Journal of Diabetes and Its Complications 27 (2013) 280–286
Contents lists available at SciVerse ScienceDirect
Journal of Diabetes and Its Complications
j o u r n a l h o m e p a g e : W W W. J D C J O U R N A L . C O M
The potential of sodium glucose cotransporter 2 (SGLT2) inhibitors to reduce
cardiovascular risk in patients with type 2 diabetes (T2DM)☆
Jan N. Basile ⁎
Seinsheimer Cardiovascular Health Program, Medical University of South Carolina, Charleston, SC 29425, USA
a r t i c l e
i n f o
Article history:
Received 10 December 2012
Accepted 18 December 2012
Available online 1 February 2013
a b s t r a c t
Type 2 diabetes mellitus (T2DM) significantly increases morbidity and mortality from cardiovascular disease
(CVD). Treatments for patients with T2DM have the potential to reduce cardiovascular (CV) risk. This review
focuses on the potential of a new class of antidiabetic agents, the sodium glucose cotransporter 2 (SGLT2)
inhibitors, to reduce CV risk in patients with T2DM through reductions in hyperglycemia, blood pressure (BP),
and body weight. The results of clinical trials of SGLT2 inhibitors are summarized and discussed.
© 2013 Elsevier Inc. All rights reserved.
1. Introduction
Diabetes is an increasing public health problem. The UN General
Assembly has recognized that diabetes poses risks to well-being
worldwide and has calculated that diabetes prevalence has risen by
about 7% per decade, from 8.3% in 1980 to 9.8% in 2008 among
men, and from 7.5% to 9.2% among women (Tobias, 2011). The
number of adults with T2DM worldwide has more than doubled in
the last 30 years, rising from 153 million in 1980 to 347 million in 2008
(Danaei et al., 2011). This trend is set to continue, with predictions of
439 million cases by 2030 (Nolan, Damm, & Prentki, 2011).
T2DM is a major cause of morbidity and death worldwide, being
the leading cause of kidney failure, non-traumatic lower limb
amputation, and new cases of blindness among adults in the United
States, as well as a major cause of heart disease and stroke (Centers for
Disease Control and Prevention, 2011). Diabetes is the seventh
leading cause of death in the United States, and mortality rates are
projected to rise sharply over the next decade (Centers for Disease
Control and Prevention, 2011).
2. Pathogenesis of T2DM and limitations of current therapies
T2DM results from progressive β-cell dysfunction in the presence
of chronic insulin resistance, leading to a progressive decline in
plasma glucose control (Campbell, 2009). Signaling pathways
involved in glucose homeostasis are disrupted during the pathogenesis
☆ Disclosures: In the past three years, Professor Basile has received grant/research
support from the NHLBI (SPRINT); acted as a consultant to Forest Labs, Daiichi-Sankyo,
and Takeda; and been a member of the speakers’ bureau for Daiichi-Sankyo, Forest
Labs, Boehringer Ingelheim/Eli Lilly, and Takeda.
⁎ Tel.: +1 843789 6680.
E-mail address: [email protected].
1056-8727/$ – see front matter © 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jdiacomp.2012.12.004
of T2DM, resulting in increased glucagon secretion, reduced incretin
response, increased endogenous glucose production, increased renal
glucose reabsorption, impaired expansion of subcutaneous adipose
tissue, and hypoadiponectinemia (DeFronzo, Davidson, & del Prato,
2012; Nolan et al., 2011).
Most therapies available for the treatment of patients with T2DM
act by increasing insulin sensitivity or by stimulating insulin secretion
(Cefalu, Richards, & Melendez-Ramirez, 2009; DeFronzo, 2010).
Treatment success is usually defined as achieving target levels of
glycated hemoglobin (HbA1c) with low rates of hypoglycemic events
(Cefalu et al., 2009). Initial management usually consists of lifestyle
modifications (diet and exercise) often with metformin monotherapy
at the time of diagnosis or shortly thereafter (Inzucchi et al., 2012). As
the disease progresses, more complex treatment regimens, involving
more than one antidiabetic agent and ultimately insulin, are required
to keep plasma glucose levels at target (Inzucchi et al., 2012). This can
be viewed as a “treat-to-failure” approach, and results in patients
having inadequate glycemic control for much of their time on
treatment (Cefalu, 2012a). Recent recommendations have focused
on “individualizing” treatment for patients in the context of wider
disease management (Inzucchi et al., 2012). This patient-centered
approach to care goes beyond algorithms to incorporate patient
attitudes and preferences, gender, race, ethnicity, risks of therapy,
comorbidities, the presence of complications, and the resources and
support systems available to the individual (Cefalu, 2012b).
While tight glycemic control is known to reduce the microvascular
complications of T2DM, around half of all patients fail to achieve and
maintain the HbA1c target of b7% recommended by the American
Diabetes Association (ADA) and other bodies (American Diabetes
Association, 2012; Cornell, 2011; Turner, Cull, Frighi, & Holman,
1999). Estimates of the proportion of patients achieving this goal vary
considerably and depend on the type of treatment. A recent metaanalysis of 218 trials with patients with T2DM found that the
J.N. Basile / Journal of Diabetes and Its Complications 27 (2013) 280–286
proportion meeting an HbA1c target of b 7% ranged from 26% with αglucosidase inhibitors to 63% with exenatide (Esposito, Chiodini,
Bellastella, Maiorino, & Giugliano, 2012). In the short term, the
glucose-lowering efficacy of the various monotherapies recommended in the early stages of the disease is similar and other risks
and benefits (e.g. risk of hypoglycemia, effect on weight) are
considered in treatment choice (Schernthaner et al., 2010). Side
effects of current therapies, including hypoglycemia, weight gain,
fluid retention, and gastrointestinal effects, can limit their use and
reduce patients’ adherence to medication (Schernthaner et al., 2010),
making patients less likely to reach glycemic targets. A study of new
users of oral antidiabetic treatments found that patients who did not
comply with treatment were 20% less likely to achieve glycemic
targets than those who did (Penning-van Beest et al., 2008), while an
internet survey of 1984 patients with T2DM found that both
hypoglycemia and weight gain were associated with reduced quality
of life (Marrett, Stargardt, Mavros, & Alexander, 2009). Newer
therapies aim to address these limitations. An ideal glucose-lowering
agent should maintain glycemic control, preserve β-cell function,
be weight-neutral or even promote weight loss, and have a low
incidence of hypoglycemic events (Tahrani, Piya, Kennedy, &
Barnett, 2010).
3. T2DM and CVD risk
T2DM confers an increased risk of vascular disease, with diabetesinduced micro- and macrovascular complications being the major
causes of morbidity and mortality in patients with T2DM (Madonna &
De Caterina, 2011). A meta-analysis of 102 studies found that T2DM
was associated with a 2-fold increased risk of vascular diseases such
as coronary heart disease and stroke, independent of other risk factors
including age, sex, smoking, body mass index (BMI), and systolic BP
(The Emerging Risk Factors Collaboration, 2010).
Large clinical studies of the effects of intensive glucose lowering on
mortality and CV outcomes in patients with T2DM have not proved to
be straightforward, suggesting that the relationship between the two
is complex and not only related to control of hyperglycemia. Recent
data (e.g. from the ACCORD, VADT and ADVANCE trials) have
demonstrated modest but significant microvascular benefits with
aggressive glucose control. However, in these same studies, aggressive glucose control did not reduce macrovascular outcomes in
patients with characteristics such as long-standing disease, advanced
age and frailty, low awareness of hypoglycemia, significant comorbidities, and/or pre-existing macrovascular disease (ACCORD
Study Group, 2008; ADVANCE Collaborative Group, 2008; IsmailBeigi et al., 2010; Kelly et al., 2009; Terry, Raravikar, Chokrungvaranon, & Reaven, 2012). The timing of glucose control may also be
important, with the “metabolic memory” hypothesis suggesting that
tight control during the early stages of T2DM may have a legacy effect,
with benefits on CV and microvascular disease in the long term
(Holman, Paul, Bethel, Matthews, & Neil, 2008).
In addition to hyperglycemia, many patients with T2DM have comorbid conditions that increase the risk of CVD. These co-morbidities
include obesity, hypertension, and dyslipidemia, and are inter-related
epidemiologically, clinically, and metabolically (Kabakci, Koylan,
Ilerigelen, Kozan, & Buyukozturk, 2008). It has been estimated that
approximately 90% of T2DM cases are attributable, at least in part, to
excess body weight (Gregg, Cheng, Narayan, Thompson, & Williamson, 2007) and obesity increases the risk of CVD in patients with
T2DM (Cornell, 2011). Hypertension is also common in patients with
T2DM and is a significant risk factor for CVD in this patient group
(Ferrannini & Cushman, 2012). Atherosclerosis and T2DM both lead
to vascular damage and share common causative mechanisms
(including inflammation) and risk factors, including hypertension
and dyslipidemia (DeSouza & Fonseca, 2009).
281
As T2DM is a multifactorial disease, the effects of antidiabetic
agents on pathophysiological abnormalities other than hyperglycemia may warrant greater consideration than they have received to
date (Schernthaner et al., 2010). Some CV risk factors (e.g.
hypertension) are modifiable with intervention and represent a
legitimate strategy for addressing the high CV mortality in patients
with T2DM (Tahrani et al., 2010). However, it is important to note
that the effects of antidiabetic therapies on CV risk factors may have
either a positive (e.g. reduction in BP, weight loss) or negative (e.g.
weight gain, increased hypoglycemia) effect (Table 1).
4. Modulation of renal glucose reabsorption as a mechanism for
improving glycemic control in T2DM: the SGLT2 inhibitors
The kidney plays an important role in glucose homeostasis,
normally accounting for more than 10% of total glucose utilization
in the body, up to 20% of all glucose production via gluconeogenesis,
and, most importantly, mediating the reabsorption of glucose from
the glomerular filtrate (Gerich, 2010; Mather & Pollock, 2011). T2DM
augments all of these functions of the kidney. A three-fold increase in
overall glucose production has been observed in patients with T2DM,
with both the liver and the kidneys contributing to this increase via
gluconeogenesis (Mather & Pollock, 2011). In addition, renal glucose
reabsorption is increased (Gerich, 2010).
In healthy adults with a glomerular filtration rate (GFR) of
~ 125 mL/min, approximately 180 L of plasma is filtered through the
kidneys every day (Gerich, 2010). A healthy adult with an average
plasma glucose concentration of 5 mmol/L filters approximately
180 g of glucose per day into the glomerular filtrate (Gerich, 2010).
In order to maintain glucose levels in the body, virtually all of the
filtered glucose is recovered in the kidneys by sodium glucose
cotransporters (SGLTs) (Wright, Hirayama, & Loo, 2007). The SGLT
family includes SGLT1, responsible for glucose absorption in the
intestine and approximately 10% of renal glucose reabsorption, and
SGLT2, which is located in the proximal tubule of the nephron and
accounts for approximately 90% of renal glucose reabsorption
(DeFronzo et al., 2012) (Fig. 1). SGLT2 operates by coupling glucose
transport to an electrochemical sodium gradient to move glucose and
sodium ions across the luminal surface of the epithelial cells lining the
S1 and S2 segments of the proximal tubule (Mather & Pollock, 2011).
Once concentrated in the epithelial cells, glucose is transported into
the blood, facilitated by the glucose transporter, GLUT2 (DeFronzo et
al., 2012; Wright et al., 2007). Reabsorption of glucose from the
glomerular filtrate increases in proportion to the plasma glucose
concentration until the maximum transport capacity of the tubules
(the transport maximum for glucose [TmG]) is reached, above which
excess glucose is lost in the urine (Basile, 2011; Mather & Pollock,
2011). In people with T2DM, TmG is increased by up to 20%, so urinary
glucose excretion (UGE) begins to occur at higher than normal plasma
glucose levels (Gerich, 2010). Studies of renal cells isolated from urine
have shown that SGLT2 and GLUT2 expression is increased in patients
with T2DM (Rahmoune et al., 2005).
The kidney's role in the reabsorption of glucose from the
glomerular filtrate has led to investigation of SGLT2 as a potential
therapeutic target for T2DM. SGLT2 inhibitors reduce the capacity of
the proximal tubule to reabsorb glucose from the glomerular filtrate,
leading to increased UGE, which reduces hyperglycemia (DeFronzo et
al., 2012). Several SGLT2 inhibitors are now in Phase III clinical
development (Table 2). Dapagliflozin, the first agent submitted for
approval, was rejected by the US Food and Drug Administration (FDA)
in January 2012. It was recommended, however, for marketing
authorization by the European Medicines Agency (EMA) in April 2012
as monotherapy for the treatment of adults with T2DM in patients for
whom diet and exercise do not provide adequate glycemic control
and for whom metformin is considered inappropriate due to
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J.N. Basile / Journal of Diabetes and Its Complications 27 (2013) 280–286
Table 1
Effect of antidiabetic drugs on CV risk factors (Bailey, 2011; Cornell, 2011; Inzucchi, 2002; Schernthaner et al., 2010; Tahrani et al., 2010).
Intervention
CV risk factor
HbA1c
Body weight
Hypertension
Edema
Dyslipidemia
Hypoglycemia
Metformin
Sulfonylureas
Thiazolidinediones (glitazones)
Improvement
Improvement
Improvement
Loss/neutral
Gain
Gain
Neutral
Neutral
Improvement
Improvement
Variable
Improvement
Low risk
Moderate risk
Low risk
Meglitinides (glinides)
α-glucosidase inhibitors
DPP-IV inhibitors (gliptins)
GLP-1 receptor agonists
Insulin
Improvement
Improvement
Improvement
Improvement
Improvement
Gain
Neutral
Loss/neutral
Loss
Gain
Neutral
Neutral/ improvement
Improvement
Improvement
Improvement
Moderate risk
Low risk
Low risk
Low risk
High risk
SGLT2 inhibitorsa
Improvement
Loss
Neutral
Improvement
Neutral
Improvement
Hyperinsulinemia is
associated with hypertension
Improvement
Neutral
Neutral
Moderate risk of
peripheral edema
Neutral
Neutral
Neutral
Neutral
Acute insulin
edema (rare)
Neutral
Limited data
Low risk
a
Not yet approved.
intolerance, or in combination with other glucose-lowering products
when these, together with diet and exercise, do not provide adequate
glycemic control (European Medicines Agency, 2012).
5. Efficacy and safety of SGLT2 inhibitors in patients with T2DM
Clinical studies of monotherapy with SGLT2 inhibitors in patients
with T2DM have shown reductions from baseline in HbA1c ranging
from 0.63% to 1.45% (Ferrannini, Ramos, Salsali, Tang, & List, 2010a,
Ferrannini et al., 2010b; Fonseca et al., 2011; Henry et al., 2012;
Kashiwagi et al., 2011; List, Woo, Morales, Tang, & Fiedorek, 2009;
Musso, Gambino, Cassader, & Pagano, 2011). SGLT2 inhibitors are oral
therapies with a mode of action that does not interact with glucose
metabolism. Therefore, they would be expected to complement
insulin-dependent therapies in T2DM, which has been borne out in
clinical studies, demonstrating the efficacy of SGLT2 inhibitors when
used in combination with antidiabetic agents. Additional reductions
in HbA1c of up to 0.73% have been observed when an SGLT2 inhibitor
has been added to metformin (Bailey, Gross, Pieters, Bastien, & List,
2010; Nauck et al., 2011; Rosenstock et al., 2011; Rosenstock et al.,
2012a; Wilding et al., 2011). When used in combination with
glimepiride, dapagliflozin reduced HbA1c by up to 0.82%, compared
with a reduction of 0.13% with glimepiride alone (Strojek et al., 2011),
while with pioglitazone, dapagliflozin reduced HbA1c by up to 0.97%,
compared to a reduction of 0.42% with pioglitazone alone (Rosenstock, Vico, Wei, Salsali, & List, 2012b). Dapagliflozin plus insulin
reduced HbA1c by up to 0.96%, versus a reduction of up to 0.13%
achieved with insulin alone (Wilding et al., 2009; Wilding et al.,
2012), and similar results have been observed with canagliflozin
(Devineni et al., 2012).
SGLT2 inhibitors have been shown to reduce fasting plasma
glucose (FPG). Used as monotherapy, reductions in FPG in the order of
15–65 mg/dL have been observed in clinical trials (Ferrannini et al.,
2010a, 2010b; Fonseca et al., 2011; Henry et al., 2012; Kashiwagi et al.,
2011; List et al., 2009; Schwartz et al., 2011). When used in
combination with metformin, additional reductions of up to
32.7 mg/dL have been seen (Bailey et al., 2010; Henry et al., 2012;
Rosenstock et al., 2011; Rosenstock et al., 2012a; Wilding et al., 2011).
In combination with glimepiride, dapagliflozin reduced FPG by 16.7–
28.4 mg/dL, compared with a reduction of 2.0 mg/dL with glimepiride
alone (Strojek et al., 2011). With pioglitazone, dapagliflozin reduced
FPG by 24.9 –29.6 mg/dL compared with a reduction of 5.5 mg/dL
with pioglitazone monotherapy (Rosenstock et al., 2012b). A
combination of dapagliflozin plus insulin reduced FPG by 15.4–
27.4 mg/dL over insulin alone (Wilding et al., 2009), while canagliflozin plus insulin reduced FPG by a further 42.7–44.7 mg/dL over
insulin alone (Devineni et al., 2012).
In addition to reducing FPG, SGLT2 inhibitors reduce the postprandial spike in plasma glucose concentrations. Reductions in postprandial glucose (PPG) have been observed with SGLT2 inhibitors
used as monotherapy or in combination with sulfonylurea (SU),
pioglitazone or insulin therapy (List et al., 2009; Rosenstock et al.,
2012b; Strojek et al., 2011;Wilding et al., 2009).
As SGLT2 inhibitors work independently of insulin, the efficacy of
these drugs is independent of β-cell function or insulin resistance
(Zhang, Feng, List, Kasichayanula, & Pfister, 2010). Clinical studies
have shown that SGLT2 inhibitors improve glycemic control when
used in patients with both early and late stages of T2DM (Devineni et
Table 2
SGLT2 inhibitors in development.
Fig. 1. The role of SGLT2 in renal glucose reabsorption (Bailey, 2011). Adapted from
Bailey, 2011.
SGLT2
inhibitor
Company
Phase of development
Dapagliflozin
Bristol-Myers Squibb,
AstraZeneca
Canagliflozin
Johnson and Johnson,
Mitsubushi Tanabe
Boehringer Ingelheim, Eli Lilly
Astellas, Kotobuki
Taisho
Chugai
Phase III (rejected by US FDA;
recommended for approval by
European Medicines Agency)
Phase III
Empagliflozin
Ipragliflozin
Luseogliflozin
Tofogliflozin
Phase
Phase
Phase
Phase
III
III
III
III
J.N. Basile / Journal of Diabetes and Its Complications 27 (2013) 280–286
al., 2012; Henry et al., 2012; Wilding et al., 2012; Zhang et al., 2010).
The efficacy of SGLT2 inhibitors depends on both the level of glycemia
and the rate of glomerular filtration. Thus, in patients with T2DM and
moderate renal impairment, SGLT2 inhibition is associated with less
UGE than in patients with normal renal function and glucose-lowering
efficacy may be reduced (Ferrannini & Solini, 2012; Kohan, Fioretto,
List, & Tang, 2011; Yale et al., 2012). SGLT2 inhibitors have not
demonstrated any detrimental effects on renal function (DeFronzo et
al., 2012; Devineni et al., 2012; List & Whaley, 2011; Wilding et al.,
2012). Further, individuals with familial renal glucosuria (FRG), an
inherited condition caused by mutations in the gene encoding SGLT2
(SLC5A2), experience chronic UGE without signs of renal dysfunction,
or changes in plasma volume or electrolytes (DeFronzo et al., 2012;
Ferrannini & Solini, 2012).
As with all classes of drug, the benefits of SGLT2 inhibitors should
be considered against their safety and tolerability. Clinical trials of
SGLT2 inhibitors have shown a good safety and tolerability profile
(Bailey et al., 2010; Fonseca et al., 2011; Rosenstock et al., 2011;
Rosenstock et al., 2012a; Woerle et al., 2012). The insulin-independent
mode of action of SGLT2 inhibitors confers a minimal risk of
hypoglycemia (Ferrannini & Solini, 2012) and low rates of hypoglycemia have been observed in clinical studies (Musso et al., 2011;
Rosenstock et al., 2012a; Rosenstock et al., 2012b; Woerle et al., 2012).
However, increased glucose in the urine may predispose patients to
urinary tract infections (UTIs). Some studies of SGLT2 inhibitors have
shown an increased incidence of UTIs compared with placebo (Musso
et al., 2011), while others have shown rates of UTI similar to placebo
(Nicolle, Capuano, Ways, & Usiskin, 2012; Rosenstock et al., 2012a).
Most cases of UTI that have been reported have been transient and
responded to standard treatment (Bailey, 2011). SGLT2 inhibitors
have also been associated with an increased incidence of genital
infections (Musso et al., 2011; Nyirjesy, Zhao, Ways, & Usiskin, 2012);
these infections have generally been considered mild and have
responded to standard antifungal therapy (Nyirjesy et al., 2012).
More cases of breast and bladder cancer were found in patients
who received dapagliflozin during its clinical development program:
9 cases of bladder cancer (0.2% of patients) with dapagliflozin vs 1
(0.04% of patients) with comparator and 9 cases of breast cancer (0.4%
of females) with dapagliflozin vs 1 (0.09% of females) with
comparator (FDA Briefing Document, 2011). The number of cases of
breast and bladder cancer was too small to establish causality. There is
no known connection between SGLT2 inhibition and tumor risk and
in lifetime exposure studies in animals, dapagliflozin did not increase
the incidence of any tumor (FDA Briefing Document, 2011).
6. Potential of SGLT2 inhibitors to reduce CV risk in patients
with T2DM
SGLT2 inhibitors have the potential to reduce CV risk in patients
with T2DM not only through beneficial effects on glycemic control,
but also via beneficial effects on body weight, BP, lipids, and serum
uric acid.
6.1. Body weight
Moderate weight loss in patients with T2DM has been shown to be
associated with improvements in CV risk factors, including hyperglycemia, hypertension, and markers of inflammation (Klein et al., 2004).
In patients treated with SGLT2 inhibitors, loss of glucose in the urine
results in loss of calories and so a reduction in body weight; initial
weight loss may also reflect some fluid loss, as UGE results in mild
osmotic diuresis (Bailey, 2011; Ferrannini & Solini, 2012). Weight
reductions of ~ 1–3.8 kg have been observed with SGLT2 inhibitor
monotherapy in clinical trials in patients with T2DM (Ferrannini et al.,
2010a, 2010b; Fonseca et al., 2011; Henry et al., 2012; Kashiwagi et al.,
283
2011; List et al., 2009; Schwartz et al., 2011; Woerle et al., 2012);
these correspond to reductions in body weight of 2.5% − 4.0%
(Ferrannini & Solini, 2012). Reductions have also been observed when
SGLT2 inhibitors are used in combination with metformin, SU,
pioglitazone, or insulin (Bailey et al., 2010; Devineni et al., 2012;
Nauck et al., 2011; Rosenstock et al., 2011; Rosenstock et al., 2012a,
2012b; Strojek et al., 2011; Wilding et al., 2009; Wilding et al., 2011;
Wilding et al., 2012; Woerle et al., 2012). In patients treated with
dapagliflozin and metformin, reductions in weight began early and
continued over the course of the trial; around 20% of patients had
weight reductions of at least 5% after 24 weeks (Bolinder et al., 2012).
Weight loss has been shown to reflect loss of both subcutaneous and
visceral fat (Bolinder et al., 2012).
6.2. Blood pressure
Reductions in BP in patients who take an SGLT2 inhibitor are
believed to be due, at least in part, to mild osmotic diuresis, as urine
output increases due to lower reabsorption of water in the kidneys.
Initial increases in urinary volume of up to 450 mL/day have been
reported after dapagliflozin treatment (Bailey, 2011), representing
one extra void per day, but this levels off, and signs of volume
depletion such as orthostatic hypotension and tachycardia have been
reported very rarely (Bailey et al., 2010; Ferrannini et al., 2010a).
Reductions in weight and sodium ion excretion may also contribute to
BP reductions (Bailey, 2011; Ferrannini & Solini, 2012).
Maximum mean reductions in systolic BP of ~ 3–9 mmHg have
been observed in studies of SGLT2 inhibitors used as monotherapy
(Ferrannini et al., 2010a; Henry et al., 2012; Kashiwagi et al., 2011;
List et al., 2009) and in combination with metformin, SU, or
pioglitazone (Bailey et al., 2010; Nauck et al., 2011; Rosenstock et
al., 2011; Rosenstock et al., 2012a, 2012b; Strojek et al., 2011; Wilding
et al., 2011). In studies of SGLT2 inhibitors used in combination with
insulin, similar reductions in systolic BP were seen (Devineni et al.,
2012; Wilding et al., 2009; Wilding et al., 2012). Reductions in
diastolic BP have been smaller and less consistent across trials (List &
Whaley, 2011). Overall, better controlled studies are needed to
confirm the effect of SGLT2 inhibitors on BP.
6.3. Lipids
Small lipid changes have been reported in some trials of SGLT2
inhibitors. Increases in total cholesterol and HDL-cholesterol (Bailey
et al., 2010; Nauck et al., 2011; Rosenstock et al., 2012b) and a
reduction in triglycerides (Bailey et al., 2010; Nauck et al., 2011) have
been observed with dapagliflozin. With canagliflozin, increases in
HDL-cholesterol and LDL-cholesterol have been observed, with a
minimal effect on the total cholesterol:HDL-cholesterol ratio, and
small and inconsistent changes in triglycerides (Cefalu et al., 2012;
Gross et al., 2012; Rosenstock et al., 2012a).
6.4. Uric acid
Small reductions (approximately 1 mg/dL) in serum uric acid have
been reported in trials of SGLT2 inhibitors used as monotherapy
(Henry et al., 2012; List et al., 2009), and in combination with
metformin (Bailey et al., 2010; Nauck et al., 2011; Rosenstock et al.,
2012a), pioglitazone (Rosenstock et al., 2012b), SU (Strojek et al.,
2011) or insulin (Wilding et al., 2009; Wilding et al., 2012).
Reductions in serum uric acid levels may be mediated by GLUT9
(SLC2A9), a facilitative glucose transporter found in the proximal
tubule. GLUT9 functions as a high-capacity urate transporter and is
believed to secrete uric acid into the tubule in exchange for luminal
glucose (Cheeseman, 2009). Thus, an increased glucose concentration
in the proximal tubule would be expected to increase secretion of uric
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Table 3
Summary of ongoing CV outcomes trials with SGLT2 inhibitors (www.clinicaltrials.gov).
Trial name
(clinicaltrials.gov
identifier)
Treatment
groups
Patient
population
No. of
patients
Treatment
duration
Primary endpoint
Secondary CV endpoints
(only relevant
endpoints listed)
Estimated
completion date
NCT01032629
Canagliflozin
and placebo
Patients with T2DM
and high CV risk
4400
4 years
None
April 2013
(event driven)
NCT01131676
Empagliflozin
and placebo
Patients with T2DM
and high CV risk
7000
4 years
Time to first occurrence of
CV death, non-fatal MI, or
non-fatal stroke
Time to first occurrence of
CV death, non-fatal MI, or
non-fatal stroke
Composite of CV death, non-fatal
MI, non-fatal stroke, hospitalization
for unstable angina
Incidence of silent MI
March 2018
(event driven)
acid into the urine and reduce serum uric acid. A reduction in serum
uric acid could have beneficial effects on CV risk, given the increasing
evidence that elevated serum uric acid levels are an independent risk
factor for CV disease (Zoppini et al., 2009).
6.5. Overall effect on CV risk
The data submitted to the FDA as part of the application for
registration of dapagliflozin contain the most comprehensive analysis
to date of the effect of an SGLT2 inhibitor on CV outcomes. Fourteen
clinical trials were analyzed: three 12-week Phase IIb studies, ten 24week Phase III studies, and one 52-week study, with extensions of
some of these trials of up to 156 weeks. Dapagliflozin was not
associated with excess CV risk, with an overall hazard ratio of 0.67
relative to comparators for the primary composite of CV death,
myocardial infarction, stroke, and hospitalization for unstable angina
(FDA Briefing Document, 2011).
Long-term data on the effects of SGLT2 inhibitors on CV outcomes
in patients with T2DM are not yet available. In the absence of such
data, the magnitude of CV protection provided by SGLT2 inhibitors in
patients with T2DM can only be estimated based on anticipated
reductions in HbA1c, BP, and body weight. Based on meta-analyses of
randomized clinical trials, a 0.8% reduction in HbA1c would reduce CV
risk by 8%, a 4 mmHg reduction in systolic BP would provide at least
the same level of protection, and jointly these effects would be
expected to reduce vascular risk by about 15% (Foote, Perkovic, &
Neal, 2012). Such reductions in HbA1c and BP might be regarded as
conservative based on the results of clinical trials of SGLT2 inhibitors
and it is possible that reductions in body weight and serum uric acid
might add to the CV protection that SGLT2 inhibitors provide. Several
large long-term CV outcome studies are ongoing (Table 3).
7. Conclusions
T2DM increases the risk of CV morbidity and mortality and is
associated with co-morbidities that increase CV risk. SGLT2 inhibitors
are a new class of treatment for T2DM that acts independently of
insulin and can be used either early or late in the disease process to
reduce hyperglycemia by reducing renal glucose reabsorption and
increasing UGE. Clinical trials have shown that in addition to reducing
HbA1c, SGLT2 inhibitors reduce body weight, systolic BP and serum
uric acid. Inhibiting SGLT2 and exposing the nephron to an increased
sodium and glucose load may have a greater impact on CV risk than
presently perceived. Large studies are underway to elucidate the
effects of SGLT2 inhibitors on CV outcomes, the results of which are
eagerly awaited.
Acknowledgments
The author was fully responsible for all content and editorial
decisions, was involved at all stages of manuscript development, and
has approved the final version of this review that reflects the author's
interpretation and conclusions. The author has not received any
compensation for his work. Medical writing assistance, supported
financially by Boehringer Ingelheim, was provided by Tina Patrick,
PhD, and Wendy Morris, MSc., of Fleishman-Hillard Group Limited,
London, UK, during the preparation of this review. Boehringer
Ingelheim was given the opportunity to check the data used in the
review for factual accuracy only.
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