Comment
FDA approval of dapagliflozin for chronic kidney disease:
a remarkable achievement?
Chronic kidney disease (CKD) affects 12% of the
population worldwide,1 is a major cause of morbidity
and mortality, and consumes health-care resources.2
A primary therapeutic goal for the treatment of CKD is
prevention of kidney failure and cardiovascular disease
(CVD).3,4 Healthy lifestyle behaviours, blood pressure (BP)
lowering, maintaining glucose control (in people with
diabetes), and renin and angiotensin aldosterone system
(RAAS) blockers have been the cornerstone of therapy
for patients with CKD since the late 1990s.3,5 No new
drug or therapy has been shown to slow the progression
of CKD to kidney failure in the past two decades.
On April 30, 2021, the US Food and Drug Admin­
istration (FDA) approved the SGLT2 inhibitor dapagliflozin
in patients to reduce the risk of adverse kidney and
CVD outcomes in patients with CKD who are at risk of
progression.6 Dapagliflozin is the first SGLT2 inhibitor to
be approved by any regulatory agency for patients with
CKD irrespective of diabetes status.
SGLT2 inhibitors were primarily developed as
glucose-lowering agents in individuals with type 2
diabetes and have pleiotropic effects on reducing
CVD mortality, kidney failure, and related mortality.
These favourable effects were reported in major trials,
including the Empagliflozin Cardiovascular Outcome
Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-
REG),7 the Canagliflozin and Cardiovascular and Renal
Events in Type 2 Diabetes (CANVAS) programme,8 and
the Canagliflozin and Renal Events in Diabetes, and
Established Nephropathy Clinical Evaluation (CREDENCE)
trial.9 Subsequently, trials of SGLT2 inhibitors enrolled
patients with heart failure and showed the benefit
of empagliflozin and dapagliflozin on reducing
hospitalisation and CVD deaths.10,11 Empagliflozin also
slowed decline in kidney function.11 The benefit of SGLT2
inhibitors seems to be multifactorial, mediated by a
combination of natriuresis, reduced intra­ glomerular
pressure, tubuloglomerular feedback, blood pressure
lowering, and reduced oxidative stress and fibrosis.12
Several SGLT2 inhibitors are already approved by
regulatory agencies, such as the FDA and European
Medicines Agency. However, they were not licensed for
CKD due to the absence of a specific trial. Dapagliflozin
www.thelancet.com Vol 398 July 24, 2021 283
and Prevention of Adverse Outcomes in Chronic Kidney
Disease (DAPA-CKD) was the first SGLT2 inhibitor trial
in patients with proteinuric CKD with and without
Sebastian Kaulitzki/Science Photo Library
diabetes.13
The DAPA-CKD trial13 examined the effect of
dapagliflozin compared with placebo in 4304 patients
(of whom about a third were women, and half were of
White ethnicity) with primarily proteinuric CKD, and at
least 30% of whom did not have diabetes. In the DAPA-
CKD trial, dapagliflozin was superior in preventing the Published Online
June 4, 2021
primary composite of worsening of kidney function or https://doi.org/10.1016/
risk of cardiovascular or kidney death (hazard ratio 0·61; S0140-6736(21)01242-3
95% CI 0·51–0·72; p<0·001). The secondary outcome
of worsening of kidney function or kidney death was
reduced by 44% among patients in the dapagliflozin
group (p<0·001). Death from any cause was reduced by
31% in the trial participants on dapagliflozin (p=0·004).
The benefit of dapagliflozin occurred equally in patients
with and without diabetes, and was incremental to
a background therapy with RAAS blockers. No major
adverse events including hypoglycaemia were attributed
to dapagliflozin. At least a third of those without diabetes
had changes associated with ischaemic and hyper­
tensive nephropathy, and had chronic glomerulonephritis
(especially IgA nephropathy).13 As the study sample was
reasonably diverse in terms of the clinical characteristics
and the underlying causes of CKD, the trial findings were
thus generalisable to a wide spectrum of patients with
CKD in the real world. However, CKD patients without
proteinuria (albuminuria <200 mg/g) were excluded
from the DAPA-CKD trial. Patients without proteinuria
are generally at lower risk of adverse CKD outcomes.5 But
reduced estimated glomerular filtration rate, especially
below 45 mL/min per 1·73 m², is associated with
increased risk of kidney failure even in non-proteinuric
CKD.14 The Study of Heart and Kidney Protection With
Empagliflozin (EMPA-KIDNEY; NCT03594110) enrolled
CKD patients, including those without proteinuria, and
is expected to complete in 2022. Patients with type 1
diabetes, polycystic kidney disease, and recent immune
disorders have not been included in trials of SGLT2
inhibitors, and therefore the use of SGLT2 inhibitors in
these patients remains investigational.
 Comment
Several barriers need to be addressed before the wide
adoption of SGLT2 inhibitors in health systems and
clinical practices. First, endorsement of SGLT2 inhibitors
for CKD in major clinical practice guidelines, such as
Kidney Disease Improving Global Outcomes (KDIGO)
and National Institute for Health and Care Excellence
(NICE), is needed. Effectiveness and safety data from
several trials attest to the benefit of SGLT2 inhibitors
with fairly low risks of side-effects, such as genital fungal
infections, that are manageable in routine practice.15
Second, there can be physician inertia in prescribing
guideline-recommended medications appropriately.
For example, the use of RAAS blockers in patients
with proteinuric CKD remains under 50% in the USA.16
Strategies for provider training and quality improvement
initiatives could improve evidence-based prescribing.17
Third, the third-party coverage of the cost of SGLT2
inhibitors is not guaranteed. The annual cost of 10 mg
dapagliflozin is about US$4800 per person in the USA.18
Country-specific cost-effectiveness, budget impact, and
willingness-to-pay analyses in patients with CKD will
be helpful for public and private health-care systems,
including those where patients have substantial out-
of-pocket expenses. Additionally, targeted subsidies
may be needed for minority ethnic and low-income
populations with CKD to address the existing inequities
in CKD outcomes.19 Fourth, the applicability of SGLT2
inhibitors for CKD among minority ethnic populations,
although likely, requires further research.20,21 Black people
were poorly represented (about 6%) in SGLT2 inhibitor
trials. Although 34% of the participants in the DAPA-CKD
trial were people of Asian origin, they were from east
Asian countries. Future trials of SGLT2 inhibitors must
be more inclusive of the minority ethnic populations at
high risk of CVD and CKD. Finally, almost half a billion
people with CKD live in low-income and middle-income
countries where access to quality health care is poor
and deaths from kidney failure are high.1,22 Industry,
government, and non-government organisations will
need to collaborate effectively to ensure equitable access
to SGLT2 inhibitors for the management of CKD in
disadvantaged populations globally.
The FDA approval of dapagliflozin is a key step in
cementing SGLT2 inhibitors into clinical practice.
Finally, clinicians have an additional therapy to offer for
modifying prognosis in CKD patients. Concerted efforts
for wide dissemination and implementation of CKD
284 www.thelancet.com Vol 398 July 24, 2021
management programmes that include SGLT2 inhibitors
are now a priority.
I declare no competing interests.
Tazeen H Jafar
tazeen.jafar@duke-nus.edu.sg
Programme in Health Services and Systems Research, Duke-NUS Medical School,
169857 Singapore; Department of Renal Medicine, Singapore General Hospital,
Singapore; Duke Global Health Institute, Duke University, Durham, NC, USA
1 Mills KT, Xu Y, Zhang W, et al. A systematic analysis of worldwide
population-based data on the global burden of chronic kidney disease
in 2010. Kidney Int 2015; 88: 950–57.
2 GBD Chronic Kidney Disease Collaboration. Global, regional, and national
burden of chronic kidney disease, 1990–2017: a systematic analysis for the
Global Burden of Disease Study 2017. Lancet 2020; 395: 709–33.
3 Webster AC, Nagler EV, Morton RL, Masson P. Chronic kidney disease. Lancet
2017; 389: 1238–52.
4 Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney
disease and cardiovascular risk: epidemiology, mechanisms, and prevention.
Lancet 2013; 382: 339–52.
5 Jafar TH, Stark PC, Schmid CH, et al. Progression of chronic kidney disease:
the role of blood pressure control, proteinuria, and angiotensin-converting
enzyme inhibition: a patient-level meta-analysis. Ann Intern Med 2003;
139: 244–52.
6 US Food and Drug Administration. FDA approves treatment for chronic
kidney disease. April 30, 2021. https://www.fda.gov/news-events/press-
announcements/fda-approves-treatment-chronic-kidney-disease (accessed
May 26, 2021).
7 Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular
outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117–28.
8 Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and
renal events in type 2 diabetes. N Engl J Med 2017; 377: 644–57.
9 Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in
type 2 diabetes and nephropathy. N Engl J Med 2019; 380: 2295–306.
10 McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients
with heart failure and reduced ejection fraction. N Engl J Med 2019;
381: 1995–2008.
11 Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with
empagliflozin in heart failure. N Engl J Med 2020; 383: 1413–24.
12 Kidokoro K, Cherney DZI, Bozovic A, et al. Evaluation of glomerular
hemodynamic function by empagliflozin in diabetic mice using in vivo
imaging. Circulation 2019; 140: 303–15.
13 Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. Dapagliflozin in
patients with chronic kidney disease. N Engl J Med 2020; 383: 1436–46.
14 Matsushita K, Coresh J, Sang Y, et al. Estimated glomerular filtration rate
and albuminuria for prediction of cardiovascular outcomes: a collaborative
meta-analysis of individual participant data. Lancet Diabetes Endocrinol
2015; 3: 514–25.
15 Palmer SC, Tendal B, Mustafa RA, et al. Sodium-glucose cotransporter
protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor
agonists for type 2 diabetes: systematic review and network meta-analysis
of randomised controlled trials. BMJ 2021; 372: m4573.
16 Chu CD, Powe NR, McCulloch CE, et al. Angiotensin-converting enzyme
inhibitor or angiotensin receptor blocker use among hypertensive
US adults with albuminuria. Hypertension 2021; 77: 94–102.
17 Eberly LA, Yang L, Eneanya ND, et al. Association of race/ethnicity, gender,
and socioeconomic status with sodium-glucose cotransporter 2 inhibitor use
among patients with diabetes in the US. JAMA Netw Open 2021; 4: e216139.
18 Chakravarty A, Rastogi M, Dhankhar P, Bell KF. Comparison of costs and
outcomes of dapagliflozin with other glucose-lowering therapy classes
added to metformin using a short-term cost-effectiveness model in the
US setting. J Med Econ 2018; 21: 497–509.
19 Trehan A, Winterbottom J, Lane B, et al. End-stage renal disease in
Indo-Asians in the North-West of England. QJM 2003; 96: 499–504.
20 Parsa A, Kao WH, Xie D, et al. APOL1 risk variants, race, and progression of
chronic kidney disease. N Engl J Med 2013; 369: 2183–96.
21 Misra A, Tandon N, Ebrahim S, et al. Diabetes, cardiovascular disease,
and chronic kidney disease in South Asia: current status and future
directions. BMJ 2017; 357: j1420.
22 Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global
dimension and perspectives. Lancet 2013; 382: 260–72.