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SAN DIEGO -- Among patients with type 2 diabetes, canagliflozin (Invokana) was linked to a significant drop in cardiovascular events, according to the CANVAS trials.

Led by Bruce Neal, PhD, of the George Institute for Global Health in Australia, and colleagues, the program reported those treated with 100 mg or 300 mg of the SGLT-2 inhibitor reported significantly lower rates of stroke, non-fatal MI, and cardiovascular death (occurring in 26.9 versus 31.5 participants per 1,000 patient-years) (HR 0.86, 95% CI 0.75 to 0.97, P<0.001 for noninferiority and P=0.02 for superiority).

The researchers presented their results here at the American Diabetes Association meeting and they were simultaneously published online in .

The CANVAS program involved the original CANVAS study, which provided the initial cardiovascular safety data required for FDA evaluation, and CANVAS-Renal (known as CANVAS-R), which was set up after the interim CANVAS results were unmasked in regulatory documents. Instead of following the original cohort as planned, the researchers set up CANVAS-R in 2014 to capture post-approval cardiovascular safety instead. The study also assesses the effects of canagliflozin on albuminuria.

"Both of the studies were done with the same oversight group, the same adjudication processes, the same operational teams, etc.," Neal told 口袋女优. "And they were always planned to be analyzed as a program that brings together the two sets of data."

Sanjay Kaul, MD, of Cedars-Sinai Medical Center in Los Angeles, who was not involved in the study, called the 14% reduction in major adverse cardiovascular events "modest," though he acknowledged that it "meets the criterion for non-inferiority using the 1.3 risk margin."

"The inference of superiority," he noted, "is open to debate. First, it was not prespecified in the testing sequence, even though the investigators stated that if the null hypothesis is rejected and the upper bound of the HR is <1.0, it will be concluded that canagliflozin is superior to placebo."

Kaul added that the P-value of 0.02 regarding superiority is "not robust enough to meet the FDA statutory criterion of 'substantial evidence' that requires a persuasive P-value of <0.001 based on a single trial."

The CANVAS program, which had a mean follow-up of 188.2 weeks, was conducted at 667 centers in 30 countries and included 10,142 type 2 diabetes patients at high cardiovascular risk, including 65.6% with a history of cardiovascular disease. Their mean age was 63 and about 36% were female.

Renal outcomes were not found to be statistically significant, although there was a suggested protective benefit regarding the progression to albuminuria (HR 0.73, 95% CI 0.67-0.79). Neal's group also reported a renal benefit in the form of a 40% drop in eGFR, renal-related mortality, and need for renal-replacement therapy (HR 0.60, 95% CI 0.47-0.77).

Again, Kaul offered criticism: "The favorable renal outcomes results (even though exploratory) are driven by endpoints that are of questionable clinical relevance -- progression of albuminuria or 40% reduction in eGFR which are not approvable endpoints," he said.

With regard to adverse events, incidence of diabetic ketoacidosis was very low in the trials, and was not significantly higher compared with placebo.

However, amputation risk was notable with use of canagliflozin during the trial, and was most prevalent among the toe and metatarsal (6.3 versus 3.4 participants per 1;000 patient-years; HR 1.97, 95% CI 1.41-2.75).

Neal said the explanation for the increased amputation risk isn't clear. He also stated that individuals most at risk for amputation were individuals who had a prior amputation, those with bad peripheral vascular disease, and people with chronic foot ulcers.

"Unless there's a very good reason, you're not going to want to put [them] on canagliflozin," Neal said.

Last month, the FDA required that all canagliflozin-containing medications (Invokana, Invokamet, and Invokamet XR) carry a boxed warning about the risk of leg and foot amputation based on its review of data from the CANVAS program.

Robert Eckel, MD, of the University of Colorado Anschutz Medical Campus, who was not involved with the study, told 口袋女优 that the amputation risk is "just one of those findings that can't be well explained, and I really don't have a good reason to think canagliflozin rather than empagliflozin should cause amputation."

Neal and colleagues also found that fracture risk was significantly higher with use of canagliflozin (15.4 versus 11.9 participants per 1,000 patient-years; HR 1.26, 95% CI 1.04-1.52).

"I think these [risks] may dampen the enthusiasm for this trial," Eckel said, "but I look at it really as a confirmatory study that makes us a little bit more serious in considering this class of drugs as a second-line therapy beyond metformin for patients with type 2 diabetes."

In comparison to prior trials in this area, Kaul warned, that the "51% reduction in mortality reported with SGLT2 inhibitors in CVD-REAL (a non-randomized study) was not replicated in the CANVAS program. This should serve as a cautionary tale for the enthusiastic advocates of 'real-world evidence' generated from registry data to inform regulatory decisions and guide clinical practice."

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