Kishan Patel, Mercer University College of Pharmacy
Canagliflozin is a sodium-glucose cotransporter 2 (SGLT-2) inhibitor that allows for lower blood glucose in patients with type 2 diabetes (T2D) by increasing the urinary excretion of glucose.  There is a large amount of data that suggests T2D is an independent risk factor for cardiovascular disease. Furthermore, cardiovascular disease is also the cause of death for the majority of patients with T2D.  Current evidence suggests that canagliflozin may be more effective than comparative options such as dipeptidyl peptidase-4 (DPP-4) inhibitors in lowering glycated hemoglobin (HbA1C), body weight, and blood pressure when used as an add-on therapy with metformin. Canagliflozin also appears to be superior when used in combination with metformin than sulfonylureas (SU) in regard to lowering body weight, blood pressure, and risk of hypoglycemia. However, direct evidence from comparative studies is only limited to sitagliptan (DPP-4 inhibitor) and glimepiride (SU) for their respective drug classes. Therefore, conclusions for canagliflozin’s comparative effectiveness against other agents in the same class as DPP-4 inhibitors and sulfonylureas have been deduced from indirect evidence in network meta-analyses. 
Another SGLT-2 inhibitor, empagliflozin, is currently approved by the Food and Drug Administration (FDA) for the reduction of cardiovascular outcomes in T2D patients based on Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) study. Like empagliflozin, short-term data has shown canagliflozin to be beneficial in regard to cardiovascular outcomes, but evidence has been limited for long-term outcomes.  Therefore, the Canagliflozin Cardiovascular Assessment Study (CANVAS) program was conducted to evaluate long-term cardiovascular benefits of canagliflozin in T2D patients. The CANVAS program consisted of two sister trials: CANVAS and CANVAS-R. The CANVAS trial compared canagliflozin versus placebo in cardiovascular outcomes, whereas the CANVAS-R study compared canagliflozin and placebo in regard to renal outcomes. These two studies were then merged in order to assess overall long-term cardiovascular outcomes. 
|Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes|
|Design||Multicenter, randomized, double-blind, placebo-controlled trial; (N= 10,142)|
|Objective||To find whether once daily canagliflozin reduced cardiovascular (CV) death, nonfatal myocardial infarction (MI), or nonfatal stroke in type 2 diabetes (T2D) patients with high CV risk|
|Study Groups||CANVAS: canagliflozin 100 mg vs 300 mg vs placebo (n= 4,330)
CANVAS-R: canagliflozin 100 mg + optional increase to 300 mg vs placebo (n= 5,812)
– Age ≥ 30 years-old with history of symptomatic atherosclerotic cardiovascular disease (ASCVD) OR ≥ 50 years-old with two of the following risk factors: diabetes ≥10 years, systolic blood pressure > 140 mmHg with antihypertensive medications, smoking, microalbuminuria or macroalbuminuria, or high-density lipoprotein (HDL) < 38.7 mg/dL
– estimated glomerular filtration rate > 30 mL/min per 1.73 m2 of body surface area
All potential participants first completed a 2 week, single-blind, placebo run-in before being randomized. Patients were scheduled for three face-to-face follow-ups in the first year, and a follow-up every 6 month thereafter. Urinary albumin-to-creatinine ratio was measured after every 26 weeks for the CANVAS-R trial, and was measured for participants in the CANVAS trial after 12 weeks and annually thereafter. Serum creatinine was measured every 12 weeks for both trials every 26 weeks.
|Duration||January 16, 2014 to February 23, 2017|
|Primary Outcome Measure||– Death from CV causes
– Nonfatal MI
– Nonfatal stroke
* Plus–minus values are means ±SD. The CANVAS Program comprised two trials: the Canagliflozin Cardiovascular Assessment Study (CANVAS) and CANVAS–Renal (CANVAS-R).
† One participant underwent randomization at two different sites; only the first randomization is included in the intention-to-treat analysis set.
‡ Race was determined by investigator inquiry of the participant. Other includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiple races, other race, and unknown.
§ Some participants had more than one type of atherosclerotic disease.
¶ A history of cardiovascular disease was defined as a history of symptomatic atherosclerotic vascular disease (coronary, cerebrovascular, or peripheral).
** Values for estimated glomerular filtration rate (eGFR) were calculated with data from 5,794 participants in the canagliflozin group, 4,346 in the placebo group, and 10,140 in the total population.
†† The albumin-to-creatinine ratio was measured in milligrams of albumin and grams of creatinine.
|Adverse Events||Common Adverse Events: not disclosed|
|Serious Adverse Events: acute pancreatitis (adjudicated), cancer (renal, bladder, and breast), photosensitivity, diabetic ketoacidosis (adjudicated), amputation, fracture (adjudicated), venous thromboembolic events, and infection of male genitalia|
|Percentage that Discontinued due to Adverse Events: Canagliflozin 35.5%; Placebo 32.8 (p= 0.07)|
|Study Author Conclusions||Patients with type 2 diabetes taking canagliflozin had a lower risk of cardiovascular events compared to placebo. However, patients taking canagliflozin had a greater risk of amputation of the toe or metatarsal.|
The CANVAS program revealed that T2D patients lowered the risk of cardiovascular events with the use of canagliflozin when compared to placebo. However, a surprisingly new finding was the increased risk of amputation with canaglifozin (HR 1.97; 95% CI, 1.41 to 2.75). The primary limitation of the study was the lack of events for many outcomes such as end-stage kidney disease. Furthermore, a relatively limited number of participants with established kidney disease at baseline possibly circumcised any observations in this patient population. Other limitations include a greater risk of false positives due to large number of analyses and relatively fewer events in comparison. Strengths of the program include: a large number of participants in the combined trials, a long duration for both trials, a randomized study design, a wide range of studied participants, and that the trials were conducted according to high standards. The studies also included participants with or without established cardiovascular disease; thus, allowing for a greater number of the population to be correlated with the data available.
When prescribing canagliflozin, clinicians will need to weigh the risks and benefits with the patient before making a decision. Type 2 diabetic patients with cardiovascular disease and a low risk for amputation may be the patient population that will benefit the most with the addition of canagliflozin to their therapy. A future comparative study on whether canagliflozin is non-inferior and/or superior to empagliflozin in reducing cardiovascular outcomes may be beneficial to understand where to place each medication in the standards of care. The increased risk of amputations shown in the CANVAS study may be a concern, and further studies involving other SGLT-2 inhibitors may reveal whether the amputation risk of canagliflozin is a class effect.
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 Karagiannis T, Bekiari E, Tsapas A. Canagliflozin in the treatment of type 2 diabetes: an evidence-based review of its place in therapy. Core Evid. 2017;12:1-10.
 Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017.