More detailed data from the CANVAS program on the effect of the new diabetes drug canagliflozin (Invokana, Janssen) on stroke have been reported showing reassuring results on all stroke types and a significant reduction in hemorrhagic stroke.

"These are interesting data showing a trend towards reduced stroke rates across all subtypes with canagliflozin. While the point estimates for all types of strokes suggest a possible small benefit which is not significant, hemorrhagic stroke was significantly reduced.

This is a very intriguing result, although I wouldn't want to emphasize it too much as it is based on small numbers — with only 30 events," corresponding author, Richard Lindley, MD, The George Institute for Global Health, Newtown, Australia, commented to Medscape Medical News.

These latest results were published online on December 28 in Stroke.
https://www.ahajournals.org/doi/abs/10.1161/STROKEAHA.118.023009

The CANVAS program, comprising two similarly designed and conducted clinical trials, randomly assigned 10,142 participants with type 2 diabetes and high cardiovascular risk to canagliflozin or placebo. The primary outcome was a composite of major adverse cardiovascular events.

The main results, reported in 2017, showed that canagliflozin reduced cardiovascular events by 14% and cut the rate of renal decline by 40% but the drug was also associated with a doubling of the risk for lower-limb amputation.
https://www.medscape.com/viewarticle/881499

Canagliflozin is a member of the new class of diabetes drugs known as sodium-glucose cotransporter type 2 (SGLT2) inhibitors. Two other agents in this class, empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) and dapagliflozin (Farxiga/Forxiga, AstraZeneca), have also shown reassuring cardiovascular safety, with empagliflozin associated with a particularly striking reduction in cardiovascular mortality in the EMPA-REG trial.
https://www.medscape.com/viewarticle/851114

Dapagliflozin did not show a significant benefit on major adverse cardiovascular outcomes in the DECLARE trial, but like the other two SGLT2 inhibitors, was associated with a large reduction in heart failure, 17% reduction in cardiovascular death or hospitalization for heart failure, also an effect in T2DM with multiple risk factors. Neither empagliflozin nor dapagliflozin showed any increase in amputations.  
https://www.medscape.com/viewarticle/904739#vp_1

"The SGLT2 inhibitors are proving to be very important," Lindley noted. "Type 2 diabetes is increasing in prevalence with hundreds of millions of people with the condition in the world. These trials have been mandated to show these new drugs are safe for vascular events. Now we can definitely say they are safe in that regard, but more than that, they are actually beneficial on vascular events." 

In terms of stroke, reported results from EMPA-REG and DECLARE showed a nonsignificant increase in risk of stroke (any type) with empagliflozin and a neutral effect on ischemic stroke with dapagliflozin.
https://emedicine.medscape.com/article/1916852-overview
Effects on hemorrhagic stroke have not been specifically reported with these two agents.

"These trials were not powered to look at individual vascular events such as MI and stroke separately but we can still glean some interesting information on these outcomes," Lindley commented.

In the current Stroke article, the authors note that because type 2 diabetes is associated with an approximate doubling in the risk of stroke, "it is important to understand more about the effects of these drugs on stroke and whether those with established cerebrovascular disease have any additional risks or benefits compared with those without."

n the CANVAS program, there were 309 participants with stroke events during follow-up at a rate of 7.93/1000 patient-years among the canagliflozin group and 9.62/1000 patient-years among the placebo group (hazard ratio [HR], 0.87; 95% CI, 0.69 - 1.09). 

Analysis of stroke subtypes found no effect on ischemic stroke (n = 253; HR, 0.95; 95% CI, 0.74 - 1.22), a significant reduction in hemorrhagic stroke (n = 30; HR, 0.43; 95% CI, 0.20 - 0.89), and no effect on undetermined stroke (n = 29; HR, 1.04; 95% CI, 0.48 - 2.22).

There were 1958 (19%) participants with prior stroke or transient ischemic attack (TIA) at baseline. These individuals were older, more frequently women, and had higher rates of heart failure, atrial fibrillation, and microvascular disease compared with those without such a history. 

Patients with stroke or TIA at baseline were at higher absolute risk of subsequent stroke and all other vascular outcomes, with 123 stroke events occurring in those 1958 patients with prior stroke or TIA versus 186 in the 8184 patients without.

The proportional effects of canagliflozin versus placebo were comparable in patients with and without cerebrovascular disease at baseline for cardiovascular, kidney, and death outcomes.

Effects of canagliflozin treatment on stroke were similar for most patient subgroups, although there was some suggestion of greater protection in older patients, those with a lower estimated glomerular filtration rate, and those on antithrombotics.

"The stroke data have been mixed between the different agents so far. Empagliflozin showed a trend towards an increased stroke rate so these data with canagliflozin are reassuring," Lindley said. "We can say canagliflozin looks safe with regard to stroke risk and there is a potential benefit in hemorrhagic stroke. Patients with diabetes have high rates of stroke — if we can reduce this with diabetic medication then this is definitely a win-win.

On the mechanism behind a reduction in hemorrhagic stroke, Lindley said it could be mediated by blood pressure reduction. "We know these agents work by increasing the excretion of sodium and glucose, and they bring about weight loss. These effects will lead to a blood pressure reduction, and this again should lead to a reduced stroke risk."

Hemorrhagic stroke is much more dependent on blood pressure than ischemic stroke, he noted, "so this may well be the mechanism behind our result showing a significant reduction in hemorrhagic stroke with canagliflozin. And hemorrhagic stroke is more common in low- and middle-income countries, because blood pressures are higher in these countries, so this result could be of particular benefit for these areas. All in all, it's a nice safety signal." 

It's not clear at this time what the explanation is for the differences seen between the drugs in this class, he added. "I don't think the trials are powered to show differences between the individual agents in individual endpoints; we probably just have to look at the overall results. To me as a clinician, I would say these results are a reassuring safety signal on stroke for the whole drug class."

On the increased rate of amputations seen with canagliflozin in the CANVAS program, Lindley said it was difficult to know if this was a real effect or not as it hasn't been seen with the other drugs in this class.

"More information on this and other outcomes including stroke will come from another large trial with canagliflozin — CREDENCE — which is studying the drug in renal patients," he said. "This has now finished recruitment with results expected to be presented later this year."

From www.medscape.com

ABSTRACT

Canagliflozin and Stroke in Type 2 Diabetes Mellitus

Results From the Randomized CANVAS Program Trials
Originally published28 Dec 2018https://doi.org/10.1161/STROKEAHA.118.023009Stroke. 2018;0:STROKEAHA.118.023009

Background and Purpose

This study reports the detailed effects of canagliflozin on stroke, stroke subtypes, and vascular outcomes in participants with and without cerebrovascular disease (stroke or transient ischemic attack) at baseline from the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program.

Methods

The CANVAS Program, comprising 2 similarly designed and conducted clinical trials, randomly assigned 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk to canagliflozin or placebo. Its primary outcome was a composite of major adverse cardiovascular events. The main outcome of interest for this report was fatal or nonfatal stroke. Additional exploratory outcomes were stroke subtypes and other vascular outcomes defined according to standard criteria.

Results

There were 1 958 (19%) participants with prior stroke or transient ischemic attack at baseline. These individuals were older, more frequently women, and had higher rates of heart failure, atrial fibrillation, and microvascular disease (all P<0.001) compared with those without such a history. There were 309 participants with stroke events during follow-up (123 had prior stroke or transient ischemic attack at baseline and 186 did not), at a rate of 7.93/1000 patient-years among those assigned canagliflozin and 9.62/1000 patient-years among placebo (hazard ratio, 0.87; 95% CI, 0.69–1.09). Analysis of stroke subtypes found no effect on ischemic stroke (n=253, hazard ratio, 0.95; 95% CI, 0.74–1.22), a significant reduction for hemorrhagic stroke (n=30, hazard ratio, 0.43; 95% CI, 0.20–0.89) and no effect on undetermined stroke (n=29, hazard ratio, 1.04; 95% CI, 0.48–2.22). Effects on other cardiovascular outcomes were comparable among participants with and without stroke or transient ischemic attack at baseline.

Conclusions

There were too few events in the CANVAS Program to separately define the effects of canagliflozin on stroke, but benefit is more likely than harm. The observed possible protective effect for hemorrhagic stroke was based on small numbers but warrants further investigation.

Clinical Trial Registration

URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754.

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