GENERAL STUDY OVERVIEW

Title Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Citation N Engl J Med 2016; 375;4:311-322
Journal  Massachusetts Medical Society
Background
Funding Novo Nordisk and the National Institutes of Health
Study Background Liraglutide (Victoza®) is an analogue of glucagon-like peptide 1 (GLP-1) approved
for treatment of type 2 diabetes. In addition to lowering blood glucose, it has been
proven to be effective in weight and blood pressure reductions; however, the
cardiovascular effect was known.
Trial design Randomized, multicenter, international, double-blind, placebo-controlled trial
The trial protocol was reviewed and approved by the institutional review board or
ethics committee at each center.
Objectives The study was conducted to determine the long-term effects of liraglutide in
addition to standard care on cardiovascular outcomes and other clinically important
events.
Hypothesis Liraglutide would be noninferior to placebo with regard to the primary outcome
Enrollment Conducted at 410 sites in 32 countries from September 2010 through December
2015
METHODS
Patient selection Inclusion criteria:
 Patients with Type 2 DM
 A1c levels of ≥7.0%
 Patients not previously treated with oral antihyperglycemic agents or insulin
(human neutral protamine, long-acting analogue or premixed) or a
combination of these agents.
 Patients ≥ 50 years with ≥ 1 existing cardiovascular coexisting condition:
coronary heart disease, peripheral vascular disease, chronic kidney disease
of stage 3 or higher, cerebrovascular disease, or chronic heart failure of
New York Heart Association class II or III.
 Patients ≥ 60 years with ≥ 1 cardiovascular risk factor: proteinuria,
hypertension, left ventricular hypertrophy, left ventricular systolic or
diastolic dysfunction, or an ankle-brachial index of less than 0.9.
Exclusion criteria:
 Type 1 DM
 Use of GLP-1 receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors,
pramlintide, or rapid-acting insulin
 Familial or personal history of multiple endocrine neoplasia type 2 or
medullary thyroid cancer
 Occurrence of an acute coronary or cerebrovascular event within 14 days
before screening and randomization
Interventions Liraglutide(n=4668) 1.8 mg of liraglutide SC daily + standard of care
Patients
(n= 9340) Placebo(n=4672) 1.8 mg of placebo SC daily + standard of care
Patients were randomized to receive liraglutide 0.6 mg SC daily and doses were
titrated to 1.8 mg based on tolerability.
Endpoints  The primary endpoint was the first occurrence of death from cardiovascular
causes, nonfatal myocardial infarction or nonfatal stroke.
 The secondary endpoint was an expanded primary outcome, death from any
cause, death from renal disease or onset of diabetes-related blindness
Statistical analyses  Both outcomes were determined using a Cox proportional-hazards model.
 Sensitivity analysis was also used for the exploratory outcome
RESULTS
Baseline  Demographic and clinical characteristics of the patients were similar in both
characteristics groups
 The mean duration of diabetes was 12.8 years and the mean glycated
hemoglobin level was 8.7%
Primary Endpoint Liraglutide Placebo Hazard ratio P value
(N =4668) (N = 4672) 95% CI
no. of no. of patients
patients (%) (%)
Primary composite 608 (13.0) 694 (14.9) 0.87 (0.78-0.97) 0.01
outcome
Secondary Liraglutide Placebo Hazard ratio P value
Endpoint (N =4668) (N = 4672) 95% CI
no. of no. of patients
patients (%) (%)
Death from 219 (4.7) 278 (6.0) 0.78 (0.66-0.93) 0.007
cardiovascular
causes
Death from 162 (3.5) 169 (3.6) 0.95 (0.77-1.18) 0.66
noncardiovascular
causes
Myocardial 292 (6.3) 339 (7.3) 0.86 (0.73-1.00) 0.046
infarction
Stroke 173 (3.7) 199 (4.3) 0.86 (0.71-1.06) 0.16
Transient ischemic 48 (1.0) 60 (1.3) 0.79 (0.54-1.16) 0.23
attack
CRITIQUE/DISCUSSION
Strengths  Large sample size
 Similar baseline characteristics in both arms
 Randomized, double-blind, International study
Statistics  Cox proportional hazards model is a survival model so it was an appropriate
test for the study.
Limitations  It was funded partly by Novo Nordisk, manufacturer of liraglutide
 4 out of 15 steering committee members were employees of Novo Nordisk
 2/3 of the participants were male (6003: liraglutide-3011, placebo-2992)
 Study period was only 3.5-5 years, so safety efficacy data for long-term was
not observed.
Conclusion / Liraglutide, a GLP-1 agonist used in treatment of type 2 diabetes mellitus, in
Impact addition to reducing weight and blood pressure, decreases the rate of death from
cardiovascular causes, myocardial infarction, or stroke in patients with type 2
diabetes mellitus.

REFERENCES
N Engl J Med 2016; 375;4:311-322