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11-10-2018 | SGLT2 inhibitors | At a glance | Article

Updated June 2020

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.


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:

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: Published

Medication: ertugliflozin, 5 or 15 mg/day

Patient population: N=8246, with established CV disease

Contrary to the rest of the medication class, ertugliflozin achieved noninferiority but not superiority to placebo. 

As reported at the virtual ADA 80th sessions, 11.9% of participants given ertugliflozin and 11.9% of those given placebo experienced a MACE endpoint (CV death, nonfatal myocardial infarction, or nonfatal stroke), giving a nonsignificant hazard ratio of 0.97.

Other key secondary endpoints followed approximately the same pattern, with the exception of heart failure hospitalization, the rate of which was lower in the ertugliflozin than placebo group, at 2.5% versus 3.6%.

Related news story: VERTIS-CV: Similar MACE risk with ertugliflozin vs placebo in type 2 diabetes

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.

By Eleanor McDermid

medwireNews is an independent medical news service provided by Springer Healthcare. © 2018 Springer Healthcare part of the Springer Nature group


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