye exams; a 2024 cohort also linked GLP-1 use with rare NAION—absolute risk is low but new vision symptoms warrant urgent evaluation. PubMedJAMA Network
Standard contraindications still apply (e.g., personal/family history of medullary thyroid carcinoma or MEN2 for GLP-1 RAs). Pancreatitis risk remains debated; avoid in active pancreatitis and use caution with history.
Practical takeaways:
Conditions with established or strong evidenceType 2 diabetes and cardiovascular disease (CVD).
Multiple large outcomes trials show GLP-1 RAs lower major adverse cardiovascular events (MACE) in people with T2D at high CV risk—e.g., liraglutide (LEADER), semaglutide (SUSTAIN-6), and dulaglutide (REWIND). Benefits include fewer CV deaths, nonfatal MI/stroke, with signal toward stroke reduction in particular. New England Journal of Medicine+1The Lancet
Cardiovascular prevention in people with obesity without diabetes.
SELECT showed once-weekly semaglutide reduced MACE in adults with established CVD and overweight/obesity, even when diabetes was absent, expanding GLP-1 use as a CV prevention drug. The FDA also added a Wegovy® indication to reduce risk of CV death, MI, and stroke. New England Journal of MedicineU.S. Food and Drug Administration
Chronic kidney disease (CKD).
The 2024 FLOW trial found semaglutide slowed eGFR decline and reduced a composite of kidney outcomes and CV death in patients with T2D and CKD, suggesting direct kidney protection beyond glycemia/weight. New England Journal of Medicinemediacenteratypon.nejmgroup-production.org
Heart failure with preserved EF (HFpEF) in obesity.
In STEP-HFpEF, semaglutide 2.4 mg improved symptoms, physical limitations, and exercise capacity over 1 year vs placebo—likely via weight loss plus anti-inflammatory and decongestive effects. New England Journal of Medicine+1
Obstructive sleep apnea (OSA) in adults with obesity.
Two phase 3 SURMOUNT-OSA trials showed tirzepatide reduced apnea–hypopnea index, hypoxic burden, hs-CRP, and BP; in Dec 2024 the FDA approved tirzepatide (Zepbound®) as the first drug for moderate–severe OSA in adults with obesity. mediacenteratypon.nejmgroup-production.orgU.S. Food and Drug Administration
Metabolic dysfunction–associated steatotic liver disease (MASLD/MASH, formerly NAFLD/NASH).
Semaglutide improved MASH resolution in a phase 2 biopsy-proven NASH trial (though fibrosis improvement was not significant), and tirzepatide (SYNERGY-NASH, 2024) achieved higher rates of MASH resolution and clinically meaningful fibrosis responses at 52 weeks. Larger/longer studies are ongoing. New England Journal of Medicine+1
Conditions with emerging or investigational evidence:
Addiction biology (alcohol, nicotine).
A 2025 randomized trial in adults with alcohol use disorder found weekly semaglutide reduced drinking and craving over 9 weeks; prior mechanistic work and small RCTs with related incretins show dampened reward-cue reactivity. Promising, but early and off-label. JAMA NetworkPMC
Cognitive outcomes/dementia risk.
Recent observational syntheses suggest GLP-1 RAs may be associated with lower dementia risk in people with diabetes/obesity; causality is unproven and RCTs are needed. Treat as hypothesis-generating for now. PMCJAMA Network
Polycystic ovary syndrome (PCOS).
Meta-analyses indicate GLP-1 RAs (often added to metformin/lifestyle) improve weight and insulin resistance and may aid menstrual/metabolic parameters in PCOS; long-term reproductive outcomes remain under study. BioMed CentralNature
- Long-term effects and benefits to expect
Durable cardiometabolic risk reduction.
CV benefits are now shown across diabetes and obesity populations; kidney protection is supported by FLOW. These effects likely reflect both weight loss and direct organ-level actions. New England Journal of Medicine+1The Lancet
Renal trajectory slowing.
Expect a modestly slower eGFR decline and fewer kidney events with semaglutide in T2D+CKD. New England Journal of Medicine
Symptom and function gains in obesity-related HFpEF and OSA.
Improvements track with weight loss but include reductions in inflammation and congestion/sleep-disordered breathing burden. New England Journal of Medicinemediacenteratypon.nejmgroup-production.org
Liver histology improvement is plausible but not yet “proven” to reverse fibrosis broadly.
Semaglutide resolves steatohepatitis more than placebo; tirzepatide shows stronger biopsy responses at 1 year—confirmation with longer outcomes is in progress. New England Journal of Medicine+1
Safety, monitoring, and who should avoid them
Common adverse effects are GI (nausea, fullness, constipation/diarrhea). Class-wide, there’s a small but real increase in gallbladder/biliary disease risk—higher with larger doses, longer duration, and rapid weight loss—so monitor biliary symptoms. JAMA Network
Eyes: In SUSTAIN-6, semaglutide had a signal for early worsening of diabetic retinopathy (likely from rapid A1c drops), so people with pre-existing DR should get baseline and follow-up eye exams; a 2024 cohort also linked GLP-1 use with rare NAION—absolute risk is low but new vision symptoms warrant urgent evaluation. PubMedJAMA Network
Standard contraindications still apply (e.g., personal/family history of medullary thyroid carcinoma or MEN2 for GLP-1 RAs). Pancreatitis risk remains debated; avoid in active pancreatitis and use caution with history.
Practical takeaways:
- Today, GLP-1–based therapies are more than “weight-loss shots.” They are cardiometabolic risk–modifying drugs with evidence for CV event reduction, kidney protection, HFpEF symptom improvement, OSA treatment (tirzepatide), and steatotic liver disease activity reduction. U.S. Food and Drug Administration+1New England Journal of Medicine+2New England Journal of Medicine+2
- Emerging areas (addiction, cognition, PCOS) are promising but should be considered investigational/off-label until larger, longer RCTs confirm benefit. JAMA NetworkPMC
- Long-term use can confer sustained risk reduction when tolerated, but monitor gallbladder and ocular risks, especially during rapid glycemic improvement or major weight loss. JAMA NetworkPubMed