Round-up of the SGLT2 inhibitor CV outcome trials
Of the four sodium-glucose cotransporter (SGLT)2 inhibitors currently available in the USA and/or Europe, two have published their cardiovascular (CV) outcomes data, one is due to publish in full within days, and the fourth is due to complete next year.
As required by the regulatory authorities, patients with type 2 diabetes recruited to these trials were randomly assigned to receive either the SGLT2 inhibitor in question or placebo and were followed up for CV endpoints.
Here we give an overview of the trials published so far, and outline those still in progress.
EMPA-REG OUTCOME: Published
|Medication: empagliflozin, 10 or 25 mg/day
||Patient population: N=7020; all with established CV disease
EMPA-REG OUTCOME was the first trial to publish, in The New England Journal of Medicine in 2015. The primary outcome was a three-point major adverse cardiac events (MACE) composite outcome, of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.
During a median 3.1 years of follow-up, MACE events occurred in 10.5% of patients taking empagliflozin and 12.1% of the placebo group, giving a significant 14% risk reduction and meaning the trial met both its noninferiority and superiority endpoints.
The CANVAS Program: Published
|Medication: canagliflozin, 100 or 300 mg/day
||Patient population: N= 10,142, with established CV disease (65.6%) or high CV risk
The combined findings from the CANVAS and CANVAS-R trials were also published in The New England Journal of Medicine, in 2017.
The investigators used the same three-point MACE endpoint as EMPA-REG OUTCOME, and this occurred at rates of 26.9 versus 31.5 per 1000 patient–years in the canagliflozin and placebo groups, respectively, during a median 2.4 years of follow-up, giving a significant 14% risk reduction – identical to that seen with empagliflozin.
However, this appeared to come at the price of an increased amputation risk, with active treatment associated with an increased amputation rate of toes, feet, or legs per 1000 patient–years, being 6.3 in the active treatment group versus 3.4 in the placebo group.
This increased risk has not yet been replicated in other SGLT2 trials, where analyses of real-world data have produced a more mixed picture.
Related news stories:
- Integrated CANVAS: canagliflozin offers cardioprotection at amputation cost
- Research adds to SGLT2 inhibitor amputation risk debate
- No significant increase in amputation risk with SGLT2 inhibitors in real-world study
- OBSERVE-4D: Canagliflozin amputation risk not replicated in real-world data
DECLARE-TIMI 58: Published
|Medication: dapagliflozin 10 mg/day
||Patient population: N=17,160; with established CV disease (40.6%) or multiple CV risk factors
The DECLARE-TIMI 58 trial is by a considerable margin the largest of the SGLT2 inhibitor CV outcome trials, and like the CANVAS trial specifically included both a primary and secondary prevention population. The co-primary endpoints were a three-point MACE endpoint and the combination of CV death or hospitalization for HF.
As reported in The New England Journal of Medicine, dapagliflozin had a significant effect on the second of these endpoints, with a rate of 4.9% versus 5.8% with placebo, driven entirely by a reduction in HF hospitalization risk.
There was no significant effect on the MACE endpoint overall or in patients with multiple CV risk factors. Patients with established CV disease had a risk reduction with dapagliflozin which, although nonsignificant, was nevertheless in line with the size of the effect seen in EMPA-REG OUTCOME and CANVAS, at rates of 13.9% versus 15.3% for a hazard ratio of 0.90 (95% confidence interval: 0.79 to 1.02).
Related news story: DECLARE-TIMI 58 supports CV benefits for SGLT2 inhibitor class
VERTIS CV: In progress (completed recruitment)
|Medication: ertugliflozin, 5 or 15 mg/day
||Patient population: N=8246; all patients have established CV disease
VERTIS CV is ongoing, due to complete in September 2019. Like the other trials, its primary endpoint is the three-point MACE outcome and it is powered to assess superiority as well as noninferiority.
Ipragliflozin, luseogliflozin, and tofogliflozin are approved for use in Japan.
The CV safety of the dual SGLT1/SGLT2 inhibitor sotagliflozin is being tested in the SCORED trial. This is aiming to recruit 10,500 patients with moderate renal impairment and high CV risk, and is scheduled to complete in 2022.
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