Nephrol Dial Transplant (2015) 30: 1272–1276
doi: 10.1093/ndt/gfu299
Advance Access publication 17 September 2014
Full Reviews
Sodium-glucose cotransport inhibitors: mechanisms,
metabolic effects and implications for the treatment
of diabetic patients with chronic kidney disease
George Vlotides and Peter R. Mertens
Department of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, Magdeburg, Germany
Correspondence and offprint requests to: Peter R. Mertens; E-mail: [email protected]
diabetics has a huge potential to meet patients’ needs. However,
it awaits quick results from clinical trials with meaningful
clinical endpoints.
A B S T R AC T
Remarkable progress has been achieved in the field of diabetes
with the development of incretin analogues, dipeptidyl peptidase IV inhibitors and novel insulin analogues; nevertheless,
there is an unmet need for additional therapeutic options. Individualization of HbA1c target levels is a recent progress
within the field. Approximately 50% of diabetics do not reach a
previously aspired treatment goal of glycosylated HbA1 levels
below 7% and often face a vicious circle with accelerated weight
gain. Current antidiabetic therapeutics mainly target the decline
in insulin secretion and ameliorate insulin resistance. In this
regard a new generation of drugs, denoted gliflozines, that specifically interfere with sodium-glucose cotransporters (SGLT)-2
and exhibit a favourable impact on glucose metabolism in patients with type 2 diabetes are emerging as hopeful avenues.
The resultant negative energy balance caused by glucosuria
results in long-term weight losses, significantly reduced HbA1c
levels approximating 0.5–1.0% and may in addition exert beneficial effects on blood pressure, reactive oxygen products and inflammatory mediators. Recent studies indicate improvement in
β-cell glucose sensitivity and insulin sensitivity in patients
treated with gliflozines, a decrease in tissue glucose disposal and
interestingly an increase in endogenous glucose production.
The list of side effects observed under SGLT2 inhibition
includes increased rates of genitourinary infections, balanitis,
vulvovaginitis, hypotensive episodes and acute deterioration of
kidney function. Main questions towards the safety profile are
still unanswered given that long-term clinical outcome data
with SGLT2 inhibition are lacking and the cardiovascular safety
profile is under scrutiny in large trials. Thus, the successful development of selective SGLT2 inhibitors for therapeutic use in
© The Author 2014. Published by Oxford University Press
on behalf of ERA-EDTA. All rights reserved.
Keywords: diabetes, gliflozines, glucosuria, inflammation,
nephropathy
G L U C O S E M E TA B O L I S M I N T H E K I D N E Y
The kidney is a key player in glucose metabolism. Under
physiological conditions, the kidney filters ∼180 L of plasma
per day [1, 2]. At ∼90–100 mg/dL plasma glucose levels,
almost all glucose (∼162–180 g) is filtered and reabsorbed primarily in the proximal tubule and returned to the circulation
[1, 2]. At glucose concentrations exceeding a ‘threshold’ of
160–180 mg/dL, the maximum capacity of glucose transport
(Tm) of the proximal tubule (on average ∼375 mg/min) is exceeded, resulting in excretion of glucose in the urine [1, 2].
Renal glucose reabsorption in the proximal tubule is regulated by sodium-glucose transporters (SGLTs) and facilitative
glucose transporters (GLUTs) [1, 2] (Figure 1). GLUTs facilitate
glucose movement from the extracellular to the intracellular
space along its chemical gradient without energy consumption,
while SGLTs actively transport glucose against its concentration
gradient using the energy provided by sodium cotransport
[3–5].
Seven different SGLTs have been identified so far [6];
SGLT2 and SGLT1 are best characterized in humans and have
a defined role in renal glucose reabsorption [5, 6]. The human
SGLT1 transporter is expressed in the intestinal mucosa transporting glucose and galactose across the intestinal mucosa. In
the kidney, it is expressed in the S3 segment of the proximal
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F I G U R E 1 : Schematic overview on the predominant distribution of
SGLT1 and SGLT2 receptors along the nephron.
H I S T O R I C A L O V E R V I E W A N D D E V E LO P M E N T
O F S G LT 2 I N H I B I T O R S
The first model for active transport of glucose and other molecules was proposed by Bob Crane in 1960 at the Symposium
on Membrane Transport and Metabolism in Prague [11],
where he described the Na+/glucose cotransport hypothesis.
According to Crane’s hypothesis, glucose is actively transported across the plasma membrane by a Na+/glucose cotransporter driven by the inward Na+ gradient maintained by the
Na+ pump. This process could be blocked directly by phlorizin-mediated inhibition of cotransport or indirectly through
strophantidin-mediated inhibition of the Na+ pump and associated reduction of the Na+ gradient (discussed in [6]).
Experimental data in support of the presence of higherand lower-affinity Na+/glucose transporters at different renal
sites [12–14], as well as the absence of clinical overlap in inherited defects of glucose transport in the kidney (such as familial
renal glucosuria) or intestine (such as intestinal glucose/galactose malabsorption), suggested the presence of at least two different Na+/glucose transporters and ultimately led to the
cloning and characterization of SGLT1 (chromosome 22
q13.1) and SGLT2 (chromosome 13 p11.2) [15–17].
Phlorizin was isolated from the bark of apple trees in 1835
by the French chemist Petersen with first reports on its
SGLT2 inhibition: effects and side effects
SODIUM-GLUCOSE COTRANSPORTER 2
I N H I B I T I O N : E F F E C T S I N E X P E R I M E N TA L
DIABETES MODELS
Approximately 60% of filtered glucose is lost into the urine of
animals with genetic deficiency of SGLT2. Experimental evidence have been collected to determine whether dapagliflozin
acts in a nephroprotective manner in diabetes. To this extent
experimental models have been set up in rodents. In db/db
mice, dapagliflozin applied for 12 weeks markedly reduced the
inflammatory response in the kidney, such as less macrophage
infiltrates, lower cytokine levels (e.g. TGF-β and MCP-1) as
well as lower apoptosis rates. These alterations were recapitulated in an in vitro tubular cell model [25]. Most importantly,
extensive experimental studies indicate anti-oxidative effects
by SGLT2 inhibition, that is suppressed high-glucose induced
ROS generation, with dapagliflozin. Such protective effects
were also seen in a type 2 diabetic rat model [25].
SODIUM-GLUCOSE COTRANSPORTER 2
INHIBITION: EFFECTS BEYOND
GLUCOSURIA
In the April issue of the Journal of Clinical Investigation,
Ferrannini and colleagues report the metabolic response to
SGLT2 inhibition in type 2 diabetic patients [26]. Sixty-six
patients with type 2 diabetes were evaluated at baseline, after a
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FULL REVIEW
tubule and is responsible for ∼10% of glucose reabsorption
[1, 7]. Human SGLT2 is primarily expressed in the S1 segment
of the proximal tubule. It is a low-affinity and high-capacity
transporter responsible for ∼90% of glucose reabsorption
[1, 8].
In the light of the evolutionary process, increased renal
SGLT2 expression in response to high plasma glucose concentrations, as observed in experimental settings [9], may contribute to conservation of energy and particularly glucose for the
brain. However, in patients with type 2 diabetes and increased
Tm for glucose [10], this mechanism increases hyperglycaemia. Therefore, efforts have been undertaken to block renal
glucose reabsorption leading to the development of SGLT2
inhibitors.
glucosuric action [2]. It was the first SGLT inhibitor to be
identified [18, 19]. Phlorizin is a 20 -0-glucoside of phloretin,
belonging to a group of dihydrochalcones, a type of flavonoids
[2] and inhibits both SGLTs in the proximal tubule with a 6fold higher affinity for SGLT2 than SGLT1. The main disadvantages of phlorizin are its limited bioavailability (∼15%) and
adverse gastrointestinal (GI) effects [1, 2].
The first orally available derivative of phlorizin, T-1095,
was developed in 1999 [20]. However, due to lack of selectivity
and safety concerns, further development was discontinued [1,
2]. Other SGLT inhibitors developed at an early stage include
serigliflozin and remogliflozin [1, 2], which showed SGLT2 selectivity and promising glucosuric effects in patients with type
2 diabetes [2, 21]. Atigliflozin [22] and TS-033 [23] also displayed SGLT2 selectivity and reached phase II clinical trials
[2] but further development was discontinued. Despite initial
promising results, the development of these O-glucoside compounds was discontinued at an early stage, probably because
of hydrolytic susceptibility to β-glucosidase degradation and
associated gastrointestinal adverse effects [2]. The discovery of
C-glucoside derivatives, such as canagliflozin and dapagliflozin, enabled bypass of glucosidase susceptibility and degradation, thus reducing gastrointestinal side effects of these
compounds. At present, at least eight SGLT2 inhibitors with
differing characteristics have been developed and are being
tested in clinical trials, selectivity ranges from 155- to 2912fold for SGLT2 over SGLT1 [24].
FULL REVIEW
single 25 mg empagliflozin dose (acute study), and after a 4week daily treatment (chronic study).
Every time the patients received a mixed meal coupled with
dual-tracer glucose, enabling the quantification of the separate
contribution of meal-derived glucose, endogenous glucose
production (EGP) and whole-body glucose disposal to plasma
glucose concentrations. With the use of indirect calorimetry,
changes in substrate utilization and energy expenditure were
assessed.
Acute study
A single dose of 25 mg empagliflozin induced glucosuria
during fasting (3 h preceding meal ingestion) and after meal
ingestion. Fasting plasma glucose dropped and plasma insulin
decreased more than glucagon, resulting in a decreased prehepatic molar concentration ratio. After meal ingestion, glucose
and insulin decreased, while the glucagon response increased.
Fasting EGP was increased ∼30%, and EGP was also greater
throughout meal absorption. Oral glucose appearance was
unchanged, but tissue glucose disposal (TGD) was reduced
(20%) due to decreased non-oxidative glucose disposal,
despite an improvement in insulin sensitivity. No changes
were observed in lipid or protein oxidation, resting energy
expenditure or meal-induced thermogenesis. Empagliflozin at
25 mg increased glucose sensitivity and decreased total insulin
output, enhanced the GLP-1 response to the meal and blunted
free fatty acid (FFA) suppression.
Chronic study
Administration of 25 mg empagliflozin daily for 4 weeks
also induced fasting and post-prandial glucosuria and decreased HbA1c and plasma glucose. Similar to the results
obtained in the acute study, empagliflozin increased EGP, decreased fasting and post-prandial plasma insulin levels and the
glucagon response was still increased, but somewhat less than
in the acute study. Fasting and post-prandial TGD was also
decreased, with both glucose oxidation and non-oxidative
glucose disposal contributing to the decrease. There was a concomitant rise in lipid oxidation, while no changes in protein
oxidation or meal-related energy expenditure were observed.
The effects on β-cell glucose and insulin sensitivity, GLP-1
response and FFA suppression were similar to those in the
acute study.
as metformin, sulfonylurea and pioglitazone or with insulin
results in significant reduction in HbA1c and fasting plasma
glucose levels [1, 2]. Adverse side effects include genital mucotic
and urinary tract infections, polyuria with associated reduction
of intravascular volume and hypotension, increased low-density
lipoprotein cholesterol, increased serum creatinine levels and decreased eGFR (usually transient), electrolyte disorders (such as
hyperkalaemia, hypermagnesemia and hyperphosphatemia) and
a slightly higher incidence of fracture compared with placebo [1,
2].
Treatment is contraindicated in patients with an eGFR <
45 mL/min/1.73 m2, end-stage renal disease undergoing renal
replacement therapy, furthermore prescription for children
and adolescent at age <18 years is not recommended, pregnancy and lactation are contraindications [2].
Dapagliflozin
The C-glucoside dapagliflozin (Forxiga) was approved by
the European Medicines Agency (EMA) in April 2012 and by
the US FDA in January 2014 (once daily 5 or 10 mg tablet) for
the treatment of patients with type 2 diabetes [1, 2, 28]. It is
not recommended for patients with an eGFR < 60 mL/min/
1.73 m2.
Completed phase III trials show that treatment with dapagliflozin (5 or 10 mg daily) consistently decreases HbA1c
(>0.5%) compared with placebo. Reductions in fasting and
post-prandial plasma glucose contributed equally to the reductions in HbA1c [1]. In addition to monotherapy, dapagliflozin
is also recommended in combination with metformin, insulin
and insulin sensitizers [2]. Reductions in HbA1c were independent of the duration of diabetes: Zhang et al. [29] treated
151 patients with new-onset diabetes and 58 patients with
long-standing diabetes and obtained comparable reductions in
HbA1c.
Adverse effects include increased risk of vulovaginitis and
balanitis, probably associated to dapagliflozin-associated glucosuria and dehydration-associated hypotension [28]. As an
increased number of bladder cancers were diagnosed among
dapagliflozin users in the clinical trials, the use is not recommended for patients with active bladder cancer [28].
Other C-glucosides in late stages of clinical development
include empagliflozin and ipragliflozin, which both cause
dose-dependent glucosuria, decrease HbA1c and fasting
plasma glucose, as well as body weight [1, 30–33].
G L I F LO Z I N E S I N T H E C L I N I C A L S E T T I N G
Canagliflozin
The C-glucoside canagliflozin (Invokana) was approved by
the US Food and Drug Administration (US FDA) in 2013 (once
daily 100 or 300 mg tablet) for the treatment of type 2 diabetes
[2, 27]. Appropriate dosing depends on renal function: at an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2
the starting dose is 100 mg and can be increased to 300 mg once
daily. At an eGFR ≤ 60 mL/min/1.73 m2 the recommended dose
is 100 mg daily, while at an eGFR < 45 mL/min/1.73 m2 canagliflozin is not recommended [2, 27]. Treatment with canagliflozin
as monotherapy or in combination with other oral agents such
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E F F I C AC Y A N D S A F E T Y O F T H E U S E O F
T H E S E D R U G S , E S P E C I A L LY I N P AT I E N T S
WITH CHRONIC KIDNEY DISEASE
Safety issues for SGLT2 inhibitors mainly concern the frequency
and severity of urinary tract and genital infections with predominance in females, ranging between 2.8 and 7.2%, which has
been confirmed in meta-analyses [34]. In placebo-controlled
studies, episodes of hypoglycaemia do not seem to be more
often in SGLT2 monotherapy, but may be more frequent in
combination therapies with sulfonylurea and insulin.
G. Vlotides and P.R. Mertens
O U T LO O K
The novel mode of action of gliflozines resulting in a negative
energy balance with weight loss or neutral weight development
as well as positive effects on whole-body metabolic effects
renders SGLT2 inhibition attractive.
Future studies are needed to address the potential synergistic effects of pharmacotherapy with SGLT2 inhibitors in combination with other antidiabetics and will address safety issues
that relate to cardiovascular outcome, cancerogenesis as well
as side effects on kidney function. Experimental data suggest
SGLT2 inhibition: effects and side effects
that gliflozines may provide beneficial effects for patients with
incipient diabetic nephropathy. If confirmed in future studies,
this would render them even more appealing, especially for
kidney patients.
C O N F L I C T O F I N T E R E S T S TAT E M E N T
The results presented in this paper have not been published
previously in whole or part.
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In one trial the relative risk of bladder and breast cancer
was increased in a dapagliflozin treatment group, resulting in a
transient hold signal of the FDA advisory committee board.
Given that additional clinical data with 8000 person-years exposure did not show any differences in cancer incidence, the
approval by the FDA was thereafter provided in 2014 [24]. In
patients suffering from bladder or breast cancer, gliflozines
should not be prescribed until more clinical data are available.
One of the major issues still under debate is the cardiovascular risk profile of SGLT2 inhibition. The incidence of cardiovascular events was observed to be increased in the first 30
days post-initiation of treatment with a hazard ratio of 6.5
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patients undergoing hypotensive episodes. A large prospective
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pressure [35]. According to the FDA recommendation, dapagliflozin should not be used in diabetics with ketoacidosis and
is contraindicated in those with moderate-to-severe renal
impairment or dialysis. Nonetheless more clinical data are
urgently needed. The mild diuretic effect with an excess diuresis of 200–400 mL/day in the first 2–3 days following initiation of therapy is not accompanied by electrolyte disorders.
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Received for publication: 24.7.2014; Accepted in revised form: 15.8.2014
Nephrol Dial Transplant (2015) 30: 1276–1285
doi: 10.1093/ndt/gfu309
Advance Access publication 7 October 2014
Kidney paired donation: principles, protocols and programs
Paolo Ferrari1,2,3*, Willem Weimar4,5, Rachel J. Johnson6, Wai H. Lim2,7 and Kathryn J. Tinckam8,9
1
Department of Nephrology, Fremantle Hospital, Fremantle, WA, Australia, 2School of Medicine and Pharmacology, University of Western
Australia, Perth, Australia, 3Organ and Tissue Authority, Canberra, ACT, Australia, 4Department of Internal Medicine and Transplantation,
Erasmus MC, University Medical Center, Rotterdam, The Netherlands, 5Dutch Transplant Foundation, Leiden, The Netherlands, 6NHS Blood
and Transplant, NHS, Bristol, UK, 7Department of Nephrology, Sir Charles Gairdner Hospital, Perth, Australia, 8Division of Nephrology,
Department of Medicine and HLA Laboratory, Laboratory Medicine Program, University Health Network, Toronto, ON, Canada and
9
Canadian Blood Services, Organ Donation and Transplantation, Toronto, ON, Canada
*Correspondence and offprint requests to: Paolo Ferrari; E-mail: [email protected]
pairs in order to find potentially compatible transplant solutions. Given the significant immunologic barriers with fewer
donor options, single-center or small KPD programs may be
less successful in transplanting the more sensitized patients;
the optimal solution for the difficult-to-match patient is access
to more potential donors and large multicenter or national
registries are essential. Multicenter KPD programs have
become common in the last decade, and now represent one of
the most promising opportunities to improve transplant rates.
A B S T R AC T
Due to the ongoing shortage of deceased-donor organs, novel
strategies to augment kidney transplantation rates through expanded living donation strategies have become essential.
These include desensitization in antibody-incompatible transplants and kidney paired donation (KPD) programs. KPD
enables kidney transplant candidates with willing but incompatible living donors to join a registry of other incompatible
© The Author 2014. Published by Oxford University Press
on behalf of ERA-EDTA. All rights reserved.
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