Clinical Context
Patients with type 2 diabetes face substantially elevated cardiovascular risk—the leading cause of morbidity and mortality in this population. For decades, diabetes medications were evaluated primarily on glucose-lowering efficacy, with cardiovascular effects largely unknown. Following safety concerns with some diabetes drugs, regulatory agencies began requiring cardiovascular outcome trials (CVOTs) to ensure new agents don’t increase cardiovascular risk.
SUSTAIN-6 was designed as a cardiovascular safety trial for semaglutide. Unlike superiority trials designed to prove benefit, non-inferiority CVOTs aim to demonstrate that a drug doesn’t increase cardiovascular events compared to placebo. SUSTAIN-6 exceeded its safety mandate by demonstrating not just non-inferiority but actual cardiovascular risk reduction—a finding that transformed understanding of GLP-1 RA benefits beyond glucose lowering.
This trial established semaglutide as a cardiovascular risk-reducing therapy for patients with type 2 diabetes and established cardiovascular disease or high cardiovascular risk. However, an unexpected finding—increased diabetic retinopathy complications—raised important safety questions requiring clinical interpretation and management.
PICO Summary
Population: Adults with type 2 diabetes (n=3,297), aged ≥50 years with established cardiovascular disease or chronic kidney disease, or aged ≥60 years with cardiovascular risk factors.
Intervention: Once-weekly subcutaneous semaglutide at 0.5 mg or 1.0 mg for a median of 104 weeks (2 years).
Comparison: Matching placebo administered weekly.
Outcome: Semaglutide reduced the primary composite cardiovascular endpoint (cardiovascular death, nonfatal MI, nonfatal stroke) by 26% (HR 0.74, 95% CI 0.58-0.95). Nonfatal stroke was reduced by 39%. However, diabetic retinopathy complications increased (HR 1.76, 95% CI 1.11-2.78). Gastrointestinal side effects were more common with semaglutide.
Clinical Pearls
1. First GLP-1 RA to Demonstrate Cardiovascular Benefit: SUSTAIN-6 was among the first trials to demonstrate that a GLP-1 RA reduces cardiovascular events. This shifted the paradigm from “cardiovascular safety” to “cardiovascular benefit,” establishing semaglutide as a disease-modifying therapy for patients with T2D and elevated cardiovascular risk.
2. Stroke Reduction Particularly Notable: The 39% reduction in nonfatal stroke represents the most robust individual component of the composite endpoint. Stroke prevention is clinically meaningful given the devastating disability that often follows. The mechanism may involve blood pressure reduction, anti-inflammatory effects, or direct vascular protection.
3. Retinopathy Finding Requires Context: The increased diabetic retinopathy complications (vitreous hemorrhage, need for photocoagulation or intravitreal injections) occurred primarily in patients with pre-existing retinopathy who experienced rapid glucose lowering. This mirrors the “early worsening” phenomenon seen with intensive insulin therapy. It reflects rapid HbA1c reduction in vulnerable retinas, not a direct toxic effect of semaglutide.
4. Benefits Outweigh Retinopathy Risk in Most Patients: The cardiovascular mortality and morbidity benefits substantially outweigh the retinopathy risk for most patients. However, this finding mandates ophthalmologic evaluation before and after initiating semaglutide in patients with existing retinopathy, and consideration of slower dose titration in high-risk eyes.
Practical Application
SUSTAIN-6 supports preferential use of semaglutide in patients with type 2 diabetes and established atherosclerotic cardiovascular disease (prior MI, stroke, peripheral vascular disease) or high cardiovascular risk. For these patients, semaglutide offers dual benefits: glycemic control plus cardiovascular risk reduction.
Before initiating semaglutide, assess retinopathy status through dilated fundoscopic examination or retinal imaging. For patients with moderate-severe non-proliferative or proliferative retinopathy, consider ophthalmology co-management, slower semaglutide titration, and close monitoring during the first year of therapy when glucose improvement is most rapid.
Don’t withhold semaglutide from patients with retinopathy who would benefit from cardiovascular protection—the absolute cardiovascular benefit generally exceeds retinopathy risk. Instead, implement appropriate monitoring and collaborate with ophthalmology for high-risk cases.
Broader Evidence Context
SUSTAIN-6 established semaglutide’s cardiovascular benefits, which were subsequently confirmed in the SELECT trial (non-diabetic obesity population) and contributed to guideline recommendations positioning GLP-1 RAs as preferred agents for patients with type 2 diabetes and cardiovascular disease. The FLOW trial extended benefits to kidney outcomes.
The retinopathy finding has been studied further: it appears specific to rapid glucose lowering in vulnerable eyes rather than a direct semaglutide effect. Other GLP-1 RAs have shown similar phenomena. Current guidance emphasizes ophthalmologic monitoring rather than semaglutide avoidance.
Study Limitations
The trial was designed primarily for cardiovascular safety (non-inferiority) rather than powered to demonstrate superiority for individual endpoints. The retinopathy finding may reflect rapid glucose improvement rather than a direct drug effect. The 2-year duration may not capture all long-term cardiovascular or retinal outcomes.
Bottom Line
Semaglutide reduces major adverse cardiovascular events by 26% in patients with type 2 diabetes at high cardiovascular risk, with particularly notable stroke reduction. The increased diabetic retinopathy complications reflect rapid glucose lowering in vulnerable eyes and mandate ophthalmologic evaluation, but should not preclude use in patients who would benefit from cardiovascular protection.
Source: Marso SP, et al. “Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.” New England Journal of Medicine, 2016;375(19):1834-1844. Read article
