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Semaglutide improves cardiovascular outcomes
in type 2 diabetes
Comment by Benjamin Scirica,
MD
U
nexpectedly, in the SUSTAIN-6 study,
a small safety study of the once-weekly
GLP1 analog semaglutide, semaglutide
significantly reduced the risk of cardiovascular
death, MI, or stroke by 26% compared with
placebo in 3297 patients with diabetes and at
high cardiovascular risk. Designed to assess
safety, and thus fulfill the first step of the regu-
latory approval process by excluding significant
excess risk, the study was neither planned nor
powered to test for superiority, and is therefore
one-third to one-fifth the size of other ongoing
or completed cardiovascular outcome trials
with antihyperglycaemic agents.
Although semaglutide is now the third
glucose-lowering agent after empagliflozin
(EMPA-REG) and liraglutide (LEADER) to
show a cardiovascular benefit, the design
and size of SUSTAIN-6 should temper the
excitement until a larger study with follow-up
extended beyond 2 years can confirm these
preliminary findings. There are for example,
differences between the LEADER and SUS-
TAIN-6 results that are difficult to reconcile.
In LEADER, the 22% reduction in cardiovas-
cular death with liraglutide drove the lower risk
of the primary composite endpoint, while MI
and stroke were only reduced by 12% and 11%,
respectively. In contrast, in SUSTAIN-6 there
was no difference in cardiovascular mortality,
but a 26% reduction in MI and 49% reduction
in stroke. These differences, combined with
the lack of benefit with the GLP1 analogue
lixisenatide in the ELIXA study, highlight the
fact that there is still much to learn about the
role of GLP1 in cardioprotection.
The data from SUSTAIN-6 are neverthe-
less encouraging for the entire field of cardio-
metabolic drug development. The decades-long
equipoise surrounding the choice between
first- or second-line glucose-lowering agents
appears to be crumbling as several agents now
have proven cardiovascular benefit. But, it is
only through further randomised trials powered
for “superiority” that continued progress will be
made.
Dr Scirica is Attending
Cardiologist and Director,
Quality Initiatives,
Cardiovascular Division,
Brigham and Women’s
Hospital; Associate Professor
of Medicine, Harvard
Medical School; Senior Investigator, TIMI
Study Group, Boston, Massachusetts.
The decades-long equipoise surrounding the choice between first- or second-line
glucose-lowering agents appears to be crumbling as several agents now have
proven cardiovascular benefit. But, it is only through further randomised trials
powered for “superiority” that continued progress will be made.
Semaglutide and cardiovascular outcomes in patients with type 2 diabetes
The New England Journal of Medicine
TAKE-HOME MESSAGE
•
The authors of this study evaluated the efficacy of weekly semaglutide compared with placebo
in 3297 patients with type 2 diabetes, most of whom had cardiovascular disease and/or kidney
disease. The primary composite outcome, defined as the first occurrence of cardiovascular
death, nonfatal MI, and nonfatal stroke, occurred in fewer patients in the semaglutide group than
the placebo group (6.6% vs 8.9%, respectively; P < 0.001 for noninferiority). Compared with the
placebo group, the semaglutide group had lower rates of nonfatal MI (3.9% vs 2.9%, respectively)
and nonfatal stroke (2.7% vs 1.6%, respectively), whereas no between-group difference was
found in rates of cardiovascular death. The semaglutide group had lower rates of nephropathy
and serious adverse events but higher rates of retinopathy and drug discontinuation due to
adverse events.
•
Patients with type 2 diabetes who are at high cardiovascular risk may benefit from weekly
semaglutide treatment.
Abstract
BACKGROUND
Regulatory guidance specifies the
need to establish cardiovascular safety of new
diabetes therapies in patients with type 2 diabetes
in order to rule out excess cardiovascular risk. The
cardiovascular effects of semaglutide, a glucagon-
like peptide 1 analogue with an extended half-life
of approximately 1 week, in type 2 diabetes are
unknown.
METHODS
We randomly assigned 3297 patients with
type 2 diabetes who were on a standard-care regi-
men to receive once-weekly semaglutide (0.5 mg
or 1.0 mg) or placebo for 104 weeks. The primary
composite outcome was the first occurrence of car-
diovascular death, nonfatal myocardial infarction, or
nonfatal stroke. We hypothesized that semaglutide
would be noninferior to placebo for the primary
outcome. The noninferiority margin was 1.8 for the
upper boundary of the 95% confidence interval of
the hazard ratio.
RESULTS
At baseline, 2735 of the patients (83.0%)
had established cardiovascular disease, chronic
kidney disease, or both. The primary outcome
occurred in 108 of 1648 patients (6.6%) in the
semaglutide group and in 146 of 1649 patients
(8.9%) in the placebo group (hazard ratio, 0.74;
95% confidence interval [CI], 0.58 to 0.95; P<0.001
for noninferiority). Nonfatal myocardial infarction
occurred in 2.9% of the patients receiving semaglu-
tide and in 3.9% of those receiving placebo (hazard
ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal
stroke occurred in 1.6% and 2.7%, respectively
(hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04).
Rates of death from cardiovascular causes were
similar in the two groups. Rates of new or worsen-
ing nephropathy were lower in the semaglutide
group, but rates of retinopathy complications (vitre-
ous hemorrhage, blindness, or conditions requiring
treatment with an intravitreal agent or photoco-
agulation) were significantly higher (hazard ratio,
1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious
adverse events occurred in the semaglutide group,
although more patients discontinued treatment
because of adverse events, mainly gastrointestinal.
CONCLUSIONS
In patients with type 2 diabetes who
were at high cardiovascular risk, the rate of car-
diovascular death, nonfatal myocardial infarction,
or nonfatal stroke was significantly lower among
patients receiving semaglutide than among those
receiving placebo, an outcome that confirmed the
noninferiority of semaglutide.
N Engl J Med
2016 Sep 16;[Epub ahead of print],
Marso SP, Bain SC, Consoli A, et al.
Optimised mealtime insulin dosing for fat and
protein in type 1 diabetes
Comment by
Deborah Wexler,
MD
I
nsulin users know that blood glucose
is higher after high-fat, high-protein
(HFHP) meals than those low-fat,
low-protein (LFLP) meals with identi-
cal carbohydrate content. Smith et al
determined the incremental difference
in postprandial hyperglycaemia following
high-fat, high-protein meals and deter-
mined the additional insulin required to
cover such meals in 10 adults with type 1
diabetes using insulin pumps and con-
tinuous glucose monitors with optimised
insulin settings. Dosing insulin for carbo-
hydrate content of the meal alone using
the standard carbohydrate-to-insulin
ratio resulted in glucose incremental
area under the curve that was elevated
over twofold for HFHP compared with
LFLP. Insulin doses were 65% +/− 10%
higher than those calculated from the
carbohydrate-to-insulin ratio alone.
The optimal bolus delivery pattern was
a dual-wave bolus with 30%/70% split,
on average, over 2.5 hours with a large
degree of variability.
For diabetologists who have been
advising patients to increase dosing for
larger meals, this study allows them to
give more precise advice: adept patients,
especially those with CGM, may wish
to experiment with increasing their
bolus dose by 50% to 75% or more and
delivering it in a dual-wave pattern when
consuming high-fat, high-protein meals.
Dr Wexler is Associate Professor of
Medicine at Harvard
Medical School,
Associate Clinical
Chief of the MGH
Diabetes Unit, and
Co-Clinical Director of
the MGH Diabetes Center, Boston.
Optimized mealtime insulin dosing
for fat and protein in type 1 diabetes:
application of a model-based approach
to derive insulin doses for open-loop
diabetes management
Diabetes Care
Take-home message
•
The authors of this study evaluated insulin dosing for meals
that are high in fat and protein in 10 adults with type 1 dia-
betes. Compared with low-fat, low-protein meals, high-fat,
high-protein meals with the same carbohydrate content
required 65% more insulin with a 30%/70% split over 2.4
hours to achieve target postprandial glucose control.
•
Regardless of carbohydrate content, the fat and protein
content of meals appears to increase insulin requirements
in patients with type 1 diabetes.
Abstract
OBJECTIVE
To determine insulin dose adjustments required for
coverage of high-fat, high-protein (HFHP) meals in type 1 diabetes
(T1D).
RESEARCHDESIGNANDMETHODS
Ten adults with T1D received low-fat,
low-protein (LFLP) andHFHPmeals with identical carbohydrate con-
tent, coveredwith identical insulin doses. On subsequent occasions,
subjects repeated theHFHPmeal with an adaptivemodel-predictive
insulin bolus until target postprandial glycemic control was achieved.
RESULTS
With the same insulin dose, the HFHP increased the
glucose incremental area under the curve over twofold (13,320
± 2,960 vs. 27,092 ± 1,709 mg/dL ⋅ min; P = 0.0013). To achieve
target glucose control following the HFHP, 65% more insulin
was required (range 17–124%) with a 30%/70% split over 2.4 h.
CONCLUSIONS
This study demonstrates that insulin dose calcula-
tions need to consider meal composition in addition to carbohy-
drate content and provides the foundation for new insulin-dosing
algorithms to cover meals of varying macronutrient composition.
Diabetes Care
2016;39:1631-1634, Bell KJ, Toschi E, Steil GM,
et al.
DIABETES
VOL. 1 • No. 3 • 2016
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