Canagliflozin: An emerging treatment option for type 2 diabetes mellitus

Diabetes mellitus is a group of complex metabolic disorders characterized by insufficient action of insulin (insulin resistance) and pancreatic β-cell dysfunction.¹  Inadequate glycemic control contributes to micro- and macrovascular complications such as retinopathy, nephropathy, neuropathy, and accelerated cardiovascular disease.²  The Centers for Disease Control and Prevention has listed diabetes as the seventh leading cause of death in the United States, and states that diabetes increases the risk of heart disease and stroke by 2- to 4-fold.³  At present, more than 23 million children and adults, approximately 8% of the US population, have diabetes mellitus. In 2007, the total direct and indirect cost of diabetes exceeded $170 billion.³ Type 2 diabetes accounts for more than 90% of all diagnosed cases of diabetes, and  is a progressive condition that makes treatment more challenging as β-cell function declines.⁴  In the UK Prospective Diabetes Study, nearly 50% of the study population required combination therapy within 3 years of diagnosis, with the percentage increasing to 75% by the ninth year of disease.⁴

Type 2 diabetes develops when pancreatic β-cells are unable to secrete sufficient insulin to overcome insulin resistance.¹ Before type 2 diabetes is fully manifested, there is a several-year period of insulin resistance that emerges as a consequence of the interaction of genetic and numerous environmental factors (pregnancy, puberty, physical inactivity, quality and quantity of nutrients, aging).  Insulin resistance associated with obesity may involve several pathways: (1) hormonal imbalance (eg, increased leptin, decreased adiponectin, and increased glucagon); (2) elevated concentrations of cytokines (eg, tumor necrosis factor α, interleukin 6); (3) suppression of cytokine signaling; and (4) other inflammatory signals (eg, nuclear factor κβ).¹  Impairment of insulin post-receptor signaling occurs when increased release of non-esterified fatty acids (eg, from intra-abdominal adipose tissue in obesity) increases concentrations of intracellular diacylglycerol and fatty acyl-CoA. Chronic hyperglycemia, sustained exposure to non-esterified fatty acids, oxidative stress, inflammation, and amyloid formation contribute to the decline in pancreatic β-cell function.   Pancreatic α-cell dysfunction leads to increased (or non-suppressed) glucagon secretion in the presence of hyperglycemia and possibly decreased prandial GLP-1 (glucagon-like peptide 1) secretion.  GLP-1 is an incretin secreted by L cells of the intestine during meals, resulting in satiety by slowing gastric emptying and leading to noticeable weight loss.¹

The 2013 American Diabetes Association (ADA) criteria for the diagnosis of diabetes mellitus includes any of the following: (1) hemoglobin A_1c (A_1c)  ≥6.5%; (2) fasting plasma glucose ≥126 mg/dL, with fasting defined as no caloric consumption for at least 8 hours; (3) 2-hour plasma glucose ≥200 mg/dL during an oral glucose tolerance test, with the glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water; (4) classic symptoms of hyperglycemia and a random plasma glucose ≥200 mg/dL; or (5) in the absence of unequivocal hyperglycemia, results confirmed by repeat testing.⁵

Initial treatment focuses on diabetes self-management education, medical nutrition therapy, and physical exercise.  Key elements of diabetes education include information on disease progression, treatment options, nutrition, exercise, prescribed medications, self-monitoring of blood glucose, diabetes complications, psychosocial concerns, and individualized plans.⁵ Medical nutrition therapy usually targets weight loss through ingestion of fewer carbohydrates and saturated fat, along with increased consumption of dietary fiber.  Regarding exercise, diabetic patients should incorporate at least 2.5 hours of moderate-intensity aerobic physical activity (50% to 70% of maximum heart rate) into their weekly schedule, spread over a minimum of 3 days, with no more than a 2 day lapse in activity.⁵

The ADA “Standards of Medical Care in Diabetes-2013” guidelines recommend starting metformin therapy concurrently with lifestyle modifications in newly diagnosed patients.⁵  Furthermore, if maximal tolerated doses of noninsulin monotherapy fails to achieve or maintain the hemoglobin A_1c targets over 3 to 6 months, ADA recommends the addition of a second oral agent (insulin of GLP-1 analog).⁵ However, achieving and maintaining glycemic targets can be challenging and problematic with the currently available treatment options. 

Sulfonylureas (glipizide, glyburide, glimepiride) increase insulin secretion by binding to sulfonylurea receptor 1 on pancreatic β-cells, but excessive insulin release may cause weight gain and hypoglycemia.^1,5 Although agents in this class may produce troublesome side effects, they are low in cost and have the potential to reduce cardiovascular events.¹ Meglitinides (nateglinide, repaglinide) act by binding to a different part of the sulfonylurea receptor than sulfonylurea drugs. Use of these agents has been associated with weight gain and hypoglycemia, and they appear to be shorter-acting than the sulfonylureas.¹ Thiazolidinediones (pioglitazone) increase insulin sensitivity in muscle and liver through activation of the peroxisome-proliferator-activated –receptor-γ. These drugs also cause weight gain and increase the risk of cardiovascular events. Alpha-glucosidase inhibitors (acarbose, miglitol) are weight-neutral agents that inhibit carbohydrate degradation in the gut, but can cause intolerable gastrointestinal side effects such as flatulence.¹

GLP-1 analogs (exenatide, liraglutide) promote satiety, slow gastric emptying, and enhance glucose-dependent insulin secretion (in conjunction with suppression of glucagon secretion) by binding to glucagon-like peptide-1 receptors.¹ These injectable agents induce weight loss in patients with type 2 diabetes,  and exert moderately favorable effects on blood pressure and lipid profile. Animal studies have demonstrated an increased risk of medullary thyroid tumors associated with liraglutide use. Another safety concern with this class of medication, is the increased risk of pancreatitis in users of exenatide or liraglutide, which needs to be evaluated in long-term safety studies.¹ Dipeptidyl peptidase IV (DPP-IV) inhibitors (sitagliptin, saxagliptin, linagliptin) are weight-neutral drugs that prolong the survival of endogenously released incretin hormones, thereby increasing the levels of incretin (peptide hormones that modulate glucose metabolism). The long-term safety of this class of drugs has yet to be established, but cases of pancreatitis, urticaria, and angioedema have been reported.¹  Pramlintide, an injectable amylin analog, is thought to exert its action through suppression of postprandial glucagon secretion, and by increasing satiety. This agent promotes weight loss in type 2 diabetic patients and it serves as an adjunct to insulin therapy.¹  Pramlintide users have a heightened risk for hypoglycemia, as this agent is used in combination with insulin therapy; the long-term safety of this drug has not been established.  Colesevelam, a bile acid sequestrant used for the management of patients with dyslipidemia, acts by binding to bile acids/cholesterol, but the mechanism of its hypoglycemic effects need to be determined in studies.

CANAGLIFLOZIN

Because current type 2 diabetes therapies are often limited by their significant adverse effects, researchers have been investigating alternative agents with more favorable side-effect profiles. Canagliflozin, a sodium glucose co-transporter (SGLT) inhibitor, offers a novel approach to the treatment of type 2 diabetes mellitus, and is under investigation for the treatment of this condition. A new drug application (NDA) for canagliflozin was submitted to FDA on May 31, 2012 by ­Janssen Pharmaceuticals.⁶  On January 10, 2013, the US Food and Drug advisory panel voted 10 to 5 in support of approving canagliflozin (Invokana) for the management of adult type 2 diabetes mellitus patients.⁷

CHEMISTRY AND PHARMACOLOGY

Canagliflozin [C₂₄H₂₅FO₅S] belongs to the SGLT inhibitor class of drugs, and has a molecular weight of 444.52 g/mol.⁸  SGLTs are a family of proteins expressed in various human tissues including the heart, small intestine, trachea, and the luminal wall of the S1 segment of the proximal tubules of the kidney.^8,9 Among SGLTs, which transport glucose, amino acids, vitamins, ions, and osmolytes across these tissue membranes, SGLT1 and SGLT2 regulate glucose reabsorption.⁹ SGLT1 chiefly regulates glucose transport in the small intestine, whereas SGLT2 is predominantly expressed on the surface of epithelial cells lining the S1 segment of the proximal convoluted tubule. SGLT2 is a high-capacity, low-affinity transporter believed to account for the majority of renal glucose reabsorption.⁹  Given its role in glucose transport within the kidney, SGLT2 inhibitors offer a novel approach for treatment of diabetes.

Translocation of sodium and glucose across the apical cell membrane occurs as SGLT2 binds sodium and glucose in tubule fluid.  The electrochemical gradient of sodium between the tubule and the cell drives this process of translocation.⁹ Estimates of maximal glucose reabsorption of renal tubules have varied, but average 375 mg/min.  In non-diabetic individuals, the filtered glucose load does not surpass 375 mg/min, and the entire load of filtered glucose is reabsorbed into the systemic circulation. Since diabetic individuals often display filtered glucose levels in excess of 375 mg/min, reabsorption capacity is exceeded, leading to urinary excretion of excess glucose.⁹

SGLT2 inhibitors have been a focus of clinical research in the management of type 2 diabetes over the past two decades.¹⁰ To date, dapagliflozin and canagliflozin are further along in clinical development than are other SGLT2 inhibitors, as shown by progression to phase 2b/3 studies in recent years. Of note, because of concerns for increased risk of breast and bladder cancers, FDA declined to approve  dapaglifozin for treatment of partients with type 2 diabetes mellitus.¹⁰  The first SGLT inhibitor to be identified was phlorizin, an O-glucoside analog first extracted from the root bark of an apple tree in 1835. Phlorzin did not, however, progress to clinical trials due to  its low bioavailability and high susceptibility to degradation by lactase-phlorizin hydrolase.⁹  Canagliflozin has been shown to be selective for SGLT2 (~450-fold over SGLT1; half maximal inhibitory concentrations (IC₅₀) of 2.2 nM for SGLT2 and 910 nM for SGLT1), and because of its C-glucoside chemical structure, has improved metabolic stability in comparison to phlorizin.⁸

PHARMACOKINETICS AND PHARMACODYNAMICS OF CANAGLIFLOZIN

Devineni and associates conducted a randomized, double-blind, placebo-controlled, parallel-group, 4-week phase 1b study to determine maximum plasma concentrations (C_max), times to maximum concentration (T_max), half-life, area under the plasma concentration time-curve (AUC), and pharmacodynamic effects of canagliflozin.¹¹   Subjects qualified for study inclusion if they met the following criteria: (1) 18 years and older, but not older than 65 years; (2) at least 6 months duration of type 2 diabetes mellitus; (3) stabilized insulin therapy for at least 2 weeks, with or without metformin, sitagliptin and/or a thiazolidinedione; (4) body mass index (BMI) ranging from 25 to 45 kg/m²; (5) fasting plasma glucose of 59 to 270 mg/dL; (6) A_1c ranging from 7% to 10.5%; and (7) serum creatinine levels below 1.5 mg/dL and 1.4 mg/dL, respectively, for males and females 3 days prior to randomization.

Following an overnight fast of at least 8 hours, subjects underwent a 3-day lead-in phase during which they received placebo before randomization (on day 1).¹¹ In cohort 1, 15 subjects were randomized to receive canagliflozin 100 mg once daily (N=10) or placebo (N=5).  In the second cohort, 14 subjects were randomly assigned to receive canagliflozin 300 mg twice daily (N=10) or placebo (N=4). Both cohorts received study drug or placebo prior to breakfast, and cohort 2 subjects received their second dose of study drug or placebo before their evening meal. Subjects stayed  at the investigation site until the morning of day 3 and returned for weekly visits on days 7, 14, and 21 for blood sampling.  The final stay at the investigation site occurred on days 27 through 29.  Subjects continued to receive the same insulin regimen throughout the duration of the study and received fixed stable doses of oral antidiabetic agents.¹¹

Oral consumption of canagliflozin 100 mg once daily and 300 mg twice daily yielded a mean (standard deviation [SD]) C_max of 773 (213) ng/mL and 3,556 (945) ng/mL, respectively.¹¹   Similarly, dose-dependent increases in AUC occurred with dose escalation, as demonstrated by a mean (SD) AUC_0-24 of 5957 (1580) ng/mL and 42,308 (6461) ng/mL, respectively, for canagliflozin 100 mg once daily and canagliflozin 300 mg twice daily.  The median T_max of canagliflozin 100 mg once daily occurred at 4 hours (range, 1.5-6.0) and at 2.75 hours (range, 1.5-3.0) for canagliflozin 300 mg twice daily.  Mean elimination half-lives (SD) of 14.7 (4.1) hours and 11.8 (2.9) hours were reported for canagliflozin 100 mg once daily and canagliflozin 300 mg twice daily, respectively.¹¹

Urinary glucose excretion (UGE) and renal threshold for glucose (RT_G) represented the 2 pharmacodynamic parameters of interest in this phase 1b study.¹¹ The least square mean difference (90% CI) in UGE approached statistical significance with the higher dose of canagliflozin compared with placebo (153.6 g/day, 90% CI 125.2 to 181.9 g/day; P<.05), but not with canagliflozin 100 mg once daily (67.2 g/day, 90% CI 39.6 to 94.8 g/day; p-value not reported).  In contrast, both doses of canagliflozin showed significant reductions in RT_G (least square mean differences (90% CI) of -119.3 mg/dL (-154.8, -114.4)) with canagliflozin 100 mg once daily and -161.1 mg/dL (-181.4, -140.9) with canagliflozin 300 mg twice daily), with maximal reduction occurring on day 1, which was sustained on day 27.¹¹

PHASE 3 CLINICAL TRIALS

The NDA for canagliflozin included supporting data from 9 clinical trials that included more than 10,300 patients, of which 5 phase 3 clinical trials were presented at the American Diabetes Association (ADA) 72^nd Annual meeting.⁶ The safety and efficacy of this agent was evaluated for therapy as a daily oral regimen (100 and 300 mg) in patients with renal impairment (primarily on background insulin therapy) or with inadequate response to diet and exercise, or as add-on therapy to patients with inadequate control on metformin, with or without a sulfonylurea.^12–16 Furthermore, phase 3 trial investigators assessed comparative glycemic control achieved by: (1) patients who received canagliflozin or a sulfonylurea agent as add-on therapy to metformin, and (2) patients who received canagliflozin as add-on therapy to metformin in combination with a sulfonylurea agent, compared with patients who received placebo or patients who received sitagliptin added to background therapy with metformin and a sulfonylurea agent.^13,14 Baseline characteristics of the 3,527 patients enrolled in 5 of the most recently presented phase 3 trials did not differ substantially across the studies.^12-16  Mean age ranged from 55.4 to 68.5 years, baseline mean A_1c ranged from 7.8 to 8.1%,  and mean BMI ranged from 31.7 to 33 kg/m².  Table 1 (page 70) provides a summary of key features of phase 3 trials.

Cefalu and associates assessed the efficacy of canagliflozin in a 52-week, randomized, double-blind, active-controlled  trial that included 1450 patients with type 2 diabetes mellitus already on metformin monotherapy.¹²  Following randomization, patients either received add-on therapy with glimepiride (titrated up to 6 or 8 mg/day) or canagliflozin (100 mg/day or 300 mg/day).  The study population consisted of subjects with a mean baseline A_1c of 7.8%; at the end of the titration period, the mean dose of glimepiride was 5.6 mg/day.  At week 52, the A_1c adjusted mean change from baseline (least squares mean (standard error, SE) was -0.82% (0.04) for canagliflozin 100 mg/day, and glimepiride-treated patients showed an adjusted mean change from baseline of -0.81% (0.04), which represented statistical noninferiority. Patients on canagliflozin 300 mg/day showed superior reductions in A_1c compared with glimepiride-treated patients, with glimepiride-subtracted mean (95% CI) A_1c of -0.12 (-0.22, -0.02).  Compared with glimepiride-treated patients, patients on canagliflozin 100 mg/day and 300 mg/day lost more weight by week 52, as demonstrated by respective glimeripide-subtracted mean weight changes of -5.2 % (95% CI, -5.7, -4.7; P<.001) and -5.7% (95% CI, -6.2, -5.1; P<.001).

The combination of canagliflozin with metformin and a sulfonylurea agent was tested in a phase 3 study conducted by Gross et al that differed from other phase 3 studies because it used sitagliptin as a comparator.¹³  In this study, 755 patients with type 2 diabetes (mean baseline A_1c of 8.1%) inadequately controlled on combination therapy with metformin and a sulfonylurea underwent randomization to 1 of 2 treatment groups: canagliflozin 300 mg/day, or sitagliptin 100 mg/day.  The primary outcome involved the mean change in A_1c from baseline to week 52.  Least squares mean changes (SE) in A_1c were -0.66% for the sitagliptin group and -1.03% (sitagliptin-subtracted difference, -0.37; 95% CI, -0.50 to -0.25) for canagliflozin 300 mg/day.  In the corresponding order, this study also found least squares mean changes in body weight and systolic blood pressure to be -2.5% (sitagliptin-subtracted difference, -2.8; 95% CI -3.3, -2.2, P<0.001) and -5.1 mmHg (sitagliptin-subtracted difference, -5.9; 95% CI, -7.6, -4.2, P<.001).

Wilding and colleagues conducted a 26-week, randomized, double-blind, placebo-controlled  study that included 469 patients with type 2 diabetes inadequately controlled with metformin in combination with a sulfonylurea, who received canagliflozin (100 mg/day or 300 mg/day) or placebo.¹⁴  This study included patients with a mean age of 56.7 years, baseline mean A_1c of 8.1%, and mean BMI of 33.0 kg/m². Results at 26 weeks showed significant placebo-adjusted least squares mean changes in A_1c (from baseline) with canagliflozin 100 mg/day (-0.71%, P<.001) and canagliflozin 300 mg/day (-0.92%, P<.001). Compared with placebo-treated patients, patients on canagliflozin 100 mg/day and 300 mg/day lost more weight by week 26, as demonstrated by respective placebo-subtracted least squares mean weight reductions of 1.4% (P<.001) and 2% (P<.001). 

The role of canagliflozin as monotherapy was explored in a randomized, double-blind, placebo-controlled phase 3 study conducted by Yale and associates that included patients with type 2 diabetes (N=269) with moderate renal impairment (estimated glomerular filtration rate (eGFR), 30-49 mL/min/1.73 m²).¹⁵ Mean baseline characteristics were as follows:  age, 68.5 yrs; A_1c, 8.0%; fasting plasma glucose, 163.8 mg/dL; BMI, 33.0 kg/m²; eGFR, 39.4 mL/min/1.73 m².  Of note, nearly 75% of the patients enrolled in this study were on background insulin therapy.  The results showed a significant reduction in mean A_1c, with a placebo-subtracted least squares mean change of -0.30% (SE, 0.12; P<.05) in the canagliflozin 100 mg/day group, and -0.40% (SE, 0.12; P<.001) in the canagliflozin 300 mg/day group.  canagliflozin-treated patients had higher rates of hypoglycemia (51.2%-52.9%) compared with placebo-treated patients (36.4%, P-value not reported).

A similar randomized, double-blind, placebo-controlled clinical trial performed by Kajstenlof et al compared the A_1c-lowering effect of canagliflozin with placebo, involving 584 patients with type 2 diabetes with inadequate response to diet and exercise.¹⁶  Patients enrolled in this study had a mean baseline A_1c of 8%, and mean BMI of 31.7 kg/m². Placebo-adjusted least squares mean changes (SE) in A_1c were -0.91% for the canagliflozin 100 mg/day group (P<.001) and -1.15% (P<.001) for canagliflozin 300 mg/day.  In the corresponding order, this study also found placebo-adjusted least squares mean changes in body weight and systolic blood pressure to be -2.2% to -3.3% for canagliflozin 100 to 300 mg/day (P<.001 for both groups) and -3.71 to -5.42 mmHg for canagliflozin 100 to 300 mg/day (P<.001 for both groups).

ADVERSE EFFECTS

In phase 3 clinical trials of canagliflozin, hypoglycemia, superficial genital fungal infection, urinary tract infection, and osmotic diuresis/volume related effects were the most commonly experienced adverse effects in patients with type 2 diabetes.^12–16  In patients with type 2 diabetes on background metformin therapy, hypoglycemia (classified as plasma glucose ≤ 70 mg/dL) occurred in 4.9% and 5.6% of patients who received daily doses of canagliflozin 100 mg and 300 mg, respectively.¹²  The percentage of patients experiencing at least 1 hypoglycemic event while receiving canagliflozin (100 mg/day; 300 mg/day) ranged from 28.8% to 52.9% (higher rates seen in study with 74% of patients on background insulin) in other phase 3 clinical trials.^13–16 Superficial genital fungal infections occurred in 6.3% to 14.3% of females on once-daily canagliflozin 100 mg, and in 4.9% to 23.8% of females on once-daily canagliflozin 300 mg.^12,13,15 A smaller number of males experienced superficial genital infections, with rates ranging from 1.7% to 6.7% with once-daily canagliflozin 100 mg and 2.1% to 9.2% with once-daily canagliflozin 300 mg.^12,13,15  Similar rates of urinary tract infections were observed in patients receiving once-daily canagliflozin 100 mg and 300 mg, ranging from  6.4% to 7.9%.^12,15  Osmotic diuresis/volume-related adverse drug events such as hypotension (6.7% of patients on once-daily canagliflozin 300 mg in 1 study) and dizziness (5.6% of patients on once-daily canagliflozin 300 mg in 1 study) have been reported in a few phase 3 studies, with 2 studies showing rates of 3% or lower.^12,14,15  To date, there have been no reports of breast cancer,   bladder cancer, or liver dysfunction associated with canagliflozin treatment.

Of note, combined data from trials showed that the primary endpoint for the cardiovascular safety analyses (MACE-plus (major adverse cardiovascular events plus); composite outcome that included cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina) occurred in 18.9% of canagliflozin recipients and in 20.5% of patients treated with comparator agents (HR, 0.91; 95% CI, 0.68-1.21).⁷  Interestingly, the hazard ratio for the individual MACE-plus outcome of stroke was elevated, at 1.5 (95% confidence interval, 0.8-2.6). Preliminary data from the ongoing Canagliflozin Cardiovascular Assessment Study (CANVAS) trial   was presented by the sponsor, showing that 13 cardiovascular events occurred in canagliflozin recipients during the first 30 days after randomization (0.45%) and in 1 placebo recipient (0.07%; HR, 6.5; 95% CI, 0.85-49.66).⁷

DRUG INTERACTIONS

Drug interaction information for canagliflozin has not been published.

DOSING AND ADMINISTRATION

Canagliflozin dosages ranging from 100 mg/day to 300 mg/day have been evaluated in five phase 3 trials.^12–16  Daily regimens of canagliflozin 100 mg and 300 mg consistently resulted in reductions in A_1c that were significantly greater than reductions in placebo-treated patients, regardless of whether canagliflozin was used as add-on therapy to metformin and sulfonylurea, or as therapy in patients with renal impairment or type 2 diabetes inadequately controlled with diet and exercise.^14-16 Canagliflozin 100 mg/day demonstrated non-inferiority to glimepiride in patients with type 2 diabetes on background metformin, whereas canagliflozin 300 mg/day showed superior A_1c reductions compared with glimepiride-treated patients.¹² Similarly, canagliflozin 300 mg/day demonstrated superior A_1c reductions compared with sitagliptin, in patients with type 2 diabetes requiring background metformin and sulfonylurea therapy.¹³ Based on these data, 100 to 300 mg daily would be a reasonable dosage range for patients with type 2 diabetes receiving canagliflozin as add-on therapy to metformin, with or without a sulfonylurea. The same dosage range would be appropriate for patients with renal impairment and in patients with type 2 diabetes who fail to show adequate response to diet and exercise.

FORMULARY CONSIDERATIONS

Two factors that should be considered when reviewing any anti-glycemic agent for formulary addition are the degree to which an agent changes A_1c from baseline either as monotherapy or as add-on therapy, and its impact on weight gain, blood pressure, and risk for hypoglycemia. At present, despite the vast array of medications in the US market with differing mechanisms of action, patients with type 2 diabetes often fail to achieve and maintain the targets of glycemic control that have been established by the ADA. Due to the progressive nature of this disease, many patients will require combination therapy to achieve and maintain control of this chronic condition.  Unfortunately, the majority of available antidiabetic agents have treatment-limiting side effects.  Weight gain can occur in patients with type 2 diabetes  receiving insulin, sulfonylureas, and thiazolidinediones. Gastrointestinal side effects can be problematic for patients taking amylin analogs, bile acid sequestrants, and α-glucosidase inhibitors. While GLP-1 analogs offer the advantage of inducing weight loss, serious adverse effects such as pancreatitis and medullary thyroid cancer need to be evaluated in long-term safety studies.

Canagliflozin, both as monotherapy and in combination with other traditional first-line agents, has demonstrated efficacy with minimal side effects. One exception, however, is that in one study that included patients with a background insulin therapy (74% on insulin), a higher percentage of patients experienced hypoglycemia. Phase 3 clinical trials have compared the A_1c-lowering effect of this agent, to that of glimepiride in patients with type 2 diabetes already on metformin therapy, along with sitagliptin and placebo in diabetic patients on metformin therapy in combination with a sulfonylurea.  In addition, the A_1c-lowering effect of canagliflozin has been compared with placebo in phase 3 trials that have included patients with type 2 diabetes with moderate renal impairment (mostly on insulin) and in patients who failed to respond adequately to diet and exercise.  Results indicate that daily canagliflozin 100 mg and 300 mg have superior efficacy in lowering A_1c in treatment-naïve and treatment-experienced patients with type 2 diabetes compared with placebo.  Canagliflozin 300 mg administered daily shows superior efficacy in lowering A_1c when used as add-on therapy to metformin with or without a sulfonylurea, compared with glimepiride and sitagliptin. 

Phase 3 clinical trials have also examined outcome measures such as reduction in body weight and decrease in mean systolic and diastolic blood pressures.  Body weight reductions of up to 4.7% have been reported in phase 3 trials, with 4 studies showing significant differences between canagliflozin and comparators (glimepiride, sitagliptin, placebo). In general, canagliflozin therapy resulted in nonsignificant decreases in diastolic blood pressures, and modest, but statistically significant reductions in systolic blood pressure in 2 phase 3 trials.

Based on its ability to lower A_1c this agent may be useful as a second or third-line agent added to current standard regimens including metformin and sulfonylureas.  Additionally, canagliflozin provides a first-line alternative for patients with contraindications to biguanides, sulfonylureas or thiazolidinediones.  Issues that need to be addressed in longer-term clinical trials include the risk for hypoglycemia associated with adding canagliflozin to insulin therapy, risks of breast or bladder cancer, risk of major adverse cardiovascular events, and liver dysfunction.  Until these safety issues are further assessed in clinical trials, canagliflozin’s place on a formulary remains unclear.

REFERENCES

1. Tahrani AA, Bailey CJ, Del Prato S, Barnett AH. Management of type 2 diabetes: new and future developments in treatment. Lancet. 2011;378:182–197.

2. Musso G, Gambino R, Cassader M, Pagano G. A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors. Systematic review and meta-analysis of randomized trials. Ann Med. 2011 [Epub ahead of print]; DOI: 10.3109/07853890.2011.560181.

3. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011.

4. Turner RC, Cull CA, Frighi V, Holman RR, for the UK Prospective Diabetes Study (UKPDS) Group. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA. 1999;281:2005–2012.

5. American Diabetes Association. Standards of medical care in diabetes – 2013. Diabetes Care.2013;(Suppl 1): S11–S66.

6. Janssen Research & Development to Present Results from Five Phase 3 Studies Evaluating Investigational Canagliflozin for the Treatment of Type 2 Diabetes. Janssen Research & Development, LLC, June 5, 2012. Available at: http://www.prnewswire.com/news-releases/janssen-research--development-to-present-results-from-five-phase-3-studies-evaluating-investigational-canagliflozin-for-the-treatment-of-type-2-diabetes-157201155.html. Accessed September 29, 2012.

7. FDA Advisory Panel Supports Diabetes Drug Canagliflozin.  Medscape Medical News, January 10, 2013.  Available at: http://www.medscape.com/viewarticle/777503. Accessed January 11, 2013.

8. Nomura S, Sakamaki S, Hongu M, et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem. 2010;53:6355–6360.

9. Neumiller JJ, White JR Jr., Campbell RK. Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus. Drugs. 2010;70:377–385.

10. FDA Rejects Dapaglifozin for Type 2 Diabetes. MedPage Today, January 19, 2012. Available at: http://www.medpagetoday.com/Endocrinology/Diabetes/30747. Accessed October 1, 2012.

11. Devineni D, Morrow L, Hompesch M, et al. Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab. 2012;14:539–545.

12. Cefalu WT, Leiter LA, Niskanen L, et al. Efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, compared with glimepiride in patients with type 2 diabetes on background metformin [poster session abstract 38-LB].  Presented at the American Diabetes Association (ADA) 72nd Annual Scientific Sessions, Philadelphia, PA, June 8-12, 2012.

13. Gross JL, Schernthaner G, Fu M, et al. Efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, compared with sitagliptin in patients with type 2 diabetes on metformin plus sulfonylurea [poster session abstract 50-LB]. Presented at the American Diabetes Association (ADA) 72nd Annual Scientific Sessions, Philadelphia, PA, June 8-12, 2012.

14. Wilding JP, Mathieu C, Vercruysse F, Usiskin K, Deng L, Canovatchel W. Canagliflozin (CANA), a sodium glucose co-transporter 2 inhibitor, improves glycemic control and reduces body weight in subjects with type 2 diabetes (T2D) inadequately controlled with metformin (MET) and sulfonylurea (SU) [poster session abstract 1022-P]. Presented at the American Diabetes Association (ADA) 72nd Annual Scientific Sessions, Philadelphia, PA, June 8-12, 2012.

15. Yale JF, Bakris G, Xi L, et al. Canagliflozin (CANA), a sodium glucose co-transporter 2 (SGLT2) inhibitor, improves glycemia and is well-tolerated in type 2 diabetes mellitus (T2DM) subjects with moderate renal impairment [poster session abstract 41-LB]. Presented at the American Diabetes Association (ADA) 72nd Annual Scientific Sessions, Philadelphia, PA, June 8-12, 2012.

16. Kajstenlof K, Cefalu WT, Alba M, Usiskin K, Zhao Y, Canovatchel W. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves glycemic control and lowers body weight in subjects with type 2 diabetes inadequately controlled with diet and exercise [oral presentation abstract 81-OR]. Presented at the American Diabetes Association (ADA) 72nd Annual Scientific Sessions, Philadelphia, PA, June 8-12, 2012.