A new class of oral agents to treat type 2 diabetes is on the way. The FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted in favor of canagliflozin (Invokana, Janssen), a novel sodium-glucose cotransporter-2 inhibitor (SGLT-2), in January of this year.1 The SGLT-2 inhibitors work by blocking glucose reabsorption in the kidneys, leading to glycosuria. This action is independent of insulin, and also leads to increased excretion of calories. According to a recent systematic review, these agents have produced a reduction in hemoglobin A1C of 0.6-1% in monotherapy and in combination with other agents.2 Beneficial side effects in these studies include weight loss (up to 8 lbs) and systolic blood pressure reduction (up to 5 mmHg), as well as reduced serum uric acid levels. Adverse effects were mostly urinary and genital tract infections that resolved with standard treatment in all cases. There was no overall difference found in hypoglycemia risks with SGLT-2 inhibitors, except when used in combination with insulin.
The advisory committee previously rejected dapagliflozin, another SGLT-2 agent, in 2011 based upon concern of increased breast and bladder cancer risks.2 There were 9 cases each of breast and bladder cancers in dapagliflozin-treated groups compared to zero and one case in placebo groups, respectively. The manufacturers’ incidence analysis reported no association. Dapagliflozin (Forxiga, AstraZeneca/Bristol-Myers Squibb), though, was approved for use in Europe in November 2012. Maybe the FDA committee was being extra cautious due to the developments with pioglitazone?
Canagliflozin itself is not without safety concerns. Canagliflozin was associated with a dose-dependent increase in LDL cholesterol, as well an increased incidence of volume depletion in patients with moderate renal impairment.1 Other cardiovascular risk data that was presented to the committee was from the Major Adverse Cardiovascular Events Plus (MACE-plus) analyses. The endpoint reported in MACE-plus was a composite of nonfatal stroke, cardiovascular death, nonfatal myocardial infarction, and hospitalization for unstable angina and risks were similar for dapagliflozin and placebo. There was concern regarding increased stroke risk, but the data presented was insufficient. More clarification regarding cardiovascular risks hopefully will come with the results of the Canagliflozin Cardiovascular Assessment Study (CANVAS), expected in 2015.
Not all patients will be candidates for these agents. It would be hard to justify their use in patients with impaired renal function, electrolyte abnormalities, or those at risk for such conditions, ie elderly. Cost will be prohibitive as well as these agents will likely be expensive. The SGLT2 inhibitors appear to have moderate effect on A1C, comparable to the dipeptidyl peptidase-4 (DPP4) inhibitors. The added benefits of weight loss and blood pressure reduction may prove key factors in choosing them in younger patients, probably in combination with other drugs. The idea that these drugs work independently of insulin may also be promising in patients who have had diabetes for many years.
Even with the prospect of weight loss, and blood pressure and A1C reduction, NICE has yet to include dapagliflozin in their guidelines for type 2 diabetes and recently requested more information from the manufacturer related to efficacy and safety. As for the US, the FDA is expected to make a decision on canagliflozin by the end of March. Are the SGLT2 inhibitors the answer we are waiting for in diabetes management? I’m not certain.
1. Tucker m. Most FDA advisors support diabetes drug canagliflozin, despite CV concerns. Heartwire [internet] January 11, 2013. http://www.theheart.org/article/1494769.do. accessed 2/21/13
2. Clar C, Gill JA, Court R, Waugh N. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open. 2012 Oct 18;2(5). pii: e001007. doi: 10.1136/bmjopen-2012-001007. accessed 2/21/13
3. news release. FORXIGA™ (dapagliflozin) now approved in European Union for treatment of type 2 diabetes. November 14, 2012. http://www.astrazeneca.com/Media/Press-releases/Article/20121114--forxiga-eu-approval-type-2-diabetes. accessed 2/21/13