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Another SGLT-2 Diabetes Drug Cuts CV Risks

— CV outcomes trials at ADA meeting support canagliflozin but neutral for insulins

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Cardiovascular events in type 2 diabetes were reduced with use of canagliflozin (Invokana) but not increased with insulin degludec, according to separate FDA-mandated cardiovascular safety trials reported at the American Diabetes Association meeting in San Diego.

In the CANVAS (Canagliflozin Cardiovascular Assessment Study) program, the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin given at 100 or 300 mg daily reduced the primary endpoint of stroke, non-fatal myocardial infarction (MI), and cardiovascular death compared with placebo, with a modest difference of 26.9 versus 31.5 participants per 1,000 patient-years (HR 0.86, P<0.001 for noninferiority and P=0.02 for superiority).

The combined findings from the CANVAS trial (unblinded to provide the initial cardiovascular safety data required for FDA evaluation) and CANVAS-Renal (designed to look for superiority and albuminuria from post-approval data) were released simultaneously online in the . The two trials included 10,142 type 2 diabetes patients at high cardiovascular risk, of whom 65.6% had a history of cardiovascular disease.

Trial Concerns

The "modest" effect of canagliflozin on cardiovascular events clearly met the FDA's threshold for safety, commented Sanjay Kaul, MD, of Cedars-Sinai Medical Center in Los Angeles, who was not involved with the study. However, he called the conclusion of superiority "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. Secondly, the P-value of 0.02 for superiority was 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."

How the FDA will view the data remains to be seen. The agency granted a cardiovascular death prevention indication to a fellow SGLT-2 inhibitor, empagliflozin (Jardiance), after it became the first type 2 diabetes drug to go beyond non-inferiority in one of these safety trials with a similar 14% major adverse cardiovascular event reduction in the EMPA-REG trial.

Whereas EMPA-REG subanalysis showed slower progression of kidney disease with empagliflozin, renal outcomes did not benefit significantly with canagliflozin in CANVAS on the basis of the prespecified hypothesis testing sequence despite some exploratory endpoint benefits that Kaul called "of questionable clinical relevance" and "not approvable endpoints."

As the FDA warned last month when it 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 CANVAS data, amputation occurred in 6.3 participants on the drug versus 3.4 placebo-treated participants per 1,000 patient-years (HR 1.97, 95% CI 1.41-2.75).

The trials also showed higher fracture risk with 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," Robert Eckel, MD, director of the Lipid Clinic at the University of Colorado Hospital, Anschutz Medical Campus -- who was also not involved with the research -- commented to 鶹ý. "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."

Insulin Safety

In the DEVOTE trial, ultra-long-acting basal insulin degludec (Tresiba) was found to be noninferior to long-acting basal insulin glargine (Lantus) among patients with type 2 diabetes who were at high risk for major cardiovascular events.

Adjudicated death from cardiovascular causes, nonfatal MI, or nonfatal stroke occurred in 8.5% of degludec-treated patients and 9.3% of glargine-treated patients (HR 0.91, P<0.001 for noninferiority).

Despite the overall similar cardiovascular safety, insulin degludec held the upper hand for hypoglycemia, with fewer patients having severe hypoglycemia at 2 years (OR 0.73, 95% CI 0.60-0.89) and less nocturnal severe hypoglycemia (RR 0.47, 95% CI 0.31-0.73).

Still, Eckel said that the hypoglycemia findings would probably not change his prescribing patterns: "Degludec has a longer half life so ... giving it once a day would allow for insulin levels to remain stagnant for a longer period of time, while glargine often tails off after about 18 hours. When I prescribe insulins, I give glargine twice a day, not once a day, so the idea that there was less hypoglycemia just means that for a steady-state insulin, one might choose that instead of glargine unless you go twice a day with glargine."

DEVOTE, simultaneously published in the, is the first double-blind cardiovascular outcomes trial to compare basal insulins head-to-head. The trial included 7,637 people with type 2 diabetes, most of whom had a history of cardiovascular disease or chronic kidney disease, and the remainder of whom had multiple cardiovascular risk factors.

Disclosures

CANVAS was supported by Janssen Research and Development.

The lead author disclosed relationships with Janssen, Abbott, Novartis, Pfizer, Roche, Servier, Merck Schering Plough, and grants from the National Health and Medical Research Council. Other authors also disclosed relevant relationships.

DEVOTE was supported by Novo Nordisk, The Medicines Company, and Terumo Medical; the authors disclosed relevant relationships with Abbott Vascular, Novo Nordisk, the University of Oxford, AstraZeneca, and Bristol-Myers Squibb.

Primary Source

New England Journal of Medicine

Neal B, et al "Canagliflozin and cardiovascular and renal events in type 2 diabetes" N Engl J Med 2017; DOI: 10.1056/NEJMoa1611925.

Secondary Source

New England Journal of Medicine

Marso SP, et al "Efficacy and safety of degludec versus glargine in type 2 diabetes" N Engl J Med 2017; DOI: 10.1056/NEJMoa1615692.