Long-Term Effects of Ozempic: SUSTAIN-6, Real-World Diabetes Outcomes, and the Open Questions

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> Reviewed by FormBlends Medical Team · Last updated May 2026 · 12 sources cited · Topic: extended-duration semaglutide in type 2 diabetes

Key Takeaways

• SUSTAIN-6 (Marso et al. NEJM 2016) anchors the long-term cardiovascular case for Ozempic in diabetes: 26% reduction in major adverse cardiovascular events over a median 2.1 years
• Multi-year glycemic effects show durable HbA1c reductions of ~1-2 percentage points in patients who continue therapy
• Renal benefits have been documented in pooled analyses and dedicated studies; retinopathy effects are nuanced and reflect a general phenomenon of rapid glucose improvement in patients with pre-existing eye disease
• Long-term side effects remain primarily GI, with rare events under continued pharmacovigilance
• Semaglutide was approved in 2017; multi-decade safety continues to be characterized as the longest cohorts mature

Direct answer

In type 2 diabetes patients, the most clearly established long-term effects of Ozempic are durable HbA1c reduction (~1-2 percentage points), reduced cardiovascular events (26% MACE reduction in SUSTAIN-6 over 2.1 years), modest sustained weight loss, and reduced progression of diabetes complications including renal disease. Long-term side effects are primarily GI tolerability concerns, with rare events including NAION, pancreatitis, gallstones, and the ongoing boxed warning about thyroid C-cell tumors under continued surveillance. Multi-decade safety profile is still being characterized.

Table of contents

1. Why the diabetes long-term picture is distinct from the obesity picture
2. SUSTAIN-6: the foundational cardiovascular outcome trial
3. Multi-year glycemic outcomes
4. Renal outcomes in long-term semaglutide use
5. Retinopathy and the early-worsening phenomenon
6. Weight and metabolic effects over time
7. Long-term side effects and tolerability
8. The remaining open questions
9. Decision framework for long-term Ozempic use
10. The contrary view: real-world vs trial outcomes
11. FAQ
12. Sources

Why the diabetes long-term picture is distinct from the obesity picture

Ozempic and Wegovy are the same molecule at different doses, used for different indications. The long-term evidence base differs in important ways.

Ozempic's long-term data center on diabetes outcomes: HbA1c control, cardiovascular events in diabetic patients, renal disease progression, and diabetes-related complications. The pivotal trials are the SUSTAIN program (1-10), particularly SUSTAIN-6 for cardiovascular outcomes.

Wegovy's long-term data center on weight management and cardiovascular outcomes in non-diabetic patients with obesity. The pivotal trials are the STEP program and SELECT.

Many long-term effects overlap because the molecule is the same. Others differ because the populations and dose ranges differ. The diabetes population trends older and sicker than the typical obesity-indication population, which affects how outcomes look in absolute and relative terms.

SUSTAIN-6: the foundational cardiovascular outcome trial

SUSTAIN-6 (Marso et al., NEJM 2016) was the cardiovascular outcomes trial that supported the inclusion of semaglutide on guideline-preferred lists for diabetic patients with high cardiovascular risk. It randomized 3,297 patients to semaglutide 0.5 mg or 1.0 mg weekly or matching placebo over a median follow-up of 2.1 years.

Primary endpoint (composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke):

• Semaglutide: 6.6% experienced the primary endpoint
• Placebo: 8.9%
• Hazard ratio: 0.74 (95% CI 0.58-0.95)
• Relative risk reduction: 26%

The cardiovascular benefit was driven primarily by reductions in nonfatal stroke and to a lesser extent nonfatal MI. Cardiovascular death was numerically lower but did not reach statistical significance individually.

Notable secondary findings: a small increase in retinopathy complications in patients with pre-existing retinopathy (an issue revisited below), and the standard GI tolerability profile that has remained consistent across the semaglutide development program.

Multi-year glycemic outcomes

The SUSTAIN program provided extensive HbA1c data across patient profiles and combination regimens. Across SUSTAIN 1-5 and 7-10, semaglutide consistently reduced HbA1c by 1-2 percentage points compared to placebo or comparator agents, with the largest effect in patients starting with higher baseline HbA1c.

Real-world data extending beyond trial follow-up have shown durable glycemic control in patients who continue therapy. Apparent loss of effect over time is more often related to weight regain, dose stability issues, or diabetes progression than to direct loss of pharmacologic activity. Dose escalation (from 0.5 mg to 1.0 mg, or to the 2.0 mg dose where available) restores effect in many patients.

The clinical implication is that semaglutide can be a durable component of multi-year diabetes management. The choice to continue is straightforward in most patients who are tolerating therapy and achieving glycemic targets.

Renal outcomes in long-term semaglutide use

Renal endpoints have favored semaglutide in several analyses. The SUSTAIN-6 prespecified secondary outcome of new or worsening nephropathy was significantly reduced. The FLOW trial (Perkovic et al. NEJM 2024) was a dedicated kidney outcome trial for semaglutide in patients with type 2 diabetes and chronic kidney disease; it reported a 24% reduction in the composite of kidney failure, substantial loss of kidney function, and kidney-related or cardiovascular death.

The renal benefit is consistent with the broader cardiometabolic effect of the medication. Blood pressure reduction, weight loss, glycemic improvement, and possibly direct effects on renal hemodynamics all contribute. The net result is that long-term semaglutide use is associated with reduced renal disease progression in diabetic patients with renal risk factors.

This has clinical importance because diabetic kidney disease is the leading cause of end-stage renal disease in the United States. A medication that meaningfully reduces progression has long-horizon value.

Retinopathy and the early-worsening phenomenon

SUSTAIN-6 reported a small but statistically significant increase in retinopathy complications in patients with pre-existing diabetic retinopathy. This finding initially attracted concern but was subsequently understood in the context of the broader "early worsening" phenomenon: any aggressive glycemic improvement in patients with established retinopathy can transiently worsen the eye disease.

This is not a semaglutide-specific effect. It was first documented with insulin intensification in the DCCT trial in type 1 diabetes and has been observed across multiple intensive-glucose-lowering therapies. The mechanism involves microvascular adaptation to lower glucose levels.

Clinical implications:

• Patients with established retinopathy benefit from ophthalmology evaluation before starting or shortly after starting semaglutide
• Slower titration may reduce early-worsening risk
• Retinal monitoring at 3, 6, and 12 months in patients with retinopathy is appropriate
• After the glycemic transition, longer-term semaglutide use is associated with overall reduction in microvascular complications

The recent NAION signal (Hathaway et al. JAMA Ophthalmology 2024) is a separate concern about a different eye condition; details are covered in a dedicated FormBlends article.

Weight and metabolic effects over time

At the Ozempic doses used in diabetes (0.5 mg, 1.0 mg, and 2.0 mg weekly), patients typically lose 4-7 kg over the first year, with maintenance thereafter. This is less weight loss than seen with Wegovy at 2.4 mg, which is the obesity indication dose.

Even modest weight loss in diabetic patients contributes meaningfully to glycemic and cardiometabolic outcomes. The combination of weight loss with direct GLP-1 effects on insulin secretion, glucagon suppression, and gastric emptying produces metabolic benefits beyond what weight loss alone would achieve.

Metabolic effects sustained over multi-year therapy include reduced blood pressure (typically 3-6 mmHg systolic), improved lipid profile (reduced triglycerides, modest improvements in HDL), and reduced inflammatory markers.

Long-term side effects and tolerability

The most common long-term side effects continue to be GI: nausea, diarrhea, constipation, and occasional vomiting. In most patients, these attenuate after the first 3-6 months. In a subset, they persist or recur during dose escalation.

Less common but documented:

• Gallstones, especially during periods of rapid weight loss
• Acute pancreatitis (uncommon)
• Hypoglycemia (mainly when combined with insulin or sulfonylureas)
• Cosmetic facial volume loss with significant weight reduction
• Hair shedding during rapid weight loss

Rare events under continued surveillance:

• NAION (recent association from 2024 JAMA Ophthalmology paper)
• Thyroid cancer (boxed warning based on rodent data; human evidence has not confirmed a measurable signal at population scale)
• Pancreatic cancer (early signal not confirmed in subsequent studies)

The boxed warning and contraindications (MTC, MEN-2) apply across all durations of therapy.

The remaining open questions

Multi-decade questions that the current evidence base cannot fully answer:

• Long-latency cancer risk profile beyond 10 years of continuous use
• Bone density and fracture risk in patients on therapy for many years
• Sarcopenia and muscle aging in older diabetic patients on long-term therapy
• Cognitive trajectory in elderly diabetic patients on extended therapy
• Outcomes after eventual discontinuation in patients who have been on the drug for decades
• Effects in pregnancy in patients who conceive after long use (medication is contraindicated during pregnancy)

The first cohorts to provide answers to some of these questions are reaching 8-10 years of continuous exposure now. Data publication will follow over the coming years.

Decision framework for long-term Ozempic use

Patients most likely to benefit from sustained therapy:

• Type 2 diabetes with cardiovascular disease (SUSTAIN-6 population)
• Type 2 diabetes with chronic kidney disease (FLOW population)
• Type 2 diabetes with high cardiometabolic risk factors
• Patients tolerating therapy well and achieving glycemic targets

Considerations during long-term therapy:

• Annual review of risk-benefit with your prescriber
• Maintenance of routine diabetes monitoring (HbA1c, blood pressure, lipids, renal function)
• Eye care including baseline and periodic retinopathy evaluation
• Awareness of thyroid symptoms; maintenance of MTC/MEN-2 contraindications
• Adequate protein intake and resistance training, especially in older patients

Reasons to reassess:

• Persistent severe side effects
• Development of new contraindication
• Pregnancy planning
• Apparent loss of glycemic effect that does not respond to dose adjustment

The contrary view: real-world vs trial outcomes

Trial outcomes set the expectation for what a medication can achieve. Real-world outcomes show what it does achieve in routine practice. The gap between the two is sometimes meaningful.

Real-world long-term experience with Ozempic in diabetes has been broadly consistent with trial findings on glycemic and cardiovascular outcomes, with some texture worth noting:

Adherence is lower than in trials. Many patients discontinue within 1-2 years due to side effects, cost, or other reasons. Discontinuers lose benefit. Persistent users tend to do well.

Dose titration in real practice is often slower or incomplete compared to trials. Some patients are maintained at sub-target doses for tolerability reasons. This dilutes effectiveness on average.

Pre-specified comparator conditions in trials are different from comparator conditions in practice. Trial patients receive intensive overall diabetes care. Real-world patients may have less intensive background care.

None of this means the medication does not work long-term. It means the average real-world patient should expect outcomes somewhere between the trial average and what their personal adherence and dose tolerance produce. The trial outcomes are achievable; they require adherence and appropriate titration.

FAQ

What are the long-term effects of Ozempic in diabetes?

Durable HbA1c reductions, 26% reduction in major cardiovascular events (SUSTAIN-6), reduced renal disease progression, and modest sustained weight loss.

Does Ozempic reduce cardiovascular events long-term in diabetes?

Yes. SUSTAIN-6 reported a 26% reduction in MACE over 2.1 years; real-world data largely support this.

What was the SUSTAIN-6 trial?

The cardiovascular outcomes trial for semaglutide in type 2 diabetes, enrolling 3,297 patients with cardiovascular risk.

Does Ozempic stop working after years of use?

For most patients, glycemic and weight effects are maintained. Apparent loss of effect is often related to weight regain or diabetes progression.

What long-term complications of diabetes does Ozempic reduce?

Cardiovascular events, renal disease progression, and overall mortality in cardiovascular-risk diabetic patients.

What are the long-term side effects of Ozempic in diabetes?

GI issues, gallstones, occasional pancreatitis, hypoglycemia when combined with insulin or sulfonylureas, and rare events under continued surveillance.

Is Ozempic safe to take for 10+ years?

Available data have not shown major safety concerns emerging in 8-9 years of continuous real-world use. Multi-decade safety is still being characterized.

Should I stay on Ozempic indefinitely if it is working?

For diabetes, ongoing therapy is typical because diabetes is chronic. Annual review of risk-benefit is appropriate.

What about retinopathy on long-term Ozempic?

Early-worsening risk exists for patients with pre-existing retinopathy during rapid glycemic improvement. Longer-term, microvascular outcomes generally improve.

How does long-term Ozempic compare to long-term Wegovy?

Same molecule, different doses, different populations. The cardiometabolic benefits overlap; the magnitude of weight loss differs.

Can I switch from Ozempic to another medication after years of use?

Yes, with planning. Glycemic deterioration and weight regain are likely without alternative therapy. Switching is appropriate when clinically indicated.

Related guides

• Long-Term Effects of Wegovy: A Honest Read of STEP 5, SELECT, and What We Don't Yet Know
• How Long Can Zepbound Be Unrefrigerated? Real-World Storage Limits
• Is Ozempic Safe Long-Term? The Honest Answer From the Current Evidence Base
• What to Eat on Ozempic: The Long-Term Dietary Framework
• How Long Can Ozempic Be Unrefrigerated? Cold-Chain Failures and Real Limits
• How Long Does Nausea Last with Ozempic? The Real Timeline

Sources

1. Marso SP et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (SUSTAIN-6). New England Journal of Medicine. 2016.
2. Perkovic V et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes (FLOW). New England Journal of Medicine. 2024.
3. Sorli C et al. Efficacy and Safety of Once-Weekly Semaglutide (SUSTAIN-1). The Lancet Diabetes & Endocrinology. 2017.
4. Ahrén B et al. Efficacy and Safety of Once-Weekly Semaglutide vs Sitagliptin (SUSTAIN-2). The Lancet Diabetes & Endocrinology. 2017.
5. Pratley RE et al. Semaglutide vs Dulaglutide Once Weekly in Patients with Type 2 Diabetes (SUSTAIN-7). The Lancet Diabetes & Endocrinology. 2018.
6. Lincoff AM et al. Semaglutide and Cardiovascular Outcomes in Obesity Without Diabetes (SELECT). New England Journal of Medicine. 2023.
7. American Diabetes Association. Standards of Care in Diabetes 2025.
8. Wang Y et al. Glucagon-Like Peptide-1 Receptor Agonist Use and Risk of Thyroid Cancer. JAMA. 2024.
9. Hathaway JT et al. Risk of Nonarteritic Anterior Ischemic Optic Neuropathy in Patients Prescribed Semaglutide. JAMA Ophthalmology. 2024.
10. Diabetes Control and Complications Trial Research Group. Early Worsening of Diabetic Retinopathy in the DCCT. Archives of Ophthalmology. 1998.
11. FDA. Ozempic Prescribing Information. 2024 update.
12. Bain SC et al. Worsening of Diabetic Retinopathy with Rapid Improvement in Systemic Glucose Control: A Review. Diabetes, Obesity and Metabolism. 2019.

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Platform Disclaimer. FormBlends is a telehealth platform connecting patients with independent licensed clinicians and U.S. pharmacies. We do not provide direct medical care. Long-term treatment decisions belong to you and your clinician.

Compounded Medication Notice. Compounded semaglutide is not FDA-approved. It is prepared by state-licensed 503A pharmacies in response to individual prescriptions. Compounded preparations are not interchangeable with branded Ozempic or Wegovy.

Results Disclaimer. Trial outcomes summarized here reflect average findings in defined populations. Individual response, adherence patterns, and concurrent care all affect real-world outcomes.

Trademark Notice. Ozempic and Wegovy are registered trademarks of Novo Nordisk A/S. Mounjaro and Zepbound are registered trademarks of Eli Lilly and Company. FormBlends has no affiliation with, endorsement from, or sponsorship by Novo Nordisk, Eli Lilly, the FDA, or any other entity referenced in this article.