Correspondence
GLP-1 receptor agonists,
See Online for appendix
764 www.thelancet.com/diabetes-endocrinology Vol 6 October 2018
mechanistic studies that assessed acute
CKD, and eGFR trajectory
The goal of renoprotective therapy is
to slow irreversible loss of functional
nephrons, thereby preserving
glomerular filtration rate (GFR) and
delaying the onset of kidney failure.
As such, the secondary renal outcomes
in the AWARD-7 trial reported by
Katherine Tuttle and colleagues1 are
of high clinical interest. At 52 weeks,
estimated GFR (eGFR) was higher
with the glucagon-like peptide-1
(GLP-1) receptor agonist dulaglutide
than with titrated insulin glargine
in patients with type 2 diabetes and
moderate-to-severe chronic kidney
disease (CKD), more than 90% of
whom were on renin–angiotensin
system blockade. Moreover, although
decreases in urine albumin-to-
creatinine ratio (UACR) from baseline
showed no between-group differences
in the overall study population,
dulaglutide 1·5 mg reduced UACR to
larger extent than did insulin glargine
in the subgroup of patients with
baseline macroalbuminuria.
Notably, glycaemic equipoise
was established between groups
throughout follow-up, which allows
direct exploration of the mechanisms
underlying these results. Besides
improving traditional renal risk
factors (ie, bodyweight and systolic
blood pressure), we agree with
the investigators that dulaglutide
(compared with insulin glargine)
might have ameliorated (renal)
inflammation and oxidative stress, as
suggested in experimental studies.2
The investigators also speculate that
dulaglutide might have favourably
modulated renal haemodynamics,
which in our opinion merits a closer
look at current and historical trial
data. As noted by David Cherney
and colleagues in their Comment
on AWARD-7,3 eGFR did not acutely
decrease after initiation of dulaglutide,
suggesting that intraglomerular
pressure is unlikely to be reduced. This
point is in line with findings from
type 2 diabetes and stage 4 CKD in the
and long-term effects of GLP-1 receptor
agonists on renal haemodynamics
in patients with type 2 diabetes, and
with eGFR trajectories seen in other
registration trials and cardiovascular
outcome studies.2 Surprisingly, the
eGFR trajectory in AWARD-7 suggests
that dulaglutide acutely increases
eGFR, possibly via vasodilation of
afferent renal arterioles,2 which might
affect clinical interpretation.
The pattern of eGFR trajectory
in response to an intervention and
timing of trial end have important
implications for the interpretation
of renal outcomes. Use of
renin–angiotensin system inhibitors
or sodium-glucose co-transporter-2
(SGLT2) inhibitors causes early
reversible reduction in GFR (via acute
amelioration of intraglomerular
pressure), opposite in direction to
their hypothesised beneficial effect
of slowing the irreversible loss
of nephrons; thus, an early faster
GFR decline is followed by a later
deceleration.4 If the SGLT2 inhibitor
cardiovascular outcome trials
EMPA-REG OUTCOME (empagliflozin)
and CANVAS (canagliflozin) had
been stopped before week 52, eGFR
difference between groups as an
endpoint would have been misleading
as mean eGFR was still lower in the
SGLT2 inhibitor group compared
with the placebo group. Conversely,
bardoxolone methyl produces an
early dose-dependent increase in
eGFR, paralleled by an increase
in albuminuria, in patients with
type 2 diabetes and CKD.5 Although this
finding initially generated interest in
this drug having the potential to delay
CKD progression, because glomerular
hyperfiltration and albuminuria are
associated with a faster decline in GFR,
bardoxolone might actually accelerate
GFR decline (appendix).
The suggestion of an early
increase in eGFR with dulaglutide in
AWARD-7 corresponds with the eGFR
trajectory associated with liraglutide
in a subgroup of 219 patients with
LEADER trial.6 Although exploratory,
in this subgroup, an initial rise in
eGFR seemed to be followed by
an accelerated eGFR decline until
study end at month 36. As such, we
encourage the AWARD-7 investigators
to explore the initial eGFR response
and perform slope analyses (omitting
the acute phase) to further detail the
effects of dulaglutide on renal function
over time. We also call for longer-
term trials of GLP-1 receptor agonists
beyond 52 weeks to assess eGFR and
albuminuria trajectories in patients
with type 2 diabetes and CKD, and to
ascertain the net balance between, on
the one hand, suggested unfavourable
drug-induced hyperfiltration and,
on the other hand, favourable
anti-inflammatory actions and benefits
on traditional risk factors on long-term
renal outcome in patients with renal
impairment. Unfortunately, dedicated
renal outcome studies in patients with
type 2 diabetes and advanced CKD
are not currently ongoing or planned
for GLP-1 receptor agonists, and
uncertainties surrounding the glucose-
independent benefits of this drug class
on hard renal endpoints are likely to
endure for years to come.
DHvR serves on advisory boards of AstraZeneca,
Boehringer-Ingelheim, MSD, Novo Nordisk and
Sanofi, with all honoraria paid to his employer.
MHAM is a consultant to Eli Lilly and Company and
NovoNordisk, with all honoraria paid to his
employer. Through DHvR, the VU University Medical
Center has received research grants from
AstraZeneca, Boehringer Ingelheim, Novo Nordisk,
and Sanofi. MJBvB declares no competing interests.
Michaël J B van Baar,
Daniël H van Raalte,
*Marcel H A Muskiet
ma.muskiet@vumc.nl
Diabetes Centre, Department of Internal Medicine,
VU University Medical Center, De Boelelaan 1117,
1081 HV Amsterdam, Netherlands
1 Tuttle KR, Lakshmanan MC, Rayner B, et al.
Dulaglutide versus insulin glargine in patients
with type 2 diabetes and moderate-to-severe
chronic kidney disease (AWARD-7):
a multicentre, open-label, randomised trial.
Lancet Diabetes Endocrinol 2018; 6: 605–17.
2 Muskiet MHA, Tonneijck L, Smits MM, et al.
GLP-1 and the kidney: from physiology to
pharmacology and outcomes in diabetes.
Nat Rev Nephrol 2017; 13: 605–28.

3 Cherney DZI, Verma S, Parker JD.
Dulaglutide and renal protection in type 2
diabetes. Lancet Diabetes Endocrinol 2018;
6: 588–90.
4 Tonneijck L, Muskiet MH, Smits MM, et al.
Glomerular hyperfiltration in diabetes:
mechanisms, clinical significance, and
treatment. J Am Soc Nephrol 2017;
28: 1023–39.
5 Pergola PE, Raskin P, Toto RD, et al.
Bardoxolone methyl and kidney function in
CKD with type 2 diabetes. N Engl J Med 2011;
365: 327–36.
6 Mann JFE, Orsted DD, Brown-Frandsen K, et al.
Liraglutide and renal outcomes in type 2
diabetes. N Engl J Med 2017; 377: 839–48.
Authors’ reply
We thank Michaël van Baar and
colleagues for encouraging closer
scrutiny of estimated glomerular
filtration rate (eGFR) in the AWARD-7
trial, which actively compared
weekly dulaglutide with daily
insulin glargine as basal therapy in
patients with type 2 diabetes and
moderate-to-severe chronic kidney
disease (CKD).1 The correspondents
propose three hypothetical GFR
trajectories for the effects of sodium-
glucose co-transporter-2 inhibitors,
glucagon-like peptide-1 (GLP-1)
receptor agonists, and bardoxolone
methyl. Between-group eGFR
comparisons might have very different
inferences if studies are stopped
before acute and chronic effects can
be discerned. In studies of individuals
with normal kidney function, use of
GLP-1 receptor agonists does not
seem to alter GFR.2,3 Among patients
with type 2 diabetes, acute exenatide
infusion did not induce glomerular
hyperfiltration based on directly
measured GFR, filtration fraction, or
calculated glomerular pressure.4
In AWARD-7, the early increase
in eGFR with dulaglutide was
slight (<2 mL/min per 1·73 m²), not
sus­tained, and accompanied by albu­
min­­uria reduction, an indicator of
protection from kidney damage.
eGFR measurements 4 weeks after
study end were almost identical
to end-of-treatment eGFR, sup­
porting the notion of largely non-
haemodynamic mechanisms.
Moreover, the dulaglutide-induced
www.thelancet.com/diabetes-endocrinology Vol 6 October 2018 765
mitigation of eGFR decline (about
50% less) was most evident in
patients with macroalbuminuria and
CKD stages 3b and 4. Similarly, in the
LEADER trial, the eGFR decline in a
type 2 diabetes subgroup with an eGFR
of 30–59 mL/min per 1·73 m² was
significantly slower (about 50% less)
in the liraglutide-treated group than
in the placebo group over 36 months.
In a much smaller subgroup with
eGFR below 30 mL/min per 1·73 m²,
liraglutide was associated with a slight
initial eGFR rise (about 3 mL/min per
1·73 m² after 6 months), followed
by decline, without a significantly
different trajectory from placebo.
Limited by small sample size, this
underpowered analysis must be
interpreted cautiously.5
Overall, the results of AWARD-7
and LEADER are complementary and
corroborative for favourable effects
of GLP-1 receptor agonists on kidney
function in patients with type 2
diabetes and CKD. Most importantly,
we agree that long-term studies of
GLP-1 receptor agonists are urgently
needed to ascertain clinical events
and outcomes that matter most to
patients, such as overall and kidney
survival and quality of life.
KRT is a consultant for Eli Lilly and Company,
Boehringer Ingelheim, Gilead Sciences, and
AstraZeneca. BR is part of advisory boards for
Boehringer Ingelheim and AstraZeneca, part of
speakers’ bureaux for Servier, Novartis, and Cipla,
and was a clinical trial investigator for Litha. RSB is
on advisory boards for Boehringer Ingelheim,
Janssen, Novo Nordisk, and Sanofi, was part of
speakers’ bureaux for Eli Lilly and Company,
Boehringer Ingelheim, Sanofi, Regeneron,
AstraZeneca, and Amarin, and has received research
support from Amgen, Novo Nordisk, Janssen,
Amarin, AstraZeneca, Eisai, and Sanofi. MCL, DBW,
and FTB are employees and shareholders of Eli Lilly
and Company and have a patent pending for the
use of dulaglutide for chronic kidney disease.
AGZ retired in December, 2017; he was an
employee and shareholder of Eli Lilly and Company
at the time that this study was done and has a
patent pending for the use of dulaglutide for
chronic kidney disease.
*Katherine R Tuttle,
Mark C Lakshmanan, Brian Rayner,
Robert S Busch, Alan G Zimmermann,
D Bradley Woodward, Fady T Botros
katherine.tuttle@providence.org
Correspondence
Providence Health Care, University of Washington,
Spokane, WA 99204, USA (KRT); Eli Lilly and
Company, Indianapolis, IN, USA (MCL, AGZ, DBW,
FTB); Division of Nephrology and Hypertension,
Groote Schuur Hospital and University of Cape
Town, Cape Town, South Africa (BR); and Albany
Medical Center Division of Community
Endocrinology, Albany, NY, USA (RSB)
1 Tuttle KR, Lakshmanan MC, Rayner B, et al.
Dulaglutide versus insulin glargine in patients
with type 2 diabetes and moderate-to-severe
chronic kidney disease (AWARD-7):
a multicentre, open-label, randomised trial.
Lancet Diabetes Endocrinol 2018; 6: 605–17.
2 Tuttle KR, McKinney TD, Davidson JA, Anglin G,
Harper KD, Botros FT. Effects of once-weekly
dulaglutide on kidney function in patients
with type 2 diabetes in phase II and III clinical
trials. Diabetes Obes Metab 2017; 19: 436–41.
3 von Scholten BJ, Persson F, Rosenlund S, et al.
The effect of liraglutide on renal function:
a randomized clinical trial. Diabetes Obes Metab
2017; 19: 239–47.
4 Tonneijck L, Smits MM, Muskiet MHA, et al.
Acute renal effects of the GLP-1 receptor
agonist exenatide in overweight type 2
diabetes patients: a randomised, double-blind,
placebo-controlled trial. Diabetologia 2016;
59: 1412–21.
5 Mann JFE, Orsted DD, Brown-Frandsen K, et al.
Liraglutide and renal outcomes in type 2
diabetes. N Engl J Med 2017; 377: 839–48.
Work stress and
mortality in people with
cardiometabolic disease
In The Lancet Diabetes & Endocrinology,
Mika Kivimäki and colleagues1
reported findings from a multicohort
study from the IPD-Work consortium
in working populations, showing that,
in men with cardiometabolic disease,
high job strain was associated with
increased risk of death, independently
of conventional risk factors and
lifestyle factors. Notably, job strain
was not associated with risk of
mortality in individuals without
cardiometabolic disease. However,
in a collaborative meta-analysis of
individual participant data from the
same consortium,2 job strain was
shown to be a risk factor for coronary
heart disease in people without
baseline cardiovascular disease. The
inconsistency between the finding
of the recent study and the earlier
report might be due to differences in
sample size, baseline characteristics,