CANVAS Finds Lower Risk of CV Events for Invokana

The long-awaited results from CANVAS show a reduced risk of cardiovascular events. The study's lead author said clinicians should balance the significant benefits of the drug against the potential harms for a small number of patients with known risks.

Canagliflozin, the sodium glucose co-transporter-2 (SGLT2) inhibitor sold by Janssen as Invokana, offers patients with type 2 diabetes (T2D) a reduced risk of cardiovascular (CV) events and decline in kidney function, according to findings from a 10,000-person trial reported at the 77th Scientific Sessions of the American Diabetes Association in San Diego, California.

The long-awaited CANVAS and CANVAS-R studies, which simultaneously appeared in the New England Journal of Medicine (NEJM), reported that canagliflozin clearly demonstrated cardiovascular safety and that the components of the primary outcome—death from CV causes, nonfatal heart attack, and nonfatal stroke—were all lower with the drug. Janssen said in a statement that these were reduced by 14%. The findings further showed a 40% reduction in overall decline in kidney function and a 33% reduction in hospitalization for heart failure—both are areas of increased interest for researchers and payers alike.

Lead study author Bruce Neal, MB, ChB, PhD, of the George Institute for Global Health in Australia, said in prepared statements that the results show the “clear benefit of canagliflozin over current standard-of-care treatments.” Besides glucose control, “We found it also reduced blood pressure and led to weight loss.”

However, the published study in NEJM said the individual effects of the primary outcome “did not reach significance.” And, in a new finding, the results also showed those taking canagliflozin were twice as likely to need amputations, especially at the toe or metatarsal. In its statement, Janssen said that the highest risk of amputations occurred among patients with a history of amputation or peripheral vascular disease.

In an interview with The American Journal of Managed Care® (AJMC®) Neal said the findings call for clinicians to weigh the substantial benefits of canagliflozin against potential harms for certain patients with known risks. “We believe that for most patients with diabetes who are at high risk, there’s going to be a net positive benefit/risk ratio, but there’s going to be a subset of patients who are at very high risk of amputation for whom this is probably not going to be the drug of choice.” Neal went on to outline what the findings meant in hard numbers for 1000 patients treated for 5 years: prevention of about 23 major vascular events, 16 hospitalizations for heart failure, and 17 major declines in renal function; with an associated 15 amputations (10 toe/forefoot, 5 above the ankle).

In the NEJM article, the authors reported, “The increased rate of amputation is a new finding for which the mechanism is unknown.” The findings support the FDA’s recent decision to issue a boxed warning on therapies containing canagliflozin. Regulators are concerned about this issue, he said, not just for canagliflozin but for all drugs in the SGLT2 inhibitor class.

Nevertheless, the results suggest a cardioprotective class effect for SGLT2 inhibitors, which treat diabetes by expelling excess glucose through the urine. Experts have anticipated this since August 2015, when the diabetes world was stunned by the news that another SGLT2 inhibitor, empagliflozin, had reduced CV events by 14% and CV death by 38%.

Trial results for the 2 drugs are hard to compare, because the study populations in CANVAS and the earlier trial, EMPA-REG OUTCOME, differ in a key way: a third of the 10,142 patients in CANVAS did not have a history of CV disease, while all of the 7020 patients in EMPA-REG OUTCOME did. When asked about canagliflozin’s performance in the high-risk vs the primary prevention populations, Neal said, “There is no evidence that the drug is behaving differently,” in the 2 groups.

A statement from Neal’s George Institute states that the more diverse study population of CANVAS shows that canagliflozin offers protection “not just for people already suffering cardiovascular disease, but for all with type 2 diabetes.”

The CV results for empagliflozin led the FDA to grant the drug, sold as Jardiance, an additional indication to reduce CV death in adults with T2D. Right now, empagliflozin is the only diabetes drug that can make this claim. At a press conference prior to the presentation of the results, Neal was asked about the fact that the P value for the superiority results for the primary outcome was 0.0158 (it was rounded in the NEJM article to 0.02), and whether this would be enough for FDA to grant canagliflozin the same indication. He said that would be a matter of negotiation.

Canagliflozin was the first SGLT2 inhibitor to reach the US market in March 2013 and led rivals dapagliflozin (Farxiga) and empagliflozin, but the EMPA-REG OUTCOME results allowed the later entrant from Eli Lilly and Boehringer-Ingelheim to close the gap.

In 2008, when the FDA directed drug companies to perform cardiovascular outcomes trials for new diabetes and obesity therapies, the idea was to rule out harmful effects for high-risk patients; there was no expectation that diabetes drugs would prevent heart attacks or early death. Since EMPA-REG OUTCOME, however, the possibility that the entire SGLT2 class may offer these benefits prompted Merck and Pfizer to expand the VERTIS CV trial for its investigational therapy, ertugliflozin, which has an FDA approval deadline in December 2017. Results for the DECLARE trial for dapagliflozin are expected in 2019.

Christina Mattina contributed to this report.


Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes [published online June 12, 2017]. N Engl J Med. 2017. DOI: 10.1056/NEJMoa1611925.

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