Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - LEADER
The goal of the trial was to assess the cardiovascular (CV) safety of liraglutide in patients with type 2 diabetes mellitus (DM2) at high risk for CV events.
Contribution to the Literature: The LEADER trial showed that liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, was superior to placebo in improving glycemic control and reducing CV events in patients with DM2 and high CV risk.
Patients were randomized in a 1:1 fashion to either liraglutide 1.8 mg once daily (n = 4,668) or matching placebo (n = 4,672). Both medications were administered as a subcutaneous injection.
- Total number of enrollees: 9,340
- Duration of follow-up: 3.8 years
- Mean patient age: 64 years
- Percentage female: 46%
- Age ≥50 years and concomitant CV, cerebrovascular, or peripheral vascular disease or chronic renal failure or chronic heart failure OR age ≥60 years and other specified risk factors of vascular disease (microalbuminuria/proteinuria, hypertension, left ventricular [LV] hypertrophy, LV systolic or diastolic dysfunction, ankle-brachial index <0.9)
- Glycated hemoglobin ≥7.0%
- Antidiabetic drug-naive or treated with one or more oral antidiabetic drugs or treated with human NPH insulin or long-acting insulin analogue or premixed insulin, alone or in combination with oral drugs
- Type 1 diabetes
- Use of a GLP-1 receptor agonist (exenatide, liraglutide, or other) or pramlintide or any dipeptidyl peptidase 4 (DPP-4) inhibitor within the 3 months prior
- Use of insulin other than human NPH insulin or long-acting insulin analogue or premixed insulin within 3 months prior
- Familial or personal history of multiple endocrine neoplasia type 2 or medullary thyroid cancer
- Acute coronary syndrome or cerebrovascular accident within 14 days
Other salient features/characteristics:
- Established coronary artery disease: 72%; chronic kidney disease ≥3: 24.7%; both: 15.8%
- For patients with estimated glomerular filtration rate ≤59, approximately 60% were on metformin at baseline; for the remainder, approximately 79% were on metformin at baseline
The primary outcome, CV death, nonfatal myocardial infarction (MI), or stroke for liraglutide vs. placebo: 13.0% vs. 14.9%, hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.78-0.97, p < 0.001 for noninferiority; p = 0.01 for superiority; CV death: 4.7% vs. 6.0%, p = 0.007; all MI: 6.3% vs. 7.3%, p = 0.046; all stroke: 3.7% vs. 4.3%, p = 0.16
Secondary outcomes for liraglutide vs. placebo:
- All-cause mortality: 8.2% vs. 9.6%, p = 0.02
- Chronic heart failure hospitalization: 4.7% vs. 5.3%, p = 0.14
- Coronary revascularization: 8.7% vs. 9.4%, p = 0.18
- Confirmed hypoglycemic event: 43.7% vs. 45.6%, p = 0.06
- Nephropathy: 5.7% vs. 7.2%, p = 0.003
- Acute gallstone disease: 3.1% vs. 1.9%, p < 0.001
- Acute pancreatitis: 0.4% vs. 0.5%, p = 0.44; pancreatic carcinoma: 0.3% vs. 0.1%, p = 0.06
The results of this trial indicate that liraglutide is superior to placebo in improving glycemic control and reducing CV events in patients with DM2 and high CV risk. There was also a significant mortality benefit with liraglutide. These are really important findings and suggest that agents such as liraglutide and empaglifozine with documented CV benefits may need to be considered as second-line therapy in similar high-risk patients going forward.
Liraglutide is a novel drug for the treatment of DM2 and functions as a GLP-1 agonist. These drugs reduce hyperglycemia in patients with DM2 and are also known to cause slight reductions in weight and blood pressure. However, pulse can increase with the use of these agents, but in this trial, suggests no adverse CV consequences.
Following the much publicized CV safety concerns with rosiglitazone, the Food and Drug Administration (FDA) mandated that all new diabetes drugs conduct studies demonstrating CV safety. The upper limit of the 95% CI for the HR had to be <1.8 for premarketing studies and <1.3 for postmarketing studies. This trial thus establishes the CV safety profile of liraglutide for use in patients with DM2, and is in fact, one of the first large-scale DM2 trials to show an improvement in hard CV outcomes with simultaneous improvements in glycemic control in a high-risk population. The mechanisms for this benefit will need to be established in future trials. Other trials with GLP-1 agonists are ongoing and will help establish whether this is a class effect. There was no increase (and in fact this trial was numerically lower) in CHF hospitalizations with liraglutide, as was previously noted with saxagliptin and some of the other DPP-4 inhibitors.
Marso SP, Daniels GH, Brown-Frandsen K, et al., on behalf of the LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;Jun 13:[Epub ahead of print].
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