2. The Liraglutide Effect and Action in Diabetes:
Evaluation of Cardiovascular Outcome Results
(LEADER) trial was initiated in 2010
To assess long-term effects of liraglutide on
CV outcomes and other clinically important
events
3. Liraglutide is a GLP-1 agonist
GLP -1 is an important “incretin” released
from the gut in response to ingested glucose.
INCRETINS-enhance the rate of insulin release
in response to an increase in plasma glucose.
Incl.
1.GIP … K cells of prox. Intest.
2. GLP-1…L cells of ileum and colon
4. MOA: ⊕s glucose dependent insulin release
Suppresses glucagon secretion and ↓ses HGO
Slows down gastric emptying
Decreases appetite
↑es β-cell mass and maintains β-cell
efficiency
5. Multicenter, double-blind, placebo-controlled
randomized trial
9340 patients
Median follow-up for 3.8 years
Patients:
T2DM pts. with HbA1C≥7%
6. Age≥50 years with at least one cardiovascular
coexisting condition
(CAD,CVD,CKD ≥stage3,CHF of class II/III)
Age ≥ 60 years with at least one
cardiovascular risk factor
(microalb/proteinuria, HTN & LVH,LV
syst./diast. dysfunction, ABI<0.9)
7. Type-I DM
Use of GLP-1–receptor agonists,DPP-4
inhibitors, pramlintide, rapid-acting insulin;
A familial or personal H/O MEN type 2 or MTC
Occurrence of ACS/CVA within 14 d before
screening
8. Death from any cause was lower in Liraglutide
grp(8.2% vs. 9.6%)
Cardiovasc. Outcome:
Death from cardiovascular causes-fewer
(4.7% vs. 6.0%)
Non-fatal MI – 6.0% vs. 6.8%
10. Safety and Adv. Outcomes:
Rate of benign and malign. Neoplasms- ↑ but
not significant
Fewer pts. with prostate Ca.(26 pts vs. 47)
Fewer with leukemia(5 vs. 14)
NEOPLASMS Liraglutide(%) Placebo(%)
Benign 3.6 3.1
Malignant 6.3 6.0
Pancreatic Ca. 0.3 0.1
Med.Thyr. Ca. 0 <0.1
11. A/E Liraglutide Placebo
Acute pancreatitis 0.4 0.5
Chronic pancreatitis 0 <0.1
Cholelithiasis 1.5 1.1
Acute cholecystitis 0.8 0.4
Adverse events leading to permanent
discontinuation of the trial regimen was more
common with liraglutide (GI S/E)
12. Concern abt risk of hospitalization for HF
with various agents used to treat DM.
In this trial-fewer hosp. for HF in the Liraglut.
grp.
Fewer add-on therapies for DM, lipid
lowering agents and diuretics in Liraglut. grp.
13. Greater benefit in pts with CKD ≥stage3 and
Cardiovasc ds.
Renal microvasc. benefits were higher.
Rate of retinopathy events were higher but
the diff. was not significant
14. The effects on CV outcome were consistent
with Liraglutide whereas heterogeneous with
Empagliflozin(EMPA-REG OUTCOME TRIAL)
Benefits in EMPA-REG OUTCOME TRIAL
related to hemodyn. changes whereas
LEADER-to the modified progression of
atheroscl. vasc. disease
15. Evaluation of Lixisenatide in ACS trial-shorter
acting than and structurally dissimilar-no CV
benefit in pts with DM & recent ACS.
Other trials with TZDs, Insulin, DPP-IV
inhibitors-no significant CV benefits
16. ↑incidence of Pancreatic Ca. and pancreatitis
and also ↑ levels of lipase and amylase
No episodes of C-Cell hyperplasia/MTC (seen
among rodents)-but the possibility cannot be
excluded.
17. Follow-up period – 3.5 to 5 yrs
Safety and efficacy data restricted to that time
period
Only pts of high risk for cardiovascular events
and who had a baseline HbA1C≥7%
not applicable to patients at lower risk
18. In conclusion, among patients with ty2DM
who were at high risk for CV events while
they were taking std therapy, those in the
liraglutide group had lower rates of CV events
and death from any cause than did those in
the placebo group
Editor's Notes
GIP
has little effect on augmenting insulin secretion in type 2
DM, whereas GLP-1 significantly augments glucose dependent
insulin secretion
circulating GLP-1 is rapidly (1 to 2 minutes) inactivated
by the dipeptidyl peptidase IV enzyme (DPP-IV).
GLP-1 receptor agonists that maintain
the physiologic effects of the native incretin &
resistant to the actions of DPP-IV
This article was published on June 13, 2016,
at NEJM.org.