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LEADER

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Year of Publication: 2016

Authors: Steven P. Marso, Gilbert H. Daniels, Kirstine Brown-Frandsen, ..., Peter Kristensen

Journal: New England Journal of Medicine

Citation: Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375:311–322.

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa1603827

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1603827

Clinical Question

Does liraglutide reduce major cardiovascular events in patients with type 2 diabetes at high cardiovascular risk compared with placebo?

Study Overview

Objective

Liraglutide – To evaluate cardiovascular safety and efficacy of liraglutide in patients with type 2 diabetes at high cardiovascular risk.

Study Summary

Liraglutide significantly reduced major cardiovascular events in high-risk type 2 diabetes patients.
Stroke risk was numerically lower but not statistically significant.

Intervention

Randomized, double-blind, placebo-controlled trial. Patients with type 2 diabetes and high cardiovascular risk were randomized to receive liraglutide (up to 1.8 mg daily) or placebo, both on top of standard care, with median follow-up of 3.8 years.

Patients per Arm

Liraglutide: 4668; Placebo: 4672

Bottom Line

Liraglutide significantly reduced the risk of major cardiovascular events and all-cause mortality in high-risk type 2 diabetes patients, supporting its role in cardiovascular risk reduction.

        Major Points
        Landmark trial establishing liraglutide (GLP-1 RA) as the first diabetes drug to demonstrate cardiovascular benefit beyond glucose lowering: 9,340 patients across 410 centers in 32 countries.
Liraglutide reduced 3-point MACE by 13% (13.0% vs 14.9%, HR 0.87, 95% CI 0.78–0.97, P=0.01) — the first injectable GLP-1 RA superiority result for CV outcomes.
Significant reduction in CV death (HR 0.78, P=0.007) and all-cause mortality (HR 0.85, P=0.02) — one of the few diabetes trials to show a mortality benefit.
Nonfatal MI (HR 0.88, 95% CI 0.75–1.03, P=0.11) and nonfatal stroke (HR 0.89, 95% CI 0.72–1.11, P=0.30) showed favorable but non-significant trends — the MACE benefit was primarily driven by CV death reduction.
Benefit observed on top of standard-of-care therapies including statins, antihypertensives, and antiplatelets — demonstrating incremental value of GLP-1 RA therapy.
GI events were the most common cause of permanent discontinuation (nausea 1.6% vs 0.4%, vomiting 0.7% vs <0.1%, diarrhea 0.6% vs 0.1%; all P<0.001). Acute pancreatitis was similar (0.4% vs 0.5%, P=0.44). Acute gallstone disease was more frequent with liraglutide (3.1% vs 1.9%, P<0.001). No episodes of medullary thyroid carcinoma occurred in the liraglutide group.
Together with SUSTAIN 6 (semaglutide injectable) and PIONEER 6/SOUL (semaglutide oral), established the GLP-1 RA class as a pillar of cardiovascular risk reduction in T2DM.
Changed ADA/EASD guidelines: GLP-1 RAs recommended as first injectable after metformin in T2DM patients with established ASCVD, independent of HbA1c level.
72.4% (6764/9340) had established cardiovascular disease and 81.3% (7598/9340) had established CVD, CKD stage ≥3, or both — the trial was overwhelmingly a secondary prevention population.
NNT of 66 over 3 years to prevent one MACE event — clinically meaningful given the also-observed mortality reduction.

      

Design

Study Type: Multicenter, randomized, double-blind, placebo-controlled trial

Randomization: 1

Blinding: Double-blind

Enrollment Period: September 2010 to April 2012

Follow-up Duration: Median 3.8 years

Centers: 410

Countries: 32 countries globally

Sample Size: 9340

Analysis: Time-to-event analysis using Cox proportional hazards model; randomization stratified by screening eGFR (<30 or ≥30 ml/min/1.73 m²).

Inclusion Criteria

Type 2 diabetes with HbA1c ≥7.0%
Age ≥50 years with ≥1 established cardiovascular coexisting condition: coronary heart disease, cerebrovascular disease, peripheral vascular disease, chronic kidney disease stage ≥3, or NYHA class II–III heart failure
Age ≥60 years with ≥1 cardiovascular risk factor: microalbuminuria or proteinuria, hypertension with left ventricular hypertrophy, LV systolic or diastolic dysfunction, or ankle-brachial index <0.9

Exclusion Criteria

Type 1 diabetes
Use of GLP-1 receptor agonists, DPP-4 inhibitors, pramlintide, or rapid-acting insulin
Personal or family history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma
Acute coronary or cerebrovascular event within 14 days before screening and randomization

Baseline Characteristics

Characteristic	Control	Active
Age (mean)	64.2	64.3
Female (%)	36%	35%
HbA1c (%)	8.7	8.7
BMI (kg/m²)	32.5	32.5
eGFR (ml/min/1.73m²)	80.6	80.9
CVD, CKD stage ≥3, or both	81.3%	81.1%
Established CVD (pooled)	72.4%	72.4%
CKD stage ≥3 (pooled)	24.7%	24.7%
Insulin use (%)	44%	43%

Arms

Field	Liraglutide	Control
Intervention	1.8 mg liraglutide daily subcutaneous injection (or max tolerated dose)	Matching placebo injection
Duration	Median 3.8 years	Median 3.8 years

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (3-point MACE)	Primary	14.9%	13.0%	0.87	0.01
Death from cardiovascular causes	Secondary	6.0%	4.7%	0.78	0.007
All-cause mortality	Secondary	9.6%	8.2%	0.85	0.02
Nonfatal MI	Secondary	6.8%	6.0%	0.88	0.11
Nonfatal stroke	Secondary	3.8%	3.4%	0.89	0.30
Expanded composite CV outcome	Secondary	22.7% (1062)	20.3% (948)	0.88	0.005
Microvascular event (composite renal/retinal)	Secondary	8.9% (416)	7.6% (355)	0.84	0.02
Nephropathy	Secondary	7.2% (337)	5.7% (268)	0.78	0.003
Hospitalization for heart failure	Secondary	5.3% (248)	4.7% (218)	0.87	0.14
Confirmed hypoglycemia	Adverse	45.6% (2130)	43.7% (2039)	Rate ratio 0.80 (95% CI 0.74–0.88)	0.06
Severe hypoglycemia	Adverse	3.3% (153)	2.4% (114)	Rate ratio 0.69 (95% CI 0.51–0.93)	0.02
Acute gallstone disease	Adverse	1.9% (90)	3.1% (145)		<0.001
Acute pancreatitis	Adverse	0.5% (23/4672)	0.4% (18/4668)		0.44
Chronic pancreatitis	Adverse	<0.1% (2/4672)	0 (0/4668)		0.16
Pancreatic carcinoma	Adverse	0.1% (5/4672)	0.3% (13/4668)		0.06
Medullary thyroid carcinoma	Adverse	<0.1% (1/4672)	0 (0/4668)		0.32
Any AE leading to permanent discontinuation	Adverse	7.3% (339/4672)	9.5% (444/4668)		<0.001
Nausea (leading to discontinuation)	Adverse	0.4% (18/4672)	1.6% (77/4668)		<0.001
Vomiting (leading to discontinuation)	Adverse	<0.1% (2/4672)	0.7% (31/4668)		<0.001
Diarrhea (leading to discontinuation)	Adverse	0.1% (5/4672)	0.6% (27/4668)		<0.001

Criticisms

No benefit and possibly harm was seen in the primary-prevention subgroup (age ≥60 with risk factors only): HR 1.20 (0.86–1.67), interaction P=0.04 — cardiovascular benefit was concentrated in patients with established CVD.
Permanent discontinuation for adverse events was higher with liraglutide (9.5% vs 7.3%, P<0.001), driven by GI events — a real-world tolerability limit that may bias per-protocol estimates.
GI side effects were common causes of discontinuation (nausea, vomiting, diarrhea all P<0.001) and may have unblinded patients and investigators, compromising the double-blind design.
Open-label placebo run-in period may introduce selection bias by excluding patients with poor adherence or GI intolerance before randomization.
MACE benefit driven primarily by CV death — nonfatal MI and stroke reductions were not individually significant, raising questions about the breadth of cardiovascular protection.
Industry-sponsored by Novo Nordisk (liraglutide manufacturer) — potential bias in trial design, conduct, and publication strategy, though NIH also contributed funding.
Cannot determine whether the CV benefit is mediated by glucose lowering, weight loss, anti-inflammatory effects, or direct vascular mechanisms.
Numerical excess of pancreatic carcinoma (13 vs 5, P=0.06) and acute gallstone disease (P<0.001) with liraglutide represent residual safety signals despite reassuring pancreatitis rates.
Underrepresentation of women (35–36%) and certain ethnic groups limits generalizability.
Daily subcutaneous injection requirement may limit real-world adherence compared to the controlled trial setting.

Funding

Novo Nordisk and the National Institutes of Health (NIH grants).

Based on: LEADER (New England Journal of Medicine, 2016)