Canakinumab does not appear to prevent diabetes onset
The interleukin-1 beta (IL-1β) inhibitor canakinumab did not prevent the progression from pre-diabetes to diabetes in patients with prior myocardial infarction (MI), according to results of the CANTOS* trial.
“Canakinumab is an effective therapy to prevent major cardiovascular [CV] events in patients with and without diabetes. It seems to prevent CV events without increasing the development of type 2 diabetes [T2D] among patients who are at risk for the disorder,” said study lead author Dr Brendan Everett from the Brigham and Women’s Hospital, Boston, Massachusetts, US at ACC.18.
“[However], canakinumab does not prevent the progression from pre-diabetes to diabetes among patients with prior MI and high-sensitivity C-reactive protein [hsCRP] ≥2 mg/L,” he said.
“[This data] indicate that previously reported benefits on major CV events in CANTOS as a whole do not relate to the prevention of diabetes or to changes in glucose metabolism,” said Everett and co-authors.
A total of 10,061 patients with a history of MI and hsCRP ≥2 mg/L were randomized to receive subcutaneous canakinumab (50, 150, or 300 mg) or placebo once every three months. Patients were followed up for a median 3.7 years.
Of these patients, 40.3 percent (n=4,057) had diabetes (history of T2D, on anti-diabetic medication, HbA1c ≥6.5 percent, fasting plasma glucose [FPG] ≥126 mg/dL, or a combination of the latter two) and 49.3 percent (n=4,960) had pre-diabetes (HbA1c 5.7 to <6.5 percent or FPG 100–125 mg/dL) at baseline.
Of the 1,044 patients without diabetes at baseline (HbA1c <5.7 percent and FPG <100 mg/dL), higher baseline levels of hsCRP and IL-6 were predictors of new onset of T2D (relative risk [RR], 1.29 and 1.36 for increasing tertiles of hsCRP; p<0.001 and RR, 1.42 and 1.93 for increasing tertiles of IL-6; p<0.001; comparisons vs lowest tertile). [ACC.18, abstract 18-LB-18790-ACC; J Am Coll Cardiol 2018;doi:10.1016/j.jacc.2018.03.002]
In patients with pre-diabetes, hsCRP levels reduced by a median 49.2, 61.5, and 67.1 percent with one dose of 50, 150, or 300 mg canakinumab, respectively, compared with placebo while IL-6 levels reduced by 25.7, 37.4, and 43.4 percent, respectively,.
There was no reduction in incidence of new onset diabetes with canakinumab compared with placebo (hazard ratio [HR], 1.02, 95 percent confidence interval, 0.87–1.18; p=0.85), with incidence rates of 4.20, 4.24, 4.35, and 4.12 per 100 person-years with placebo, canakinumab 50 mg, 150 mg, and 300 mg, respectively.
Canakinumab also did not appear to improve new onset diabetes rates in individuals with normal glucose levels at baseline, nor in patients whose hsCRP and IL-6 levels reduced to <2 mg/L and <1.54 ng/L, respectively.
Compared with patients without diabetes, those with diabetes had a higher risk for serious and fatal infections (HR, 1.58 and 2.42, respectively; p<0.0001 for each comparison). While canakinumab did not affect the risk of infections compared with placebo in diabetics (HR, 1.05; p=0.63), it was associated with an increased risk of fatal infections (HR, 1.86).
“Interleukin-1β inhibition with canakinumab reduces HbA1c in patients with pre-diabetes for approximately 9–12 months, but effects were attenuated over time,” said Everett. While the reasons for the attenuation are yet unestablished, study design which allowed for lifestyle and treatment modification may have played a part, said Everett and co-authors, acknowledging that the results were specific to those with previous MI and hsCRP ≥2 mg/L.
“The results were surprising, because we demonstrated there was an effect on blood glucose that didn’t translate into a reduced rate of T2D diagnosis,” said Everett. “It suggests that inflammatory pathways may be more critical to the development of diabetes than inhibition of IL-1β, which was the specific mechanism we tested in this study.”
Potential CV benefits in moderate CKD
In a separate analysis of the CANTOS study, patients with normal renal function (n=8,184, eGFR ≥60 mL/min/1.73m2) and moderate to severe chronic kidney disease (CKD; n=1,875, eGFR 30–60 mL/min/1.73m2) appeared to derive benefit from canakinumab vs placebo with a reduced incidence of major vascular events (HR, 0.86; p=0.01 [normal renal function] and HR, 0.82; p=0.05 [moderate CKD]). [ACC.18, abstract 18-LB-18798-ACC]
The effects of canakinumab on various CV outcomes was most evident among those whose hsCRP levels reduced to <2 mg/L following the first dose of canakinumab with 31, 34, and 24 percent reductions in major adverse CV events, CV mortality, and total mortality, respectively (HR, 0.69; p=0.0039, HR, 0.66; p=0.0223, and HR, 0.76; p=0.05, respectively).
In contrast, the effects of canakinumab on patients with hsCRP ≥2 mg/L were insignificant (HR, 0.81; p=0.11, HR, 0.96; p=0.81, and HR, 0.99; p=0.93 for major adverse CV events, CV mortality, and total mortality, respectively).
“The current data demonstrate that anti-inflammatory therapy – at least with canakinumab – has considerable CV efficacy in high risk patients with moderate to severe CKD,” said study author Dr Paul Ridker from the Brigham and Women’s Hospital, Boston, Massachusetts, US.
“[As patients with eGFR 15–30 mL/min/1.73m2 were excluded from the CANTOS trial], moving forward, it will be important to extend these data and test the efficacy of canakinumab in patients with end-stage renal failure and/or those undergoing dialysis,” he said. “[A] new clinical trial of canakinumab in patients with severe renal failure recently initiating haemodialysis – a group with very high vascular risk and considerable unmet need – is warranted.”