New England Journal of Medicine November 10, 2016

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Steven P. Marso, Stephen C. Bain, Agostino Consoli, et al.

Bottom Line

In patients with type 2 diabetes at high cardiovascular risk, once-weekly subcutaneous semaglutide significantly reduced the risk of major adverse cardiovascular events compared to placebo, an effect primarily driven by a reduction in nonfatal stroke.

Key Findings

1. Semaglutide significantly reduced the primary composite outcome of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), which occurred in 6.6% (108/1,648) of patients in the semaglutide group versus 8.9% (146/1,649) in the placebo group (HR 0.74; 95% CI, 0.58-0.95; P<0.001 for noninferiority) [2.1.4].

2. The reduction in the primary outcome was largely driven by a significant decrease in nonfatal stroke (1.6% vs. 2.7%; HR 0.61; 95% CI, 0.38-0.99; P=0.04).

3. Rates of nonfatal myocardial infarction were nominally reduced but not statistically significant (2.9% vs. 3.9%; HR 0.74; 95% CI, 0.51-1.08; P=0.12).

4. There was no significant difference in the rate of cardiovascular death between the semaglutide and placebo groups (2.7% vs. 2.8%; HR 0.98; 95% CI, 0.65-1.48).

5. Rates of new or worsening nephropathy were significantly lower in the semaglutide group (3.8% vs. 6.1%; HR 0.64; 95% CI, 0.46-0.88; P=0.005).

6. Unexpectedly, complications of diabetic retinopathy were significantly higher in the semaglutide group compared to placebo (3.0% vs. 1.8%; HR 1.76; 95% CI, 1.11-2.78; P=0.02).

Study Design

Design

RCT

Double-Blind

Sample

3,297

Patients

Duration

104 weeks

Median

Setting

Multicenter, 32 countries

Population Adults with type 2 diabetes (HbA1c 7.0% or higher) at high cardiovascular risk, defined as being 50 years of age or older with established cardiovascular or chronic kidney disease, or 60 years of age or older with at least one cardiovascular risk factor.

Intervention Once-weekly subcutaneous semaglutide (0.5 mg or 1.0 mg) added to standard-of-care therapy.

Comparator Once-weekly volume-matched placebo added to standard-of-care therapy.

Outcome Time to the first occurrence of a major adverse cardiovascular event (MACE), defined as a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

Study Limitations

• The trial was primarily designed and statistically powered for noninferiority (to rule out unacceptable cardiovascular risk) rather than superiority, limiting the interpretation of secondary efficacy endpoints.

• The 104-week follow-up period was relatively short for comprehensively assessing long-term macrovascular events and the full trajectory of diabetic retinopathy.

• The trial population was highly selected (83% of patients had established cardiovascular disease or chronic kidney disease at baseline), which limits the generalizability of the findings to lower-risk patients with early or uncomplicated type 2 diabetes.

• The lack of standardized baseline retinal imaging or staging limited the mechanistic understanding of the observed increase in early retinopathy complications, which is hypothesized to be related to rapid glycemic improvement.

Clinical Significance

SUSTAIN-6 established once-weekly subcutaneous semaglutide as a cardioprotective therapy, cementing the role of GLP-1 receptor agonists in the algorithmic management of high-risk patients with type 2 diabetes. However, it also introduced a critical clinical caveat regarding the potential for early worsening of diabetic retinopathy associated with rapid glycemic improvement, prompting modern guideline recommendations to carefully evaluate and monitor ophthalmologic status in susceptible patients before initiating therapy.

Historical Context

Following the rosiglitazone controversy, the FDA issued a 2008 mandate requiring all novel diabetes drugs to undergo dedicated cardiovascular outcomes trials (CVOTs) to definitively rule out excess ischemic risk. Building on the paradigm-shifting success of the EMPA-REG OUTCOME (empagliflozin) and LEADER (liraglutide) trials, SUSTAIN-6 confirmed that GLP-1 receptor agonists as a class confer profound cardiovascular benefits that extend well beyond glycemic control. This landmark trial laid the scientific and commercial foundation for the subsequent explosion of semaglutide development, paving the way for further practice-changing trials like STEP and SELECT in obesity.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanism of action of GLP-1 receptor agonists like semaglutide, and how might rapid glycemic control explain the unexpected increase in diabetic retinopathy complications observed in the SUSTAIN-6 trial?

Key Response

GLP-1 receptor agonists stimulate glucose-dependent insulin release, inhibit glucagon secretion, slow gastric emptying, and promote satiety. Rapid improvements in HbA1c have been historically associated with an early, transient worsening of diabetic retinopathy (a phenomenon first noted in the DCCT trial with insulin), which likely explains the retinopathy signal observed in SUSTAIN-6.

Resident

When evaluating a patient with type 2 diabetes who has a history of ischemic stroke versus a history of heart failure, how do the results of SUSTAIN-6 compared to SGLT2 inhibitor trials influence your choice of second-line add-on therapy?

Key Response

SUSTAIN-6 showed that semaglutide's cardiovascular benefit was primarily driven by a significant 39 percent relative risk reduction in nonfatal stroke. In contrast, SGLT2 inhibitors have robust data for reducing heart failure hospitalizations. Therefore, a history of stroke strongly favors the addition of a GLP-1 RA like semaglutide, while a history of heart failure favors an SGLT2 inhibitor.

Fellow

The MACE reduction in SUSTAIN-6 was driven primarily by nonfatal stroke rather than cardiovascular death, contrasting with the early cardiovascular mortality benefits seen in EMPA-REG OUTCOME. What pathophysiological mechanisms explain this differential impact on atherosclerotic versus hemodynamic cardiovascular events?

Key Response

GLP-1 receptor agonists likely exert anti-atherogenic, anti-inflammatory, and plaque-stabilizing effects, which modify atherothrombotic risk but require longer follow-up to manifest as stroke or MI reductions. Conversely, SGLT2 inhibitors rapidly alter hemodynamics, natriuresis, and myocardial energetics, providing early reductions in heart failure events and cardiovascular death, highlighting distinct mechanisms of macrovascular protection.

Attending

Given the dichotomy of a neuroprotective effect (stroke reduction) and a microvascular risk (increased retinopathy complications) observed with semaglutide in SUSTAIN-6, how should you counsel and manage high-risk cardiovascular patients with pre-existing baseline diabetic eye disease in clinical practice?

Key Response

This requires nuanced shared decision-making. For patients with active or advanced proliferative diabetic retinopathy, the rapid HbA1c reduction from semaglutide may transiently worsen their eye disease. Clinicians must ensure proper baseline ophthalmologic screening and coordinate with a retina specialist before initiating therapy to safely balance the macrovascular stroke benefits against microvascular retinal risks.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

SUSTAIN-6 was originally designed as a pre-approval cardiovascular outcomes trial to prove non-inferiority, but it ultimately demonstrated statistical superiority for MACE reduction. How does the hierarchical testing strategy employed in such event-driven trials handle the transition from non-inferiority to superiority without inflating the type I error rate?

Key Response

In hierarchical (or closed) testing procedures, the hypothesis of non-inferiority is tested first. If the non-inferiority margin is met, the statistical alpha is entirely preserved, allowing investigators to subsequently test for superiority using the same data set without requiring a penalty for multiple comparisons. This maintains the overall study-wide type I error rate at 0.05 while maximizing the inferential yield of the trial.

Journal Editor

In analyzing the SUSTAIN-6 trial design, what critical appraisal concerns arise from the fact that investigators were allowed to adjust background antihyperglycemic and cardiovascular medications, and how might this confounding by indication affect the isolated effect size of semaglutide?

Key Response

Because glycemic and blood pressure targets had to be maintained, patients in the placebo group likely received more rescue medications (such as insulin, sulfonylureas, or statins) to match the semaglutide group's control. A seasoned reviewer would flag that this differential addition of cardioprotective or hypoglycemia-inducing rescue therapies could either dilute or artificially inflate the observed cardiovascular benefit, complicating the isolation of semaglutide's independent pleiotropic effects.

Guideline Committee

Based on the evidence from SUSTAIN-6 and subsequent GLP-1 RA cardiovascular outcome trials, how should current guidelines classify the strength of recommendation for semaglutide in patients with T2DM and established ASCVD, and does this supersede the traditional HbA1c-centric algorithmic approach?

Key Response

Current ADA and EASD guidelines (Level of Evidence A) recommend GLP-1 RAs with proven cardiovascular benefit, such as semaglutide, for patients with T2DM and established ASCVD, independent of baseline HbA1c or individualized A1c targets. This evidence from SUSTAIN-6 drove a paradigm shift from a purely glucose-centric management strategy to a risk-centric approach, mandating these agents be prescribed for cardioprotection regardless of whether metformin is at maximum dose or glycemic targets are already met.

Clinical Landscape

Noteworthy Related Trials

2015

EMPA-REG OUTCOME Trial

n = 7,020 · NEJM

Tested

Empagliflozin 10 mg or 25 mg daily

Population

T2DM patients with established cardiovascular disease

Comparator

Placebo

Endpoint

3-point MACE

Key result: Empagliflozin significantly reduced the risk of the primary composite cardiovascular outcome and death from cardiovascular causes.

2016

LEADER Trial

n = 9,340 · NEJM

Tested

Liraglutide up to 1.8 mg daily

Population

T2DM patients with high CV risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Liraglutide significantly reduced the risk of the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke compared to placebo.

2019

REWIND Trial

n = 9,901 · Lancet

Tested

Dulaglutide 1.5 mg weekly

Population

T2DM patients with or without established cardiovascular disease

Comparator

Placebo

Endpoint

3-point MACE

Key result: Dulaglutide significantly reduced the risk of the primary composite outcome of cardiovascular events across a broader primary and secondary prevention population.

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