ANAHEIM, CALIF. (FRONTLINE MEDICAL NEWS) – The first large randomized trial to report results on a sodium glucose cotransporter 2 inhibitor for primary prevention of cardiovascular events in patients with type 2 diabetes who are at risk for cardiovascular events or death failed to show a significant benefit in the CANVAS program, Kenneth W. Mahaffey, MD, said at the American Heart Association scientific sessions.

The impressive reductions in cardiovascular and renal events seen in the overall CANVAS (Canagliflozin Cardiovascular Assessment Study) program turned out to be focused in the two-thirds of participants with a prior cardiovascular event at enrollment, according to Dr. Mahaffey, a cardiologist who is professor and vice chair of the department of medicine at Stanford (Calif.) University.

The CANVAS program included 10,142 patients with type 2 diabetes randomized to canagliflozin (Invokana) or placebo and prospectively followed for a mean of 3.6 years. The 66% of subjects with a prior cardiovascular event comprised the secondary prevention cohort. The 34% of CANVAS program participants in the primary prevention cohort all had two or more cardiovascular risk factors at baseline.

The primary outcome has previously been reported: The canagliflozin group had a highly significant 14% reduction in the risk of the composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke ( N Engl J Med. 2017 Aug 17;377[7]:644-57 ).

At the AHA scientific sessions, Dr. Mahaffey presented a prespecified subgroup analysis comparing the impact of SGLT2 inhibitor for primary versus secondary cardiovascular prevention. Canagliflozin proved to be a big win for secondary prevention: The composite primary endpoint was reduced by 18%, compared with placebo; the composite renal outcome of worsening estimated glomerular filtration rate (eGFR), renal replacement, or renal death was reduced by 41%; and heart failure hospitalizations were reduced by 32%.

All of those benefits were strongly statistically significant. They came at the cost of roughly a fourfold increase in readily treatable male and female genital infections – a known class effect of the SGLT2 inhibitors – as well as an unexpected twofold increase in lower extremity amputations, which fortunately were uncommon. Of the amputations, 29% were above the ankle; the other 71% were less drastic toe or transmetatarsal procedures.

Dr. Mahaffey estimated that for every 1,000 patients with type 2 diabetes who were taking canagliflozin for secondary cardiovascular prevention for 5 years, there would be 36 fewer cardiovascular deaths, nonfatal MIs, or nonfatal strokes; 20 fewer hospitalizations for heart failure; 21 fewer patients who experienced the composite renal outcome; and 21 additional patients with a lower extremity amputation.

Rates of cardiovascular and renal endpoints were at least twofold higher in the secondary prevention group than in the primary prevention cohort. For prevention, the size of the relative risk reductions in heart failure hospitalizations and renal outcomes with canagliflozin, compared with placebo, were similar to the secondary prevention experience. So was the magnitude of the increased risk of lower extremity amputation. However, none of these differences achieved statistical significance, perhaps because of the lower absolute event rates in the primary prevention group.

Moreover, there was no signal of benefit for canagliflozin in terms of the composite outcome of cardiovascular death, nonfatal MI, or nonfatal stroke in the primary prevention group; those event rates were virtually identical to those seen in the placebo-treated controls.

That being said, the CANVAS Program wasn’t designed with sufficient statistical power to draw definitive conclusions regarding outcome differences in the primary and secondary prevention groups, Dr. Mahaffey noted.

Putting the SGLT2 cardiovascular prevention results in perspective

Discussant Angelyn Bethel, MD, said the impressive outcomes for canagliflozin for secondary prevention in the CANVAS Program are consistent with the results of the earlier 7,020-patient EMPA-REG trial of the SGLT2 inhibitor empagliflozin (Jardiance) versus placebo for secondary prevention in type 2 diabetes ( N Engl J Med. 2015 Nov 26;373[22]:2117-28 ). The relative risk reductions in the primary composite endpoint, as well as in heart failure hospitalizations and renal outcomes, were quite similar in the secondary prevention setting in the two large trials.

The one difference was in all-cause mortality: a striking 32% reduction with empagliflozin, compared with placebo, versus a more modest 11% relative risk reduction in the CANVAS program, which narrowly missed statistical significance.

The mechanisms for the important cardiovascular benefits seen in the secondary prevention setting in the two large SGLT2 trials are still under debate, according to Dr. Bethel, an endocrinologist who is deputy director of the diabetes trial unit at the University of Oxford (England).

“I think what’s obvious to most of us is that we’ve moved now beyond the conventional risk factors. These drugs cause only very small reductions in weight, systolic blood pressure, and diastolic blood pressure; they result in small increases in LDL and HDL; and the timeline of the impact that we see for the SGLT2 inhibitors on the cardiovascular outcomes in particular is much too short to be looking for glucose- or atherosclerotic-mediated processes,” she said.

“The mechanisms probably involve invoking the cardiorenal axis in some way,” Dr. Bethel speculated. “We know these drugs have a diuretic effect and we believe that some of the mortality benefit is probably mediated by heart failure outcomes, with changes in volume status. And there’s also a drive toward ketone metabolism, which is more efficient for the compromised heart.”

As for canagliflozin’s lack of significant benefit for primary prevention in the CANVAS program, it’s possible that this was a statistical power problem, Dr. Bethel said, but she has her doubts.

“If we had more people followed for longer in the primary prevention cohort, would we get there? I think it’s a big ask, but we do have more data coming,” she noted.

Indeed, two major phase 3 clinical trials of SGLT2 inhibitors for both primary and secondary cardiovascular prevention in mixed populations are due to report results in 2019: the roughly 4,500-patient CREDENCE trial of canagliflozin and the 17,0000-patient DECLARE trial, featuring dapagliflozin. Both involve about 5 years of follow-up.

Dr. Bethel advocated waiting until those studies report their primary prevention outcomes before introducing SGLT2-inhibitor therapy for primary cardiovascular prevention in clinical practice.

“In this instance, we do have some evidence that there may be a difference in the way that various events behave in the primary and secondary prevention settings, and we may have an overestimate of the benefits for primary prevention if we were to put this stuff in the water and give it to everybody,” she cautioned.

The CANVAS program analysis of primary versus secondary prevention has been published ( Circulation. 2018 Jan 23;137[4]:323-34 ).

The CANVAS program was supported by Janssen. Dr. Mahaffey reported receiving research grants from and serving as a consultant to Janssen and numerous other companies.

SOURCE: Mahaffey KW et al. AHA Scientific Sessions.