ORLANDO – according to the latest safety data from the CANVAS (Canagliflozin Cardiovascular Assessment Study) program.
CANVAS included two studies (CANVAS and CANVAS-R) involving a total of 10,142 patients, which established the superiority of canagliflozin (Invokana) over placebo for reducing the risk of a three-point major adverse cardiac event endpoint, including cardiovascular death, nonfatal MI, and nonfatal stroke. The sodium-glucose cotransporter-2 (SGLT2) inhibitor also improved other cardiovascular outcomes.
For the current analysis, outcomes in the CANVAS participants were compared with those from a general population of 8,114 patients with type 2 diabetes mellitus (T2DM) who participated in 12 non-CANVAS studies of canagliflozin. As previously reported, the risks for fracture or amputation were novel safety findings associated with canagliflozin in the CANVAS program and, in the current analysis, the incidence of fractures per 1,000 patient-years in CANVAS was 15.4 vs. 11.9 with treatment vs. placebo, whereas no significant difference was seen in the non-CANVAS studies (incidence rate of 11.8 vs. 10.8 per 1,000 patient-years for treatment vs. placebo), Priscilla Hollander, MD, reported at the annual meeting of the American Diabetes Association.
Of note, when the CANVAS and CANVAS-R studies were compared, the imbalance was seen only in CANVAS (incidence rates of 16.9 vs. 10.9 for treatment vs. placebo [hazard ratio, 1.55], compared with incidence rates of 11.3 and 13.2 , respectively, in CANVAS-R [HR, 0.86]), said Dr. Hollander, Baylor Scott & White Endocrine Center in Dallas.
“Ongoing analyses are trying to determine why there is a difference between the two studies,” she noted.
For the novel safety finding of increased amputation risk with canagliflozin, an excess of three events per 1,000 patient years was seen in both CANVAS (incidence of 6.3 vs. 3.4; HR, 1.97) and CANVAS-R (incidence of 5.9 vs. 2.8; HR, 2.12). No difference in risk was seen among the non-CANVAS population (incidence of 0.5 and 2.2 with treatment vs. placebo; HR, 0.23).
“Amputations were primarily at the level of the toe or the metatarsal. Patients with a history of amputation or peripheral vascular disease had the highest risk of amputation,” she said, adding that this was true in both treatment and placebo groups.
“Again, ongoing analyses are being done to look at the mechanism in this regard,” she said.
For safety outcomes known to be related to the mechanism of SGLT2 inhibition, including osmotic diuresis, volume depletion, and genital mycotic infection (GMI), similar differences between canagliflozin and placebo groups were seen in the CANVAS and non-CANVAS studies at 6.5 years, Dr. Hollander said.
Hazard ratios in the canagliflozin vs. placebo groups for the CANVAS and non-CANVAS studies, respectively, were 2.80 and 2.66 for osmotic diuresis, 1.44 and 1.35 for volume depletion, 4.37 and 4.32 for female GMI, and 3.76 and 6.26 for male GMI.
No imbalances were observed in other AEs of interest – including hypoglycemia, urinary tract infections, or hypersensitivity reactions – in either the CANVAS or the non-CANVAS studies.
“The point estimate for [diabetic ketoacidosis] was 2.3, but with very wide confidence intervals due to a very low number of events, so it really did not reach significance,” Dr. Hollander noted. “Again, due to the mechanism of action of canagliflozin, and the warning for acute kidney injury on the label, renal adverse events were also of interest, but there was no imbalance observed in the renal-related AEs between the CANVAS program and the non-CANVAS program.”
A closer look at renal-related adverse events (AEs) of interest in the CANVAS program only (not in comparison with the non-CANVAS findings) also showed no significant difference with canagliflozin vs. placebo in blood creatinine increase, blood urea increase, glomerular filtration rate decrease, acute kidney injury, renal impairment, renal failure, oliguria, acute prerenal failure, hypercreatininemia, nephritis, or prerenal failure, she said.
Furthermore, although hyperkalemia is noted as a risk with canagliflozin in patients with moderate renal impairment who are taking medications that interfere with potassium excretion, no significant differences were observed between the treatment and placebo groups over 6.5 years in the CANVAS program, she added, noting that “this was also supported by the lack of imbalance between the laboratory changes for serum potassium in the two groups.”
There also were no differences seen between the treatment and placebo groups in the rates of all serious AEs or in the rates of AEs leading to discontinuation, she said.
Canagliflozin has been generally well tolerated in both placebo-controlled trials and trials in which the SGLT2 inhibitor was compared with other active treatments. The non-CANVAS studies used for comparison in the current analysis included phase 3/4 canagliflozin clinical development program studies lasting up to 104 weeks and involving a general T2DM patient population, Dr. Hollander noted.
The CANVAS program, which was launched in 2009, included patients with T2DM and established cardiovascular disease or high cardiovascular disease risk who received a 2-week placebo run-in followed by placebo or either 100- or 300-mg doses of canagliflozin. CANVAS participants had hemoglobin A1c of 7%-10.5%; estimated glomerular filtration rate of 30 mL/min per 1.72m2 or greater; age of 30 years or greater plus a history of a prior cardiovascular event, or age of 50 years or greater with at least 2 cardiovascular risk factors, including diabetes for 10 years or more; systolic blood pressure greater than 140 mm Hg on at least one medication; current smoking status; micro- or macroalbuminuria; and an HDL cholesterol level less than 1 mmol/L.
The current analysis provides the longest-term safety data to date for the program, Dr. Hollander said.
The CANVAS Program is sponsored by Janssen Research & Development. Dr. Hollander is an advisory panel member for Eli Lilly, Merck, and Novo Nordisk.
SOURCE: Hollander P et al. ADA 2018, Abstract 259-OR.