Researchers Dig Deeper on SGLT2 Inhibitors and Find Plenty of News

The big news on sodium glucose co-transporter-2 (SGLT2) inhibitors may already be out: these therapies for type 2 diabetes (T2D) appear to have a class effect that reduces cardiovascular (CV) risk through a unique mechanism of action that researchers are still trying to understand.

After digging deeper into the data from 2 of the most important diabetes trials of recent years—EMPA-REG OUTCOME, the 2015 cardiovascular outcomes trial for empagliflozin, and CANVAS, the June 2017 counterpart for canagliflozin—researchers appearing at the 2017 American Heart Association Scientific Sessions in Anaheim, California, shared results that have implications for some of the highest-risk patients, as well others with less risk.

The populations in the 2 cardiovascular outcomes trials reported to date differed a key way: a third of the 10,142 patients in CANVAS (sold as Invokana by Janssen) did not have a history of CV disease, while all of the 7020 patients in the EMPA-REG OUTCOME trial did. When results for CANVAS were reported in June, the study’s lead author said that there was no indication the drug was behaving differently in the 2 populations.

In presenting new findings for canagliflozin Monday, Kenneth W. Mahaffey, MD, of Stanford University, put data behind that statement: the results showed that the SGLT2 inhibitor was effective in reducing the risk of CV outcomes in patients with and without a prior history of cardiovascular disease. Patients in the primary prevention group—those with CV risk factors, but not disease—had a hazard ratio (HR) of 0.98 (95% confidence interval [CI]: 0.74 to 1.30), while those in the secondary prevention group—those with a history of CV disease—had a HR of 0.82 (95% CI: 0.72 to 0.95).

In a statement, James F. List, MD, PhD, Janssen global therapeutic area of Cardiovascular and Metabolism, said, “All people with type 2 diabetes have an increased risk of developing cardiovascular and renal diseases. This new CANVAS analysis is clinically important, because it shows that Invokana may offer a broad range of patients an effective treatment option to reduce their risk of cardiovascular and renal disease."

The study's authors, reporting in the journal Circulation concluded, “Canagliflozin reduced cardiovascular and renal outcomes with no statistical evidence of heterogeneity of the treatment effect across the primary and secondary prevention groups.”¹

A discussant at Monday’s session, Angelyn Bethel, addressed the lack of separation in the curves for the CV outcomes in the primary prevention group in CANVAS. As a trial to find out if the drug was safe, she said, it was never designed or powered to answer the question of whether the SGLT2 inhibitor could be used widely for prevention. Other results have raised that question, including the recent CVD-REAL findings, which found a reduction in CV deaths and heart failure hospitalization for patients using SGLT2 inhibitors, based on registry and claims data from more than 300,000 patients.

At the same session, new results for empagliflozin (sold as Jardiance by Boehringer Ingelheim and Eli Lilly) showed substantial benefits for patients with peripheral artery disease (PAD), a serious complication of T2D that can lead to amputations. Patients with PAD accounted for 21% of the study population in EMPA-REG, and these patients experienced even greater reductions in CV events, including CV death, than the overall study group. Patients with PAD in the trial experienced:

• A 43% reduction in CV death
• A 44% reduction in hospitalization for heart failure
• A 38% reduction in death for any cause
• A 16% reduction in 3-point MACE (major adverse cardiovascular event, which includes CV death, non-fatal heart attack, or non-fatal stroke)
• A 46% reduction in new or worsening kidney disease.²

Canagliflozin’s benefits for renal outcomes of great interest to researchers, too. A separate trial, called CREDENCE, is fully enrolled, and will look specifically at canagliflozin in patients with diabetic nephropathy. Bethel said the research community looks forward to those results, as well as the results of DECLARE, the cardiovascular outcomes trial for dapagliflozin (Farxiga, Astra Zeneca), for more insights on the question of primary prevention.

References

1. Mahaffey KW, Neal B, Perkovic V, et al. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS program [published online November 13, 2017]. Circulation. 2017; doi:10.1161/CIRCULATIONAHA.117.032038.
2. Verma S, Mazer CD, Fitchett D, et al. Empagliflozin reduces mortality and hospitalization for heart failure in patients with type 2 diabetes and peripheral artery disease: a sub-analysis of the EMPA-REG OUTCOME trial. Presented at the 2017 American Heart Association Scientific Sessions, Anaheim, California. November 11-15, 2017. LS-3.