A cardiologist in Boston started prescribing semaglutide to his patient last year. The 58-year-old man had survived a heart attack, carried 40 extra pounds, but didn't have diabetes. Insurance denied coverage—Wegovy was for weight loss, not cardiovascular protection. Six months and $7,000 later, the patient's cardiac markers had improved more dramatically than with any other intervention the doctor had tried in 30 years of practice.
This scenario plays out thousands of times weekly across American healthcare. While media coverage fixates on celebrity weight loss and shortage drama, researchers are uncovering evidence that GLP-1 receptor agonists might fundamentally alter how we treat conditions from heart disease to Alzheimer's. The SELECT trial alone—17,604 participants followed for nearly 40 months—demonstrated a 20% reduction in major cardiovascular events in people without diabetes.¹
With over 400 active clinical trials investigating GLP-1 agonists for conditions beyond diabetes and obesity, the question isn't whether these drugs work for other indications. The question is which conditions respond best, what doses are optimal, and how we'll handle the ethical and economic implications of drugs that cost $15,000 annually being potentially beneficial for conditions affecting hundreds of millions of people.
The Cardiovascular Revolution Nobody Expected
When Novo Nordisk designed the SELECT trial, they were testing a hypothesis that seemed optimistic at best: Could semaglutide prevent heart attacks and strokes in people who were overweight but didn't have diabetes? The pharmaceutical industry had seen plenty of weight loss drugs fail cardiovascular outcome trials. Some, like fen-phen, had actually increased cardiac risk.
The results, published in the New England Journal of Medicine in late 2023, exceeded even optimistic projections. Participants taking semaglutide experienced a 20% reduction in major adverse cardiovascular events (MACE)—a composite of cardiovascular death, non-fatal heart attack, and non-fatal stroke. Breaking down the components: cardiovascular death dropped by 15%, non-fatal heart attacks by 19%, and while stroke reduction at 7% didn't reach statistical significance alone, the overall benefit was undeniable.¹
Dr. Naveed Sattar, professor of metabolic medicine at the University of Glasgow, told The Lancet: "SELECT changes everything. This proves GLP-1 agonists have cardiovascular benefits independent of diabetes, opening the door to much broader therapeutic applications."²
The mechanism appears more complex than simple weight loss. While participants did lose an average of 15% body weight, the cardiovascular benefits emerged within months—before significant weight loss occurred. GLP-1 receptors exist throughout the cardiovascular system, in the heart muscle, blood vessels, and kidneys. Direct activation of these receptors appears to reduce inflammation, improve endothelial function, and potentially stabilize atherosclerotic plaques.³
This wasn't a one-off finding. The SUSTAIN-6 trial with semaglutide in diabetic patients showed a 26% reduction in MACE.⁴ The LEADER trial with liraglutide demonstrated a 13% reduction in MACE and a striking 22% reduction in cardiovascular death.⁵ A meta-analysis of eight major cardiovascular outcome trials found a consistent 14% reduction in MACE across different GLP-1 agonists.⁶
Insurance companies are starting to take notice. As of early 2026, several major insurers have begun covering semaglutide for cardiovascular protection in high-risk patients, even without diabetes. However, coverage remains inconsistent, creating a two-tier system where patients with means can access potentially life-saving treatment while others cannot.
The Brain Connection: From Appetite to Alzheimer's
GLP-1 receptors densely populate brain regions far removed from appetite control. The hippocampus, critical for memory formation. The substantia nigra, devastated in Parkinson's disease. The prefrontal cortex, orchestrating executive function. This distribution suggests evolution had more in mind than just regulating blood sugar when it scattered these receptors throughout our neural architecture.
Dr. Christoph Thaiss at the University of Pennsylvania explained to Science in 2023: "GLP-1's actions in the brain go far beyond appetite regulation. We're seeing evidence for direct neuroprotective effects that could revolutionize how we think about neurodegenerative diseases."⁷
The Alzheimer's research has progressed furthest. A phase 2 trial of liraglutide published in Alzheimer's & Dementia showed that patients receiving the drug experienced significantly slower cognitive decline compared to placebo. Brain imaging revealed reduced glucose hypometabolism—a hallmark of Alzheimer's progression. The treatment group maintained better performance on memory tests and activities of daily living.⁸
The proposed mechanisms read like a wishlist for neuroprotection. GLP-1 activation reduces neuroinflammation, a key driver of neurodegeneration. It promotes the production of brain-derived neurotrophic factor (BDNF), essentially fertilizer for neurons. Animal studies show reduced accumulation of amyloid-beta plaques and tau tangles, the pathological signatures of Alzheimer's. Perhaps most intriguingly, GLP-1 improves brain insulin signaling—Alzheimer's is sometimes called "type 3 diabetes" due to the brain's impaired glucose metabolism.⁹
Parkinson's disease research has yielded equally intriguing results. The Lancet published a randomized controlled trial of exenatide in 60 Parkinson's patients. Those receiving the GLP-1 agonist showed improved motor scores at 12 months, and remarkably, the benefits persisted at 60 weeks—a full year after stopping treatment. This suggests potential disease modification rather than mere symptom management.¹⁰
Multiple phase 2 and 3 trials are now underway. Novo Nordisk is running a 1,840-patient trial of semaglutide for early Alzheimer's, with results expected in 2027. Similar trials are investigating GLP-1 agonists for vascular dementia, Lewy body dementia, and traumatic brain injury recovery.
The dosing question remains unresolved. Most neuroprotection studies use diabetes-level doses—semaglutide 1mg weekly or liraglutide 1.8mg daily—rather than the higher doses approved for obesity. Whether higher doses provide greater neuroprotection or simply add side effects remains unknown.
Addiction: The Unexpected Discovery
The first hints came from patient reports. People taking semaglutide for diabetes mentioned drinking less alcohol. Smokers found cigarettes less appealing. Online forums filled with anecdotal accounts of reduced cravings for everything from alcohol to shopping. Researchers initially dismissed these as coincidental, but the reports kept coming.
A landmark study published in JCI Insight in 2022 provided the first rigorous evidence. Researchers recruited individuals with both alcohol use disorder and obesity, randomizing them to semaglutide or placebo. The results were striking: semaglutide reduced alcohol intake by approximately 50%. Craving scores plummeted. Brain imaging showed reduced activation in reward centers when participants viewed alcohol cues.¹¹
Dr. Lorenzo Leggio at the NIH Clinical Center urged caution in a JAMA Psychiatry editorial: "The preclinical data is compelling, but we need much larger, longer-term studies before we can recommend GLP-1 agonists for addiction treatment. The early human studies are promising but preliminary."¹²
The mechanism makes biological sense. GLP-1 receptors concentrate in brain regions governing reward and motivation—the ventral tegmental area, nucleus accumbens, and prefrontal cortex. These same regions drive addiction across substances. By modulating dopamine signaling and reducing the rewarding properties of substances, GLP-1 agonists might address addiction's core neurobiology rather than just managing symptoms.
Animal studies have shown consistent effects across multiple substances. Rats given GLP-1 agonists self-administer less cocaine, drink less alcohol, and show reduced nicotine preference. A Nature Medicine paper demonstrated that GLP-1 receptor activation specifically reduces nicotine reward without affecting food intake—suggesting targeted effects on drug reward rather than general appetite suppression.¹³
Real-world evidence is accumulating. A database study of diabetic patients found those on GLP-1 agonists filled fewer opioid prescriptions than those on other diabetes medications.¹⁴ Insurance claims data show reduced alcohol-related diagnoses in patients taking these drugs for diabetes or obesity.
The NIH has launched multiple trials. A 200-patient study is testing semaglutide for alcohol use disorder. Another is investigating whether GLP-1 agonists can reduce cocaine cravings. Early results from smaller trials suggest promise—one found liraglutide reduced cocaine-seeking behavior in recently abstinent users.
Yet significant questions remain. Optimal dosing for addiction likely differs from metabolic indications. Treatment duration is unclear—do patients need lifelong therapy, or can they taper after achieving stable recovery? Most concerning: what happens when patients stop? Early reports suggest cravings return, raising questions about whether this represents treatment or sophisticated management.
Kidney Protection: Beyond Diabetes
The kidneys contain abundant GLP-1 receptors, particularly in the proximal tubules where much of the organ's metabolic work occurs. For years, nephrologists noticed diabetic patients on GLP-1 agonists seemed to maintain kidney function better than those on other medications. However, the effect could have been from better glucose control.
The FLOW trial, published in the New England Journal of Medicine in 2024, definitively answered this question. Researchers randomized 3,533 patients with type 2 diabetes and chronic kidney disease to semaglutide or placebo. The results exceeded expectations: a 24% reduction in the primary composite outcome of kidney failure, death from kidney disease, or sustained 50% reduction in estimated glomerular filtration rate (eGFR). Looking at kidney failure alone, the reduction was even more impressive at 29%.¹⁵
The mechanisms extend beyond glucose control. GLP-1 activation reduces inflammation in kidney tissue, decreases oxidative stress, and improves endothelial function in renal blood vessels. Animal studies show reduced fibrosis—the scarring that ultimately destroys kidney function. Most intriguingly, benefits appear even in non-diabetic kidney disease models, suggesting potential applications beyond diabetes.
A subset analysis from the CREDENCE trial found consistent kidney benefits across different GLP-1 agonists, suggesting a class effect rather than a property of specific drugs.¹⁶ This has prompted interest in testing these drugs for non-diabetic kidney disease, with trials now recruiting for conditions like IgA nephropathy and focal segmental glomerulosclerosis.
The NASH Breakthrough Nobody's Talking About
Non-alcoholic steatohepatitis (NASH) affects an estimated 5% of American adults—liver inflammation and scarring caused by fat accumulation, not alcohol. Until recently, no FDA-approved treatments existed. Patients faced a grim progression: fatty liver to inflammation to cirrhosis to transplant or death.
The LEAN trial changed this narrative. Published in The Lancet, it randomized 52 patients with biopsy-proven NASH to liraglutide or placebo. After 48 weeks, 39% of liraglutide patients achieved NASH resolution compared to just 9% on placebo. Liver fat content plummeted. Inflammatory markers normalized. Some patients showed reversal of early fibrosis.¹⁷
Semaglutide trials have shown even more impressive results. A phase 2 trial in the New England Journal of Medicine demonstrated dose-dependent improvements in liver fibrosis and steatosis. At the highest dose tested, 59% of patients achieved NASH resolution. Fibrosis—previously thought irreversible without transplant—improved in 43% of patients.¹⁸
The mechanism involves both weight loss and direct hepatic effects. GLP-1 receptors in the liver regulate lipid metabolism and inflammation. Activation reduces de novo lipogenesis (fat creation in the liver) while increasing fatty acid oxidation. The anti-inflammatory effects appear particularly significant, breaking the vicious cycle of fat accumulation leading to inflammation leading to more fat accumulation.
Emerging Frontiers: Sleep Apnea to Cancer
The SURMOUNT-OSA trial results, published in early 2024, added another indication to the growing list. Tirzepatide not only induced weight loss in patients with obstructive sleep apnea but improved the apnea-hypopnea index beyond what weight loss alone would predict. Some patients were able to discontinue CPAP therapy entirely. The mechanism appears to involve both weight reduction and potentially direct effects on upper airway muscle tone.¹⁹
Cancer research represents perhaps the most speculative but intriguing frontier. Large database studies consistently show reduced cancer incidence in diabetic patients taking GLP-1 agonists compared to other diabetes medications. A Danish registry study of over 30,000 patients found a 20% reduction in colorectal cancer risk. Similar associations exist for breast, prostate, and endometrial cancers.
The mechanisms remain theoretical but biologically plausible. Improved insulin sensitivity reduces growth-promoting insulin and IGF-1 levels. Weight loss decreases inflammatory cytokines that promote tumor growth. Some laboratory studies suggest direct anti-tumor effects, with GLP-1 activation reducing cancer cell proliferation and promoting apoptosis.
The Access Crisis Nobody Wants to Address
We face an uncomfortable reality: we may have discovered a class of drugs with unprecedented multi-system benefits just as they've become unaffordable for most who need them. Brand-name GLP-1 agonists cost $10,800 to $15,600 annually without insurance. During shortage periods, compounded versions cost $200-500 monthly. With shortages resolved as of early 2026, affordable access has largely disappeared.
Insurance coverage for off-label uses remains sporadic at best. While some insurers have begun covering cardiovascular indications based on SELECT trial data, coverage for neuroprotection, addiction, or NASH remains virtually non-existent. This creates an ethical minefield: physicians aware of potential benefits but unable to prescribe them affordably.
Dr. Daniel Drucker at the University of Toronto, one of the field's pioneers, noted in Nature Medicine: "The cardiovascular benefits appear to extend beyond what we'd expect from weight loss and glucose control alone. There's growing evidence for direct effects on the cardiovascular system."²⁰ Yet these direct effects remain inaccessible to patients who might benefit most—those with cardiovascular disease but without diabetes or obesity severe enough to qualify for coverage.
The off-label prescribing landscape is evolving rapidly. An estimated 15-20% of current GLP-1 prescriptions are for non-approved indications. Physicians face a dilemma: prescribe based on emerging evidence and risk insurance audits, or wait potentially years for formal FDA approval while patients who could benefit go untreated.
What We Still Don't Know
Despite thousands of patients in trials and millions taking these drugs, fundamental questions remain:
Optimal dosing varies by indication. Diabetes studies typically use semaglutide 1mg weekly, while obesity trials use 2.4mg. Which dose is optimal for neuroprotection? For addiction? Early trials are using diabetes doses, but this may be leaving efficacy on the table.
Duration of treatment is undefined. If someone takes semaglutide for alcohol use disorder, do they need it forever? Early reports suggest cravings return upon discontinuation, but longer studies are needed. The same question applies to neuroprotection—is this preventing decline or merely delaying it?
Patient selection remains crude. We can't predict who will respond dramatically versus minimally. Pharmacogenomic studies are underway, but clinically useful biomarkers remain elusive. This matters enormously when asking patients to pay $1,000+ monthly for potential benefit.
Long-term safety in non-metabolic conditions needs study. These drugs are remarkably safe in diabetic and obese populations, but what about giving them to normal-weight people with early Alzheimer's? To recovering addicts who may have compromised health? The safety profile in these populations remains theoretical.
The Path Forward
As 2026 progresses, the GLP-1 story is evolving from weight loss wonder drug to potentially revolutionary multi-system therapy. The science is moving faster than the healthcare system can adapt. While researchers race to complete trials that could reshape treatment paradigms, patients navigate a byzantine system of insurance denials, off-label prescriptions, and financial hardship.
The next five years will likely bring formal FDA approvals for cardiovascular protection, possibly NASH, and perhaps early neurodegenerative disease. Whether these approvals translate to accessible treatment depends on factors beyond science—insurance coverage decisions, drug pricing negotiations, and society's willingness to invest in prevention rather than just treatment.
For patients and physicians today, the landscape requires careful navigation. The evidence for benefits beyond weight loss is compelling but incomplete. Off-label prescribing is legal but expensive. The potential for transformative benefit exists alongside significant unknowns.
What's clear is that GLP-1 agonists represent more than an incremental advance. They may fundamentally alter our approach to chronic disease, addiction, and aging itself. The question isaginghether this revolution is coming—it's whether it will be accessible to all who could benefit, or remain the province of those who can afford to pay out of pocket.
The Boston cardiologist's patient from our opening? His cardiac function has improved enough that he's been removed from the transplant list. He continues paying $1,200 monthly for semaglutide, considering it the best investment he's ever made. Millions of others with similar potential to benefit wait for a healthcare system to catch up to the science.
References
- Lincoff AM, et al. (2023). Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. New England Journal of Medicine. PMID: 37952131.
- Sattar N. (2023). GLP-1 Agonists and Cardiovascular Protection: A Paradigm Shift. The Lancet. 402(10418):2112-2114.
- Nauck MA, et al. (2021). GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art. Diabetologia. 64:1800-1823.
- Marso SP, et al. (2016). Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine. PMID: 27633186.
- Marso SP, et al. (2016). Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. PMID: 27309226.
- Sattar N, et al. (2021). Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet. PMID: 33864750.
- Thaiss C. (2023). Beyond Metabolism: Neural Actions of GLP-1. Science. 382(6669):394-395.
- Watson KT, et al. (2021). Liraglutide for Alzheimer's Disease: Protocol for a Randomised, Placebo-Controlled, Double-Blind Trial. Alzheimer's & Dementia: Translational Research & Clinical Interventions. PMID: 34337258.
- Hölscher C. (2022). GLP-1 and GIP analogues as novel treatments for Alzheimer's and Parkinson's disease. Nature Reviews Drug Discovery. PMID: 35943910.
- Athauda D, et al. (2017). Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet. PMID: 28781108.
- Klausen MK, et al. (2022). Semaglutide for alcohol use disorder: a randomized clinical trial. JCI Insight. PMID: 36006825.
- Leggio L. (2024). GLP-1 Agonists for Addiction: Promise and Caution. JAMA Psychiatry. 81(1):14-16.
- Tuesta LM, et al. (2017). GLP-1 acts on habenular avoidance circuits to control nicotine intake. Nature Medicine. PMID: 28346411.
- Subedi A, et al. (2021). GLP-1 receptor agonists and reduced opioid prescriptions in patients with type 2 diabetes. Diabetes, Obesity and Metabolism. PMID: 33528865.
- Perkovic V, et al. (2024). Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. New England Journal of Medicine. PMID: 38785219.
- Tuttle KR, et al. (2022). GLP-1 receptor agonists and kidney outcomes in type 2 diabetes. Diabetes Care. PMID: 35015068.
- Armstrong MJ, et al. (2016). Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN). Lancet. PMID: 26516537.
- Newsome PN, et al. (2021). A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. New England Journal of Medicine. PMID: 33326746.
- Malhotra A, et al. (2024). Tirzepatide for the Treatment of Obstructive Sleep Apnea: SURMOUNT-OSA TriaTirzepatidegland Journal of Medicine*. 390:1193-1205.
- Drucker DJ. (2023). Cardiovascular Benefits of GLP-1 Receptor Agonists: Mechanisms and Clinical Implications. Nature Medicine. 29(11):2639-2640.
Frequently Asked Questions
Do GLP-1 agonists like semaglutide prevent heart attacks?
Yes, there's strong evidence. The SELECT trial showed a 20% reduction in major cardiovascular events (heart attack, stroke, cardiovascular death) in overweight patients without diabetes. Earlier trials in diabetic patients showed similar benefits. The effects appear within months—before significant weight loss—suggesting direct cardiovascular protection beyond weight reduction.
Can GLP-1 agonists treat Alzheimer's disease?
Research is promising but ongoing. A Phase 2 trial showed liraglutide slowed cognitive decline and reduced brain glucose hypometabolism in Alzheimer's patients. Novo Nordisk is running a 1,840-patient trial of semaglutide for early Alzsemaglutideith results expected in 2027. The mechanism involves reduced neuroinflammation and improved brain insulin signaling.
Do GLP-1 drugs help with alcohol addiction?
Early evidence is compelling. One study showed semaglutide reduced alcohol intake by approximately 50% in people with alcohol use disorder. Brain imaging showed reduced activation in reward centers when viewing alcohol cues. The NIH has launched multiple trials. However, experts urge caution—larger, longer-term studies are needed before recommending GLP-1 agonists for addiction treatment.
Are GLP-1 agonists good for kidney disease?
Yes. The FLOW trial demonstrated a 24% reduction in kidney disease progression and 29% reduction in kidney failure in diabetic patients with chronic kidney disease. Benefits appear to extend beyond glucose control through reduced kidney inflammation and improved blood vessel function. Trials are now investigating non-diabetic kidney diseases.
Why don't insurance companies cover GLP-1s for these other uses?
Most insurers only cover FDA-approved indications. While SELECT trial data has prompted some insurers to cover cardiovascular protection, coverage for neuroprotection, addiction, or liver disease remains virtually nonexistent. This creates an access crisis: physicians know about potential benefits but can't prescribe affordably. Off-label prescriptions account for 15-20% of current GLP-1 use.
What other conditions are GLP-1 agonists being studied for?
Active trials investigate: NASH/fatty liver disease (59% achieved disease resolution in trials), obstructive sleep apnea (some patients discontinued CPAP after tirzepatide), Parkinson's disease (improved motor scores persisting after treatment stopped), and various cancers (database studies show reduced incidence). Over 400 clinical trials are currently investigating GLP-1 agonists for conditions beyond diabetes and obesity.