Correspondence
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
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,