Practice Update: Diabetes

18 / 24

Differential Effects of Dapagliflozin on
Cardiovascular Risk Factors at Varying
Degrees of Renal Function
Clinical Journal of the American Society of Nephrology: CJASN
Take-home message
• Dapagliflozin, a glucose-lowering
drug, selectively inhibits SGLT2
and has been shown to decrease
HbA1c, body weight, BP and urinary
albumin-to-creatinine ratio. Previous
studies suggest that HbA1c-lowering
effects of dapagliflozin are attenu-
ated with impaired renal function.
The authors in this study investigated
other cardiovascular risk factors at
different eGFR levels. Data from 11
phase III clinical trials were pooled
to assess the effect of 10 mg dapag-
liflozin vs placebo over 24 weeks in
patients with type 2 diabetes with
different baseline eGFR. Effects of
dapagliflozin on body weight, BP,
and urinary albumin-to-creatinine
ratio were similar and were not influ-
enced by baseline eGFR. Adverse
events occurred more frequently in
the lowest eGFR subgroup in both
dapagliflozin and placebo-treated
patients.
• The effect of dapagliflozin may be
partly mediated via non-glucosuric
dependent mechanisms.
Abstract
BACKGROUND AND OBJECTIVE Sodium
glucose cotransporter 2 inhibition with
dapagliflozin decreases hemoglobin A1c
(HbA1c), body weight, BP, and albuminu-
ria (urinary albumin-to-creatinine ratio).
Dapagliflozin also modestly increases
hematocrit, likely related to osmotic
diuresis/natriuresis. Prior studies sug-
gest that the HbA1c-lowering effects of
dapagliflozin attenuate at lower eGFR.
However, effects on other cardiovascu-
lar risk factors at different eGFR levels
are incompletely understood.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
This pooled analysis of 11 phase 3 clinical tri-
als assessed changes in HbA1c, body weight,
BP, hematocrit, and urinary albumin-to-creati-
nine ratio with placebo (n=2178) or dapagliflozin
10 mg (n=2226) over 24 weeks in patients with
type 2 diabetes according to baseline eGFR
(eGFR≥45 to <60 ml/min per 1.73 m(2), eGFR≥60
to <90 ml/min per 1.73 m(2), and eGFR≥90 ml/
min per 1.73 m(2)).
RESULTS Compared with placebo, reductions
in HbA1c with dapagliflozin were 0.6%, 0.5%,
and 0.3%, respectively, for each consecu-
tive lower eGFR subgroup (P value interaction
<0.001). Effects of dapagliflozin on hematocrit,
body weight, and BP were similar regardless of
baseline eGFR, suggesting that effects poten-
tially related to volume and natriuresis are eGFR
independent. Moreover, among individuals with
baseline urinary albumin-to-creatinine ratio ≥30
mg/g, placebo-adjusted reductions in urinary
albumin-to-creatinine ratio were larger in the low-
est eGFR subgroup (P value interaction <0.001).
Adverse events occurred more frequently in the
lowest eGFR subgroup; this was true for both
dapagliflozin- and placebo-treated patients.
CONCLUSIONS The HbA1c-lowering effects
of dapagliflozin decrease as renal function
declines. However, dapagliflozin consistently
decreases body weight, BP, and urinary albu-
min-to-creatinine ratio regardless of eGFR.
These effects in conjunction with the finding of
similar effects on hematocrit, a proxy for vol-
ume contraction, suggest that the effects of
dapagliflozin are partly mediated via nongluco-
suric-dependent mechanisms.
Differential effects of dapagliflozin on cardi-
ovascular risk factors at varying degrees of
renal function. Clin J Am Soc Nephrol 2017
May 08;12(5)751-759, S Petrykiv, CD Sjöström,
PJ Greasley, et al.
COMMENT
By Mark E Molitch MD
In this paper, Petrykiv et al report that
the SGLT2 inhibitor dapagliflozin causes
similar reductions in body weight, blood
pressure (BP), and albumin excretion, and
an increase in hematocrit regardless of
the degree of chronic kidney disease
(CKD), based on eGFR levels of 45-60,
61-89, and >90 mL/min/1.73 m2, despite
reductions in the efficacy of dapagliflozin
in improving hemoglobin A1c as the GFR
decreased.1 These data were obtained
from a pooled analysis of 11 phase III clinical
trials. Similar results have been found in
a prospective, placebo-controlled trial of
patients with CKD with empagliflozin and
with canagliflozin from a pooled analysis
of 4 clinical trials of patients with CKD.2,3
Prospective, randomized trials of patients
with CKD treated with canagliflozin and
dapagliflozin are ongoing.
If these results do not parallel the changes
in glucose levels, what is causing them?
We diabetologists tend to forget the first
letter of SGLT2; the “S” stands for sodium.
In addition to glucose, these drugs also
block sodium reabsorption in the proximal
tubule. This results in a greater delivery
of sodium to the macula densa, which
increases tubuloglomerular feedback,
resulting in reduced intraglomerular
pressure.4,5 The increased urinary sodium
loss and volume contraction also lead to
the BP and weight reduction.4 In the EMPA-
REG study, both cardiovascular and renal
long-term outcomes were very significantly
improved, likely substantially due to these
nonglycemic factors.6,7 The results of
the cardiovascular outcomes study for
canagliflozin (CANVAS) will be presented at
the American Diabetes Association annual
meeting in San Diego in June 2017, and a
similar study for dapagliflozin is still ongoing.
So, what is the clinician to do with these
drugs as the GFR falls? Clearly, these drugs
are less effective from a glycemic control
perspective when the eGFR is <60 mL/
min/1.73 m2. Dapagliflozin is not approved
for use when the eGFR falls below this
point, but empagliflozin and canagliflozin
can be used down to an eGFR <45 mL/
min/1.73 m 2, albeit the dose of canagliflozin
CARDIOVASCULAR COMPLICATIONS 18
PRACTICEUPDATE DIABETES