Achal Patel, Mercer University College of Pharmacy
Type 2 diabetes (T2D) is the more common form of diabetes mellitus compared to type 1 diabetes (T1D) and accounts for ~90% of all diabetes patients.  Complications of diabetes include cardiovascular, macrovascular, microvascular, peripheral nerve, and renal diseases. Evidence shows that use of SGLT2 inhibitors may help in reducing the risk of cardiovascular complications, albuminuria, and renal diseases. 
Canagliflozin (Invokana®), is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that lowers the renal threshold for glucose and increases urinary glucose excretion by interfering with the reabsorption of renally-filtered glucose across the tubular lumen of the proximal renal tubules.  Sodium-glucose cotransporter 2 inhibitors are the most recent type of diabetic agents approved for T2D management in the U.S. Previously, the Food and Drug Administration published a guidance for industry that new diabetic agents should be assessed for their cardiovascular safety.  The article below summarizes two canagliflozin trials that assessed its effect on CV risks (CANVAS) and albuminuria (CANVAS-R).
|Canagliflozin and cardiovascular and renal events in type 2 diabetes|
|Design||Double-blind, randomized, placebo-controlled trial; N= 10,142|
|Objective||To determine the effects of canagliflozin on cardiovascular, renal, and safety outcomes as indicated by evidence about SGLT2 inhibitors|
|Study Groups||Canagliflozin (n= 5,795), Placebo (n= 4,347)|
– T2DM with HbA1c ≥7.0% to ≤10.5% at screening
– Not currently on antihyperglycemic agent therapy or on antihyperglycemic monotherapy or combination therapy with approved class of agents
– History or high risk of CV disease defined on basis of either:
o Age ≥30 years with documented symptomatic atherosclerotic CV disease or amputation secondary to vascular disease.
o Age ≥ 50 years with 2+ following risk factors at screening: duration of T2DM ≥10 years, SBP>140 mmHg, while on ≥1 BP-lowering medication, current smoker, microalbuminuria or macroalbuminuria, or HDL <1mmol/L
– Women of childbearing potential must have negative urine beta-HCG pregnancy test at screening
– History of DKA, type 1 DM, pancreas or beta-cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy
– On antihyperglycemic agent and not on stable regimen for at least 8 weeks
– History of ≥1 severe hypoglycemic episode within 6 months screening
– History of hereditary glucose-galactose malabsorption or primary renal glucosuria
– GFR <30 at screening
– Serum Cr ≥1.4 mg/dL for men or ≥1.3 for women for those taking metformin
– Life expectancy <1 year
– Current use of other SGLT2 inhibitor
– Pregnant or breastfeeding
The study was a non-inferiority trial which calculated that 688 cardiovascular safety events to achieve a 90% power.
Participants in the CANVAS trial were randomly assigned in a 1:1:1 ratio to receive canagliflozin at a dose of 300 mg, 100 mg, or matching placebo
Participants in CANVAS-R were randomly assigned in a 1:1 ratio to receive canagliflozin 100 mg daily. or placebo with an option to increase canagliflozin to 300 mg daily or matching placebo.
|Duration||December 2012 – March 2014|
|Primary Outcome Measure||Composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke|
* These are significant outcomes.
|Adverse Events||Common and Serious Adverse Events: event rate/1,000 patients
** p< 0.001
≠ Low-trauma fracture was the pre-specified primary outcome, all fracture was a secondary outcome
|Percentage that Discontinued due to Adverse Events: canagliflozin (35.5%), placebo (32.8%)|
|Study Author Conclusions||Daily doses of canagliflozin 100 mg daily significantly reduced the risk of cardiovascular causes, nonfatal MI, or nonfatal stroke compared to those patients who received placebo. There is also an increased risk of UTI infections as well as an increased risk of amputations in patients taking canagliflozin.|
For this article, the study had a high internal validity because of its double-blind, randomized design. The external validity of the study was also strengthened with the large sample size. However, the study included only a small percentage of non-white population (< 25%) who may be at an increased risk of cardiovascular and renal diseases, especially African Americans. Although the subgroup analysis (not shown in the table) showed no significant differences based on race (p= 0.40), the confidence intervals of non-white population are wider compared that of white race suggesting racial differences may be present and variable results may be expected from non-white population. However, the study was not designed to detect the differences among the racial groups; therefore, whether this observation is true cannot be determined.
The wider confidence interval may be due to the smaller number of patients in non-white racial groups. Subgroup analysis showed several patient characteristics (eg. Baseline eGFR, RAAS inhibitor use, blood pressure control, duration of diabetes, and hemoglobin A1c) did not result in significant differences, suggesting the beneficial outcomes may be independent of these factors. For adverse events, the risk of urinary tract infection was increased with the study drug; however, such outcome may be expected based on the mechanism of action of canagliflozin. However, there is no known mechanism for the increased risk of amputations. Despite the limitations, there were multiple strengths in the study that helped provide safety data in the use of canagliflozin compared to placebo for cardiovascular and renal safety in diabetic patients. Therefore, it may be reasonable to consider canagliflozin in type 2 diabetics with high risk of cardiovascular events, and such recommendation is also reflected in the 2018 American Diabetes Associations Standards of Care. 
 Cefalu WT et al. American Diabetes Association Standards of medical care in diabetes – 2017. Journal of Clinical and Applied Res and Ed., 2017;40(1):S1-S132.
 Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;
 Canagliflozin. Micromedex 2.0. Greenwood Village, CO: Truven Health Analytics, 2017.
 American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes 2018. Diabetes Care 2018;41(Suppl. 1):S73–S85