LIRAGLUTIDE AND

CARDIOVASCULAR
OUTCOMES
IN TYPE 2 DIABETES

TH E NEW ENGLAND JOURNAL O F MEDICINE

 DIABETES

WHAT ?
WHO ?
WHEN ?
WHERE ?
WHY ?
HOW ?
 BACKGROUND
 Type 2 Diabetes is a Complex Metabolic Disorder
which is characterized by hyperglicemia and
affect in high risk of cardiovascular
complication.(Diabetes Care Introduction.2016)
 Glycemic control is just effective for
Microvascular,but less for Macrovascular.Thats
why need new diabetes treatment.
 Liraglitude(GLP-1) able to reduce glucose,reduce
weight and blood pressure,Increase pulse rate
 The Cardiovascular effect of Liraglitude remains
unknown.
 Evaluation Of Liraglitude effect on
Cardiovascular Outcome needed.
 METHODS
 Using Double-blind trial Design,Randomly assigned
patients with type 2 diabetes and high
cardiovascular risk to receive liraglitude or placebo
 FollowUp planned minimum 42 months,maximum 60
months and additional 30 days followup afterward
 The Trial was overseen by Steering Committee and
All authors had access to the final results and vouch
for the fidelity of the trial to the protocol.
 Criteria for patients are eligible such as : age 50
years or more with at least one cardiovascular risk
factor(CHD,CVD,CKD,CHF).Age 60 years or more
with at least one Cardiovascular risk factor
(Proteinuria,HT)
 Major exclusion criteria were Diabetes type 1,Using
rapid-acting Insulin,etc
 •PROCEDURE
 2 week placebo run-in phase,patients were
randomly assigned to receive 1,8mg of
liraglitude/Placebo once daily as subcutaneous
injection
 Randomization was stratified according on GFR

 Patients who didn’t meet recommended target

for glycemic control,after randomization,the
addition of antyhyperglicemic agents was
permitted.
 Patient were Scheduled for follow-up visits at
months 1,3 and 6 also every 6 months thereafter
OUTCOMES & STASTITICAL ANALYSIS
 The primary composite outcome was the first
occurrence of death from cardiovascular
causes,stroke,myocardial infarction,renal disease,etc
 The statistical analysis plan is available with protocol
at NEJM.org.furthermore the primary & exploratory
analyses for the outcomes in the time event analyses
based on a Cox proportional hazards Model.
 RESULT
 A total of 9340 patients underwent randomization
 The primary outcome occurred significantly fewer patients
in the Liraglutide group(13%) than placebo group(14.9%).
 Fewer Patients died from cardiovascular causes in the
Liraglitude group(4.7%)than in placebo group(6.0%)
 The death rate from any cause lower in liragutide
group(8.2%)than placebo group(9.6%)
 The rates of nonfatal myocardial infarction,nonfatal stroke
were non significantly lower in liraglitude group than in
placebo group.
 The most common adverse events to the discontinuation of
liraglitude were gastrointestinal events
 The Incidence of Pancreatitis was nonsignificantly lower in
liraglitude group than in placebo group
Table 2. Selected Adverse Events Reported during the Trial.*

Liraglutide Placebo
Event (N = 4668) (N = 4672) P Value

no. of patients (%)

Adverse event
Any adverse event 2909 (62.3) 2839 (60.8) 0.12
Serious adverse event 2320 (49.7) 2354 (50.4) 0.51
Confirmed hypoglycemia† 2039 (43.7) 2130 (45.6) 0.06
Severe adverse event 1502 (32.2) 1533 (32.8) 0.51
Severe hypoglycemia† 114 (2.4) 153 (3.3) 0.02
Acute gallstone disease 145 (3.1) 90 (1.9) <0.001
Cholelithiasis 68 (1.5) 50 (1.1) 0.09
Acute cholecystitis 36 (0.8) 21 (0.4) 0.046
Hypothyroidism 44 (0.9) 33 (0.7) 0.21
Hyperthyroidism 13 (0.3) 8 (0.2) 0.27
Diabetic foot ulcer 181 (3.9) 198 (4.2) 0.38
Allergic reaction 59 (1.3) 44 (0.9) 0.14
Injection-site reaction 32 (0.7) 12 (0.3) 0.002
Adverse event leading to permanent discontinuation
of trial regimen
Any adverse event 444 (9.5) 339 (7.3) <0.001
Serious adverse event 192 (4.1) 245 (5.2) 0.01
Severe adverse event 164 (3.5) 188 (4.0) 0.20
Nausea 77 (1.6) 18 (0.4) <0.001
Vomiting 31 (0.7) 2 (<0.1) <0.001
Diarrhea 27 (0.6) 5 (0.1) <0.001
Increased lipase level‡ 15 (0.3) 11 (0.2) 0.43
Abdominal pain 11 (0.2) 3 (0.1) 0.03
Decreased appetite 11 (0.2) 2 (<0.1) 0.01
Abdominal discomfort 10 (0.2) 0 0.002
Pancreatitis or neoplasm§
Acute pancreatitis 18 (0.4) 23 (0.5) 0.44
Chronic pancreatitis 0 2 (<0.1) 0.16
Any benign neoplasm 168 (3.6) 145 (3.1) 0.18
Any malignant neoplasm 296 (6.3) 279 (6.0) 0.46
Pancreatic carcinoma 13 (0.3) 5 (0.1) 0.06
Medullary thyroid carcinoma 0 1 (<0.1) 0.32
 CONCLUSION
 In the time to even analysis,the rate of the first
occurrence of death from cardiovascular causes
nonfatal myocardial infarction, or nonfatal stroke
among patients with type 2 diabetes mellitus was
lower with liraglutide than with placebo. (Funded by
Novo Nordisk and the National Institutes of Health;
LEADER ClinicalTrials.gov number, NCT01179048.)
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