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Developments in Diabetology in 2016
Department of Endocrinology, Bharti Hospital, Karnal, India
T wo major trials, LEADER and SUSTAIN 6, published in 2016, reported the cardiovascular and microvascular benefits of liraglutide and
semaglutide respectively. This communication describes the results of these trials, and analyses the subtle differences in their outcomes.
While semaglutide significantly reduces the risk of non-fatal myocardial infarction (primary prevention), liraglutide reduces the risk of
all-cause mortality and cardiovascular mortality (secondary prevention). Both drugs significantly improve renal outcomes, but semaglutide
increased the risk of retinal events. The time taken to achieve benefit was much less (4-6 months) with semaglutide than with liraglutide
(12–18 months). LEADER and SUSTAIN 6 have made 2016 a landmark year in the history of diabetes care. Their positive results will help promote
better, comprehensive diabetes care, using minimal drugs (therapeutic parsimony), encourage use of rational combinations to improve outcomes,
and stimulate exaptation of these drugs for non-glycemic purposes.
Keywords GLP1RA, long acting GLP1RA, liraglutide,
semaglutide, LEADER, SUSTAIN6,
cardiovascular outcome trials
Disclosure: Sanjay Kalra has nothing to disclose in relation
to this paper. No funding was received for the publication
of this article. This article is a short opinion piece and
has not been submitted to external peer reviewers.
Authorship: All named authors meet the International
Committee of Medical Journal Editors (ICMJE) criteria
for authorship of this manuscript, take responsibility
for the integrity of the work as a whole, and have
given final approval to the version to be published.
Open Access: This article is published under the
Creative Commons Attribution Noncommercial License,
which permits any noncommercial use, distribution,
adaptation, and reproduction provided the original
author(s) and source are given appropriate credit.
Received: October 23, 2016
Published Online: December 20, 2016
Citation: US Endocrinology, 2016;12(2):78–80
Corresponding Author: Sanjay Kalra,
Department of Endocrinology, Bharti Hospital,
Karnal, India. E: firstname.lastname@example.org
2016 has been a landmark year for diabetology. While the last decade has seen various pharmacological
advances, 2016 stands out for consolidation of existing drugs. Not one, but two, glucose-lowering
molecules demonstrated beneficial effects on cardiovascular health this year. These drugs have also
been able to show renal safety and benefit in diabetes.
A tale of two trials
The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A
Long Term Evaluation (LEADER) trial proved the cardiovascular benefit of liraglutide when used in
participants with diabetes at high risk of, or established, cardiovascular disease (CVD). 1 Liraglutide
use was associated with a lower risk of cardiovascular mortality and lower all-cause mortality
(see Tables 1 and 2). A 13% reduction of the primary endpoint (hazard ratio [HR] 0.87; 95% confidence
interval [CI], 0.78–0.97; p<0.001 for non-inferiority; p=0.01 for superiority) for liraglutide-treated
compared to placebo-treated subjects. For the individual components of the primary endpoint, 22%
reduction of cardiovascular death (HR 0.78; 95% CI, 0.66–0.93; p=0.007) was noted. Reduction in non-
fatal stroke and non-fatal myocardial infarction (MI) was noted. Non-significant reductions of non-
fatal myocardial infarction (HR 0.88; 95% CI, 0.75–1.03; p=0.11) and non-fatal stroke (HR 0.89; 95% CI,
0.72–1.11; p=0.30) were found. For the expanded cardiovascular (CV) endpoint, there was a 12%
reduced risk (HR 0.88; 95% CI, 0.81–0.96; p=0.005). There was a non-significantly reduced risk of
hospitalization for heart failure (HR 0.87; 95% CI, 0.73–1.05; p=0.14).
There was also a lower risk of renal events. A 16% reduction in the composite microvascular endpoint
(HR 0.84; 95% CI, 0.67–0.92; p=0.02) for liraglutide-treated versus placebo-treated subjects in which
22% reduction in the risk of the composite nephropathy outcome (HR 0.78; 95% CI, 0.73–0.97; p=0.003)
Liraglutide was able to reduce insulin requirement, reduce body weight, and reduce hypoglycemic
episodes, while achieving lower glycated haemoglobin (HbA 1c ). An estimated treatment difference
(ETD) in HbA 1c between liraglutide and placebo of -0.40 % (95% CI -0.45 to -0.34) was observed at 36
months. Severe hypoglycemia occurred in 114 liraglutide- and 153 placebo-treated subjects, yielding
a rate ratio of 0.68 (95% CI, 0.51–0.91). Similarly, the rate ratio for confirmed hypoglycemia (<56 mg/dl)
was 0.80 (95% CI, 0.74–0.88), which corresponds to a 32% lower risk for severe hypoglycemia and
20% lower risk for confirmed hypoglycemia (<56 mg/dl) for liraglutide-treated subjects compared to
placebo-treated subjects. An ETD in body weight between the liraglutide and placebo arm of -2.3 kg
(95% CI, -2.5–-2.0) was observed at 36 months. The major part of the weight loss was achieved within
the first six months of the trial, and remained stable during the rest of the trial.
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