0ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
Issue: Pharmaceutical Science to Improve the Human Condition: Prix Galien 2014
Canagliflozin: a sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes mellitus
Norm Rosenthal,1 Gary Meininger,1 Kirk Ways,1 David Polidori,2 Mehul Desai,1 Rong Qiu,1 Maria Alba,1 Frank Vercruysse,1 Dainius Balis,1 Wayne Shaw,1 Robert Edwards,1 Scott Bull,3 Nicholas Di Prospero,1 Sue Sha,1 Paul Rothenberg,1 William Canovatchel,1 and Keith Demarest1
1Janssen Research & Development, LLC, Raritan, New Jersey. 2Janssen Research & Development, LLC, San Diego, California. 3Janssen Research & Development, LLC, Fremont, California
Address for correspondence: Norm Rosenthal, Janssen Research & Development, LLC, 920 Route 202 South, Raritan, NJ 08869. NRosenth@its.jnj.com
The sodium glucose co-transporter 2 (SGLT2) inhibitor canagliflozin is a novel treatment option for adults with type 2 diabetes mellitus (T2DM). In patients with hyperglycemia, SGLT2 inhibition lowers plasma glucose levels by reducing the renal threshold for glucose (RTG) and increasing urinary glucose excretion (UGE). Increased UGE is also associated with a mild osmotic diuresis and net caloric loss, which can lead to reductions in body weight and blood pressure (BP). After promising results from preclinical and phase I/II studies, the efficacy and safety of canagliflozin was evaluated in a comprehensive phase III development program in over 10,000 patients with T2DM on various background therapies. Canagliflozin improved glycemic control and provided reductions in body weight and BP versus placebo and active comparators in studies of up to 2 years' duration. Canagliflozin was generally well tolerated, with higher incidences of adverse events (AEs) related to the mechanism of action, including genital mycotic infections and AEs related to osmotic diuresis. Results from the preclinical and clinical studies led canagliflozin to be the first-in-class SGLT2 inhibitor approved in the United States, and support canagliflozin as a safe and effective therapeutic option across a broad range of patients with T2DM.
Keywords: SGLT2 inhibitor; antihyperglycemic agent; canagliflozin; type 2 diabetes
Introduction
Type 2 diabetes mellitus (T2DM) is well recognized as a major public health problem worldwide.1-3 Despite the availability of a range of therapeutic options, many patients with T2DM do not achieve or maintain glycemic goals as recommended by international medical societies.4 Many of the currently available T2DM treatments are associated with safety or tolerability issues, including hypoglycemia, edema, or gastrointestinal adverse experiences, which can preclude their use in some patients or limit dose and, hence, therapeutic benefit.4-6 Further, some antihyperglycemic agents (AHAs) are associated with weight gain, which is particularly problematic as many patients with T2DM are overweight or obese.4,5
Most patients with T2DM are initially managed with single-agent therapy, usually metformin.4,7 Over time, patients often require more intensive regimen combinations of two or three agents and eventually require insulin to maintain target glycemic control.4,8,9 Underlying this need for increasingly intensive treatment is a progressive loss of beta-cell mass and function, with consequent diminished insulin secretion. Thus, there remains a substantial unmet medical need for new medications to treat patients with T2DM that beneficially impact beta-cell function and insulin secretion, and are associated with weight loss, which improves insulin sensitivity.
In healthy individuals, circulating glucose is freely filtered through the renal glomerulus, reabsorbed
doi: 10.1111/nyas.12852
28 Ann. N.Y. Acad. Sci. 1358(2015) 28-43 ® 2015 The Authors. Annals of the New York Academy of Sciences
published by Wiley Periodicals Inc. on behalf of The New York Academy of Sciences. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Figure 1. The role ofSGLT2 in glucose reabsorption in the renal proximal tubule.12'13 SGLT, sodium glucose co-transporter; GLUT, glucose transporter. Figure 1 reprinted from Trends in Pharmacological Sciences 32(2): 63-71, Copyright (2011), with permission from Elsevier; and Current Medical Research and Opinion 25(3): 671-681, Copyright (2009), Informa Healthcare, adapted with permission from Informa Healthcare.
in the proximal tubule, and then released back into the circulation. The renal threshold for glucose (RTg) is the plasma glucose concentration above which tubular reabsorption of glucose cannot increase further, and glucose is excreted into the urine in direct proportion to the plasma glucose concentration above this threshold. Glucose reabsorption in the renal tubules is largely due to
two key glucose transporters: sodium glucose co-transporter 2 (SGLT2), responsible for the majority of filtered glucose reabsorption in the S1 segment of the proximal renal tubules, and SGLT1, responsible for glucose reabsorption in the S2/S3 segment of the proximal renal tubules (Fig. 1).10-13 Patients with diabetes have elevated renal glucose reabsorption mostly due to the increased expression
Figure 2. Inhibition of SGLT2 by canagliflozin leads to increased renal glucose excretion and improved glucose homeostasis.18 SGLT2, sodium glucose co-transporter 2; UGE, urinary glucose excretion; RTg, renal threshold for glucose; T2DM, type 2 diabetes mellitus; CANA, canagliflozin. Adapted from Metabolism 63(10): 1228-1237 (2014), under the terms of the Creative Commons Attribution License, http://creativecommons.org/licenses/by-nc-nd/3.0/.
of SGLT2,14 which may contribute to persistent elevated glucose concentrations15 and to diabetic nephropathy.16
Canagliflozin (INVOKANA®) was the first SGLT2 inhibitor available in the United States. It is currently approved as an adjunct to diet and exercise to lower blood glucose in adults with T2DM. A large number of countries across North America, Europe, Latin America, and Asia-Pacific have approved canagliflozin for the treatment of adults with T2DM. Other SGLT2 inhibitors approved to treat T2DM include dapagliflozin, empagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin. Only canagliflozin, dapagliflozin, and empagliflozin are approved for use in the United States and Europe.17 Pharmacologic inhibition of SGLT2 is a novel mechanism to reduce reabsorption of filtered glucose and lower the RTG (Fig. 2),18 thereby increasing urinary glucose excretion (UGE) and lowering elevated plasma glucose concentrations in patients with T2DM. The increased UGE with SGLT2 inhibition also translates to an osmotic diuresis, with the diuretic effect offering the potential for reductions in systolic blood pressure (BP). In addition, increased UGE results in a loss ofcalories and, therefore, could lead to a reduction in body weight. This mechanism is independent of insulin secretion, and thus canagliflozin would be expected to be effective across the spectrum of beta-cell function, from new-onset patients with moderate impairment of beta-cell function, to patients with greater beta-cell
functional loss, such as those with long-standing diabetes who require insulin. In addition, as this mechanism is distinct from other current classes of AHAs, canagliflozin has the potential for use in combination with a wide range of other agents in the treatment of patients with T2DM. Thus, canagliflozin is an insulin-independent approach for control of hyperglycemia and maybe used across the continuum of the disease, providing glycemic efficacy in combination with a wide range of other glucose-lowering agents, as well as the additional benefits of weight loss and BP reduction.
History of the discovery and development of canagliflozin
The first known inhibitor of renal glucose reabsorption was phlorizin, a natural product isolated from the bark of apple trees.19 Phlorizin was shown to cause glucosuria in dogs, and subsequent studies found that administration of phlorizin to diabetic rats reduced plasma glucose levels and improved insulin sensitivity.19,20 However, phlorizin has not been developed for use in humans because it has poor oral bioavailability, modest SGLT2 inhibition, and its active metabolite phloretin inhibits facil-itative glucose transporters.19,21 The involvement of Janssen Research & Development in SGLT2 inhibitor development began as a collaboration with Mitsubishi Tanabe Pharma Corporation in August 2000 to develop T-1095, an orally available
Figure 3. Structural illustration of phlorizin, T-1095, and canagliflozin. SGLT, sodium glucose co-transporter; CYP, cytochrome P450.
analogue of phlorizin. T-1095 selectively inhibits SGLT2 in vitro, increases UGE, and decreases fasting and prandial blood glucose levels in rodent models of diabetes. Clinical development of T-1095 began in May 2001 and included phase I and phase Ila proof-of-concept trials. T-1095 was well tolerated, but had a short half-life in humans, showed cytochrome P450 inhibition, and did not meaningfully lower blood glucose in patients with T2DM, despite promoting UGE. The failure of this key phase Ila trial cast significant doubt on SGLT2 inhibition as an effective mechanism for treating T2DM, and clinical development of T-1095 was terminated in January 2003.
To understand why T-1095 lacked clinical efficacy, a new physiologically based model of human glucose homeostasis was developed, which included the role of renal glucose transport and incorporated SGLT2 inhibitor drug pharmacoki-netics and pharmacodynamics (unpublished work). Insights from this modeling explained why the key phase IIa trial with T-1095 failed and, importantly, provided a clear rationale for expecting that meaningful glycemic efficacy in patients with T2DM might be obtained with an SGLT2 inhibitor drug that had appropriate pharmacokinetic and pharmacodynamic properties. The modeling effort also established quantitative criteria (based on 24-hour UGE in the first single oral-dose phase I trial of canagliflozin in healthy participants) for deciding whether any new SGLT2 inhibitor could, in principle, yield meaningful therapeutic
efficacy in longer-duration trials in patients with T2DM.
A collaborative effort was initiated to discover a replacement for T-1095 with improved potency and bioavailability, which resulted in the discovery of canagliflozin. The C-glycoside canagliflozin was significantly more stable and showed greater selectivity for SGLT2 than T-1095. Canagliflozin exhibited greatly improved bioavailability and efficacy in animal models of diabetes and entered phase I clinical development in December 2006. A structural illustration of phlorizin, T-1095, and canagliflozin is shown in Figure 3.
Pharmacodynamics and pharmacokinetics of canagliflozin
Canagliflozin is rapidly absorbed in humans, with an oral availability of 65%; peak plasma concentrations are reached within 1-2 hours.22 The mean half-life of canagliflozin 100 and 300 mg in healthy individuals is 10.6 and 13.1 hours, respectively, which supports once-daily dosing.23 Canagliflozin is glucuronidated by uri-dine diphosphate-glucuronosyltransferase (UGT) enzymes into two inactive O-glucuronide metabolites, M5 and M7.24 Approximately 60% and 33% of the administered dose is excreted in the feces and urine, respectively.24
Canagliflozin treatment dose-dependently lowered RTg, and maximally effective doses lowered RTg to approximately 40-60 mg/dL in healthy individuals and 70-90 mg/dL in patients with
Progression of Therapy Monotherapy
Diet & exercise
DIA3005:
PBO-controlled Monotherapy
Dual combo Triple combo Insulin +/-
therapy therapy AHA(s)
DIA3006: DIA3002: DIA3008
PBO- and active- PBO-controlled (insulin substudy):
controlled (SITA) Add-on to MET + SU PBO-controlled
Add-on to MET DIA3012: Add-on to insulin
DIA3009: PBO-controlled
Active-controlled Add-on to MET + PIO
(GLIM)
Add-on to MET DIA3015: Active-controlled
DIA3008 (SITA)
(SU substudy): Add-on to MET + SU
PBO-controlled
Add-on to SU
Specific Safety/Outcome Studies
DIA3004: PBO-controlled add-on to current therapy (moderate renal impairment)
DIA3010: PBO-controlled add-on to current therapy (older patients; bone/body composition study)
DIA3008: CV outcomes study (CANVAS)
Figure 4. Overview of the canagliflozin phase III clinical program. AHA, antihyperglycemic agent; PBO, placebo; SITA, sitagliptin; MET, metformin; SU, sulfonylurea; GLIM, glimepiride; PIO, pioglitazone; CV, cardiovascular; CANVAS, CANagliflozin Cardiovascular Assessment Study.
T2DM.25-29 Because RTG typically remains above the threshold for hypoglycemia (70 mg/dL) in patients with T2DM, and very little UGE occurs when plasma glucose levels are below RTG, treatment with canagliflozin is not expected to induce hypoglycemia. Canagliflozin 300 mg provided near-maximal suppression of RTg over 24 h, while canagliflozin 100 mg provided near-maximal suppression of RTg for the first 13 h after dosing, with a slight attenuation of the effect in the overnight period.26,27 In addition, higher canagliflozin doses ( >200 mg) were found to lower plasma glucose levels to a greater extent than could be explained by UGE alone; this additional effect is likely due to transient inhibition of gastrointestinal SGLT1 during the period of drug absorption.26 In addition to inhibiting SGLT2, canagliflozin is a low-potency inhibitor of SGLT1, which is highly expressed in the intestine and is largely responsible for intestinal glucose and galactose absorption.30,31 Canagliflozin 300 mg, dosed just before a meal, delayed intestinal glucose absorption in healthy individuals; because free plasma drug concentrations were not high enough to inhibit renal SGLT1, it is believed that transiently high local concentrations of canagliflozin within the gut lumen results in transient and local inhibition of SGLT1 in the intestine.31
Clinical development program for canagliflozin in adults with T2DM
The canagliflozin clinical program was designed to assess its efficacy and safety in patients with T2DM. This program consisted of 52 completed or ongoing clinical studies, collecting data from 10,285 participants (who received at least one dose of doubleblind study drug) in nine phase III studies, 1210 participants in three phase II studies, and 1300 participants in 40 phase I studies. The nine placebo-controlled and active comparator-controlled (versus glimepiride and sitagliptin) phase III studies spanned a range of clinical uses (as monotherapy or as combination therapy) across a broad population of patients with T2DM, including older adults, patients with moderate renal impairment, and patients who had or were at high risk for cardiovascular (CV) disease (Fig. 4).32-44
Canagliflozin clinical development program results
HbA1c-iowering response
Results of the phase III studies confirmed the efficacy of canagliflozin in reducing glycated hemoglobin (HbAic) across a broad range of patients with T2DM, both in patients with recent
Figure 5. Study-by-study comparison of efficacy with canagliflozin: (A) change from baseline in HbA1c, (B) proportion of patients achieving HbA1c <7.0%, (C) percent change from baseline in body weight, and (D) change from baseline in SBP (LOCF).32'34-36'38-40'42'44'63'" HbA1c, glycated hemoglobin; SBP, systolic blood pressure; LOCF, last observation carried forward; PBO, placebo; CANA, canagliflozin; GLIM, glimepiride; SITA, sitagliptin; LS, least squares; SE, standard error; MET, metformin; SU' sulfonylurea; PIO' pioglitazone; CANVAS' CANagliflozin CardioVascular Assessment Study; SD' standard deviation. "Data are LS mean ± SE changes from baseline in HbAic (panel A)' body weight (panel C)' and SBP (panel D); and percentage ± SD achieving HbA1c < 7.0% (panel B). bP < 0.001 vs. PBO' GLIM' or SITA. cP < 0.05 vs. PBO. dPatients receiving >30 IU/day. eP < 0.01 vs. PBO. fP < 0.025 vs. PBO. ^Statistical comparison vs. GLIM not performed (not prespecified). Continued on next page.
onset as well as long-standing diabetes and those on different background AHA therapies. A clinically meaningful improvement in glycemic control was seen when canagliflozin was given as monotherapy and in dual combinations (add-on to metformin or to sulfonylurea agents), triple oral AHA
combinations (add-on to metformin plus a sul-fonylurea agent or metformin plus pioglitazone), combinations with insulin (alone or with other oral agents), or as an add-on to existing diabetes therapy (any approved oral or parenteral therapy).32-44 In the placebo-controlled studies, canagliflozin
Figure 5. Continued
100 and 300 mg provided statistically significant reductions in HbA1c compared with placebo (Fig. 5A). In the active-controlled studies, canagliflozin 100 mg demonstrated noninferiority to sitagliptin and glimepiride in lowering HbA1c, whereas canagliflozin 300 mg demonstrated statistical superiority to sitagliptin and glimepiride. Across all studies, an incremental HbA1c reduction was observed for the 300 mg dose relative to the 100 mg dose. In addition, a greater proportion of
patients treated with canagliflozin achieved the recommended treatment goal of HbAic <7.0% compared with those treated with placebo (Fig. 5B). Canagliflozin was also associated with sustained reductions in HbA1c over 104 weeks compared with glimepiride as an add-on to metformin (Fig. 6A), demonstrating the durability of HbA1c lowering with canagliflozin.37
Given its mechanism of action, in which the extent of UGE is proportional to renal function,
Figure 6. Change in HbAic (A), percent change in body weight (B), and mean eGFR (C) over 104 weeks in the add-on to metformin versus glimepiride study (DIA3009; LOCF).37 Data in panels A and B are LS mean ± SE, and data in panel C are mean ± SE. HbAic, glycated hemoglobin; eGFR, estimated glomerular filtration rate; LOCF, last observation carried forward; GLIM, glimepiride; CANA, canagliflozin; LS, least squares; CI, confidence interval; SE, standard error. Figure 6 reprinted from American Diabetes Association, Diabetes Care, 2015. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.
it was anticipated that the efficacy of canagliflozin would be dependent on estimated glomerular filtration rate (eGFR). A phase I study of canagliflozin in patients with renal impairment demonstrated that the amount of UGE declined as renal function decreased.45 Therefore, it was important to determine whether adequate benefit would be retained in patients with moderate renal impairment. The phase III study in patients with moderate renal impairment (DIA3004) demonstrated meaningful and statistically significant glycemic efficacy of canagliflozin in patients with eGFR >30 to <50 mL/min/1.73 m2, even though the reductions in HbAic and fasting plasma glucose were smaller than those seen in patients with higher baseline eGFR values.43,44 These observations were confirmed and extended with a pooled population analysis of patients with baseline eGFR >30 to <60 mL/min/1.73 m2, consistent with the full range of stage 3 chronic kidney disease (CKD).46 In this pooled population, the glycemic efficacy of canagliflozin was modestly greater than that observed in the DIA3004 study, consistent with the slightly higher mean and range of baseline eGFR values in patients analyzed. Canagliflozin provided greater HbA1c reductions in patients with stage 3A CKD (eGFR >45 and <60 mL/min/1.73 m2) than in patients with stage 3B CKD (eGFR >30 and <45 mL/min/1.73 m2).46 Overall, these results demonstrate that canagliflozin provides clinically useful efficacy in patients with moderate renal impairment. While phase III studies of canagliflozin included patients with eGFR between 30 and 45 mL/ min/1.73 m2, canagliflozin is not recommended for these patients. In the United States, canagliflozin 100 mg can be initiated in patients with eGFR >45 mL/min/1.73 m2. In Europe, patients must have baseline eGFR >60 mL/min/1.73 m2 to initiate canagliflozin treatment; however, patients can continue treatment with canagliflozin 100 mg if eGFR falls persistently to <60 mL/min/1.73 m2.47
Reductions in body weight
In addition to the observed glycemic improvements, treatment with canagliflozin has been shown to provide statistically significant reductions in body weight relative to placebo. Weight loss with canagliflozin was dose related and generally consistent across the phase III studies (Fig. 5C).32-44 The observed reductions in body weight were sustained
over 104 weeks with canagliflozin as add-on to metformin, compared with small increases seen with glimepiride (Fig. 6B).37
Results of body composition analyses using dual-energy X-ray absorptiometry in two of the phase III studies (DIA3009, DIA3010) demonstrated that the body weight reduction seen with canagliflozin was attributable to a greater decrease in body fat mass (—2/3) relative to lean body mass.34,48 Importantly, the fat loss observed was both visceral and subcutaneous, with slightly greater visceral fat loss observed.
BP-lowering effects
Patients with T2DM commonly have hypertension, contributing to the increased risk that these patients have for both CV and microvascular complications. Reductions in systolic BP were observed with canagliflozin across phase III studies that were generally statistically significantly greater for both canagliflozin doses compared with placebo or active comparator (Fig. 5D).32-44 Canagliflozin treatment was also associated with consistent reductions in diastolic BP across the phase III studies. Importantly, canagliflozin had no meaningful effect on pulse.
Effects on beta-cell function
Canagliflozin was associated with improvements in fasting measures of beta-cell function (i.e., homeostatic model assessment of beta-cell function (HOMA2-%B) and proinsulin/C-peptide ratio).39,40,42 In patients given a mixed-meal tolerance test, dose-related increases in the C-peptide area under the curve (AUCC) to glucose area under the curve (AUCG) were seen with canagliflozin compared with placebo or sitagliptin, suggesting an increase in insulin secretion relative to glucose with canagliflozin.39,40,42 Improvements in beta-cell glucose sensitivity and the insulin secretion rate at specified plasma glucose concentrations were also observed with canagliflozin treatment.49 Representative beta-cell function data for the placebo-controlled add-on to metformin plus sulfonylurea study are shown in Figure 7. The improvements in beta-cell function associated with canagliflozin treatment suggest that canagliflozin may slow T2DM progression, although longer studies are needed to assess the impact of sustained treatment on disease progression.
Figure 7. Effects on beta-cell function: (A) changes in HOMA2-%B and (B) ISR per plasma glucose values in the PBO-controlled add-on to metformin plus sulfonylurea study (DIA3002) at week 26.42,49 HOMA, homeostatic model assessment; ISR, insulin secretion rate; PBO, placebo; CANA, canagliflozin; LS, least squares; SE, standard error. Data in panel A are LS mean change (±SE) from baseline, and data in panel B are mean change (±SE) from baseline. Figure 7B adapted from Diabetologia 57(5): 891-901 (2014) under the terms of the Creative Commons Attribution License, http://creative commons.org/licenses/by-nc-nd/3.0/.
Overall safety and tolerability
Across phase III trials, canagliflozin was generally well tolerated (Table i).32-44,50,51 The incidence of discontinuations due to adverse events (AEs) was low overall, but slightly higher with canagliflozin compared with control due to an increased incidence of specific AEs likely related to canagliflozin's mechanism of action. The incidence of serious AEs was similar across treatment groups in all studies.
Specific AEs associated with canagliflozin treatment include genital mycotic infections in both men and women, urinary tract infections (UTIs), and AEs related to osmotic diuresis and volume
depletion. Genital mycotic infections with canagliflozin were generally mild or moderate in intensity, were often self-treated, responded to standard antifungal therapies in expected time frames, and led to few discontinuations across studies.50,52 Among canagliflozin-treated females, an increased risk of genital mycotic infections was most prominent in those who had a prior history of vulvovaginitis. Among canagliflozin-treated males, genital mycotic infections were more common in those who had a history of balanitis/balanoposthitis and were not circumcised. A modest increase in the incidence of AEs of
UTI was observed with canagliflozin relative to control.50,53 UTIs were generally mild or moderate in intensity, clinically manageable, and rarely associated with study discontinuation. Canagliflozin was not associated with increased rates of upper UTIs or serious UTIs. Canagliflozin was associated with an increase in osmotic diuresis-related AEs (e.g., pollakiuria, polyuria, and thirst) that were generally mild or moderate in intensity and infrequently led to discontinuation.50,54 Small mean percent changes in serum electrolytes were seen with canagliflozin treatment; elevations in serum potassium occurred with canagliflozin 300 mg, more frequently in patients with reduced eGFR.55 AEs associated with changes in serum electrolytes were low across treatment groups. Increases in hemoglobin and hematocrit were seen with canagliflozin that were likely the result of hemoconcentration associated with the osmotic diuretic effects ofcanagliflozin; these increases were generally not reported as AEs.50 The incidence of AEs associated with reduced intravascular volume (e.g., hypotension, postural dizziness, orthostatic hypotension) was low across treatment groups. A higher incidence of AEs related to volume depletion was seen with canagliflozin 300 mg compared with canagliflozin 100 mg and placebo during the first 18 weeks of treatment, after which differences between the groups narrowed.50 All AEs related to volume depletion with canagliflozin were considered mild to moderate in intensity; discontinuations due to volume depletion AEs and serious volume depletion AEs were similar across groups.47 Higher incidences of volume depletion AEs were observed in patients >75 years of age, in patients with moderate renal impairment, and in patients taking loop diuretics; however, these factors did not increase the risk of serious AEs or discontinuations.
Since the maximal canagliflozin-induced RTG level is above the threshold for hypoglycemia (70 mg/dL) and UGE is minimal when plasma glucose concentrations are below the RTG, the risk of hypoglycemia with canagliflozin is expected to be low. Across phase III studies, the incidence of documented hypoglycemia episodes was generally low in patients who were not on background AHA therapy associated with an increased risk of hypoglycemia.50 In patients on background AHAs associated with an increased hypoglycemia risk (i.e.,
insulin or a sulfonylurea), an expected increase in hypoglycemia episodes was observed across treatment groups, with a moderately higher incidence seen with canagliflozin compared with placebo, and a similar incidence with canagliflozin relative to sitagliptin, despite the greater lowering of HbAic with canagliflozin versus sitagliptin.
Effects on fasting plasma lipids
Increases in high-density lipoprotein cholesterol (HDL-C) were observed with canagliflozin in all phase III studies;32-44 in the pooled placebo-controlled studies, increases of 5.4% and 6.3% were seen with canagliflozin i00 and 300 mg versus placebo, respectively, at week 26.50 Numerically larger reductions in fasting triglycerides were seen with canagliflozin doses compared with placebo in most of the phase III studies,32-44 but the treatment difference was generally not statistically significant for individual studies; placebo-subtracted reductions of -5.2% and -7.6% with canagliflozin i00 and 300 mg, respectively, were observed in the pooled placebo-controlled studies at week 26.50 Increases in low-density lipoprotein cholesterol (LDL-C) were observed across the phase III studies;32-44 in the pooled placebo-controlled studies, placebo-subtracted increases of 4.5% and 8.0% were seen with canagliflozin 100 and 300 mg, respectively, at week 26.50 Relative to LDL-C, smaller increases in non-HDL-C were seen across studies.32-44 In studies in which percentage increases in apolipoprotein B and LDL-C particle number (measured by nuclear magnetic resonance spectroscopy) were assessed, changes from baseline were typically about half as large as the increases in LDL-C.36,40,56 The mechanism for the increase in LDL-C and HDL-C with canagliflozin is not known. These effects may be related to hemoconcentration resulting from the mild osmotic diuretic effects of canagliflozin and/or downstream metabolic effects of increasing UGE (e.g., shift in energy substrate utilization affecting hepatic triglyceride levels).
The impact of canagliflozin treatment, including changes in lipids, on CV risk is being assessed as part of the long-term CANagliflozin CardioVascular Assessment Study (CANVAS)57 and CANVAS-R (renal endpoints). The initial CV meta-analysis based on CANVAS as part of a cross-program metaanalysis confirmed the lack of a signal for an increase in the CV hazard ratio (based on major adverse CV
Table 1. Safety findings from the phase III program5
Parameter
CANA32,34,36,39,40,42,44,47,55
Overall safety and tolerability Genital mycotic infections
Osmotic diuresis-related AEs (e.g., pollakiuria, polyuria, thirst)
Volume depletion-related AEs (e.g., orthostatic hypotension, dizziness postural) Hypoglycemia
Fasting plasma lipids
Clinical laboratory parameters
Generally well tolerated, with low incidences of serious AEs and AEs leading to study discontinuation
Higher incidence versus PBO, SITA, and GLIM Few events led to study discontinuation
Generally mild or moderate in intensity and responded to standard treatments Higher risk in patients with prior genital mycotic infection and in uncircumcised males Low recurrence rate in women and men
Higher incidence versus PBO and GLIM, and similar incidence versus SITA Generally mild or moderate in intensity
Not associated with upper UTIs or serious UTIs and few led to study discontinuation Incidence generally low, but higher than with PBO and SITA Few events led to study discontinuation
Incidence generally low, dose dependent Few events led to study discontinuation
Increased risk in patients aged > 75 years, patients with moderate renal impairment, and patients taking loop diuretics
Low incidence, similar to that with PBO, as monotherapy
Significantly lower incidence versus GLIM, similar low incidence versus SITA as add-on to MET Incidence similar to that with SITA as add-on to MET + SU, despite greater HbA1c improvement seen with CANA Increases in HDL-C
Increases in LDL-C and smaller increases in non-HDL-C Decreases in triglycerides Moderate increases in blood urea nitrogen
Small decreases in eGFR with nadir observed early in treatment and values trending toward baseline for duration of study; commensurate increases in serum creatinine Moderate reductions in alanine aminotransferase and gamma glutamyl transferase, and moderate increases in bilirubin Small increases in hemoglobin Moderate reduction in serum urate
Small changes in serum electrolytes (potassium, sodium, magnesium, bicarbonate, phosphate, calcium)
Similar AE rates versus PBO
Slightly higher incidences of UTIs (8% with CANA 300 mg versus 6% with both CANA 100 mg and PBO)
Low incidence of AEs related to osmotic diuresis and volume depletion that was slightly higher with CANA versus PBO
Transient reductions in eGFR that were largest at week 3 and attenuated toward baseline over time (-9.1%, -10.1%, and -4.5% with CANA 100 and 300 mg and PBO, respectively, at week 26)
Median percent reductions in ACR versus PBO (approximately -30%, -21%, and -8% with CANA 100 and 300 mg and PBO, respectively, at week 26) Transient elevations in serum potassium with CANA 300 mg
Safety profile in patients aged >65 years and >75 years consistent with other studies • Higher risk of AEs related to volume depletion (e.g., postural dizziness, orthostatic hypotension, hypotension) in patients aged >75 years
CANA, canagliflozin; AE, adverse event; PBO, placebo; SITA, sitagliptin; GLIM, glimepiride; UTI, urinary tract infection; MET, metformin; SU, sulfonylurea; HbA1c, glycated hemoglobin; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; ACR, albumin-creatinine ratio. Adapted from Brunton S and Reid TS. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, for the management of type 2 diabetes. Hosp. Pract. 42(3): 96-108 (2014) with permission from Taylor & Francis Ltd.
Safety in special populations Patients with moderate renal impairment
Older patients
events plus hospitalized unstable angina), with the upper bound of the 95% confidence interval (CI) <1.8. A subsequent planned CV meta-analysis to rule out an upper bound of the 95% CI of 1.3 will provide further information on the CV safety of canagliflozin.
Renal safety
Across studies, including those in patients with moderate renal impairment, canagliflozin treatment was generally associated with early reductions in eGFR that trended back toward baseline over the treatment period.32-44 Reductions in eGFR were reversible after treatment discontinuation.58 Representative data from the 104-week study of canagliflozin versus glimepiride as add-on to metformin demonstrated no meaningful effect of canagliflozin treatment on eGFR over time (Fig. 6C).37 In studies in which urinary albumin-to-creatinine ratio (ACR) was assessed, reductions from baseline were observed with canagliflozin in patients with baseline albuminuria; no changes in urinary ACR were seen in normoalbumin-uric patients.34,37,38,43,44 In CANVAS and in the DIA3004 study of patients with moderate renal impairment, a smaller proportion of patients in the canagliflozin 100 and 300 mg groups relative to the placebo group progressed from normo- to microalbuminuria or micro- to macroalbuminuria at week 52.38,43 In patients with moderate renal impairment, the incidence of renal-related AEs (e.g., GFR decreased, blood creatinine increased, renal failure) was higher with canagliflozin 100 and 300 mg compared with placebo; rates of serious renal-related AEs were low and similar across groups.46 The increased incidence of renal-related AEs likely reflects the early, reversible reductions in eGFR seen with canagliflozin treatment. In the pooled placebo-controlled studies, the incidence of renal-related AEs was low overall, but higher with canagliflozin 300 mg versus canagliflozin 100 mg and placebo, with one serious renal-related AE reported with canagliflozin 100 mg.50
Fractures
In the pooled placebo-controlled studies, the incidence of fractures with canagliflozin 100 and 300 mg and placebo was 0.7%, 0.6%, and 0.3%, respectively, over 26 weeks.47 Among patients with T2DM not enrolled in CANVAS, the incidence offractures was similar with canagliflozin and placebo or active
comparator.47 In CANVAS, the incidence rates of fractures were 1.6, 1.6, and 1.1 per 100 patient-years of exposure with canagliflozin 100 and 300 mg and placebo, respectively; most fractures occurred within the first 26 weeks of treatment.47 A study assessing the effects of canagliflozin on bone health in patients with T2DM found that canagliflozin did not adversely affect bone mineral density over 104
weeks.47
Conclusions
The comprehensive results of a large phase III clinical development program demonstrate that canagliflozin 100 and 300 mg provide substantial and sustained reductions in HbA1c, with additional potentially valuable clinical benefits on BP and body weight, and with a well-defined safety and tolerabil-ity profile that supports the use across a broad population of patients with T2DM. Care should be taken with patients that may be vulnerable to the volume-depletion effects of canagliflozin (i.e., patients aged >75 years, patients with moderate renal impairment, and those taking loop diuretics). Findings from ongoing studies will help further define the effects of canagliflozin on CV outcomes, as well as the impact of canagliflozin on micro - and macrovas-cular complications in patients with T2DM.
Future directions
Diabetic nephropathy is one of the microvascu-lar complications of diabetes and is characterized by persistent albuminuria and a progressive decline in renal function. Hyperglycemia and renal hyperfiltration are important contributors to the onset and progression of diabetic nephropathy. In phase III studies, canagliflozin treatment was associated with an early decrease in eGFR and a reduction in albuminuria when studied in the presence of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs). These findings are not unlike the reduction in albuminuria and the early reduction in eGFR seen with ACE inhibitor and ARB therapy in patients with diabetic nephropathy, for whom these agents act by vasodi-lating the efferent arteriole and reducing intra-glomerular pressure.59 A recently initiated 5-year renal outcomes trial (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation Trial; CREDENCE) is intended to determine whether canagliflozin has a renal protective
effect in patients with T2DM, stage 2 or 3 CKD, and macroalbuminuria, who are receiving standard of care and treatment with an ACE inhibitor or ARB. The renal-protective effect of canagliflozin relative to placebo will be assessed by the reduction in progression to end-stage kidney disease, doubling of serum creatinine, and renal or CV death.
Obesity is a common comorbidity of T2DM.4 The American Medical Association recently recognized obesity as a complex disease associated with comorbidities, including T2DM and CV disease.60 The body weight reductions observed with canagliflozin treatment across phase III studies of patients with T2DM, as well as in a phase II study of overweight and obese individuals without diabetes,61 suggest that canagliflozin may be an effective adjunctive treatment for obesity. Of note, the weight reduction associated with canagliflozin treatment across clinical studies is less than would be predicted based on observed UGE, with an increase in energy intake among patients treated with canagliflozin being one possible explanation for this finding. The weight loss provided by canagliflozin treatment has been shown to improve weight-related quality of life and satisfaction with physical and emotional health in patients with T2DM.62 A phase II study of a fixed-dose combination of canagliflozin and the appetite suppressant phentermine is ongoing, with the expectation that phentermine may blunt any potential increase in food consumption associated with canagliflozin treatment. This combination of a centrally acting medication with an agent acting on a peripheral target represents a novel strategy for obesity treatment.
Canagliflozin is not indicated for use in patients with type 1 diabetes mellitus (T1DM); however, due to its insulin-independent mechanism of action, canagliflozin may have potential use in the treatment of T1DM. Canagliflozin treatment may allow some patients with T1DM to reach glycemic goals with a reduced risk of hypoglycemia and a lower total insulin dose. The weight loss benefits of canagliflozin could also be important for these patients as a part of diabetes management. Of note, canagliflozin is not recommended for the treatment of diabetic ketoacidosis. A phase II clinical trial is currently underway to evaluate the efficacy and safety of canagliflozin in patients with T1DM. Given that canagliflozin treatment is associated with improvements in beta-cell function, canagliflozin
could also potentially be used to reduce or delay the progression to T2DM in patients with prediabetes. A reduction in the progression to T2DM could reduce or delay the onset of the long-term microvascular complications of diabetes.
In summary, the SGLT2 inhibitor canagliflozin is an important innovation for patients with T2DM and has the potential to not only help patients improve glycemic control, but also reduce body weight and BP. As it gains additional approvals in different countries and is studied in other T2DM patient populations, canagliflozin will provide a new treatment option for increasing numbers ofpatients with T2DM worldwide.
Acknowledgments
This invited review article was sponsored by Janssen Global Services, LLC. Editorial assistance was provided to the authors by Kimberly Fuller, PhD, of MedErgy, and was funded by Janssen Global Services, LLC. The authors were involved at all stages of manuscript development and maintained full control over the scientific content.
Conflicts of interest
All authors are full-time employees of Janssen Research & Development, LLC.
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