What were the MACE reductions in LEADER and SUSTAIN-6?

In LEADER, liraglutide reduced 3-component MACE by 13% versus placebo (HR 0.87, 95% CI 0.78–0.97, p=0.01 for superiority). In SUSTAIN-6, semaglutide 0.5 mg and 1.0 mg combined reduced MACE by 26% versus placebo (HR 0.74, 95% CI 0.58–0.95, p=0.02 for superiority). Both enrolled type 2 diabetic populations.

How do LEADER and SUSTAIN-6 differ from SELECT?

LEADER and SUSTAIN-6 enrolled patients with type 2 diabetes, whereas SELECT enrolled a non-diabetic population with obesity. LEADER and SUSTAIN-6 used diabetes doses of liraglutide (1.8 mg) and semaglutide (0.5 mg/1.0 mg) respectively, whereas SELECT used the higher obesity dose of semaglutide (2.4 mg). All three trials used a placebo comparator and a 3-component MACE primary endpoint.

Why was the SUSTAIN-6 stroke finding significant?

Non-fatal stroke was significantly reduced by semaglutide in SUSTAIN-6 (HR 0.61, 95% CI 0.38–0.99), a finding that was directionally present but not statistically significant in LEADER and SUSTAIN-6 helped solidify stroke as a plausible component of GLP-1 cardiovascular benefit. This was a mechanistically important finding given that the SELECT trial did not achieve significant stroke reduction.

Did LEADER or SUSTAIN-6 include patients with heart failure?

Both trials permitted enrolment of patients with heart failure, but neither was powered for HF-specific endpoints. Post-hoc analyses of LEADER found no signal of benefit or harm in patients with HF with reduced ejection fraction. The HF question for GLP-1 agents was subsequently addressed in dedicated trials including EMPEROR-Reduced (SGLT2 inhibitors) and STEP-HFpEF (semaglutide in HF with preserved ejection fraction, reporting 2023).

What regulatory changes followed LEADER and SUSTAIN-6 in the UK?

Following the LEADER results, the EMA and subsequently the MHRA approved an extended indication for liraglutide (Victoza) covering cardiovascular risk reduction in adults with T2DM and established CVD. SUSTAIN-6 supported the same label expansion for semaglutide 0.5 mg and 1.0 mg (Ozempic) in the T2DM setting. These approvals were precursors to the later SELECT-driven obesity indication for semaglutide 2.4 mg (Wegovy).

LEADER and SUSTAIN-6: The GLP-1 Cardiovascular Outcome Trials That Changed Practice

Two trials in one paragraph

In 2016, two landmark randomised trials published simultaneously in the New England Journal of Medicine established that GLP-1 receptor agonists could reduce major adverse cardiovascular events in people with type 2 diabetes — a finding that reshaped diabetes pharmacotherapy globally. LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results; PMID: 27295427) demonstrated that liraglutide 1.8 mg weekly reduced the 3-component MACE primary endpoint by 13% compared to placebo (HR 0.87, 95% CI 0.78–0.97, p=0.01 for superiority) in 9,340 adults with T2DM and high cardiovascular risk over a median 3.8-year follow-up. SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; PMID: 27633186) demonstrated that subcutaneous semaglutide 0.5 mg and 1.0 mg weekly reduced MACE by 26% (HR 0.74, 95% CI 0.58–0.95, p=0.02 for superiority) in 3,297 adults with T2DM and high cardiovascular risk over a median 2.1-year follow-up. Together, these trials earned the GLP-1 receptor agonist class its first cardiovascular indication labels and laid the scientific and regulatory groundwork for all subsequent GLP-1 cardiovascular outcome programmes, including the SELECT trial in obesity.

LEADER: design and population

LEADER was an event-driven, multicentre, double-blind, randomised, placebo-controlled superiority trial with a 1:1 randomisation to liraglutide 1.8 mg once daily subcutaneous injection or matched placebo. It enrolled 9,340 adults with T2DM (HbA1c ≥7%) and established cardiovascular disease or chronic kidney disease stage 3 or above, or age ≥60 with at least two cardiovascular risk factors. Median age was 64.3 years; 64.3% were male; mean HbA1c was 8.7%; mean BMI 32.5 kg/m². The median follow-up was 3.8 years, with a minimum of 3.5 years guaranteed by the event-driven design.

Liraglutide was dose-escalated from 0.6 mg over two weeks to the maintenance 1.8 mg dose. Background glucose-lowering medication was permitted and adjusted at investigators' discretion under an HbA1c-guided protocol. The trial was sponsored by Novo Nordisk and pre-registered with NCT01179048.

LEADER: primary endpoint result

The primary three-component MACE endpoint (cardiovascular death, non-fatal MI, non-fatal stroke) occurred in 608 of 4,668 participants (13.0%) in the liraglutide group and in 694 of 4,672 participants (14.9%) in the placebo group — an absolute risk reduction of 1.9 percentage points over the median 3.8-year follow-up. The hazard ratio was 0.87 (95% CI 0.78–0.97, p=0.01 for superiority). Liraglutide achieved superiority, not merely non-inferiority, marking the first time a diabetes drug other than an SGLT2 inhibitor had demonstrated cardiovascular superiority in a pre-specified CVOT.

The primary benefit was driven largely by cardiovascular death, which was reduced by 22% (HR 0.78, 95% CI 0.66–0.93). Non-fatal MI showed a directional reduction (HR 0.88, 95% CI 0.75–1.03) that did not reach significance. Non-fatal stroke was not significantly reduced (HR 0.89, 95% CI 0.72–1.11). All-cause mortality was reduced by 15% (HR 0.85, 95% CI 0.74–0.97, p=0.02).

SUSTAIN-6: design and population

SUSTAIN-6 was designed as a regulatory non-inferiority safety trial but was ultimately powered to assess superiority — a distinction important to the field. It enrolled 3,297 adults with T2DM and high cardiovascular risk (established CVD or aged ≥60 with risk factors) in a 1:1:1:1 factorial randomisation to semaglutide 0.5 mg weekly, semaglutide 1.0 mg weekly, matched placebo for 0.5 mg, or matched placebo for 1.0 mg. For the primary analysis, both active semaglutide arms were pooled against both placebo arms. Median age was 64.6 years; 60.6% were male; mean HbA1c was 8.7%; mean BMI 32.8 kg/m². The median follow-up was 2.1 years — substantially shorter than LEADER's 3.8 years, which partly accounts for the smaller absolute event count.

SUSTAIN-6: primary endpoint result

MACE occurred in 108 of 1,648 participants (6.6%) receiving semaglutide and in 146 of 1,649 participants (8.9%) receiving placebo — an absolute difference of 2.3 percentage points over 2.1 years. The hazard ratio was 0.74 (95% CI 0.58–0.95, p=0.02 for superiority). The 26% relative risk reduction was larger than LEADER's 13%, though the shorter follow-up and smaller sample make direct comparison imprecise. The primary driver was a dramatic reduction in non-fatal stroke (HR 0.61, 95% CI 0.38–0.99, p=0.04) — a statistically significant finding not replicated in LEADER or, subsequently, in SELECT at the 2.4 mg obesity dose. Non-fatal MI was directionally reduced (HR 0.74, 95% CI 0.51–1.08) but without reaching significance given the trial's limited event count.

Secondary endpoints: both trials

Key secondary findings across the two trials:

All-cause mortality (LEADER): HR 0.85 (95% CI 0.74–0.97, p=0.02).
Cardiovascular death (LEADER): HR 0.78 (95% CI 0.66–0.93, p=0.007).
Non-fatal stroke (SUSTAIN-6): HR 0.61 (95% CI 0.38–0.99, p=0.04).
Nephropathy composite (LEADER): HR 0.78 (95% CI 0.67–0.92) — new or worsening nephropathy.
Nephropathy composite (SUSTAIN-6): HR 0.64 (95% CI 0.46–0.88) — new or worsening nephropathy; a large and significant effect.
HbA1c reduction (LEADER): −0.40% more than placebo at three years.
Body weight (LEADER): −2.3 kg more than placebo at year 3.
Diabetic retinopathy (SUSTAIN-6): HR 1.76 (95% CI 1.11–2.78) — a significant increase in retinopathy complications with semaglutide, attributed to rapid HbA1c reduction in patients with pre-existing advanced retinopathy. This remains a label warning for all semaglutide formulations.

Safety signals

Both trials reported gastrointestinal adverse events as the dominant class effect, consistent with GLP-1 receptor agonism: nausea (predominantly mild to moderate), diarrhoea, vomiting, and constipation. In LEADER, discontinuation due to adverse events was 9.5% liraglutide versus 7.3% placebo. In SUSTAIN-6, discontinuation was somewhat higher, at 9.6% in the pooled semaglutide group, consistent with semaglutide's higher potency at GLP-1 receptors.

Diabetic retinopathy worsening in SUSTAIN-6 (HR 1.76) was an unexpected safety signal that did not appear in LEADER. The mechanistic hypothesis — rapid HbA1c reduction causing temporary haemodynamic changes in the retinal vasculature in patients with pre-existing advanced retinopathy — is well-supported by historical precedent with intensive insulin therapy. It is not believed to represent an intrinsic GLP-1 toxicity, but it carries regulatory weight and mandates ophthalmological monitoring in high-risk patients.

Pancreatitis was rare in both trials. Cholelithiasis was numerically higher with active treatment in LEADER (3.1% vs. 1.9%). Thyroid C-cell tumours, raised as a class concern from rodent data, were not elevated in either human trial. Heart rate increased by approximately 3 bpm with liraglutide in LEADER and 2–3 bpm with semaglutide in SUSTAIN-6.

Outcomes table

Endpoint	LEADER (liraglutide 1.8 mg)	SUSTAIN-6 (sema 0.5/1.0 mg)	SELECT (sema 2.4 mg, ref)
3-component MACE	HR 0.87 (0.78–0.97)*	HR 0.74 (0.58–0.95)*	HR 0.80 (0.72–0.90)*
CV death	HR 0.78 (0.66–0.93)*	HR 0.98 (0.65–1.48)	HR 0.85 (0.71–1.01)
Non-fatal MI	HR 0.88 (0.75–1.03)	HR 0.74 (0.51–1.08)	HR 0.72 (0.61–0.85)*
Non-fatal stroke	HR 0.89 (0.72–1.11)	HR 0.61 (0.38–0.99)*	HR 0.93 (0.76–1.13)
All-cause mortality	HR 0.85 (0.74–0.97)*	HR 1.05 (0.74–1.50)	HR 0.81 (0.71–0.93)*
Nephropathy composite	HR 0.78 (0.67–0.92)*	HR 0.64 (0.46–0.88)*	Not primary
Diabetic retinopathy	Not significant	HR 1.76 (1.11–2.78)*	Non-diabetic cohort
N enrolled	9,340	3,297	17,604
Median follow-up	3.8 years	2.1 years	3.3 years

* Statistically significant (p<0.05)

Methodological strengths and caveats

Both LEADER and SUSTAIN-6 were methodologically rigorous: randomised, double-blind, placebo-controlled, event-driven trials with independent adjudication of cardiovascular outcomes. LEADER's strength lies in its large sample size (9,340) and long median follow-up (3.8 years), which enabled detection of relatively modest treatment effects. SUSTAIN-6's strength lies in its comparative pharmacological design — testing two doses of the same molecule versus placebo — which confirmed dose-independent MACE benefit across the 0.5 mg and 1.0 mg doses, though the shorter follow-up limited the absolute event counts and hence the width of the confidence intervals.

Caveats: both trials enrolled diabetic populations, which means the glycaemic and weight-loss contributions to the cardiovascular benefit are not separable from purely cardioprotective mechanisms. The SELECT trial's non-diabetic design was the explicit methodological response to this limitation. Additionally, LEADER and SUSTAIN-6 used diabetes doses of their respective molecules, not the higher obesity doses — making cross-molecule comparisons imprecise. The SUSTAIN-6 retinopathy signal, while mechanistically explicable, introduced a label constraint that has shaped prescribing caution in patients with advanced diabetic retinopathy and remains relevant to clinical practice in 2026.

UK implications

LEADER was the decisive trial that earned liraglutide its cardiovascular risk-reduction indication from the EMA, subsequently recognised by the MHRA. NICE incorporated the cardiovascular outcome data into the liraglutide appraisal (TA336, subsequently updated) and positioned it alongside SGLT2 inhibitors in the standard care pathway for T2DM with established cardiovascular disease. SUSTAIN-6 supported the semaglutide (Ozempic) cardiovascular label in T2DM, and this indication is reflected in the NICE diabetes technology appraisals covering subcutaneous semaglutide.

Mechanistically, LEADER and SUSTAIN-6 opened the conceptual door that SELECT walked through in 2023: if GLP-1 receptor agonism reduces MACE in a diabetic population partly or wholly through glycaemia-independent mechanisms — direct cardiac remodelling, anti-inflammatory effects, blood pressure reduction, plaque stabilisation — then the same benefit should be demonstrable in a non-diabetic obese population. SELECT confirmed this hypothesis and created the pathway for an obesity cardiovascular indication that is now part of the MHRA label for Wegovy. Understanding LEADER and SUSTAIN-6 is therefore essential context for interpreting both SELECT and the forthcoming SURMOUNT-MMO data, as together they form a coherent evidence base across the weight, glycaemia, and cardiovascular outcome domains of the GLP-1 receptor agonist class.

Frequently asked questions

What were the MACE reductions in LEADER and SUSTAIN-6?: In LEADER, liraglutide reduced 3-component MACE by 13% versus placebo (HR 0.87, 95% CI 0.78–0.97, p=0.01 for superiority). In SUSTAIN-6, semaglutide 0.5 mg and 1.0 mg combined reduced MACE by 26% versus placebo (HR 0.74, 95% CI 0.58–0.95, p=0.02 for superiority). Both enrolled type 2 diabetic populations.
How do LEADER and SUSTAIN-6 differ from SELECT?: LEADER and SUSTAIN-6 enrolled patients with type 2 diabetes, whereas SELECT enrolled a non-diabetic population with obesity. LEADER and SUSTAIN-6 used diabetes doses of liraglutide (1.8 mg) and semaglutide (0.5 mg/1.0 mg) respectively, whereas SELECT used the higher obesity dose of semaglutide (2.4 mg). All three trials used a placebo comparator and a 3-component MACE primary endpoint.
Why was the SUSTAIN-6 stroke finding significant?: Non-fatal stroke was significantly reduced by semaglutide in SUSTAIN-6 (HR 0.61, 95% CI 0.38–0.99), a finding that was directionally present but not statistically significant in LEADER and SUSTAIN-6 helped solidify stroke as a plausible component of GLP-1 cardiovascular benefit. This was a mechanistically important finding given that the SELECT trial did not achieve significant stroke reduction.
Did LEADER or SUSTAIN-6 include patients with heart failure?: Both trials permitted enrolment of patients with heart failure, but neither was powered for HF-specific endpoints. Post-hoc analyses of LEADER found no signal of benefit or harm in patients with HF with reduced ejection fraction. The HF question for GLP-1 agents was subsequently addressed in dedicated trials including EMPEROR-Reduced (SGLT2 inhibitors) and STEP-HFpEF (semaglutide in HF with preserved ejection fraction, reporting 2023).
What regulatory changes followed LEADER and SUSTAIN-6 in the UK?: Following the LEADER results, the EMA and subsequently the MHRA approved an extended indication for liraglutide (Victoza) covering cardiovascular risk reduction in adults with T2DM and established CVD. SUSTAIN-6 supported the same label expansion for semaglutide 0.5 mg and 1.0 mg (Ozempic) in the T2DM setting. These approvals were precursors to the later SELECT-driven obesity indication for semaglutide 2.4 mg (Wegovy).