Diabetes Ther (2014) 5:355–366
`DOI 10.1007/s13300-014-0089-4
`
`REVIEW
`
`Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors:
`A Review of Their Basic and Clinical Pharmacology
`
`Sanjay Kalra
`
`To view enhanced content go to www.diabetestherapy-open.com
`Received: August 21, 2014 / Published online: November 26, 2014
`Ó The Author(s) 2014. This article is published with open access at Springerlink.com
`
`ABSTRACT
`
`INTRODUCTION
`
`(SGLT2)
`co-transporter-2
`Sodium-glucose
`inhibitors are a newly developed class of oral
`anti-diabetic drugs
`(OADs) with a unique
`mechanism of action. This review describes
`the biochemistry and physiology underlying
`the use of SGLT2 inhibitors, and their clinical
`pharmacology, including mechanism of action
`and posology. The pragmatic placement of
`these molecules in the existing OAD arena is
`also discussed.
`
`Keywords: Anti-diabetic drugs; Cardiovascular
`safety;
`Canagliflozin;
`Dapagliflozin;
`Empagliflozin;
`Perineal hygiene;
`Sodium-
`glucose co-transporter-2 inhibitors
`
`Electronic supplementary material The online
`version of this article (doi:10.1007/s13300-014-0089-4)
`contains supplementary material, which is available to
`authorized users.
`
`S. Kalra (&)
`Bharti Hospital and B.R.I.D.E., Karnal, India
`e-mail: brideknl@gmail.com
`
`Healthy individuals are able to maintain tight
`glucose homeostasis by closely regulating
`glucose
`production,
`reabsorption,
`and
`utilization.
`The
`importance
`of
`this
`homeostatic mechanism is evident from the
`fact that,
`in spite of extreme variations in
`glucose intake, relatively few people develop
`either diabetes or hypoglycemia [1].
`In people without diabetes, about 180 g of
`glucose is filtered daily by the renal glomeruli,
`and is
`then reabsorbed in the proximal
`convoluted tubule (PCT). This is achieved by
`passive transporters, namely, facilitated glucose
`transporters
`(GLUTs),
`and
`active
`co-
`transporters,
`namely,
`sodium-glucose
`co-
`transporters (SGLTs). There are six identified
`SGLTs, of which two (SGLT1 and SGLT2) are
`considered most important [1]. These SGLTs are
`described in Table 1 [2].
`This review describes the biochemistry and
`physiology underlying the use of
`SGLT2
`inhibitors
`(SGLT2i),
`and
`their
`clinical
`pharmacology, including mechanism of action
`and posology, and discusses the pragmatic
`placement of these molecules in the existing
`oral anti-diabetic drug arena. The article is based
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`356
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`Diabetes Ther (2014) 5:355–366
`
`Table 1 Comparison of SGLT1 and SGLT2
`
`Characteristic
`
`Location
`
`Capacity
`
`Affinity
`
`Contribution to glucose reabsorption
`
`SGLT1
`
`SGLT2
`
`Small intestine; later part of PCT
`(segment 3)
`
`Early PCT (segment 1, 2)
`
`Low
`
`High
`
`10%
`
`High
`
`Low
`
`90%
`
`Disease state if mutation/deficiency occurs
`
`Glucose-galactose malabsorption
`
`Familial renal glucosuria
`
`Physical manifestations of disease state
`
`Diarrhea at few days age
`
`Course
`
`Fatal without glucose free/galactose
`free diet
`
`None
`
`Benign
`
`Currently available SGLT2i
`Phlorizin
`Inhibitors
`PCT proximal convoluted tubule, SGLT sodium-glucose co-transporter, SGLT2i sodium-glucose co-transporter-2 inhibitors
`
`on previously conducted studies, and does not
`involve any new studies of human or animal
`subjects performed by the author.
`
`Table 2 Sodium glucose
`co-transporters
`development or already approved
`
`in advanced
`
`Molecule
`
`Approval/development status
`
`HISTORY
`
`The first SGLT2i discovered was phlorizin, a
`naturally occurring compound derived from
`apple tree bark. Because of its non-selective
`nature,
`it
`caused
`severe
`gastrointestinal
`symptoms. Due to this and to its poor oral
`bioavailability, work on its development could
`not continue [3]. Drugs which specifically
`inhibit
`SGLT2,
`and
`thereby
`avoid
`gastrointestinal
`effects
`related
`to
`SGLT1
`inhibition, have now been developed, some of
`which are listed in Table 2.
`
`RATIONALE
`
`the excretion of glucose
`Glucosuria (i.e.,
`through the kidneys) only occurs
`if
`the
`maximal
`capacity
`of
`various
`glucose
`transporter proteins (350 mg glucose/min) is
`exceeded [2, 4]. Earlier, glucosuria was thought
`
`Canagliflozin
`
`Dapagliflozin
`
`40 countries including EU, USA,
`China, Russia
`
`40 countries including EU, USA,
`Japan,
`
`Empagliflozin
`
`Phase 3 [37]
`
`Ipragliflozin
`
`Japan
`
`Luseogliflozin
`
`Under review for approval in Japan
`
`Tofogliflozin
`
`Phase 3 [43, 44]
`
`to be a pathological mechanism, or a marker of
`illness. However, one may approach this
`condition from a different view point. Persons
`with ambient hyperglycemia are at risk of
`endothelial
`dysfunction
`and
`resultant
`complications, due to the high levels of
`glucose in circulation. Kidneys try to prevent
`an excessive rise in blood glucose levels by
`glucuresis,
`thereby mitigating the adverse
`effects associated with high glucose levels.
`Theoretically,
`compounds which promote
`glucuresis should help to reduce circulating
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`Diabetes Ther (2014) 5:355–366
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`357
`
`glycemia, manage diabetes, and prevent long-
`term complications.
`
`MECHANISM OF ACTION
`
`inhibitors
`co-transporter-2
`Sodium-glucose
`work by inhibiting SGLT2 in the PCT,
`to
`prevent reabsorption of glucose and facilitate
`its excretion in urine. As glucose is excreted, its
`plasma levels fall leading to an improvement in
`all glycemic parameters [4–6].
`This mechanism of action is dependent on
`blood glucose levels and, unlike the actions of
`thiazolidinediones (mediated through GLUTs),
`is independent of the actions of insulin. Thus,
`there is minimal potential for hypoglycemia,
`and no risk of overstimulation or fatigue of the
`beta cells [7]. Because their mode of action relies
`upon
`normal
`renal
`glomerular-tubular
`function, SGLT2i efficacy is reduced in persons
`with renal impairment.
`
`CLINICAL PHARMACOLOGY
`
`Dapagliflozin is rapidly absorbed after oral
`administration,
`reaching
`peak
`plasma
`concentration in 2 h, and exhibiting oral
`bioavailability of 78% [8]. Dapagliflozin is
`metabolized
`by
`uridine
`diphosphate-
`glucuronosyltransferase (UGT)1A9 in both the
`liver and kidneys [8]. Canagliflozin achieves
`maximal plasma concentration 1–2 h after oral
`administration (oral bioavailability 65%) and
`steady state after 4–5 days. It is metabolized by
`glucuronidation by UGT1A9 and UGT2B4 [9].
`Empagliflozin
`reaches
`peak
`plasma
`concentration
`1.33–3.0 h
`after
`oral
`administration, before declining in a biphasic
`manner. The
`terminal half-life has been
`calculated to be 10.3–18.8 h in multiple dose
`studies, with steady state being achieved by day
`
`6 [10]. No dosage adjustments are required in
`renal or hepatic impairment. A summary of the
`clinical pharmacology of SGLT2i is presented in
`Table 3.
`Dapagliflozin and canagliflozin have proven
`efficacy in improving glycemic parameters,
`both as monotherapy and in combination
`[11].
`A
`52-week
`comparison
`between
`canagliflozin 100 and 300 mg showed non-
`inferiority, and canagliflozin 300 mg showed
`statistical superiority to sitagliptin in lowering
`glycated
`hemoglobin
`(HbA1c)
`[12].
`Canagliflozin 100 mg and 300 mg reduced
`bodyweight versus placebo at week 26 and
`sitagliptin at week 52. The published results
`are summarized in Table 4. Four-year (208-
`week) use of dapagliflozin with metformin
`produced a sustained and durable reduction in
`blood glucose levels with significantly less
`frequent adverse reactions as compared to
`glimepiride with metformin. After 4 years, the
`difference in HbA1c reduction between two
`groups was -0.3% [95% confidence interval
`(CI) -0.51, -0.09]. The trend over a period of
`time showed further increase in the difference
`with more prolonged use [13].
`and safety of
`The
`long-term efficacy
`empagliflozin have also been investigated as
`add-on therapy to basal insulin. Patients with
`type
`2
`diabetes mellitus
`(T2DM) were
`randomized to receive empagliflozin 10 or
`25 mg once daily or placebo; the basal insulin
`regimen was kept
`constant
`for
`the first
`18 weeks, after which the treating investigator
`could adjust the regimen at their discretion for
`the
`following 60 weeks
`[14]. As well
`as
`significant improvements in HbA1c, patients
`in both of
`the empagliflozin groups had
`significant reductions in their insulin doses at
`week 78, and also registered weight loss versus a
`small weight gain in those receiving placebo
`[14]. The decrease in insulin requirements in
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`Diabetes Ther (2014) 5:355–366
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`Table 3 Clinical pharmacology of sodium-glucose co-transporter-2 inhibitors
`
`Molecule
`
`Dose range Oral
`bioavailability
`(%)
`
`Elimination pathway
`
`Dose modifications
`
`Dapagliflozin 5–10 mg
`once daily
`
`78
`
`Hepatic and renal
`UGT1A9
`
`Canagliflozin
`
`100–300 mg
`once daily
`
`65
`
`UGT1A9 and 2B4
`
`Empagliflozin 10–25 mg
`once daily
`
`N/a
`
`UGT1A3, UGT1A8,
`UGT1A9, and
`UGT2B7
`
`Should not be initiated in patients with
`eGFR\60 ml/mt/1.73 m2
`No dose adjustment in patients with
`eGFR[60 ml/min/1.73 m2
`Dose limited to 100 mg once daily in patients
`with eGFR[45\60 ml/min/1.73 m2
`Stopped in patients with eGFR\45 ml/min/
`1.73 m2
`
`Dose adjustment in patients with creatinine
`clearance\60 ml/min
`Contraindicated in patients with creatinine
`clearance\45 ml/min
`No adjustment in hepatic failure
`
`Ipragliflozin
`
`100–300 mg
`once daily
`
`65
`
`Dose limited to 100 mg once daily in patients
`with eGFR[45\60 ml/min/1.73 m2
`Not recommended in patients with
`eGFR\45 ml/min/1.73 m2
`eGFR estimated glomerular filtration rate, N/a not available, UGT uridine diphosphate-glucuronosyltransferase
`
`UGT1A9 and
`UGT2B4
`
`patients on dapagliflozin has been evaluated in
`a
`study on insulin-mediated whole-body
`glucose uptake
`and endogenous
`glucose
`production using euglycemic hyperinsulinemic
`clamp technique. Dapagliflozin treatment for
`2 weeks
`increased
`insulin-mediated
`tissue
`glucose disposal by 18% and resulted in an
`increase in endogenous glucose production
`(with increased fasting glucagon levels) [15].
`
`PLEIOTROPIC EFFECTS
`
`Sodium-glucose co-transporter-2 inhibitors use
`leads to a reduction in body weight, ranging
`from about 1 to 5 kg [16]. A greater fall is seen in
`patients with long-standing diabetes and in
`those with a higher baseline weight. This
`
`weight loss is sustained after up to 2 years of
`use of dapagliflozin, and may be linked to a
`reduction in insulin dose requirements of
`patients with long-standing diabetes
`[16].
`Analysis
`of
`208-week
`data
`comparing
`dapagliflozin in combination with metformin
`versus
`glimepiride
`in combination with
`metformin showed 4.38 kg (95% CI -5.31,
`-3.46) difference between two groups. Patients
`in the glimepiride group gained a mean of
`0.73 kg while those in dapagliflozin group lost
`3.65 kg [13].
`While it may be argued that weight loss is
`because of volume depletion, it has been shown
`that two-thirds of the decreased weight is lost
`from fat mass (especially visceral abnormal fat),
`as compared to lean mass [14]. An initially rapid
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`Diabetes Ther (2014) 5:355–366
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`Table 4 Glucose-lowering efficacy of sodium-glucose co-transporter-2 inhibitors
`
`Parameter
`
`Monotherapy Combination with other oral anti-diabetic drugs
`
`Initial
`combination
`with Met
`
`With
`Met
`
`With
`SU
`
`With
`Met 1 SU
`
`With
`Met 1 TZD
`
`Molecule
`(duration of
`study)
`
`Canagliflozin
`300 mg
`(26-week study)
`
`Dapagliflozin
`10 mg
`(24-week study)
`
`HbA1c (%) -1.03
`FPG (mg/dl) -35
`PPG (mg/dl) -59
`HbA1c (%) -0.9
`FPG (mg/dl) -28.8
`
`PPG (mg/dl) –
`HbA1c (%) -1.29
`FPG (mg/dl) -39.4
`
`–
`
`–
`
`–
`-2.0
`-60.4
`
`–
`
`–
`
`–
`
`–
`
`359
`
`As add-
`on to
`insulin
`
`-0.72
`-25
`
`–
`-0.9
`-21.7
`
`–
`
`–
`
`–
`
`–
`
`-0.94 -0.79 -1.06
`-27
`-31
`-48
`–
`–
`-0.8 -0.8 -1.0
`-23.5 -28.5 -29.6
`-60.6 -67.5
`–
`-0.48 -1.14 -0.88
`-38
`-41
`
`-1.03
`-33
`
`–
`-0.4
`-24.1
`
`–
`
`–
`
`–
`
`Ipragliflozin
`300 mg
`(24 week study)
`FPG fasting plasma glucose, HbA1c glycated hemoglobin, Met metformin, MetXR metformin extended release, PPG post-
`prandial plasma glucose, SU sulfonylurea, TZD thiazolidinedione
`
`decline in weight is followed by a slower rate of
`weight loss, and is also marked by a reduction in
`weight circumference. Concomitant use of
`SGLT2i can attenuate or neutralize weight gain
`due to insulin, if given in combination with
`insulin [16].
`Sodium-glucose co-transporter-2 inhibitors
`also cause significant
`reductions
`in both
`systolic and diastolic blood pressure (BP).
`These changes are relatively more prominent
`for systolic BP, are not dose dependent, and are
`not characterized by concomitant tachycardia
`or symptoms of hypotension/syncope in most
`of the cases. The effects on BP seem to be
`independent of glycemic or body weight
`reduction, and are greater in patients with
`high baseline systolic BP [17]. BP reduction
`with SGLT2i occurs due to osmotic diuresis
`initially, and to local rennin-angiotensin system
`inhibition later on [18]. Some studies have
`reported reduction of up to 13.4–17 mmHg in
`systolic BP with empagliflozin, a magnitude
`similar
`to that observed with many anti-
`hypersensitive drugs
`[19, 20]. A recently
`
`of
`study
`outcome
`104-week
`published
`canagliflozin showed that the 100 and 300 mg
`dose reduced systolic and diastolic BP compared
`with glimepiride, with no notable changes in
`pulse rate [20]. Analysis of 208-week data
`comparing dapagliflozin in combination with
`metformin versus glimepiride with metformin
`showed an increase of 0.2 mmHg (95% CI
`-1.66, 1.61) in the glimepiride group while
`those on dapagliflozin showed a reduction of
`3.69 mmHg (95% CI -5.24, -2.14) [13].
`Sodium-glucose co-transporter-2 inhibitors
`are either lipid-friendly or lipid-neutral drugs.
`Canagliflozin,
`for example,
`increases high-
`density lipoprotein (HDL) by 7.1–10.6%, low-
`density lipoprotein (LDL) by 7.1%, and reduces
`triglycerides by 2.3% [21, 22]. Treatment with
`canagliflozin for 104 weeks was also associated
`with increases in HDL-C and LDL-C, which is
`consistent with findings at week 52. However,
`the proportion of patients who started or
`modified therapy with lipid-modifying agents
`were
`13%,
`11.5%,
`and
`13.3% in the
`canagliflozin 100 mg, canagliflozin 300 mg,
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`Diabetes Ther (2014) 5:355–366
`
`and glimepiride groups, respectively [23]. After
`4 years of use, sustained and stable weight loss
`was observed with dapagliflozin versus weight
`gain with glimepiride (-3.95 vs. ?1.12 kg).
`Mean
`systolic
`BP was
`reduced with
`dapagliflozin but not with glimepiride [24].
`Data from 21 clinical studies, including 2
`that exclusively enrolled patients with a history
`of cardiovascular disease (CVD), were included
`in a prespecified meta-analysis (n = 9,339) to
`assess
`the
`cardiovascular
`(CV)
`safety of
`to[10 mg/day;
`dapagliflozin
`(2.5 mg
`n = 5,936) versus
`comparators
`(placebo or
`active n = 3,403) [25]. The prespecified primary
`end point was a composite of time to CV death,
`myocardial
`infarction
`(MI),
`stroke,
`or
`hospitalization for unstable
`angina. The
`secondary end point included the primary end
`point
`plus
`unplanned
`coronary
`revascularization and hospitalization for heart
`failure. The estimated hazard ratio (HR) using a
`Cox proportional hazards method was 0.787
`(95% CI 0.579, 1.070). Analyses of
`the
`secondary end point (HR 0.758; 95% CI 0.581,
`0.988) and of an ad-hoc major adverse CV
`events composite end point of CV death, MI,
`and stroke (HR 0.772; 95% CI 0.543, 1.097) were
`consistent with the primary end point results.
`These findings suggest that there is no increase
`in CV risk associated with dapagliflozin in an
`updated CV risk analysis that includes more
`patients and a substantial proportion of older
`patients ([20%) and patients with established
`CVD ([30%). Although these
`results are
`encouraging, presently the evidence is lacking
`regarding
`macro
`and
`micro-vascular
`complications of T2DM in patients managed
`with this
`class of drugs. A randomized-
`controlled clinical trial is already underway to
`explore the long-term CV outcomes in patients
`on treatment with SGLT2i as primary end point
`[26].
`
`Uric acid levels, a marker of metabolic
`dysfunction, are markedly reduced (5.9–17.8%)
`by SGLT2i, with the effect sustained for 2 years
`[27]. The drugs may affect uric acid excretion
`directly, by acting on its transport system, or
`indirectly, but reducing sodium reabsorption in
`the PCT. The beneficial impact of SGLT2i on
`uric acid is attenuated if insulin is co-prescribed.
`Renal hyperfiltration has been found to be
`closely associated with the development of
`diabetic nephropathy (DN) [28]. Pooled data
`from 2 randomized clinical trials including 600
`patients with normo- or microalbuminuria
`followed up for 4 years which demonstrated
`that hyperfiltration has
`central
`role
`in
`pathogenesis of DN [28]. SGLT2 is one of the
`main
`determinants
`of
`glomerular
`hyperfiltration and blockade of SGLT2 has
`potential nephroprotective action.
`
`POSOLOGY
`
`Dapagliflozin is approved as 10 mg once-daily
`drug,
`as monotherapy, or as
`add-on to
`metformin,
`sulfonylurea
`(SU),
`dipeptidyl
`peptidase-4 (DPP-4) inhibitors, and/or insulin.
`It can be prescribed alone to persons who do
`not tolerate or cannot take metformin safely. A
`5-mg dose is available for persons with hepatic
`insufficiency.
`In mild to moderate hepatic
`impairment, no dosage adjustment is required.
`However, in severe hepatic impairment, 5 mg
`starting dose is recommended [29].
`Canagliflozin has a two-stage dosage regime.
`The starting dose approved is 100 mg once
`daily, before the first meal of the day. In those
`who do not respond adequately, the dose can be
`increased to 300 mg, provided renal function is
`normal [10].
`Empagliflozin is being studied in daily doses
`of 10 and 25 mg. Trials have revealed dose-
`dependent
`HbA1c
`reductions
`with
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`Diabetes Ther (2014) 5:355–366
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`361
`
`empagliflozin monotherapy, which are greater
`as compared to those observed with sitagliptin,
`but
`similar
`to
`those
`experienced with
`metformin. Empagliflozin can be administered
`without relation to meal timings, in a once-
`daily frequency [30].
`Ipragliflozin has Japanese approval for the
`treatment of T2DM,
`either
`alone or
`in
`combination with metformin, pioglitazone,
`SU, a-glucosidase inhibitor, DPP-4 inhibitor, or
`with nateglinide [30].
`
`ADVERSE EVENTS
`
`The incidence of adverse events in clinical trials
`of SGLT2i is similar to that observed with other
`anti-diabetic drugs. The overall
`incidence of
`adverse events has ranged from 57.3 to 83.0%,
`while that of serious adverse events have varied
`between 1.0% and 12.6% [31].
`Uro-genital tract infections are the most
`frequently noticed adverse events in subjects
`on SGLT2i [32], especially in women and in
`uncircumcised men. Pooled data from 12
`placebo-controlled
`clinical
`trials
`of
`dapagliflozin reveal that when used in dose
`2.5, 5, and 10 mg per day, the incidence of
`clinically diagnosed uro-genital tract infection
`was 4.1%, 5.7% and 4.8%, respectively, while it
`was 0.9% in the placebo group [33]. Common
`infections include vulvitis and vulvo-vaginitis
`in women,
`as well
`as
`balanitis
`and
`balanoposthitis
`in men.
`These
`can be
`prevented by maintaining adequate perineal
`hygiene,
`and
`through
`treatment with
`antifungal
`therapy. Genital
`infections
`are
`thought to be caused by an increased glucose
`load in the urinary tract, which encourages
`fungal growth. The incidence of urinary tract
`infections does not
`increase with SGLT2i
`therapy [34].
`
`The osmotic diuresis associated with SGLT2i
`use also has the potential to cause volume
`depletion and orthostatic hypotension.
`In
`randomized-controlled trials, however,
`the
`incidence of these adverse events has been
`minimal (\3%) [25]. All such events have been
`mild to moderate in severity. The extra diuresis
`experienced per day is 350–450 ml (one extra
`void per day) [34], and does not cause nocturia.
`The diuresis seen with SGLT2i may result in
`slight transient increase in serum creatinine and
`blood urea, with a corresponding fall
`in
`glomerular filtration rate (GFR).
`The risk of hypoglycemia is minimal with
`SGLT2i, as
`they have a non-insulin-based
`mechanism of action. However, hypoglycemia
`may occur when these molecules are used in
`complication with other anti-diabetic drugs,
`including metformin. Four-year comparison
`between dapagliflozin plus metformin and
`glipizide plus metformin showed a tenfold
`decrease in the incidence of hypoglycemic
`episodes (5.4% and 51.5%, respectively) [13].
`In this 208-week study, patients treated with
`dapagliflozin
`plus metformin
`had
`35
`hypoglycemic events as compared to 1,191
`events
`in glipizide plus metformin group.
`Dose-down titration during first year was
`required in 2.7% patients in the dapagliflozin-
`treated group compared with 15.8% in the
`glipizide-treated group. This finding is very
`significant
`in
`light
`of
`the
`long-term
`consequences of hypoglycemic episodes on the
`physiology of patients and their compliance to
`treatment.
`Sodium-glucose co-transporter-2 inhibitors
`use leads
`to a slight
`reduction in bone
`formation, and a rise in bone resorption
`markers, although there are no major changes
`on bone mineral density. A 102-week study
`with dapagliflozin did not identify any changes
`in markers of bone turnover as compared to
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`Diabetes Ther (2014) 5:355–366
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`placebo when added to metformin [27]. Other
`long-term studies have not demonstrated any
`significant increase in adverse drug reactions
`related with skeletal system with any of the
`SGLT2i [35, 36].
`
`USE IN RENAL IMPAIRMENT
`
`In patients with reduced GFR, the amount of
`glucose reaching the PCT falls and the efficacy
`of SGLT2 may be suboptimal. Canagliflozin is
`prescribed in a full dose of 300 mg daily if GFR is
`above 60 ml/min and as 100 mg once daily if
`GFR is 45–60 ml/min [10]. Dapagliflozin can be
`prescribed as 5 or 10 mg once daily, depending
`upon the regulatory label
`in the country
`concerned [29]. A pooled analysis of 13
`clinical trials exploring the long-term renal
`safety of dapagliflozin 10 mg as compared to
`placebo or other oral hypoglycemic agents
`showed no change in renal functions over a
`period varying from 12 to 104 weeks [25].
`Similarly, empagliflozin is being studied in
`doses of 10 and 25 mg per day [37].
`
`DRUG–DRUG INTERACTIONS
`
`Sodium-glucose co-transporter-2 inhibitors do
`not exhibit any clinically relevant drug–drug
`interactions, including with other anti-diabetic
`drugs and diuretics. They can be combined with
`metformin, SU, pioglitazone, sitagliptin, and
`voglibose. Concomitant prescription of loop
`diuretics
`and SGLT2i
`should be
`avoided
`because of
`the potential
`risk for volume
`depletion. Co-administration of canagliflozin
`with UGT-inducer
`drugs,
`for
`example,
`rifampicin, phenytoin, phenobarbitone, and
`ritonavir, should prompt an increase in dose
`from 100 to 300 mg, if otherwise tolerated [10].
`UGT enzyme-inducing agents
`increase the
`
`metabolism of canagliflozin thus leading to a
`decrease in peak plasma levels and reduced
`efficacy [32].
`
`CLINICAL USE
`
`is
`diabetes
`of
`Current management
`characterized by opportunities, options, and
`obstacles. In spite of the availability of a wide
`array of oral and injectable options, it remains
`difficult
`to achieve good glycemic control,
`while avoiding hypoglycemia and weight gain,
`and ensuring CV safety. These adverse effects
`are
`obstacles
`to
`the
`optimal
`use
`of
`pharmaceuticals options currently available.
`Sodium-glucose co-transporter-2 inhibitors
`are a novel class of drugs with a novel
`mechanism of action, which can be useful in
`almost every stage of the natural history of
`diabetes, and represent a means of achieving
`better and safer glycemic control.
`Sodium-glucose co-transporter-2 inhibitors
`can be used as initial monotherapy in persons
`in whom metformin is not indicated, or not
`tolerated. Examples include those with hepatic
`impairment and gastrointestinal
`intolerance.
`SGLT2i can also be used as second-line drugs,
`and third-line drugs, in persons inadequately
`controlled on a single or dual glucose-lowering
`therapy. Their glucose-lowering effect may help
`some people with diabetes delay insulin
`injections. Additionally, a significantly low risk
`of hypoglycemia with these agents can improve
`outcomes and compliance considerably.
`The pleiotropic effects of SGLT2i—weight
`loss, BP reduction, and uricosuria—make them
`especially attractive for use in persons with
`metabolic syndrome, and in those with mild
`fluid
`overload.
`Their
`oral mode
`of
`administration may favor their use over the
`injectable
`glucagon-like peptide-1 receptor
`agonists.
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`Diabetes Ther (2014) 5:355–366
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`363
`
`This class of drugs can also be used in
`combination with insulin, and its
`insulin-
`sparing effect allows for more effective, well-
`tolerated glycemic control, without weight
`gain. A 24-week clinical
`trial
`comparing
`dapagliflozin versus placebo in patients taking
`a high dose of insulin demonstrated a decrease
`in insulin requirement of 0.79% and 0.39%,
`respectively [38]. Additionally,
`there was a
`significant decrease in insulin dose required by
`patients treated with dapagliflozin as compared
`to an increase in placebo group. A statistically
`significant decrease in body weight of up to
`2.4 kg in the dapagliflozin 10 mg group as
`compared to an increase of 0.43 kg in the
`placebo group was also seen [38].
`The ability to prescribe SGLT2i to persons
`with renal [39] and hepatic impairment, an easy
`two-step or one-step dose titration, a lack of
`relevant drug–drug interactions, and safety in
`combination with all routinely used CV and
`anti-diabetic drugs, are all points which will
`encourage their use.
`Counseling regarding potential side effects
`and ways
`to prevent
`them,
`for example,
`perineal hygiene and avoidance of volume
`depletion,
`must
`accompany
`SGLT2i
`prescription.
`A recent pilot study explored the potential
`role of SGLT2i
`in managing hyperglycemia
`associated with type 1 diabetes mellitus
`(T1DM) [40]. This 2-week exploratory study of
`dapagliflozin in doses ranging from 1 to 10 mg
`per day in addition to insulin, established its
`safety and pharmacokinetics, and explored the
`pharmacodynamics of a new class of drug for
`managing T1DM. Glucosuria increased by
`88 mg/day in the dapagliflozin group while it
`decreased by 21.5 mg/day in the placebo group.
`Additionally, a fall of 16.2% in the dapagliflozin
`group and an increase of 1.7% in the placebo
`group for total daily insulin dose were seen
`
`during this period [40]. More proof-of-concept
`studies
`are
`available
`documenting
`reno-
`protection provided by these agents in T1DM.
`Renal hyperfiltration which is
`an early
`hemodynamic abnormality preceding frank
`nephropathy in T1DM was improved with
`short-term use of these agents [41, 42]. Newer
`SGLT2i, still in pre-clinical and clinical phases
`of development, are expected to have a safer
`profile in view of their highly selective action
`[43, 44].
`
`CONCLUSION
`
`The SGLT2i represent a novel class of drugs
`which will certainly help a large number of
`people with diabetes achieve target control in a
`safe and well-tolerated manner. Their unique
`mechanism of action, coupled with pleiotropic
`benefits on weight and blood pressure, should
`make them attractive choices
`for add-on
`therapy to persons not controlled on other
`medications.
`
`ACKNOWLEDGMENTS
`
`No funding or sponsorship was received for this
`study or publication of this article. Sanjay Kalra
`meets the ICMJE criteria for authorship for this
`manuscript, takes responsibility for the integrity
`of the work as a whole, and has given final
`approval for the version to be published.
`
`of
`
`Conflict
`
`interest. Sanjay Kalra has
`speakership
`honoraria
`from
`received
`AstraZeneca for speaking on topics not related
`to the subject matter of this review.
`
`Compliance with ethics guidelines. This
`review article is based on previously conducted
`studies, and does not involve any new studies of
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`human or animal subjects performed by the
`author.
`
`Open Access. This article is distributed
`under the terms of the Creative Commons
`Attribution Noncommercial License which
`permits any noncommercial use, distribution,
`and reproduction in any medium, provided the
`original author(s) and the source are credited.
`
`REFERENCES
`
`1.
`
`2.
`
`3.
`
`the
`Abdul GM, DeFronzo R. Dapagliflozin for
`treatment of
`type 2 diabetes. Expert Opin
`Pharmacother. 2013;14:1695–703.
`
`Bailey CJ. Renal glucose reabsorption inhibitors to
`treat
`diabetes.
`Trends
`Pharmacol
`Sci.
`2011;32:63–71.
`
`Ehrenkranz J, Lewis N, Ronald KC, Roth J. Phlorizin:
`a review. Diabetes Metab Res Rev. 2005;21:31–8.
`
`4. Wright EM. Renal Na?-glucose cotransporters. Am J
`Physiol Renal Physiol. 2001;280(1):F10–8.
`
`5.
`
`Lee YJ, Lee YJ, Han HJ. Regulatory mechanisms of
`Na(?)/glucose cotransporters in renal proximal
`tubule cells. Kidney Int Suppl. 2007;(106):S27–35.
`
`6. Hummel CS, Lu C, Loo DD, Hirayama BA, Voss AA,
`Wright EM. Glucose transport by human renal
`NA?/D-glucose cotransporters SGLT1 and SGLT2.
`Am J Physiol Cell Physiol. 2011;300:C721.
`
`7. Nauck MA. Update on developments with SGLT2
`inhibitors in the management of type 2 diabetes.
`Drug Des Devel Ther. 2014;8:1335–80.
`
`8. Mudaliar S, Henry R, Boden G, et al. Changes in
`insulin sensitivity and insulin secretion with the
`sodium glucose
`cotransporter
`2
`inhibitor
`dapagliflozin.
`Diabetes
`Technol
`Ther.
`2014;16:137–44.
`
`9.
`
`Kasichayanula S, Liu X, LaCreta F, Griffen S,
`Boulton D. Clinical
`pharmacokinetics
`and
`pharmacodynamics of dapagliflozin, a selective
`inhibitor of sodium-glucose co-transporter type 2.
`Clin Pharmacokinet. 2014;53:17–27.
`
`Janssen
`10. Canagliflozin prescribing information,
`Pharmaceuticals. 2014. https://www.invokanahcp.
`com/prescribing-information.pdf.
`
`J, et al. Dapagliflozin
`11. Zhang L, Feng Y, List
`treatment in patients with different stages of type
`2 diabetes mellitus: effects on glycaemic control
`and
`body weight. Diabetes Obes Metab.
`2010;12:510–6.
`
`12. Lavalle-Gonza´lez FJ, Januszewicz A, Davidson J,
`et al. Efficacy and safety of canagliflozin compared
`with placebo and sitagliptin in patients with type 2
`diabetes on background metformin monotherapy: a
`randomised trial. Diabetologia. 2013;56:2582–92.
`
`13. Rohwedder K, Johnsson E, Parikh S. Reduced risk of
`hypoglycemic
`events with dapagliflozin vs.
`glipizide as add-on therapy in type 2 diabetes
`mellitus: 4-year data from a phase 3 study. In:
`Poster presented at 50th Annual meeting of the
`European Association for the Study of Diabetes.
`Vienna; 2014.
`
`14. Rosenstock J, Jelaska A, Wang F, et al. Empagliflozin
`as add- on to basal insulin for 78 weeks improves
`glycemic control with weight loss in insulin-treated
`type
`2 diabetes
`(T2DM). Can J Diabetes.
`2013;37:S32.
`
`15. Merovci A, Solis-Herrera C, Daniele G, et al.
`Dapagliflozin improves muscle insulin sensitivity
`but enhances endogenous glucose production.
`J Clin Invest. 2014;124:509–14.
`
`16. Scheen A. Pharmacokinetic and pharmacodynamic
`profile of empagliflozin, a sodium glucose co-
`transporter 2 inhibitor. Clin Pharmacokinet.
`2014;53(3):213–25.
`
`17. Vasilakou D, Karagiannis T, Athanasiadou E, et al.
`Sodium-glucose cotransporter 2 inhibitors for type
`2 diabetes: a systematic review and meta-analysis.
`Ann Intern Med. 2013;159:262–74.
`
`18. Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B,
`List J. Dapagliflozin a glucose-regulating drug with
`diuretic properties in subjects with type 2 diabetes.
`Diabetes Obes Metab. 2013;15:853–62.
`
`19. Tikkanen I, Narko K, Zeller C, et al. Empagliflozin
`improves blood pressure in patients with type 2
`diabetes (T2DM) and hypertension. In: Abstract 942
`presented at the 49th European Association for the
`Study of Diabetes Annual Meeting, September
`23–27,
`Barcelona,
`Spain.
`Diabetologia
`2013;56:S377.
`
`Januszewicz A, Gilbert RE, Lavalle
`20. Weir MR,
`Gonzalez FJ, Meininger G. Lower blood pressure
`(BP) with canagliflozin (cana) in subjects with type
`2
`diabetes
`mellitus
`(T2DM).
`Diabetes.
`2013;62(Suppl 1):Abstract 1077-P.
`
`21. Leiter LA, Yoon KH, Arias P, et al. Canagliflozin
`provides durable glycemic improvements and body
`
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`

`Diabetes Ther (2014) 5:355–366
`
`365
`
`weight reduction over 104 weeks versus glimepiride
`in patients with type 2 diabetes on metformin: a
`randomized, double-blind, phase 3 study diabetes
`care. 2014. (pii: DC_132762). [Epub ahead of print].
`
`al.
`et
`A,
`S, Devineni D, Ghosh
`22. Sha
`a
`Pharmacodynamic
`effects of
`canagliflozin,
`sodium glucose co-transporter 2 inhibitor, from a
`randomized study in patients with type 2 diabetes.
`PLoS One. 2014;9:e105638.
`
`23. Hach T, Gerich J, Salsali A et al. Empagliflozin
`improves glycaemic parameters and cardiovascular
`risk factors in patients with type 2 di