Can J Diabetes 39 (2015) S167S175

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Review

The Role of the Kidney and SGLT2 Inhibitors in Type 2 Diabetes

Pamela M. Katz MD a,*, Lawrence A. Leiter MD, FRCPC b
aDepartment of Medicine, Section of Endocrinology and Metabolism, University of Manitoba, St. Boniface Hospital, Winnipeg, Manitoba, Canada
b
Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michaels Hospital, Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario,
Canada

a r t i c l e i n f o a b s t r a c t

Article history: Effective glycemic control reduces the risk for diabetes-related complications. However, the majority of
Received 9 July 2015
patients with type 2 diabetes still do not achieve glycemic targets. Beyond metformin therapy, current
Received in revised form
practice guidelines for the management of type 2 diabetes recommend individualized treatment based
24 August 2015
Accepted 1 September 2015 on patient and agent characteristics. The sodium glucose cotransporter type 2 (SGLT2) inhibitors repre-
sent a novel treatment strategy, independent of impaired beta-cell function and insulin resistance. SGLT2
inhibitors decrease renal glucose reabsorption, thereby increasing urinary glucose excretion with sub-
Keywords:
ecacy sequent reduction in plasma glucose levels and glycosylated hemoglobin concentrations. Current evi-
kidney dence suggests that they are effective as monotherapy or as add-ons to metformin either alone, or in
safety combination with other oral glucose-lowering agents or insulin. They are generally well tolerated, though
sodium glucose cotransporter type 2 rates of lower urinary tract and genital mycotic infections are slightly increased. The advantages of this
(SGLT2) inhibitors class include modest reductions in body weight and blood pressure, and low risk for hypoglycemia. Long-
type 2 diabetes term safety data and results of ongoing cardiovascular outcome studies are awaited so we can fully under-
stand the role that SGLT2 inhibitors will play in the comprehensive management of type 2 diabetes.
2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

r s u m
Mots cls :
Une matrise ecace de la glycmie rduit le risque de complications lies au diabte. Cependant, la majorit
ecacit
rein
des patients souffrant du diabte de type 2 natteignent pas encore les cibles glycmiques. Au-del du
innocuit traitement par metformine, les lignes directrices actuelles sur la prise en charge du diabte de type 2
inhibiteurs du cotransporteur sodium- recommandent un traitement individualis fond sur les caractristiques du patient et du mdicament.
glucose de type 2 (SGLT2) Les inhibiteurs du cotransporteur sodium-glucose de type 2 (SGLT2) constituent une nouvelle stratgie
diabte de type 2 de traitement, qui est indpendante de la dtrioration du fonctionnement des cellules bta et de
linsulinorsistance. Les inhibiteurs du SGLT2 diminuent la rabsorption rnale du glucose, ce qui entrane
une diminution de lexcrtion urinaire du glucose, puis une rduction des concentrations plasmatiques
du glucose et des concentrations de lhmoglobine glyque. Les donnes actuelles suggrent quils sont
ecaces en monothrapie ou en traitement dappoint la metformine soit en combinaison avec dautres
hypoglycmiants oraux ou avec linsuline. Ils sont gnralement bien tolrs, bien que les taux dinfections
des voies urinaires basses et de mycoses gnitales soient lgrement diminus. Parmi les avantages de
cette classe, on note des rductions modestes du poids corporel et de la pression artrielle, et un faible
risque dhypoglycmie. Les donnes et les rsultats dinnocuit long terme des tudes en cours portant
sur les rsultats cliniques cardiovasculaires sont attendus an de pouvoir comprendre entirement le rle
que joueront les inhibiteurs du SGLT2 dans la prise en charge globale du diabte de type 2.
2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

Introduction

The role of the kidney in type 2 diabetes

The introduction of the sodium glucose cotransporter type 2

(SGLT2) inhibitors for the treatment of type 2 diabetes represents
* Address for correspondence: Pamela M. Katz, MD, Section of Endocrinology, St.
a paradigm shift in the management of hyperglycemia. Treatment
Boniface Hospital, C5113-409 Tache Avenue, Winnipeg, Manitoba R2H 2A6, Canada. of type 2 diabetes has traditionally focused on problems of insulin
E-mail address: pkatz@sbgh.mb.ca. resistance and impaired beta-cell function. It is now recognized that
1499-2671 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jcjd.2015.09.001
S168 P.M. Katz, L.A. Leiter / Can J Diabetes 39 (2015) S167S175
Figure 1. Renal glucose handling under healthy conditions.
the kidneys play an important role in glucose homeostasis through
gluconeogenesis and reabsorption of ltered glucose (1). Animal and
human studies have shown that the proximal tubule within the renal
cortex contains key enzymes involved in the de novo synthesis of
glucose (2). It is estimated that the kidneys contribute to 20% of total-
body glucose release in the postabsorptive state (1). In patients with
type 2 diabetes, renal glucose release is increased in both the
postabsorptive and postprandial states (1,3,4).
The kidney also contributes to glucose homeostasis by ltering
and reabsorbing glucose (Figure 1). The kidneys lter approxi-
mately 160 to 180 grams of glucose each day (5). Glucose trans-
port throughout the body is mediated by transporters in 2 gene
families: the facilitative glucose transporters (GLUTs) and the
sodium-coupled glucose transporters (SGLTs) (6); 90% of glucose
reabsorption in the proximal tubule is mediated by sodium-
glucose cotransporter 2 (SGLT2), a low-anity, high-capacity
membrane-bound protein that actively transports glucose against
its concentration gradient, using energy provided by a sodium gra-
dient across the cell membrane (5,6). The remaining 10% is removed
in the distal straight segment by SGLT1, a related high-anity, low-
capacity transporter. SGLT1 exists primarily in the gastrointesti-
nal tract, where it is the main mechanism for uptake of glucose and
galactose. GLUT2 facilitates passive diffusion of glucose along its con-
centration gradient from cells in the proximal convoluted tubule
back into the bloodstream.
The ability of the proximal tubule to reabsorb glucose increases
as the ltered glucose load increases, until the maximum glucose
transport capacity (Tm glucose) is reached (7,8). In a glucose-
tolerant individual, this corresponds to a plasma glucose level of
approximately 11.0 mmol/L. Therefore, in healthy subjects, virtu-
ally all ltered glucose is reabsorbed back into circulation by the
proximal renal tubule, and almost no glucose is excreted into the
urine. Cultured human proximal renal tubular cells from patients
with type 2 diabetes show markedly increased levels of SGLT2 mRNA
and protein as well as increased glucose transporter activity (9). This
is because in patients with both type 1 and 2 diabetes, Tm glucose
is increased and contributes to ongoing hyperglycemia due to
upregulated reabsorption, rather than excretion, of excess glucose
(10,11).
SGLT2 inhibitors
Phlorizin is a natural product found in the root bark of apple trees,
and it has been known to cause glucosuria since the 19th century
(12). It is a nonselective SGLT inhibitor which, when administered
to partially pancreatectomized rats, corrects hyperglycemia without
affecting plasma insulin concentrations and improves insulin sen-
sitivity (13). Although this provides proof of concept, phlorizin is
not a viable therapy for diabetes because of poor absorption, sig-
nicant inhibition of intestinal SGLT1 leading to osmotic diarrhea,
and a metabolic byproduct called phloretin that blocks glucose
uptake via GLUT1 in many important tissues.
Unlike most glucose transporters, SGLT2 is expressed almost
exclusively in a single locationthe renal proximal tubulesso selec-
tive inhibition of this protein promotes renal glucose excretion,
thereby lowering plasma glucose levels without affecting other meta-
bolic processes. Support for this comes from families with loss-of-
function mutations in the gene coding for SGLT2, a rare condition
known as familial renal glucosuria (14). These patients have sig-
nicant urinary glucose excretion, up to 160 grams per day, in the
absence of hyperglycemia or any other signs of renal tubular dys-
function. The vast majority of affected individuals are asymptom-
atic and do not develop any health issues over time.
All SGLT2 inhibitors produce dose-dependent glucosuria;
however, the maximal amount of glucose excreted in urine repre-
sents less than 50% of the ltered glucose load. This is hypoth-
esized to be due to upregulation of the SGLT1 glucose transport
capacity under conditions of SGLT2 inhibition (15). Therefore, the
combination of a partial SGLT1 plus SGLT2 inhibition would be
expected to produce more robust glucosuria and, therefore, yield
greater reductions in plasma glucose levels. Inhibition of SGLT1 in
the intestine also decreases intestinal glucose absorption and
increases stimulation of glucagon-like peptide-1 (GLP-1) secre-
tion, although gastrointestinal side effects could be a limiting factor.
There are currently several SGLT2 inhibitors in various phases
of clinical development. Those available in Canada include
canagliozin and dapagliozin as well as the more recently approved
empagliozin (Table 1). The selectivity of dapagliozin, expressed
as a ratio between half-maximal inhibitory concentration (IC50) for
 P.M. Katz, L.A. Leiter / Can J Diabetes 39 (2015) S167S175 S169

Table 1 In a post hoc analysis of pooled data from 4 placebo-controlled

SGLT2 inhibitors in clinical development and their SGLT2 selectivity ratios between phase 3 studies of canagliozin, larger reductions in A1C levels were
IC50 for SGLT1/SGLT2, where known
seen with increasing baseline A1C levels, which is consistent with
Agent Manufacturer SGLT2 selectivity previous ndings concerning other glucose-lowering treatments (22).
(fold) (15) Similar A1C level reductions were observed across subgroups based
Canagliozin Janssen Pharma 155 on known duration of diabetes. This is consistent with expecta-
Dapagliozin AstraZeneca 1242 tions, given that these agents operate in an insulin-independent
Empagliozin BoehringerIngelheim/Lilly 2680
Ertugliozin Pzer/Merck N/A
fashion and, therefore, should remain effective throughout various
Ipragliozin AstellasPharma and 254 stages of the disease.
Kotobuki Pharmaceutical
Company Monotherapy
Tofogliozin Roche/Chugai 2912
Luseogliozin Taisho, Novartis 1770
In treatment-naive patients with newly diagnosed diabetes,
BI 44847 BoehringerIngelheim N/A dapagliozin 10 mg reduced A1C levels by 0.66% compared with
Sotagliozin LX4211 Lexicon Pharmaceuticals 20 placebo (p<0.0001) (23). In subjects with type 2 diabetes inad-
EGT0001442 Theracos N/A equately controlled by diet and exercise, canagliozin 100 mg or
GW 869682 GlaxoSmithKline N/A
300 mg signicantly reduced A1C levels at 26 weeks compared with
IC50, half-maximal inhibitory concentration; SGLT2, sodium glucose cotransporter placebo (0.77, 1.03 and 0.14%, respectively; p<0.001 for both com-
type 2.
parisons) (24). In a 24-week trial of empagliozin monotherapy,
empagliozin reduced A1C levels by 0.74% (10 mg dose) and by 0.85%
SGLT1/SGLT2, is more than 1000-fold greater for SGLT2 than for (25 mg dose) compared with placebo (25). Patients with baseline
SGLT1 (15). Canagliozin partially inhibits SGLT1 in addition to A1C levels over 10% received empagliozin 25 mg daily and achieved
SGLT2, as does sotagliozin (LX4211) to a greater extent. It remains a mean A1C level reduction of 3.7% at 24 weeks. These studies also
to be seen whether this translates into clinically signicant differ- showed signicant reductions in fasting glucose, body weight and
ences in ecacy or tolerability. sBP compared to placebo.
The SGLT2 inhibitors are an attractive option for the manage-
ment of type 2 diabetes. Their novel mechanism of action is inde- Add-on to background metformin
pendent of insulin and, therefore, should remain effective at all stages In patients inadequately controlled by metformin monotherapy,
of the disease and work in a complementary fashion with other the addition of canagliozin 100 mg and 300 mg signicantly
classes. SGLT2 inhibition improves beta cell function, possibly by reduced A1C levels at 26 weeks compared to placebo, by 0.62% and
way of decreased glucotoxicity (16,17). Because inhibition of SGLT2 0.77%, respectively (p<0.001) (26). Empagliozin produced changes
does not increase the secretion of insulin or interfere with gluco- in A1C levels over 24 weeks of 0.57% (95% CI: 0.70, 0.43) with
neogenesis, the risk for hypoglycemia is low. Loss of excess calo- the 10 mg dose and 0.64% (95% CI:0.77, 0.50) with 25 mg daily
ries as glucose in urine results in weight loss and can mitigate the (p<0.001 for both), compared to placebo (27). In a network meta-
weight gain caused by other classes of antihyperglycemics. SGLT2 analysis, dapagliozin added to metformin monotherapy offered a
inhibitors also lower systolic blood pressure (sBP) in patients with similar mean change in A1C levels from baseline as comparators
hypertension. but with lower risks for hypoglycemia relative to sulphonylureas
and with a signicant weight reduction compared with both
Clinical ecacy dipeptidyl peptidase-4 (DPP-4) inhibitors and sulphonylureas (28).
The treatment effect of dapagliozinon on A1C levels was 0.08%
Canagliozin, dapagliozin and empagliozin have the great- (0.25, 0.10) relative to DPP-4 inhibitors; 0.02% (0.24, 0.21) rela-
est body of published clinical data and will, therefore, be the focus tive to thiazolidinediones (TZDs) and 0 (0.16, 0.16) relative to
of this review. In the largest meta-analysis to date, SGLT2 inhibi- sulphonylureas.
tors were associated with favourable effects on levels of glycated Dapagliozin has also been studied as add-on to sitagliptin, with
hemoglobin (A1C), mean difference vs. placebo (0.66% [95% CI, or without metformin. At week 24, dapagliozin signicantly
0.73% to 0.58%]) and mean difference vs. active comparators reduced A1C levels(0.5%) vs. placebo (0) (29). Dapagliozin,
(0.06% [CI, 0.18% to 0.05%]) (18). In a pooled analysis of 2477 empagliozin and canagliozin have also shown glycemic ecacy
randomized patients in 4 phase 3 trials of empagliozin, the adjusted as add-on therapy to pioglitazone, with or without metformin
mean difference in A1C levels compared to placebo was 0.62% with (3032).
empagliozin 10 mg and was 0.68% with the 25 mg dose (19).
In another meta-analysis, the reduction in A1C levels with SGLT2 Active comparators
inhibitors compared to placebo was 0.5% (0.4;0.6); 0.6% (0.6;0.5) Given their weight-neutral effects and the low risk for hypogly-
and 0.6% (0.7;0.5) at 12, 24 and 52 weeks, respectively (20). cemia, DPP-4 inhibitors could perhaps be considered the most com-
Canagliozin appeared to produce slightly greater A1C-level low- petitive class of agents for those requiring intensication of treatment
ering compared to dapagliozin; however, the difference was small beyond metformin. In an exploratory arm of a 24-week trial, which
and of questionable clinical signicance, especially given the lack was designed primarily to assess the ecacy of monotherapy,
of long-term head-to-head data. In a double blind, 2-period cross- empagliozin was also compared with sitagliptin 100 mg once daily.
over study conducted in healthy participants, canagliozin 300 mg At the end of the trial, the mean differences in A1C levels vs.
produced greater 24-hour urinary glucose excretion, lower renal sitagliptin were similar: empagliozin 10 mg (0, 95% CI, 0.15, 0.14;
threshold for glucose and less postprandial glucose excursions than p=0.9697) and empagliozin 25 mg (0.12, 95% CI, 0.26, 0.03;
dapagliozin 10 mg (21). The greater postprandial glucose reduc- p=0.106) (25).
tion with canagliozin 300 mg is likely due to transient and local Canagliozin has demonstrated noninferiority to sitagliptin, and
intestinal SGLT1 inhibition. This study represents the rst direct com- the 300 mg dose reduced A1C levels by a statistically signicant
parison of these 2 SGLT2 inhibitors at their highest approved doses. 0.15% (95% CI, 0.27, 0.03) relative to sitagliptin at 52 weeks (26).
Caution must be used in interpreting these results because there Canagliozin also signicantly reduced fasting plasma glucose, sBP
are no head-to-head studies comparing the 2 agents in patients with and body weight compared to sitagliptin at 52 weeks. These results
diabetes or over a longer period of follow up. complement a previous study comparing canagliozin 300 mg with
S170 P.M. Katz, L.A. Leiter / Can J Diabetes 39 (2015) S167S175
sitagliptin 100 mg in patients inadequately controlled by metformin
plus a sulfonylurea, in which canagliozin demonstrated
noninferiority and statistical superiority to sitagliptin in A1C-
lowering effects at 52 weeks (least squares mean difference between
groups of 0.37% (95% CI, 0.50 to 0.25) (33). Canagliozin also pro-
duced greater reductions in body weight (2.8% [2.4 kg]), with
similar low rates of hypoglycemia in both groups.
Loss of glucose-lowering ecacy over time is a common limi-
tation of existing treatments for diabetes. Over 104 weeks, reduc-
tions from baseline A1C levels with canagliozin 100 mg,
canagliozin 300 mg and glimepiride were 0.65%, 0.74% and
0.55%, respectively (34). The difference between canagliozin
300 mg and glimepiride for change in A1C levels was 0.18% (95%
CI, 0.29, 0.08). Durability analysis showed sustained A1C-level low-
ering with both canagliozin doses vs. glimepiride (coecient of
durability 0.21%, [95% CI: 0.30, 0.13) for canagliozin 300 mg vs.
glimepiride).
In the longest clinical study of an SGLT2 inhibitor, the ecacy
and tolerability of dapagliozin was evaluated as compared to
glipizide as add-on therapy to metformin in a 52-week random-
ized, double-blind phase III study with planned extensions to 104
and 208 weeks. Reductions in A1C levels were similar from base-
line to 52 weeks in both treatment groups: dapagliozin, 0.5%;
glipizide, 0.48%; between-group difference, 0.02 (95% CI, 0.14,
0.10). At week 208, dapagliozin was associated with reduced A1C
levels compared with glipizide (0.10 vs. 0.20%, respectively),
between group difference 0.30% (05% CI, 0.51, 0.09) while rates
of hypoglycemia were nearly 10-fold higher with glipizide (51.5%
vs. 5.4% at 208 weeks) (35). To date, no completed trials have com-
pared SGLT2 inhibitors to GLP1 receptor agonists.
Add-on to insulin
In a study of dapagliozin 2.5, 5 or 10 mg/day in patients with
type 2 diabetes inadequately controlled on high doses of insulin with
or without up to 2 oral antidiabetic drugs, A1C level changes from
baseline at 104 weeks were 0.4% in the placebo group vs. 0.6 to
0.8% in the dapagliozin groups (36). However, the mean insulin
dose increase was 18.3 units per day in patients who received
placebo, whereas insulin doses remained stable in the dapagliozin
groups. Also, weight increased by 1.8 kg at 104 weeks in the placebo
group vs. weight decrease of 0.9 to 1.4 kg with dapagliozin.
In a 78-week study of empagliozin as add-on to long-acting
insulin plus metformin and/or sulphonylurea, A1C levels were
reduced by 0.56% on empagliozin 10 mg (95% CI, 0.78, 0.38;
p<0.0001) and 0.62% (95% CI, 0.87, 0.38; p<0.0001) with
empagliozin 25 mg, compared with placebo (37). After the rst
18 weeks, insulin doses were adjusted at the discretion of the inves-
tigator. Changes in A1C levels were stable over time, but basal insulin
doses decreased by approximately 6 units with empagliozin com-
pared to placebo (p=0.009). In obese patients with type 2 diabetes
inadequately controlled by multiple daily injections, empagliozin
10 mg and 25 mg signicantly lowered A1C levels at 18 weeks by
0.44 and 0.47%, respectively, compared to placebo (p<0.001 for both)
(38). Treatment with empagliozin also reduced body weight and
lowered insulin doses, with no increased risk for hypoglycemia.
Therefore, SGLT2 inhibitors appear to improve glycemic control,
reduce weight and stabilize or reduce insulin requirements in
patients whose type 2 diabetes is inadequately controlled by insulin,
with or without oral agents.
Dual add-on therapy
Currently, several combination pills are available that combine
agents with different mechanisms of action. This may provide more
rapid and improved glycemic control with fewer side effects com-
pared to monotherapy at maximal doses or the late addition of a
second antihyperglycemic agent. In patients poorly controlled with
metformin (mean baseline A1C levels 8.9%), the addition of
saxagliptin 5 mg plus dapagliozin 10 mg to background metformin
produced a greater mean changes in A1C levels from baseline (1.5%)
compared to 0.9% with saxagliptin (p<0.0001) and 1.2% with
dapagliozin (p<0.02) alone, with a higher proportion of patients
achieving A1C levels <7% at 24 weeks (41% with all 3 vs. 18% with
saxagliptin and metformin and 22% with dapagliozin and
metformin) (39). Similarly, the combination of empagliozin with
linagliptin as second-line therapy in subjects with type 2 diabetes
inadequately controlled by metformin signicantly reduced A1C
levels compared with the individual components and was well tol-
erated for 52 weeks (40).
Body weight and composition
Aside from GLP-1 agonists, most glucose-lowering treatments
for diabetes are considered weight neutral or are associated with
weight gain. SGLT2 inhibitors lead to clinically signicant reduc-
tions in body weight, averaging from about 1 to 5 kg, with less weight
loss when added to agents typically associated with weight gain,
i.e. insulin and sulfonylureas. This is thought to be due to loss of
calories associated with increased urinary glucose excretion. Dual-
energy x-ray absorptiometry shows that the reduction in total body
weight is due predominantly to decreases in fat mass (41,42). Con-
sistent with this, decreases in waist circumference are also observed.
Weight loss was sustained for up to 4 years with dapagliozin
(3.65 kg) compared to glimepiride (+0.73 kg); between-group dif-
ference, 4.38 kg (95% CI, 5.31, 3.46) (35). Very similar ndings were
observed with canagliozin compared to glimepiride at 104 weeks:
3.6 kg vs. +0.8 kg, between-group difference 4.4 kg (5.2%) (95%
CI, 5.7, 4.6) for canagliozin 300 mg vs. glimepiride (34).
In patients with type 2 diabetes, weight loss is typically asso-
ciated with reductions in A1C levels and sBP (43). In a pooled analy-
sis of 4 placebo-controlled phase 3 studies with canagliozin,
patients with greater weight loss had greater reductions in A1C levels
and sBP through both weight-loss-dependent and -independent
mechanisms (44). Each 1% reduction in body weight was associ-
ated with a 0.045% reduction in A1C levels and a 0.62 mm Hg reduc-
tion in sBP. Weight loss contributed to approximately 15% of A1C
lowering and 40% of reductions in sBP. Body-weight reductions were
seen in the highest 3 quartiles of weight loss with canagliozin 100
and 300 mg compared with a small increase in the lowest quartile.
Patients in the highest weight-loss quartile had weight losses of ~7.4%
to 8.0%, demonstrating variability in canagliozin-associated weight
loss similar to that observed with GLP1-receptor agonists.
Blood pressure
In a meta-analysis of 6 studies, SGLT2 inhibitors reduced sBP by
4.5 mm Hg (95% CI, 5.7, 3.2 mm Hg) compared with other
antihyperglycemic agents (18). In a study of patients with type 2
diabetes and hypertension, empagiozin 10 and 25 mg signi-
cantly reduced mean 24-hour sBP, measured by an ambulatory BP
monitor, compared with placebo (2.96 and 3.68 mm Hg vs.
0.48 mm Hg, respectively; p<0.001 for both) (45). Using pooled data
from 4 placebo-controlled phase-3 studies, canagliozin 100 mg and
300 mg provided placebo-subtracted reductions (95% CI) in sBP from
baselines of 4.0 mm Hg (5.1 to 2.8) and 4.7 mm Hg (5.8 to 3.5)
and diastolic blood pressure 1.9 mm Hg (2.6 to 1.2) and 1.9 (2.6
to 1.1), respectively (46). In a pooled analysis of 13 placebo-
controlled trials, greater reductions in sBP from baseline were
seen with dapagliozin 10 mg vs. placebo at 24 weeks (3.7 vs.
0.5 mm Hg) (47). Patients with baseline sBP >140 mm Hg showed
greater reductions compared to patients whose baseline sBP was
140 mm Hg. No clinically meaningful changes in pulse rate have
been observed. The exact mechanism of weight-loss-independent
 P.M. Katz, L.A. Leiter / Can J Diabetes 39 (2015) S167S175
blood pressure reduction is not completely understood but may be
related to the mild osmotic diuresis or alterations in sodium reab-
sorption (44).
Chronic kidney disease
It is estimated that one-third of patients with type 2 diabetes
have some degree of renal impairment (48). Randomized con-
trolled trials have demonstrated a signicant reduction in the risk
for microvascular complications, including diabetic nephropathy,
with intensive glycemic control (49,50). However, the majority of
oral glucose-lowering agents are contraindicated in patients with
severe renal impairment. SGLT2 inhibitors are also not recom-
mended in subjects with severe renal impairment or end stage renal
disease due to decreased ecacy and a possible increased risk for
some adverse events, though the drugs are not directly nephro-
toxic. The magnitude of glucose excretion with SGLT2 inhibitors is
dependent on the ltered glucose load and is, consequently, reduced
in patients with chronic kidney disease (CKD).
Few studies have examined the effect of SGLT2 inhibitors in
patients with CKD. In subjects with stage 3 CKD (glomerular l-
tration rate [GFR] 30 to 60 mL/min/1.73 m 2 ), treatment with
dapagliozin modestly reduced A1C levels at 24 weeks by 0.41%
and 0.44% for 5 and 10 mg doses, respectively, but did not reach
statistical signicance, possibly owing to the unexpectedly robust
0.32% fall in A1C levels with placebo (51). Similar reductions of 0.33
and 0.44% were seen at 26 weeks with canagliozin 100 mg and
300 mg, respectively, in subjects with type 2 diabetes and CKD
(GFR 30 and <50 mL/min/1.73 m2); however, the fall in placebo-
treated subjects was only 0.03%, so the between-group compari-
son was statistically signicant (p<0.05) (52). At 52 weeks, placebo-
subtracted differences (95% CI) were 0.27% (0.53, 0.001) and 0.41%
(0.68, 0.14) with canagliozin 100 mg and 300 mg, respectively
(53). Osmotic-diuresis-related adverse events were more common
with both doses of canagliozin, and incidences of urinary tract
infections and volume depletion-related adverse events were higher
with canagliozin 300 mg vs. placebo. In both the dapagliozin and
canagliozin studies, acute reductions followed by stabilization in
GFR were reported.
In a larger study, patients with stage 2 CKD, dened as an esti-
mated glomerular ltration rate (eGFR) 60 to <90 mL/min/1.73 m2,
showed signicant reductions in A1C levels of 0.52% (95% CI, 0.72,
0.32) with empagliozin 10 mg and of 0.68% (0.88, 0.49) with
empagliozin 25 mg (both p<0.0001), compared with placebo (54).
In patients with stage 3 CKD, the adjusted mean treated differ-
ence vs. placebo in change from baseline A1C levels at week 24 was
0.42% (0.56, 0.28) for empagliozin 25 mg (p<0.0001). This effect
was sustained at 52 weeks. Small decreases in eGFR were again noted
with empagliozin, which returned to baseline by the end of the
3-week follow-up period after treatment completion. An interest-
ing nding was that of decreased albuminuria with empagliozin
in patients with stages 2 and 3 CKD, though it remains to be seen
whether these changes are persistent and ultimately translate into
renal protection.
The effect of glucose control with canagliozin on renal out-
comes, including progression of albuminuria, is being evaluated in
patients with inadequately controlled type 2 diabetes at high car-
diovascular risk in a prospective randomized trial, with results
expected in 2017 (55). The Canagliozin and Renal Events in Dia-
betes with Established Nephropathy Clinical Evaluation (CREDENCE)
trial will evaluate the effects of canagliozin on renal and vascu-
lar outcomes in patients with type 2 diabetes and stage 2 or 3 CKD
with macroalbuminuria (56). The primary endpoint is a compos-
ite consisting of the doubling of serum creatinine, progression to
end stage kidney disease and renal or cardiovascular death.
S171
Empagliozin was not associated with an increased risk for hypo-
glycemia in subjects with stage 2 or 3 CKD, but a higher percent-
age of patients reported hypoglycemic adverse events with
empagliozin than with placebo in the stage 4 CKD group (54). In
patients with stage 4 CKD, empagliozin 25 mg did not reduce A1C
levels at week 24 or 52, but reductions in body weight and BP were
noted. In an analysis of another empagliozin trial, placebo-
subtracted A1C level reductions appeared to decrease with decreas-
ing eGFR. In contrast, greater reductions in mean 24-hour sBP were
seen with decreasing eGFR, in patients with type 2 diabetes and
hypertension (57).
Type 1 diabetes
Interest exists in the role SGLT2 inhibitors might play as an
adjunctive therapy in type 1 diabetes. Because their mechanism of
action is independent of beta-cell function, they could potentially
improve glycemic control with low risk for hypoglycemia and
favourable effects on weight, similar to results seen in patients with
type 2 diabetes.
In an 8-week single-arm open-label trial, 40 patients with type 1
diabetes were treated with empagliozin 25 mg daily (58). The main
objective was to determine the effects of SGLT2 inhibition on renal
hyperltration. Hyperltration is an early renal hemodynamic abnor-
mality in experimental models of diabetes and is highly prevalent
in subjects with type 1 diabetes; it has been associated with an
increased risk for development of diabetic nephropathy in many
studies. Short-term treatment with empagliozin attenuated renal
hyperltration in clamped euglycemic and hyperglycemic condi-
tions, presumably through alterations in tubuloglomerular feed-
back. Mean A1C levels decreased from 8.0% to 7.6% (p<0.0001) along
with statistically signicant reductions in fasting glucose, symp-
tomatic hypoglycemia, daily insulin doses, weight and waist cir-
cumference (59). Of note, 2 patients were withdrawn after diabetic
ketoacidosis developed within 3 days of drug initiation.
In another exploratory study, 70 patients with type 1 diabetes
were randomly assigned to 1 of 4 dapagliozin doses (1, 2.5, 5 or
10 mg) for 2 weeks, with no cases of ketoacidosis and good toler-
ability (60). Urinary glucose excretion increased, and average blood
glucose and total daily insulin doses decreased. These preliminary
studies support the need for larger randomized controlled trials to
determine the role of SGLT2 inhibitors in reducing hyperglycemia
in type 1 diabetes, to explore their potential renoprotective effects
and to better quantify the risk for DKA.
Safety and tolerability
Thus far, the SGLT2 inhibitor class appears to be generally safe
and well tolerated. Rates of discontinuation due to adverse events
in clinical trials are low (<3%). In keeping with their mechanism of
action, SGLT2 inhibitors cause osmotic diuresis, which may be asso-
ciated with polyuria or pollakiuria. Events consistent with volume
depletion, including hypotension and dehydration, are infrequent
but do occur more commonly in patients on the treatment than in
those taking the placebo in some clinical trials. Populations at risk
appear to be those older than 75, patients with low baseline eGFR
(creatinine clearance <60 mL/min) and patients on loop diuretics.
Genital mycotic and lower urinary tract infections
The most commonly reported adverse event is an increased risk
for lower urinary tract infections, vulvovaginitis and balanitis. In a
pooled analysis of safety data from 12 randomized, placebo-
controlled trials of dapagliozin, urinary tract infections were diag-
nosed in 5.7% of patients on dapagliozin 5 mg and 4.3% on 10 mg,
S172 P.M. Katz, L.A. Leiter / Can J Diabetes 39 (2015) S167S175
compared with 3.7% receiving placebo (61). Genital mycotic
infections were diagnosed in 5.7% taking dapagliozin 5 mg and 4.8%
taking the 10 mg dose, compared with 0.9% taking placebo (62).
Events are more common in females than males. Most infections
tend to occur early, are mild to moderate in intensity and respond
to standard antimicrobial treatment. Very few patients required more
than 1 treatment and discontinuation due to genitourinary tract
infection was rare (<1%).
Hypoglycemia
Intensive glycemic control is associated with an increased risk
for severe hypoglycemia. In a meta-analysis of placebo-controlled
trials, SGLT2 inhibitors were associated with a signicant increase
in the incidence of hypoglycemia; however, this risk was found in
trials in which SGLT2 inhibitors were combined with sulphonylureas
and/or insulin (n=7; Mantel-Haenszel odds ratio (MH-OR) 1.41 (1.11
to 1.88; p=0.005) and not in studies in which they were used as
monotherapy or in combination with other agents (n=13, MH-OR
1.13 [0.75 to 1.72]) (20). Another meta-analysis conrmed that hypo-
glycemia risk is similar to that of other agents; OR for any hypo-
glycemia with SGLT2 inhibitors was 1.28 (CI, 0.99 to 1.65; I2=0%)
compared with placebo and 0.44 (CI, 0.35 to 0.54; I2=93%) com-
pared with other antidiabetic medications (18). Exclusion of 1
sulfonylurea-controlled study in a post hoc sensitivity analysis
resulted in similar hypoglycemia risk compared with other agents
and removed heterogeneity (OR, 1.01 [CI, 0.77 to 1.32]; I2=0%). Severe
hypoglycemia was rare in all treatment groups and occurred pri-
marily in patients receiving a sulfonylurea.
Ketoacidosis
The Federal Drug Administration (FDA) issued a warning that the
use of SGLT2 inhibitors may lead to ketoacidosis requiring hospi-
talization after a search of the Adverse Event Reporting System data-
base identied 20 cases of acidosis reported as diabetic ketoacidosis
between March 2013 and June 2014 (63). Median time of onset of
symptoms was 2 weeks (range 1 to 175 days) following the initia-
tion of drug therapy. It is surprising that many of these cases
occurred in patients with clinical diagnoses of type 2 diabetes, and
their glucose levels were far lower than those typically seen in DKA,
possibly owing to the urinary excretion of glucose. Half of cases did
not identify a triggering factor for the DKA. The FDA continues to
investigate this safety issue to determine whether changes are nec-
essary to prescribing information or labelling for this class of drugs.
The risk for ketosis requires careful evaluation in future trials. In
the interim, clinicians should not use these drugs off-label in patients
with type 1 diabetes and should be cognizant of the possibility of
DKAs occurring even in patients with type 2 diabetes, especially
in those who are relatively insulin decient and who are metaboli-
cally stressed.
Cancer
Initial data from phase 2b and phase 3 trials presented to the
FDA in 2011 suggested an increased number of male bladder cancer
events in those treated with dapagliozin compared to controls, but
the number was not statistically signicant (64). Updated data from
21 trials with 2000 additional patients-years of exposure showed
no overall imbalance of malignancies; incidence rate ratio 1.03 (95%
CI, 0.71, 1.51). Although not statistically signicant, some tumour
types were more common in the dapagliozin group, including
bladder cancer (incidence rate ratio 5.17 (95% CI, 0.68, 233.55)).
Further analysis suggests the imbalance in bladder cancer may actu-
ally have been related to increased detection of pre-existing cancer,
given the fact that the vast majority of these cases occurred in
patients with hematuria at baseline or were diagnosed within the
rst few months of therapy, while the imbalance in breast cancers
may have been related to better detection following weight loss.
Animal studies do not support a positive link between exposure to
dapagliozin and cancer risk (65), nor has a similar relationship been
observed with the other SGLT inhibitors. The relationship between
SGLT2 inhibitors and cancer risk remains inconclusive but war-
rants continued surveillance, particularly as the number of treated
patients and duration of exposure increases.
Bone
Increased phosphate reabsorption may lead to secondary hyper-
parathyroidism with resultant effects on calcium and phosphate
homeostasis that could potentially affect bone mass and, there-
fore, fracture risk. In 1 study of dapagliozin conducted in patients
with moderate renal impairment, 13 patients receiving dapagliozin
and no patients receiving placebo experienced bone fracture over
104 weeks (51). In contrast, Ljunggren et al have recently reported
no signicant changes in markers of bone formation or resorption
or in bone mineral density at any investigated anatomic region, with
dapagliozin treatment over 50 weeks vs. placebo (66). There was
also no signicant change in calcium, 25-hydroxyvitamin D, or para-
thyroid hormone levels compared to placebo. During 2 years of con-
tinued observation, only 1 fracture occurred in the treatment group.
There was also no evidence of increased fracture risk with
dapagliozin in a pooled analysis of 12 placebo-controlled trials (67).
An unpublished analysis of a broad dataset presented to the FDA
showed a small increase in the incidence of adjudicated low-
trauma fractures with canagliozin; the between-group differ-
ence in incidence rate was 2.8 (1.06; 6.73) for both doses of
canagliozin vs. the Non-CANA trial (68). In a dedicated study con-
ducted in elderly individuals, changes in bone density by dual-
energy x-ray absorptiometry (DXA) at 52 weeks were observed with
canagliozin 300 mg at the lumbar spine (placebo subtracted mean
0.7 (95% CI, 1.4, 0.1) and total hip (placebo subtracted mean 0.7
(1.3, 0.2) (68). It is noted that decreases in bone density can occur
in relation to weight loss. Assessment at 1 year does not provide
sucient information to assess this risk, and longer studies are
needed to clarify the effect of SGLT2 inhibitors on bone metabo-
lism and fracture risk.
Cardiovascular outcomes
The relationship between glycemic control and cardiovascular
events is complex. In addition to their glucose-lowering effects, SGLT2
inhibitors are associated with small increases in high-density
lipoprotein-cholesterol and a modest reduction in triglyceride levels.
This, along with the favourable effects of SGLT2 inhibitors on blood
pressure may translate into a reduction in cardiovascular risk.
However, mild increases from baseline in low-density lipoprotein-
cholesterol in the range of 0.2 to 0.5 mmol/L have also been seen,
which may offset these effects.
A meta-analysis conducted using pooled data from 21 phase 2b/3
trials of dapagliozin showed no increase in cardiovascular risk with
treatment (69). The hazard ratio for the primary endpoints of car-
diovascular death, myocardial infarction, stroke or hospitaliza-
tions for unstable angina was 0.787 (95% CI, 0.579, 1.070).
Similarly, in a prespecied cardiovascular meta-analysis of
canagliozin, the hazard ratio for the predened composite end-
point of MACE-plus (CV death, nonfatal myocardial infarction, non-
fatal stroke, hospitalized unstable angina), was 0.91 (0.68, 1.22) (68).
There was an initial imbalance in the CANVAS (canagliozin car-
diovascular assessment study) events during the rst 30 days, with
13 events in the canagliozin group vs. 1 event in placebo-treated
patients. This imbalance ipped in the opposite direction in the
 P.M. Katz, L.A. Leiter / Can J Diabetes 39 (2015) S167S175 S173

Table 2
SGLT2 inhibitors: Ongoing trials regarding cardiovascular outcomes

Treatment N Population Endpoints Results

expected

CANVAS-R (55) Canagliozin vs. placebo 3,627 CVD or high risk for CVD Primary: Progression of albuminuria 2017
Secondary: CV death, nonfatal MI or nonfatal CVA
CANVAS (70) Canagliozin vs. placebo 4,363 CVD or high risk for CVD CV death, non-fatal MI or non-fatal CVA June 2018
CREDENCE (56) Canagliozin vs. placebo 3,627 eGFR 30 and <90 mL/min/1.73 m2 Primary: ESRD, doubling of serum creatinine, renal or CV 2019
on ACEi or ARB death
Secondary: CV death, non-fatal MI or non-fatal CVA
DECLARE (71) Dapagliozin vs. placebo 27,000 CVD or high risk for CVD CVD death, nonfatal MI or nonfatal CVA 2019
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CV, cardiovascular; CVA, cardiovascular accident; CVD, cardiovascular disease; eGFR, estimated glo-
merular ltration rate; ESRD, end stage renal disease; MI, myocardial infarction; SGLT2, sodium glucose cotransporter type 2.

second month and was not seen in the overall meta-analysis so was
probably due to month-to-month variability in the frequency of
events and lowerthan-expected rates in the placebo group during
this period. Further analysis did not reveal an association with
volume-related adverse events. For the individual endpoint of stroke,
the hazard ratio was 1.48 (0.83, 2.59), though the actual number
of events was small and, therefore, longer term follow-up is required.
Several large outcome trials are ongoing to assess specically
the cardiovascular safety of the various SGLT2 inhibitors (Table 2)
(55,56,70,71). The rst of these studies, EMPA-REG OUTCOME, was
recently published (72). In this trial, patients with type 2 diabetes
at high cardiovascular risk were randomized to receive empagliozin
10 mg or 25 mg or placebo once daily. Patients treated with
empagliozin had lower rates of the primary outcome, which was
death from cardiovascular causes, nonfatal myocardial infarction,
or nonfatal stroke [10.5% vs. 12.1%, HR 0.86 (CI 0.74, 0.99)], with a
p-value of 0.04 for superiority. This was primarily driven by lower
rates of death from cardiovascular causes (3.7 vs. 5.9%, 38% rela-
tive risk reduction). In addition, hospitalization for heart failure (2.7
vs 4.1%, 35% relative risk reduction) and all-cause mortality (5.7 vs.

Figure 2. Algorithm for pharmacologic management of type 2 diabetes, adapted from Canadian Diabetes Association guidelines interim update (74). BG, blood glucose;
DPP-4, dipeptidyl peptidase 4; GLP1, glucagon-like peptide-1; GI, gastrointestinal; TID, thee times a day; qid, four times a day; UTI, urinary tract infection.
S174 P.M. Katz, L.A. Leiter / Can J Diabetes 39 (2015) S167S175
8.3%, 32% relative risk reduction) were both signicantly reduced
with empagliozin versus placebo. This is the rst study of a glucose-
lowering agent to demonstrate CV risk reduction in a dedicated car-
diovascular outcomes trial.
Role of SGLT2 Inhibitors in Clinical Practice
The Canadian Diabetes Association Clinical Practice Guidelines
recommend metformin as the rst-line antihyperglycemic agent for
most individuals with type 2 diabetes (73). Beyond this, selection
of another agent is based on the characteristics of both the patient
and the agent. In a recently published interim update to the guide-
lines, SGLT2 inhibitors have been added to the algorithm for phar-
macologic management of type 2 diabetes (Figure 2) (74). SGLT2
inhibitors have ecacy in lowering A1C levels similar to that of other
antihyperglycemic agents. Therefore, physicians may choose to pre-
scribe an SGLT2 inhibitor over other agents based on the novel
mechanism of action, low risk for hypoglycemia and favourable
effects on weight and blood pressure. This should be balanced with
the specic side-effect prole, cost and relative lack of long-term
safety data compared with other options.
Conclusions
Type 2 diabetes is a progressive disease which, if untreated, can
lead to signicant morbidity and mortality. Glycemic control is
the cornerstone of diabetes management; however, current
antihyperglycemic agents are generally limited by poor glycemic
durability, weight gain, hypoglycemia, gastrointestinal side effects
and/or concerns about cardiovascular safety. The SGLT2 inhibitors
have a novel mechanism of action that is applicable across a con-
tinuum of diabetes. They have glucose-lowering abilities similar to
those of existing treatments but have the advantages of weight loss
and blood pressure reduction and a low risk for hypoglycemia. Ben-
ecial effects on A1C levels and weight appear to be maintained in
long-term studies of up to 4 years. They are generally well toler-
ated and have favourable safety proles. Initial results indicate not
just cardiovascular safety, but a signicant reduction in major car-
diovascular events, as well as cardiovascular and total mortality,
although the results of the additional ongoing long-term studies
are awaited. Overall, the SGLT2 inhibitors represent a promising new
option for the treatment of type 2 diabetes.
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