Canagliflozin - Beginning of the journey

Sir, In March 29, 2013, the US Food and Drug Administration (FDA) approved a novel glucose-lowering agent, Canagliflozin under New Molecule Entity (NME) for the treatment of adults with type 2 diabetes mellitus. Janssen and its affiliates have rights to Canagliflozin through a license agreement with Tanabe Seiyaku Ltd., now known as Mitsubishi Tanabe Pharma Corporation.[1] Canagliflozin is the first in a new class of drug, an oral selective inhibitor of sodium glucose cotransporter 2 (SGLT2), which is mainly expressed in kidney. Inhibition of SGLT2 reduces reabsorption of glucose in the kidney, resulting in increased urinary glucose excretion (UGE), with a consequent lowering of plasma glucose levels and a loss of 300-400 kcal/day to UGE results in weight loss as well.[1] The U.S. Centers for Disease Control and Prevention estimates that nearly 26 million Americans have diabetes, 90-95% of which is type 2 diabetes. U.S. national data from 2007 to 2010 show that nearly half of the adults with type 2 diabetes were not achieving recommended levels of glucose control. If left uncontrolled, type 2 diabetes can lead to serious complications; improved glycemic control has been demonstrated to reduce the onset and progression of these complications.[1] In India, a wide range of outcomes for different groups is buried within the average diabetes prevalence of 8% higher than that in most European countries.[2] According to the Indian Diabetes Federation (IDF), the number of people in the age group of 20-79 years complaining of diabetes is approximately 61.3 millions in the year 2011 and may rise to almost 101.2 million by the year 2030. Canagliflozin is thought to work differently than other currently available hypoglycemic agents because it reduces blood glucose by acting on the kidneys as a ‘glucuretic,’ increasing the loss of glucose in the urine. What has historically been viewed as a sign of diabetes — glucose in the urine — may also reflect the efficacy of a new and unique approach to treatment. Canagliflozin is a prescription drug, supports once daily dosing, and should be taken before the first meal of the day.[2] Half life of Canagliflozin is 11-13 hours. It has a balanced renal and biliary excretion. Metabolism is mainly through glucuronidation, but no active metabolites are formed.[2] Canagliflozin is not for people with Type 1 diabetes and people with diabetic ketoacidosis.[2] Table 1 studies were conducted with Canagliflozin across the globe. The distribution of subjects was around 36% from North America, Canada, Mexico, and USA; 26% from Europe; 8% from the Central and South America and approximately 30% from the rest of the world. With Canagliflozin, consistent improvement across Phase 3 studies has been reported. More number of subjects has achieved the HbA1c goal and also a sustained response over 52 weeks. A meaningful, albeit lesser reductions in HbA1c level in subjects with renal impairment was simultaneously reported from the studies. Some other efficacy parameters like consistent reductions in body weight, consistent reductions in systolic blood pressure, additional efficacy with 300 mg relative to 100 mg were noteworthy.[3]Table 1: Clinical development program: 9 studies conductedThe common adverse effects reported are gastrointestinal disorders like diarrhea, thirst, breast disorders like balanitis, etc., The most common side effects include vaginal yeast infections and yeast infections of the penis, urinary tract infection, changes in urination, including urgent need to urinate more often, in larger amounts, or at night and serious hypersensitivity reaction. This drug is contraindicated in renal compromised cases as it causes severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal disease (ESRD).[4] FDA determined that an analysis of spontaneous postmarketing adverse events reported till now is not sufficient to assess signals of serious risks of malignancy (pheochromocytoma, Leydig cell tumor, renal cell carcinoma), pancreatitis, hypersensitivity reactions, photosensitivity reactions, hepatotoxicity, bone fractures, nephrotoxicity, and adverse pregnancy outcomes in patients treated with Canagliflozin. FDA has suggested that enhanced pharmacovigilance should continue for 10 years from the date of approval for malignancies and 5 years for all other events.[4] Use of Canagliflozin in some specific populations seems important. Use during pregnancy can be done only if the potential benefit justifies the potential risk to the fetus. There are inadequate studies conducted in pregnant women to show the safety profile. Nursing mothers should discontinue Canagliflozin. In geriatrics, a higher incidence of adverse reactions related to reduced intravascular volume was seen. In renal impaired populations, also a higher incidence of adverse reactions was encountered. Moreover, Canagliflozin is not recommended with severe hepatic impairment.[14] Others drugs in this class are Dapagliflozin, Ipragliflozin, and Empagliflozin. Dapagliflozin, approved in November 2012 is already available in Europe.[1] Canagliflozin has approval for being marketed in North America, South America, Europe, the Middle East, Africa, Australia, New Zealand, and parts of Asia excluding Japan. (Mitsubishi Tanabe Pharma is currently conducting a development Phase III for Type 2 Diabetes Mellitus in Japan.)[5] The benefit and risk profile of Canagliflozin can be conclusive. The benefits outweigh the risks associated with the drug. The risks reported are mostly dose-related higher incidence of reduced volume-related events, increase in Low Density Lipoprotein (LDL) cholesterol and a small reduction in the bone mineral density (BMD). However, the benefits are a low incidence of hypoglycemia, an unique mechanism of action of the drug complementary with other antihypoglycemic agents, improves beta-cell function, simple to administer with once daily oral dosing and a flexible dosing of 100 and 300 mg.[3] Canagliflozin is an important addition to the comprehensive platform of offerings for patients with diabetes from the Johnson and Johnson Family of Companies.

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