ANAHEIM, CA — A new subanalysis of the cardiovascular outcomes trial with the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (Invokana, Janssen) for the treatment of patients with type 2 diabetes shows that the drug lowered the risks of cardiovascular outcomes and worsening renal disease or renal death, regardless of whether the patients already had cardiovascular disease or just had risk factors[1].
These latest findings from Canagliflozin Cardiovascular Assessment Study (CANVAS) were presented in a late-breaking trial session November 13, 2017 at the American Heart Association 2017 Scientific Sessions by Dr Kenneth W Mahaffey (Stanford University, CA) and simultaneously published in Circulation.
“Canagliflozin should be considered to manage [type 2 diabetes] in patients at high risk of cardiovascular events to reduce cardiovascular and renal outcomes,” but “caution should be used in patients at risk for amputations,” say Mahaffey and colleagues in their publication.
The researchers refer to the increase in the risk of lower-limb amputation with canagliflozin vs placebo in this type 2 diabetes population in CANVAS, first noted in an interim analysis of the trial in 2016 and confirmed when CANVAS was fully reported at the American Diabetes Assocation meeting in June.
“There is the amputation risk, and it needs to be carefully considered when people are treating patients with type 2 patients with canagliflozin, but we still think there’s a favorable [risk/benefit] profile,” Mahaffey told theheart.org | Medscape Cardiology following his presentation at the AHA meeting.
Session comoderator Dr Ira J Goldberg (Columbia University, New York) said: “I think the exciting thing is in part that finally after decades we have therapies that decrease cardiovascular events in diabetes.
“But even more exciting is that we have a new class of drugs to treat heart failure,” and ongoing investigations will shed more light on this, Goldberg said in an interview.
However, assigned discussant Dr M Angelyn Bethel (University of Oxford, UK) said she wasn’t impressed by the major adverse cardiovascular end point (MACE) data in those without evidence of CVD at baseline in CANVAS.
“To my eye, it’s the MACE outcomes that are inconsistent” in the two cohorts, with a hazard ratio (HR) of 0.98 in the primary-prevention cohort and a HR of 0.82 in the secondary-prevention cohort,” she noted.
“You really don’t see any impact for primary prevention for MACE, no suggestion of separation of curves for the duration of follow-up, which is very different for [heart-failure and] renal outcomes,” she summarized.
Comparing Events Between Primary- and Secondary-Prevention Population
CANVAS included more than 10,000 patients with type 2 diabetes, 6656 of whom (66%) were age 30 or older with a prior CV event (secondary prevention). The remaining 3486 patients (34%) were 50 and older with no prior event, but at least two of the following risk factors: diabetes for 10 years or more; systolic blood pressure >140 mm Hg on at least one antihypertensive drug; current smoker; microalbuminuria or macroalbuminuria; or HDL cholesterol <1 mmol/L (primary prevention).
The current study analysis aimed to compare the effects of canagliflozin vs placebo in the primary- and secondary-prevention populations, respectively.
Compared with patients in the primary-prevention group, patients in the secondary-prevention group had greater absolute rates of the respective outcomes: they were roughly twice as likely to have a primary outcome event (CV death, nonfatal MI, or nonfatal stroke): 36.9 vs 15.7 per 1000 patient-years (P<0.001).
Patients in the secondary-prevention group were also 1.6 times more likely (8.0 vs 5.1 per 1000 patient-years) to have a poor renal outcome (a 40% reduction in estimated glomerular filtration rate, need for renal-replacement therapy, or renal death).
And they were almost three times as likely (9.9 vs 2.4 per 1000 patient-years) to undergo amputation.
But when it came to reductions in events, these were broadly similar—during an average 3.6-year follow-up, patients in the secondary-prevention group were 32% less likely to have a hospitalization for HF (HR 0.68) while those in the primary-prevention group were 36% less likely (HR 0.64) if they received canagliflozin vs placebo (P for interaction=0.91).
For renal outcomes, the story was the same.
Patients in the primary-prevention group were 37% less likely to have a poor renal outcome (HR 0.63), compared with a 41% reduction of this outcome in the secondary-prevention group (HR 0.59) if they received canagliflozin (P for interaction=0.73).
And in the new analysis, lower-extremity amputations were similarly increased in the secondary- and primary-prevention cohorts (HR 2.07 and 1.52; P for interaction=0.63) among those taking canagliflozin compared with placebo.
This translated into 21 more lower-limb amputations per 1000 patients in the secondary-prevention group and five more lower-limb amputations per 1000 patients over 5 years in the primary-prevention group among those who received canagliflozin vs placebo. These were mainly toe and metatarsal amputations (71%).
No evidence has been seen of any link between any other SGLT2 inhibitor and amputation risk, including in a new analysis of the only other CV outcomes trial with an SGLT2 inhibitor, EMPA-REG, with empagliflozin (Jardiance, Boehringer Ingelheim).
Dissecting Out Differences in Primary End Point
In her discussion, Bethel noted that EMPA-REG, unlike CANVAS, only enrolled type 2 diabetes patients with prior CV events.
The secondary-prevention patients in CANVAS and EMPA-REG were comparable, she noted, and “we see a similar reduction in 3-point MACE outcomes and comparable heart-failure and renal outcomes,” across these two trial populations.
But in CANVAS, although there was no statistical evidence of any difference between the primary- and secondary-prevention cohorts in terms of reduction in primary end point for those taking canagliflozin vs placebo (HR 0.98 vs 0.82; P for interaction=0.18), Bethel said she felt that the MACE outcomes were “inconsistent” in the two cohorts.
“Not all outcomes [in the secondary-prevention cohort] appear to translate for primary-prevention cohorts in the short term (or perhaps at all),” she asserted.
She added that two ongoing studies, among others, will provide more insights to guide therapy with this class of drugs.
These are the Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE) trial—with a third SGLT2 inhibitor, dapagliflozin (Farxiga/Forxiga, AstraZeneca) and a renal study with canagliflozin—the Canagliflozin and Renal Endpoints in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) study.
The CANVAS trial was funded by Janssen. The financial relationships of Mahaffey can be found here. Disclosures for the coauthors are listed in the paper.
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