US Pharm. 2013;38(10):HS13-HS20.
ABSTRACT: With the progressive nature of
diabetes, patients need additional methods to maintain glucose control.
Canagliflozin (Invokana), a novel medication for treatment of type 2
diabetes, provides an alternative for patients who are not well
controlled on current drug therapy or diet and exercise. It works by
inhibiting the sodium-glucose co-transporter 2 (SGLT2) in the kidney,
thus leading to increased glucose excretion. Canagliflozin is the first
FDA-approved SGLT2 inhibitor.
The kidney has historically been ignored as a potential
target organ for the pharmacologic mitigation of hyperglycemia, as it
was primarily considered an organ of elimination and a regulator of salt
and ion balance. The kidney was once mistakenly thought to be the
structural cause of diabetes, and in later years has essentially been
ignored as a regulator of glucose homeostasis. Today, however, it is now
recognized as an important contributor to glucose regulation. In line
with this, we now have a clearer understanding of the physiology of
glucose transport via specific carriers such as the sodium-glucose
co-transporters (sodium-glucose linked transporters), or
In the early 1800s, the natural compound phlorizin was
isolated. It was initially referred to as the “glycoside from the bark
of apple trees” and was later shown to cause glucosuria. Phlorizin
itself was not pursued as a medication for the treatment of diabetes in
humans because the compound is poorly absorbed from the gastrointestinal
(GI) tract and is nonselective in its inhibition of the target
transporter.1 It was recognized, however, that the effect of a
“phlorizin-like compound” on renal glucose transporters might offer a
novel mechanism for the management of hyperglycemia.
This discovery has led to the development of several SGLT2
inhibitors. Dapagliflozin is approved in Europe and is also being
developed for potential use in the United States. The initial FDA
application was rejected but was resubmitted in July 2013.2 A
New Drug Application (NDA) for a second compound, empagliflozin, was
recently submitted to the FDA and is currently under review.3
Another compound, canagliflozin, has been approved for use in the U.S.
and is currently marketed under the trade name of Invokana by Janssen
Pharmaceuticals.4 It is the first of its class approved for use in the U.S. and will be the focus of this review.
This article will discuss the role of the kidney in
glucose homeostasis, explain the mechanism of action of SGLT inhibitors,
and provide an overview of the clinical trials leading to the approval
of canagliflozin, as well as information regarding the appropriate use
of this compound.
Glucose Homeostasis and the Kidney
Glucose regulation can be divided into three main
processes: 1) glucose absorption, 2) glucose synthesis or production,
and 3) glucose utilization.
Mechanism of Action of SGLT2 Inhibitors: Endogenous
glucose production occurs primarily in the liver, with hepatic
glycogenolysis and gluconeogenesis accounting for 85% of endogenous
production.5 However, it is important to note that
gluconeogenesis is responsible for about 55% of glucose released during
the non-fed period and thus has a significant impact on glycemia.6
The kidney warrants consideration in the overall picture of endogenous
glucose synthesis because renal glucose production accounts for about
20% of all overall endogenous glucose release and is also responsible
for approximately 40% of glucose released secondary to gluconeogenesis.6 Therefore, the kidney plays an important role in glucose production.
After glucose is ingested, an increase in plasma glucose
concentration triggers insulin release, which in turn stimulates
splanchnic and peripheral glucose uptake and suppression of endogenous
glucose production. Under normal circumstances in healthy individuals,
blood glucose levels are tightly regulated within the range of 70 to 99
mg/dL and rarely exceed 140 mg/dL following postprandial consumption.1
These narrow ranges are maintained under a complex system that includes
multiple hormones (e.g., insulin and glucagon), central and peripheral
nervous system metabolic needs, and various cells and tissues (e.g.,
brain, muscle, GI tract, liver, kidney, and adipose tissue), which
regulate the uptake, metabolism, storage, and excretion of glucose.
Two groups of glucose transporters mediate most cellular
glucose transport: glucose transporters (GLUTs), which are expressed
throughout the body, and SGLTs. The function of SGLTs will be discussed
Glucose utilization takes place primarily (over 80%) in
the muscle. This glucose is utilized directly for energy or stored as
glycogen. Under normal conditions, approximately 5% of peripheral
glucose is taken up by fat tissue.6 The liver preferentially stores absorbed glucose in the form of glycogen when under the influence of insulin.
With normal kidney function, 99% of filtered glucose is
reabsorbed during periods of euglycemia. The glomerular filtration rate
(GFR) and plasma glucose concentration govern the rate of glucose
filtration. Under normal conditions, most if not all of the filtered
glucose is reabsorbed. However, there is a maximum rate at which glucose
can be reabsorbed (~375 mg/min in an average patient).1 The
most salient SGLT in the kidney is SGLT2. SGLT2 accounts for
approximately 90% of glucose reabsorption in the kidney and, because of
this, has become the focus of this new category of medications, the
SGLT2 inhibitors.1 SGLT2 transporters are found at a
relatively high density on the brush-border membrane of the S1 (early)
segment of the proximal convoluted tubule. This transporter binds with
both sodium ions (Na+) and glucose in the tubular filtrate. These compounds are then translocated across the cell membrane.7 Functionally, this process is driven by the electrochemical Na+ gradient between the tubular filtrate and the intracellular space and is called secondary active-transport (FIGURE 1).7
Glucose in the tubular epithelial cell is then transported down a
concen-tration gradient across the basolateral membrane to the systemic
circulation by GLUT1.
When the rate of glucose absorption exceeds 375 mg/min,
glucose is excreted in the urine because its concentration has exceeded
the ability of the SGLT2 transporters to reabsorb it.1 In
most nondiabetic persons, glucose concentrations will never be high
enough to exceed the kidney’s ability to reabsorb the presented glucose.
However, in patients with diabetes, glucosuria is common with blood
glucose of 180 mg/dL or higher.1 SGLT2 inhibitors modulate
this pathway by reducing the reabsorptive capacity of the renal tubules,
with a resultant elimination of excess glucose. Thus, the mechanism of
action of the SGLT2 inhibitors is to simply inhibit the transporter,
which in turn reduces the reabsorption of filtered glucose and lowers
the renal threshold for glucose. The net result is an increase in
urinary glucose excretion, which results in a reduction in blood glucose
Overview of Clinical Trials With Canagliflozin
Many studies have evaluated canagliflozin and its use in
the treatment of type 2 diabetes mellitus. Published trials have
explored its role as monotherapy and as an add-on for dual- or
triple-drug therapy. Ongoing studies are now evaluating pharmacokinetic
and pharmacodynamic effects as well as the influence of canagliflozin on
Canagliflozin has been studied in the CANTATA trials
(CANagliflozin Treatment And Trial Analysis) as mono-therapy or as
add-on therapy to metformin, metformin and sulfonylureas, and metformin
and pioglitazone. Each trial was randomized, double-blind, placebo- or
active-controlled, examining change from baseline glycated hemoglobin
(A1C) at 26 weeks or 52 weeks.8,9
The impact on A1C using canagliflozin as monotherapy was evaluated in the CANTATA-M trial.8,9
Both canagliflozin doses produced a statistically significant decrease in A1C (P <.001) and reduction of systolic blood pressure (100 mg by -3.7 mmHg and 300 mg by -5.4 mmHg from placebo, P ≤.001) as well as body weight (100 mg by -2.2 kg and 300 mg by -3.3 kg from placebo, P
≤.001). Like CANTATA-M, both CANTATA-D and CANTATA-MP showed a
significant reduction of A1C, body weight, and systolic blood pressure
for both doses of canagliflozin.8,9
The CANTATA-SU trial demonstrated similar reductions in
A1C in the glimepiride and canagliflozin 100-mg groups but trended
toward a greater reduction in A1C in the canagliflozin 300-mg group.
Both canagliflozin dosing arms were considered noninferior to the
glimepiride arm. Body weight was significantly decreased in both
canagliflozin arms compared to the glimepiride arm (P <.001).8 In CANTATA-MSU, statistically significant reductions occurred in A1C and weight for both doses of canagliflozin (P
<.001). CANTATA-D2 results demonstrated that canagliflozin 300 mg
was noninferior to sitagliptin 100 mg when added to sulfonylurea and
metformin at 26 weeks.8,9
analysis at 52 weeks showed canagliflozin 300 mg was superior to
sitagliptin 100 mg in reduction of A1C for patients not controlled on
metformin and sulfonylurea.10
Canagliflozin was also studied as an add-on to insulin
therapy in an 18-week, double-blind, placebo-controlled trial in a
subset of the CANVAS trial (CANagliflozin cardioVascular Assessment
Participants were enrolled
into the study if they were not well controlled on insulin, on ≥30 units
of insulin per day, or on insulin with oral antihyperglycemic
medications. Both canagliflozin doses of 100 and 300 mg showed a
significant reduction in A1C, weight, and systolic blood pressure (P <.001). All of the CANTATA trials, as well as the insulin trial, are summarized in TABLE 1.8,9
Two studies have been completed using canagliflozin in
special patient populations. One studied its use in adults aged 55 to 80
The trial showed
canagliflozin was safe and effective in this age group for patients not
adequately controlled with diet and exercise alone. The other trial
reviewed canagliflozin use in patients with moderate renal dysfunction.8
Two hundred sixty-nine participants with a GFR between 30 and 50 mL/min/1.73 m2
were randomized to receive either canagliflozin 100 or 300 mg or
placebo. The study demonstrated safety and efficacy for patients with
moderate renal dysfunction who are not controlled on a current diabetes
Use of Canagliflozin
Canagliflozin is a once-daily oral medication indicated
for adults with type 2 diabetes mellitus to improve glucose control in
conjunction with diet and exercise.8 It is not recommended
for the treatment of children, type 1 diabetes mellitus, or diabetic
ketoacidosis. Canagliflozin is also contraindicated for patients
receiving hemodialysis, who have severe renal dysfunction, or have a
history of severe hypersensitivity to canagliflozin. The recommended
starting dose is 100 mg by mouth daily taken 30 minutes prior to the
first meal of the day. Doses can be increased to 300 mg orally per day
in those individuals who need further glucose management. Patients who
need a dosage increase must have normal renal function and must be
tolerating the 100 mg dose. No adjustment of dosage is recommended in
mild renal impairment (GFR >60 mL/min/1.73 m2). The dosage of canagliflozin is limited to 100 mg per day in patients with a GFR of 45 to 60 mL/min/1.73 m2 and is not recommended in severe renal impairment of <45 mL/min/m2.
Coadministration with inducers of the UDP-UGT enzyme, rifampin,
phenytoin, phenobarbital, and ritonavir may require an increased daily
dose of 300 mg.8
Precautions, warnings, and adverse effects to consider
prior to initiating canagliflozin are hypotension, impairment of renal
function, hyperkalemia, hypoglycemia, genital mycotic infections,
hypersensitivity reactions, and increases in low-density lipoprotein
(LDL).8 Hypotension is caused through intravascular volume
contraction and osmotic diuresis. Prior to initiation, it is important
to ensure that the patient is euvolemic because of this potential
adverse effect. Patients at increased risk of hypovolemia due to
canagliflozin are those receiving diuretics, angiotensin-converting
enzyme (ACE) inhibitors, or angiotensin receptor blockers; the elderly;
and those who have renal impairment or low blood pressure. Decreases in
renal function can occur with canagliflozin, particularly in patients
with hypovolemia. During clinical trials, a dose-dependent increase in
serum creatinine occurred and was greater in those individuals with
decreased baseline renal function. Pooled data from four clinical trials
in which patients had normal-to-mild renal dysfunction demonstrated at
least one event of significant reduction in renal function, defined as
a 30% decrease from baseline or a GFR <80 mL/min/1.73 m2 at the end of treatment (0.5% with placebo, 0.7% with canagliflozin 100 mg, and 1.4% with canagliflozin 300 mg).8
Risk of hyperkalemia is greater in patients with renal
dysfunction who receive other medications that affect potassium
excretion. The effects on potassium are also dose related and transient.
Elevations of potassium occurred early in the course of therapy and
could be severe. Increases in both magnesium and phosphate were also
seen in the clinical trials.8
Concomitant use of canagliflozin and insulin or a
sulfonylurea can increase the rates of hypoglycemia. A lower dose of
insulin or sulfonylurea may be necessary to prevent hypoglycemia.8
Canagliflozin is generally well tolerated, with genital
mycotic infections and urinary tract infections (UTIs) being the most
commonly experienced adverse effect.8 In the four pooled
phase III clinical trials, female mycotic infections occurred at rates
of 3.2% in placebo, 10.4% in canagliflozin 100 mg, and 11.4% in the
canagliflozin 300-mg groups. Females at the highest risk for mycotic
infection had had previous genital mycotic infections. Male patients who
took canagliflozin were also at increased risk of genital mycotic
infections. This adverse effect was more common in males who were
uncircumcised and in those with a prior history of balanitis or
balanoposthitis. Both males and females who had infections were likely
to have recurrence of mycotic infections as well as require treatment
with topical or oral therapy. Among uncircumcised males, 0.3% developed
phimosis, and 0.2% of those patients required circumcision to treat that
infection. UTIs occurred at rates of 4% in the placebo, 5.9% in the
100-mg dose, and 4.3% in the 300-mg dose groups.8 Other common adverse effects included an increase in urination, vulvovaginal itching, thirst, constipation, and nausea.8 No concerns of bladder, breast, or renal cancer have been seen with canagliflozin when compared to placebo.11
CANVAS is currently an ongoing long-term trial to determine canagliflozin’s effect on cardiovascular outcomes.11 Alterations of surrogate cardiovascular endpoints have been seen.8 Specifically, increases in HDL and LDL, decreases in weight, and decreases in blood pressure have been demonstrated.8
Monitoring for canagliflozin should include monitoring for
genital mycotic infections and bacterial UTIs for both males and
females. Blood chemistries should be checked early and periodically in
the course of treatment for changes in potassium, magnesium, phosphorus,
and renal function. Blood pressure and other functions that could be
adversely affected by volume depletion should be followed in patients.
Blood glucose should also be monitored for both the safety and efficacy
Drug-drug interactions are minimal with canagliflozin.
Patients concurrently taking digoxin and canagliflozin need close
monitoring of digoxin levels. An increase of AUC and peak concentration
of digoxin was seen in patients receiving both drugs.8
Canagliflozin is a UGT enzyme substrate. As previously stated, reduction
of canagliflozin levels occurs with strong inducers of UGT enzymes,
specifically phenytoin, phenobarbital, rifampin, and ritonavir.8
Canagliflozin provides a novel mechanism of action to
treat patients with type 2 diabetes who are not currently controlled.
Recent studies demonstrate that it is safe and effective for treatment
as monotherapy or as add-on therapy to other oral antihyperglycemic
agents or insulin. Canagliflozin demonstrates significant reductions in
A1C but also provides reductions in body weight and systolic blood
pressure. The most common adverse effect is risk of UTIs and mycotic
genital infections. Further studies are being conducted to delineate the
drug-’s impact on cardiovascular outcomes. As this evidence becomes
available, the role of canagliflozin will be further evaluated.
1. White J. Apple trees to sodium glucose co-transporter inhibitors: a review of SGLT2 inhibition. Clin Diabetes. 2010;28:5-10.
2. AstraZeneca and Bristol-Myers Squibb resubmit
dapagliflozin New Drug Application for the treatment of type 2 diabetes
in the U.S. AstraZeneca press releases. July 25, 2013.
Accessed September 17, 2013.
3. Lilly and Boehringer Ingelheim submit a New Drug Application for empagliflozin to the FDA. diaTribe. March 25, 2013. http://diatribe.us/issues/54/new-now-next/5-. Accessed September 17, 2013.
4. Invokana. Janssen Pharmaceuticals, Inc. www.invokana.com. Accessed September 17, 2013.
5. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. MedClin North Am. 2004;88:787-835.
6. Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis. Diabetes Care. 2001;24:382-391.
7. Bakris GL, Fonseca V, Sharma K, Wright E. Renal
sodium-glucose transport: role in diabetes mellitus and potential
clinical implications. Kidney Int. 2009;75:1272-1277.
8. Invokana (canagliflozin) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc; March 2013.
9. Nisly SA, Kolanczyk DM, Walton AM. Canagliflozin, a new
sodium-glucose cotransporter 2 inhibitor, in the treatment of diabetes.
Am J Health Syst Pharm. 2013;70:311-319.
10. Schernthaner G, Gross JL, Rosenstock J, et al.
Canagliflozin compared with sitagliptin for patients with type 2
diabetes who do not have adequate glycemic control with metformin plus
sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013;36:2508-2515.
11. Riser Taylor S, Harris KB. The clinical efficacy and
safety of sodium glucose cotransporter-2 inhibitors in adults with type 2
diabetes mellitus. Pharmacotherapy. 2013;33:984-999.
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