Invokana (Canagliflozin): First-in-Class SGLT2 Inhibitor Approved for the Treatment of Type 2 Diabetes

Web Exclusives - FDA Approvals
Loretta Fala
Medical Writer
Download PDF

Diabetes affects an estimated 25.8 million people in the United States—a staggering 8.3% of the population.1 In addition, 35% of US adults have prediabetes and are at high risk for developing diabetes.1 Coinciding with the aging of the US population, the prevalence of diabetes is projected to increase dramatically over the next few dec­ades, from approximately 1 of 10 adults today to approximately 1 of 3 adults by 2050.2 Approximately 90% to 95% of all cases of diabetes are type 2 diabetes mellitus, and approximately 5% are type 1 diabetes mellitus.1

Associated with multiple comorbidities and potentially serious health implications, diabetes is the seventh leading cause of mortality in the United States.1 Diabetes accounted for total US healthcare costs of $245 billion in 2012, including $176 billion in direct medical costs and $69 billion in indirect costs (ie, increased absenteeism, reduced productivity, lost productivity resulting from early mortality, and the inability to work because of disability).3 An estimated $1 of $5 US healthcare dollars is spent on the care of people with diabetes.3 Medical expenses for people with diabetes are more than twice as high as expenses for people without diabetes.3

Improvements in glycemic control have been shown to decrease the morbidity and mortality of patients with type 2 diabetes mellitus by decreasing chronic complications.4 Every 1% reduction in glycated hemoglobin (Hb) A1c is associated with a 35% reduction in diabetes-related microvascular complications (ie, diabetic neuropathy, nephropathy, and retinopathy).4 In a 2013 position statement, the American Diabetes Association (ADA) recommended a general target HbA1c level of <7% for adults with diabetes, with the caveat that more-stringent or less-stringent goals may be appropriate for individual patients.5 Moreover, the target goal should be individualized based on the patient’s duration of diabetes, age, comorbidities, known cardiovascular or advanced microvascular complications, and other patient factors.5

Intensive glycemic control was shown to improve the risk of some complications. In a 5-year follow-up study of 11,140 patients with type 2 diabetes mellitus, intensive blood glucose control (mean HbA1c of ≤6.5%) compared with standard glucose control (mean HbA1c of 7.3%) showed a significant reduction in the incidence of major microvascular events (P = .01), but did not demonstrate a significant reduction in the incidence of major macrovascular events (P = .32).6 In this study, intensive glucose control was associated with a 21% relative risk reduction of nephropathy and a 9% relative risk reduction of microalbuminuria.6

Although strides have been made in the number of people in the United States who have achieved the target HbA1c of <7%, there remains a marked need and an opportunity to improve the achievement of glycemic control targets and overall outcomes for people who have, or who are at risk for, diabetes.7

The SGLT2 Inhibitor Drug Class
In recent years, the important role of the kidney in maintaining glucose homeostasis has been elucidated. Evidence suggests that in patients with type 2 diabetes mellitus, there is an increase in the amount of renal glucose that is released, thereby implicating the kidneys’ contribution to hyperglycemia.8 In hyperglycemia, excess glucose is reabsorbed by the kidney—a process that increases the renal glucose threshold and creates a cycle of chronic hyperglycemia, along with associated microvascular complications.8 The sodium-glucose cotransporter 2 (SGLT2), a cotransporter expressed in the proximal renal tubules, mediates the active transport of glucose against a concentration gradient via cotransport with sodium. SGLT2 is responsible for reabsorbing 90% of the glucose that is filtered at the glomerulus.8

The SGLT2 inhibitors represent a novel class of drugs that reduce reabsorption of filtered glucose and lower the renal threshold for glucose, thereby increasing urinary glucose excretion.8 These agents have a promising role, alongside diet and exercise, in improving glycemic control in patients with type 2 diabetes mellitus.

Invokana Receives FDA Approval
On March 29, 2013, the US Food and Drug Administration (FDA) approved Invokana (canagliflozin; Janssen Pharmaceuticals), the first SGLT2 inhibitor, as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.9 Canagliflozin is not recommended for the treatment of patients with type 1 diabetes mellitus or with diabetic ketoacidosis.10

According to Mary H. Parks, MD, Director, Division of Metabolism and Endocrinology Products at the FDA’s Center for Drug Evaluation and Research, “Invokana is the first diabetes treatment approved in a new class of drugs known as sodium-glucose cotransporter 2 inhibitors….We continue to advance innovation with the approval of new drug classes that provide additional treatment options for chronic conditions that impact public health.”9

The safety and efficacy of canagliflozin were evaluated in 9 clinical trials involving more than 10,285 patients with type 2 diabetes.9 In these studies, canagliflozin showed an improvement in A1c levels and in fasting plasma glucose.9

The FDA’s approval of canagliflo­zin included a requirement for postmarketing studies, including a cardiovascular outcomes trial; an en­hanced pharmacovigilance program to monitor for malignancies, severe pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities, and adverse pregnancy outcomes; a bone safety study; and 2 pediatric studies under the Pediatric Research Equity Act, including a safety and efficacy study and a pharmacokinetic and pharmacodynamic study.9

Dosing
The oral agent canagliflozin is available in 100-mg tablets and 300-mg tablets. The recommended starting dose of canagliflozin is 100 mg once daily, taken before the first meal of the day. The dose can be increased up to 300 mg once daily in patients tolerating canagliflozin 100 mg once daily who have an estimated glomerular filtration rate (eGFR) of ≥60 mL/min/1.73 m2 and require additional glycemic control.10

Canagliflozin dosing is limited to 100 mg once daily in patients who have an eGFR of 45 mL/min/1.73 m2 to <60 mL/min/1.73 m2. Renal function should be assessed before initiating canagliflozin therapy. If the eGFR is <45 mL/min/1.73 m2, canagliflozin therapy should not be initiated. Moreover, if the eGFR falls below 45 mL/min/1.73 m2, canagliflozin should be discontinued.10

Because the coadministration of canagliflozin and rifampin, a nonselective inducer of several UDP glucuronosyltransferase enzymes, may decrease exposure to, and the efficacy of, canagliflozin, it is recommended that the dose of canagliflozin be increased from 100 mg to 300 mg. Patients taking canagliflozin with concomitant digoxin should have their digoxin levels monitored appropriately.10

Novel Mechanism of Action
Canagliflozin is an inhibitor of SGLT2, a cotransporter that is expressed in the proximal renal tubules, that is responsible for most of the reabsorption of filtered glucose from the tubular lumen. By inhibiting SGLT2, canagliflozin reduces the reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion.

The mean absolute bioavailability of canagliflozin is approximately 65%. The coadministration of a high-fat meal and canagliflozin had no effect on the pharmacokinetics of canagliflozin; therefore, canagliflozin may be taken with or without food. However, based on its potential to reduce postprandial plasma glucose excursions as a result of delayed intestinal glucose absorption, it is recommended that canagliflozin be taken before the first meal of the day.10

The major metabolic elimination pathway for canagliflozin is O-glucuronidation. The cytochrome P450 3A4–mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans.10

Clinical Studies
Monotherapy with Canagliflozin

The safety and efficacy of canagliflozin monotherapy were evaluated in a 26-week, double-blind, placebo-­controlled study of 584 patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise. Patients were randomized to receive canagliflozin 100 mg, canagliflozin 300 mg, or placebo, administered once daily for 26 weeks.10

At the end of the treatment period, canagliflozin 100 mg and 300 mg once daily demonstrated a significant improvement in HbA1c levels (P <.001 for both doses) compared with placebo (Table 1). Monotherapy with canagliflozin 100 mg and 300 mg helped a greater proportion of patients achieve the ADA-recommended HbA1c goal of <7% over 26 weeks versus placebo.5,10 In fact, an HbA1c goal of <7% was achieved by 45% of patients receiving canagliflozin 100 mg and by 62% of patients receiving canagliflozin 300 mg compared with 21% of patients receiving placebo.10


Table 1

In addition, 100-mg and 300-mg doses of canagliflozin showed a significant reduction in fasting plasma glucose, significant improvement in postprandial glucose, and significant reduction in percent body weight compared with placebo. Furthermore, both doses of canagliflozin showed significant (P <.001) mean changes from baseline in systolic blood pressure compared with placebo (–3.7 mm Hg for canagliflozin 100 mg and –5.4 mm Hg for canagliflozin 300 mg).10

Add-On Combination Therapy: Canagliflozin plus Metformin
The safety and efficacy of canagliflozin in combination with metformin was evaluated in a 26-week, double-blind, placebo- and active-controlled trial in 1284 patients with type 2 diabetes.10

At the end of the treatment period, canagliflozin 100 mg and 300 mg once daily showed a significant improvement in HbA1c levels (P <.001 for both doses) compared with placebo when added to metformin (Table 2). Canagliflozin 100 mg plus metformin and canagliflozin 300 mg plus metformin also showed a greater proportion of patients achieving the ADA-recommended goal of HbA1c <7.0%; 46% of the canagliflozin 100-mg cohort and 58% of the canagliflozin 300-mg group compared with 30% of the group receiving placebo plus metformin achieved an HbA1c level of <7%.10


Table 2

Additional Clinical Trials
Canagliflozin was evaluated for safety and efficacy in 7 other clinical trials, and was shown to improve HbA1c levels and fasting plasma glucose in these studies.

Adverse Events
The most common adverse reactions reported in ≥2% of patients with canagliflozin include female genital mycotic infections, urinary tract infection, and increased urination (Table 3).


Table 3

Contraindications
Canagliflozin is contraindicated in patients with a serious hypersensitivity reaction to canagliflozin, as well as in patients with severe renal impairment, patients with end-stage renal disease, or patients on dialysis. There are no boxed warnings associated with the use of canagliflozin.

Warnings and Precautions
Hypotension

Canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating canagliflozin, particularly in patients with impaired renal function (eGFR of <60 mL/min/1.73 m2), elderly patients, patients receiving either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (RAAS; eg, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), or patients with low systolic blood pressure.10

Before initiating canagliflozin in patients with 1 or more of these characteristics, volume status should be assessed and corrected. The signs and symptoms of hypotension should be monitored after therapy is initiated.10

Impairment in Renal Function
Canagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating canagliflozin. More frequent renal function monitoring is recommended in patients with an eGFR of <60 mL/min/1.73 m2.10

Hyperkalemia
Canagliflozin can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the RAAS are more likely to develop hyperkalemia. Serum potassium levels should be monitored after initiating canagliflozin in patients with impaired renal function and in patients who are predisposed to hyperkalemia as a result of medications or other medical conditions.10

Hypoglycemia Associated with Concomitant Use of Insulin and Insulin Secretagogues
Insulin and insulin secretagogues are known to cause hypoglycemia. Canagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or of insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with canagliflozin.10

Genital Mycotic Infections
Canagliflozin increases the risk for genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males are more likely to develop genital mycotic infections. Patients should be monitored and treated appropriately.10

Hypersensitivity Reactions
Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported with treatment with canagliflozin; these reactions generally occurred within hours to days after initiating canagliflozin. If hypersensitivity reactions occur, canagliflozin should be discontinued, and patients should be treated according to the standard of care and monitored until the signs and symptoms resolve.10

Increases in Low-Density Lipoprotein Cholesterol
Dose-related increases in low-density lipoprotein cholesterol occur with canagliflozin. Low-density lipoprotein cholesterol should be monitored and patients should be treated per standard of care after initiating canagliflozin.10

Macrovascular Outcomes
No clinical studies have established conclusive evidence of macrovascular risk reduction with canagliflozin or with any other antidiabetic drug.10

Conclusion
In March 2013, canagliflozin, an oral SGLT2 inhibitor, became the first member in this drug class to receive FDA approval for the management of patients with type 2 diabetes. Canagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. This medication has a novel mode of action: by inhibiting the SGLT2 in the proximal renal tubules, canagliflozin reduces glucose reabsorption in the kidney and increases the amount of glucose excreted in the urine.

Canagliflozin was evaluated for safety and efficacy in 9 clinical trials involving more than 10,285 patients with type 2 diabetes. In these studies, canagliflozin was shown to improve HbA1c levels and fasting plasma glucose. The most common (incidence, ≥5%) adverse reactions associated with canagliflozin were female genital mycotic infections, urinary tract infections, and increased urination.


References
  1. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. 2011. www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed May 15, 2013.
  2. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29.
  3. American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Care. 2013;36: 1033-1046.
  4. American Diabetes Association. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care. 2002;25(suppl 1):S28-S32.
  5. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36(suppl 1): S11-S66.
  6. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
  7. Cheung BM, Ong KL, Cherny SS, et al. Diabetes prevalence and therapeutic target achievement in the United States, 1999 to 2006. Am J Med. 2009;122:443-453.
  8. Triplitt CL. Understanding the kidneys’ role in blood glucose regulation. Am J Manag Care. 2012;18(1 suppl): S11-S16.
  9. US Food and Drug Administration. FDA approves Invokana to treat type 2 diabetes: first in a new class of diabetes drugs. Press release; March 29, 2013. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm. Accessed May 3, 2013.
  10. Invokana (canagliflozin) tablets [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2013.
Related Items
FDA Oncology Update
November 2019 Vol 12, No 7 published on December 5, 2019 in FDA Approvals
November 11, 2019 — Oncology News & Updates
Web Exclusives published on November 13, 2019 in Drug Updates, FDA Approvals, In the News
October 28, 2019 – Oncology News & Updates
Yvette Florio Lane
Web Exclusives published on October 28, 2019 in FDA Approvals, In the News
Vincristine, Racial Disparities in Multiple Myeloma, and HER2 Metastatic Breast Cancer Are in the News
Yvette Florio Lane
Web Exclusives published on October 22, 2019 in Breast Cancer, FDA Approvals, In the News, Multiple Myeloma, Pediatric Cancer
FDA Approves Darzalex Combination for First-Line Treatment of Transplant-Eligible Patients with Multiple Myeloma
Web Exclusives published on September 27, 2019 in FDA Approvals, Multiple Myeloma, In the News
Last modified: February 14, 2019
  •  Association for Value-Based Cancer Care
  • Oncology Practice Management
  • Value-Based Cancer Care
  • Value-Based Care in Rheumatology
  • Rheumatology Practice Management
  • Urology Practice Management
  • Lynx CME