I am so excited to see that the results of the CANVAS program is finally released in the New England Journal of Medicine this week. Click here for the article. The results were also shared at last week’s 77th Scientific Sessions of the American Diabetes Association in San Diego, California. So what do they say? What do they mean? How do these results translate into clinical practice?
If you wonder why I am so excited about the results, let’s take a step back to recap what we know so far. Sodium Glucose cotransporter inhibitor is a relatively new class of medication indicated for the management of Type 2 diabetes. Currently, there are three sodium glucose cotransporter inhibitors available in Canada: canagliflozin, empagliflozin, dapagliflozin.
Prior to their introduction, many other oral hypoglycemia agents have only demonstrated the efficacy in glycemic control but have not consistently demonstrated other long term outcome benefits such as a reduction in mortality or cardiovascular benefits (except for metformin). This view was changed when the results of EMPA-REG OUTCOME was released demonstrating the cardiovascular benefits of empagliflozin in patients with Type 2 diabetes. See my other post which summarizes the key findings of this study. Given it was only one of the three sodium glucose cotransporter inhibitors that has demonstrated such pronounced outcome benefits, many clinicians wonder if the results can be generalized to other agents from the same drug class.
So the time has come to look at the result of the CANVAS Program.
The CANVAS Program integrated results from two studies involving 10142 subjects with type 2 diabetes and high cardiovascular risk. They were randomly assigned to receive canagliflozin or placebo. The mean follow up period was 188.2 weeks (~ 3.6 years). The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke. Below are the highlights of the study:
Here are my humble thoughts:
- Both EMPA-REG OUTCOME and the CANVAS Program have set out to evaluate the same primary outcome (death from cardiovascular causes, non fatal myocardial infarction, or nonfatal stroke).
- EMPA-REG OUTCOME: Hazard ratio, 0.86 (95% CI, 0.74-0.99)
- The CANVAS Program: Hazard ratio, 0.86 (95% CI, 0.75-0.97)
While the calculated hazard ratio may be the same from the two studies, it is interesting to note that empagliflozin was able to demonstrate the significant benefit in much shorter duration (~ 2 years) whereas it took a much longer time for canagliflozin [6.5 years (338 weeks)]. If you look at the graphical presentation of the data, you can see that the line for empagliflozin and placebo diverges rather quickly at the onset of the study. But for the results from the CANVAS program, the diversion was much less distinct.
- In EMPA-REG OUTCOME, many clinically meaningful endpoints such as death from cardiovascular causes, death from any cause, hospitalization for heart failure were able to achieve statistical significance. However in the CANVAS program, it was disappointing to see that none of these endpoints such as death from cardiovascular causes, nonfatal stroke and nonfatal myocardial infarction achieved statistical significance. It seems to me the evidence for cardiovascular benefits from canagliflozin is not as well illustrated. In fact, I think the evidence is much weaker.
- The other concerning point from the CANVAS program is the doubling of the amputation risk in the canagliflozin group (6.3 vs 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75). This was already forewarned by the FDA and they intend to carry out an investigation to identify if the higher risk of amputation risk is linked to canagliflozin. It was not seen in the EMPA-REG OUTCOME study but they also did not set out to look for such event.
I think everyone is hoping the results should validate the cardiovascular benefits of sodium glucose cotransporter inhibitors in Type 2 diabetes from the CANVAS program.
But is it true?
Yes, the CANVAS program was able to demonstrate cardiovascular benefits with canagliflozin but the results were not as impressive as those from the EMPA-OUTCOME. I am not convinced it is a class effect. But perhaps we need to look at how the study population differs between the two studies.
The doubling of the amputation risk is a red flag. While the risk is rare, it is alarming to know that the risk can be doubled in the canagliflozin group.
I think the results of the CANVAS Program raise more questions that need to be evaluated, than to confirm the existing benefits with sodium glucose cotransporter inhibitors. With time, I hope we will come to understand better the safety and benefits of sodium glucose cotransporter inhibitors in Type 2 diabetes.
What are your thoughts on the CANVAS Program? I would be interested to hear from you.
Thank you for reading my post.