Semaglutide Latest Research: New Indications, Trials & What’s Coming

Introduction

The original semaglutide trials targeted type 2 diabetes (SUSTAIN program) and weight loss (STEP program). Since 2023, the evidence base has expanded into cardiovascular disease (SELECT), kidney disease (FLOW), heart failure (STEP-HFpEF), liver disease (ESSENCE for MASH), addiction, and neurodegenerative disease. The drug has gone from a glucose and weight medication to a broad cardiometabolic platform.

The pipeline is also active. Higher-dose semaglutide, oral semaglutide for non-diabetes indications, combination drugs (CagriSema), and longer-acting variants are all in late-stage development. Real-world data from millions of patient-years are filling in the safety profile.

This article walks through the major recent trials, what they show, and what’s coming next. It also covers the controversies around suicidality signals, retinopathy progression, anesthesia complications, and the limits of current evidence.

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What Did SELECT Show for Cardiovascular Disease?

The SELECT trial (Lincoff et al. 2023, NEJM) enrolled 17,604 adults aged 45 or older with overweight or obesity (BMI 27+) and established cardiovascular disease but no diabetes. Patients were randomized to semaglutide 2.4 mg weekly or placebo and followed for a mean of 39.8 months.

Quick Answer: SELECT (Lincoff et al. 2023, NEJM): 20% MACE reduction in cardiovascular disease + obesity

The primary endpoint, a composite of cardiovascular death, nonfatal MI, and nonfatal stroke, was reduced by 20% on semaglutide vs placebo (6.5% vs 8.0%, hazard ratio 0.80). The benefit appeared within 6 to 12 months, well before maximum weight loss, suggesting non-weight-mediated mechanisms.

Secondary endpoints also improved: cardiovascular death dropped 15%, nonfatal MI dropped 28%, and heart failure events dropped 18%. Average weight loss was 9.4%. The FDA approved a new indication based on SELECT in March 2024: cardiovascular risk reduction in adults with established CVD and overweight or obesity.

What Did FLOW Show for Kidney Disease?

The FLOW trial (Perkovic et al. 2024, NEJM) enrolled 3,533 adults with type 2 diabetes and chronic kidney disease (eGFR 25 to 75 with albuminuria). Patients received semaglutide 1.0 mg weekly or placebo for a median 3.4 years. The trial stopped early for efficacy.

The primary composite endpoint (kidney failure, sustained 50% eGFR drop, kidney death, or cardiovascular death) was reduced 24% on semaglutide. The number needed to treat over 3 years was about 20 patients to prevent one major kidney or CV event.

Individual components also improved: kidney-specific events dropped 21%, cardiovascular events dropped 18%. The FDA approved a kidney protection indication for semaglutide in January 2025. The kidney benefit appeared partially independent of glucose lowering and weight change in adjusted analyses.

What’s the Heart Failure Evidence?

STEP-HFpEF (Kosiborod et al. 2023, NEJM) enrolled 529 patients with obesity-related heart failure with preserved ejection fraction. Semaglutide 2.4 mg weekly improved the Kansas City Cardiomyopathy Questionnaire symptom score by 7.8 points more than placebo and increased six-minute walk distance by 21 meters.

STEP-HFpEF DM (Kosiborod et al. 2024, NEJM) extended the finding to patients with HFpEF, obesity, and type 2 diabetes. Symptom improvements were similar to the non-diabetic cohort. NT-proBNP, a marker of cardiac stress, dropped significantly.

These results changed how cardiologists approach HFpEF, which has been a difficult condition to treat. Semaglutide is now in HFpEF treatment algorithms alongside SGLT2 inhibitors. The mechanism appears to involve direct cardiac effects beyond weight loss.

What About Liver Disease Research?

ESSENCE is the phase 3 trial of semaglutide for metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH). Interim data presented at the 2024 AASLD meeting showed significant resolution of steatohepatitis without worsening fibrosis in 36.8% of patients on semaglutide 2.4 mg vs 22.4% on placebo at 72 weeks.

Newsome et al. 2021 (NEJM) was the phase 2 trial that set up ESSENCE. Semaglutide 0.4 mg daily produced NASH resolution in 59% of patients vs 17% on placebo at 72 weeks. The phase 3 data confirmed but tempered these earlier findings.

Resmetirom (Rezdiffra®), a thyroid hormone receptor beta agonist, was the first FDA-approved drug for MASH (March 2024) based on MAESTRO-NASH (NEJM 2024). Semaglutide is expected to seek MASH approval in 2026 based on ESSENCE data, providing another option for this condition.

What’s the Addiction Research Showing?

Multiple observational studies in 2024 and 2025 have linked semaglutide to reduced alcohol and opioid use. A 2024 JAMA Psychiatry analysis of 800,000+ patients with alcohol use disorder showed semaglutide users had 50% fewer alcohol-related hospitalizations than matched controls. The mechanism likely involves dampened reward signaling in the brain.

Wang et al. 2024 (Nature) found similar reductions in opioid-related hospitalizations among semaglutide users with opioid use disorder. Cocaine and tobacco use disorder also showed signal reduction in retrospective analyses.

Randomized trials are underway. The first phase 2 RCT of semaglutide for alcohol use disorder reported preliminary results in 2025 showing reduced cravings and drinking days. Larger phase 3 trials are planned.

What About Neurodegenerative Disease?

EVOKE and EVOKE+ are phase 3 trials of oral semaglutide for early Alzheimer’s disease, enrolling 3,500+ patients. The trials read out in 2026 with mixed results. Semaglutide did not significantly slow cognitive decline on the primary endpoint, but secondary outcomes including biomarker changes showed signals worth following up.

The hypothesis is that GLP-1 signaling reduces neuroinflammation and improves brain insulin sensitivity. Mechanistic data are promising but the clinical translation has been harder than initial hopes suggested.

Parkinson’s disease trials of exenatide (an earlier GLP-1 drug) have shown more consistent signals, including the Exenatide-PD3 trial. Whether semaglutide has similar effects in PD is being studied in ongoing trials.

What Did the Suicidality Signal Turn Out to Be?

In 2023, the European Medicines Agency announced an investigation into reports of suicidal thoughts in semaglutide users. The signal came from FDA Adverse Event Reporting System data showing higher rates of suicidal ideation in GLP-1 users than expected.

Subsequent large-scale analyses largely cleared the drug. Wang et al. 2024 (Nature Medicine) studied 240,000+ semaglutide users vs matched controls and found a lower rate of suicidal ideation in the semaglutide group. The original AERS signal was attributed to reporting bias and confounding.

The FDA labeling carries general mental health monitoring guidance but no specific suicidality warning beyond standard psychiatric medication monitoring. Patients with prior suicide attempts or active depression should be monitored closely on any chronic medication.

What About the Retinopathy Issue?

SUSTAIN 6 (Marso et al. 2016, NEJM) showed a higher rate of diabetic retinopathy complications on semaglutide (3.0% vs 1.8% placebo) in patients with type 2 diabetes. The signal was attributed to the rapid glucose lowering rather than the drug itself, since fast glycemic control has been associated with transient retinopathy worsening since the DCCT trial.

Subsequent trials including SELECT and FLOW did not show clinically meaningful retinopathy concerns. The current FDA labeling recommends baseline eye exams and monitoring for diabetic patients with established retinopathy.

For non-diabetic patients on Wegovy®, retinopathy isn’t a meaningful concern. Eye exam recommendations are based on diabetes status, not semaglutide treatment.

What’s the Anesthesia Concern?

In 2023, the American Society of Anesthesiologists issued guidance recommending holding GLP-1 drugs for at least one week before elective surgery due to delayed gastric emptying and aspiration risk. The recommendation was based on case reports of food in the stomach during anesthesia in patients who had fasted appropriately.

A 2024 prospective study (Sherwin et al., Anesthesiology) found that 56% of patients on GLP-1 drugs had retained gastric contents after standard 8-hour fasting, compared to 8% of controls. Subsequent guidance has clarified specific holding periods and screening tools.

For emergency surgery, anesthesia teams treat GLP-1 patients as full-stomach regardless of fasting time, using rapid sequence induction. This adds complexity but is generally manageable.

Key Takeaway: STEP-HFpEF (Kosiborod et al. 2023, NEJM): symptom improvement in HFpEF + obesity

What’s Next in the Pipeline?

CagriSema combines cagrilintide (a long-acting amylin analog) with semaglutide. The phase 3 REDEFINE trials reported in late 2024. REDEFINE 1 showed 22.7% weight loss at 68 weeks vs 16% on semaglutide alone, though somewhat below expectations. Phase 3b trials are ongoing.

Higher-dose oral semaglutide (25 mg and 50 mg daily) is in development for weight loss. The OASIS 1 trial showed 15.1% weight loss at 68 weeks on oral 50 mg, comparable to injectable Wegovy. FDA approval is anticipated in 2026.

Other late-stage GLP-1 drugs include retatrutide (triple agonist GLP-1/GIP/glucagon) showing 24% weight loss in phase 2, mazdutide (GLP-1/glucagon), and survodutide. The field is moving toward multi-receptor agonists for greater efficacy.

What About Real-world Long-term Data?

Large database studies through 2025 have followed 3+ million GLP-1 users for up to 8 years. Key findings:

• No emerging long-term safety signals beyond those already known
• Cardiovascular and kidney benefits replicate in observational data
• Discontinuation rates of about 30 to 40% within first year, mostly driven by side effects, insurance, or cost
• About two-thirds of weight regain within 12 months of discontinuation
• Patients who stay on the drug 5+ years tend to maintain their loss

The 30 to 40% first-year discontinuation rate is a major real-world concern. Cost, side effects, and insurance barriers each contribute roughly equally. The drug’s full benefit requires sustained use.

What’s the Mortality Data?

SELECT showed a non-significant trend toward lower all-cause mortality (4.3% on semaglutide vs 5.2% placebo) over 3.3 years. The trial was not powered for total mortality, so the finding is suggestive rather than conclusive.

The FLOW trial showed lower all-cause mortality on semaglutide (5.7% vs 8.7% placebo), reaching statistical significance. The 3.0 percentage point absolute reduction over 3.4 years translates to a number-needed-to-treat of about 33 to prevent one death.

Population-level observational analyses suggest semaglutide users have lower all-cause and cardiovascular mortality than matched controls. The strength of evidence varies by source, but the direction is consistent.

What About Combination Therapy Research?

CagriSema combines cagrilintide (a long-acting amylin analog) with semaglutide in a single weekly injection. The phase 3 REDEFINE-1 trial reported in late 2024. Cagrilintide adds amylin receptor activation to GLP-1, producing additional appetite suppression and satiety effects.

REDEFINE-1 showed 22.7% weight loss at 68 weeks on CagriSema vs 16.1% on semaglutide alone and 11.8% on cagrilintide alone. The result was below initial market expectations but still represents the largest weight loss seen with semaglutide-based therapy.

Side effects on CagriSema are similar to semaglutide alone, with slightly higher rates of nausea and constipation. The combination is expected to seek FDA approval in 2026.

REDEFINE-2 studied CagriSema in patients with type 2 diabetes. Weight loss was somewhat less pronounced but HbA1c reductions were larger than semaglutide monotherapy. The diabetes label would be a separate filing.

What’s the Broader Policy and Access Landscape?

Medicare coverage of GLP-1 drugs for obesity remains the largest policy question. The Treat and Reduce Obesity Act has been introduced multiple times in Congress to allow Medicare to cover weight loss drugs but has not passed as of 2026.

CMS has expanded coverage through other indication pathways: cardiovascular risk reduction (post-SELECT), kidney protection (post-FLOW), and obstructive sleep apnea (tirzepatide post-SURMOUNT-OSA). Each new approved indication creates a coverage route for previously excluded patients.

State Medicaid coverage of GLP-1 drugs for obesity grew from 8 states in 2022 to 13 states by 2026. Coverage expansions tend to follow strong outcomes data and clinical guideline updates from organizations like the American Diabetes Association and the American Heart Association.

What’s the Impact on Related Industries?

The rapid growth of GLP-1 use has affected adjacent industries. Bariatric surgery volumes have dropped 25 to 35% since 2022 in some health systems. Weight loss program enrollments have shifted from behavioral-only to pharmacotherapy-supported approaches.

Consumer packaged food companies have reported changes in spending patterns from patients on GLP-1 drugs, with reduced snack and beverage purchases. The economic impact on these industries is being watched closely by investors and policy researchers.

Pharma pipeline investment in obesity has accelerated. More than 80 obesity drugs are in clinical development as of 2026, compared to about 20 in 2020. The space has become highly competitive, with new mechanisms (GLP-1/GIP/glucagon triple agonists, oral peptides, gene therapy approaches) emerging.

What About Long-term Cognitive and Quality of Life Data?

STEP 1 and SELECT included quality of life measures alongside primary endpoints. Patients on semaglutide reported improvements in physical functioning, body image, and weight-related quality of life. Effects on overall mental health were positive on average but with individual variation.

Some patients report mood lift during weight loss, attributed to improved physical capacity and self-image. Others report low mood, sometimes early in treatment. The patterns aren’t fully predictable and warrant ongoing monitoring.

Cognitive outcomes from EVOKE in Alzheimer’s were not as positive as hoped, but subgroup analyses suggested possible benefit in earlier disease stages. Whether semaglutide has any cognitive protective effects in healthy adults remains uncertain.

Bottom line: CagriSema: cagrilintide plus semaglutide, phase 3 obesity data showing 22.7% loss

FAQ

Will Semaglutide Be Approved for Alzheimer’s Disease?

The EVOKE phase 3 trials did not meet the primary endpoint, so a primary Alzheimer’s indication seems unlikely from the current data. Secondary findings and biomarker changes leave some opening for further study, particularly in earlier disease stages.

What’s the Timeline for CagriSema Approval?

Novo Nordisk planned to file for FDA approval in 2025 or 2026 based on the REDEFINE trial data. The drug would be a first-in-class combination of two long-acting peptides. Approval would likely follow within 12 to 18 months of filing.

Is Oral Semaglutide Going to Replace Injections?

Probably not entirely. Oral semaglutide requires precise dosing on empty stomach with limited water. The injection is more convenient for once-weekly use. Oral may capture patients who refuse injections, but injections will likely remain the dominant formulation for weight loss.

What’s the Strongest Evidence Base Now?

Cardiovascular disease (SELECT) has the largest patient population and longest follow-up. Kidney disease (FLOW) has similar strength. Weight loss (STEP program) and diabetes (SUSTAIN program) have the longest history. Other indications (addiction, NASH, HFpEF) have growing but less mature evidence.

How Does the Research Apply to Compounded Semaglutide?

The active molecule in compounded semaglutide is identical to brand. The mechanistic findings from research apply directly. The regulatory pathway is different, which is why compounded is sold under personalized prescription rather than FDA-approved indication.

What About Pediatric Long-term Data?

STEP TEENS (Weghuber et al. 2022, NEJM) showed 16.1% weight loss in adolescents at 68 weeks. Long-term follow-up data on adolescents continuing semaglutide are limited. Long-term safety and developmental outcomes are being tracked through ongoing registry studies.

Will Newer Drugs Replace Semaglutide?

Possibly for some patients. Retatrutide and other triple agonists may produce larger weight loss than semaglutide. Tirzepatide already does. Whether the newer drugs offer better cardiovascular or kidney outcomes is unknown until their outcomes trials read out. Semaglutide will likely remain a major drug for years to come given its strong outcomes data.

Disclaimer: This content is for informational purposes only and does not constitute medical advice. It is not intended to diagnose, treat, cure, or prevent any disease or condition. Individual results may vary. Always consult a qualified healthcare professional before starting any weight loss program or medication.