CVD REAL: Primary Prevention for SGLT-2 Inhibitors in Diabetes?

Marlene Busko

June 20, 2017

SAN DIEGO — A new analysis of the observational CVD REAL study of patients with type 2 diabetes starting on sodium glucose cotransporter-2 (SGLT2) inhibitors, deciphering outcomes according to baseline cardiovascular disease (CVD) status of the participants, finds benefit on all-cause mortality at 8 months in both groups.

In those with CVD, there was a 53% reduced risk of all-cause mortality at 8 months compared with patients who were started on another glucose-lowering drug. Similarly, those without cardiovascular disease — who made up 87% of the study population — who were initiated on an SGLT2 inhibitor had a 46% lower risk of this outcome, Matthew Cavender, MD, from the University of North Carolina, Chapel Hill, reported at the recent American Diabetes Association (ADA) 2017 Scientific Sessions.

In addition, all the patients who took SGLT2 inhibitors were significantly less likely to be hospitalized for heart failure (HF), with again benefit also seen in those without CVD at baseline.

The findings thus hint at a possible benefit of this drug class in the primary prevention of CVD in those with type 2 diabetes, Dr Cavender said.

"Whereas the [randomized EMPA-REG-OUTCOME study of the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim)] included only patients with established CVD, what these [new] data suggest is that the benefits of SGLT2 inhibitors could potentially apply to a broader group of patients," Dr Cavender told Medscape Medical News.

However, some questioned the apparent magnitude of survival benefit in such a brief time.

"What you're suggesting is about a 46% risk reduction in hard events in a 7- to 8-month study. This flies against [other] data presented" at ADA, namely CANVAS, the large cardiovascular-outcomes trial of the SGLT2 inhibitor canagliflozin (Invokana, Janssen), said Harpreet S Bajaj, MD, an endocrinologist from LMC Diabetes & Endocrinology, in Brampton, Ontario, and a research associate at Mount Sinai Hospital, in Toronto, Ontario, who also blogs for Medscape.

Dr Bajaj queried whether this further analysis of CVD REAL "adds anything to what we know in primary prevention."

Dr Cavender said it does give "some degree of confidence" that the data from the EMPA-REG and CANVAS randomized trials are "consistent with [what is seen in] clinical practice."

But Dr Bajaj maintains that the magnitude of relative risk reduction in death in the primary-prevention subgroup in this new analysis of CVD REAL is "improbable" after such a short follow-up time; he does not believe the findings should have any impact on clinical practice or treatment guidelines.

Invited to comment, Jay H Shubrook, DO, a family physician and diabetologist at Touro University in Vallejo, California, agreed that it was "a little surprising to see that much of a difference" in mortality benefit in such a short time, unless there were a difference in baseline characteristics between those taking SGLT2 inhibitors and other glucose-lowering agents.

No Geographic Difference Suggests Broad Effect of SGLT2 Inhibitors

CVD REAL was a pooled analysis of registry and insurance claims data from 300,000 patients in clinical practice in five European countries — Denmark, Sweden, Norway, Germany, and the United Kingdom — and the United States who were mostly already taking metformin and were then newly prescribed an SGLT2 inhibitor — canagliflozin, dapagliflozin (Farxiga/Forxiga, AstraZeneca), or empagliflozin — or another glucose-lowering drug.

CVD REAL reported an overall lower risk of death and/or heart failure with SGLT2 inhibitors and was first presented at the American College of Cardiology (ACC) meeting in March; the study was also recently published (Circulation. 2017; DOI:CIRCULATIONAHA.117.029190).

The current analysis drilled down to look for differences in these outcomes by baseline status of the patients — ie, whether or not they had preexisting CVD, excluding patients from Germany (for whom there were no linked mortality data). Only 13% of the participants had established CVD (myocardial infarction, unstable angina, peripheral arterial disease, stroke, or heart failure).

Dr Cavender and colleagues developed a country-specific propensity score for the likelihood of being prescribed an SGLT2 inhibitor, and they matched about 154,000 patients who were prescribed one with the same number of patients who were prescribed another glucose-lowering drug.

Dapagliflozin was the predominant SGLT2 inhibitor given in Europe (92% of patients), whereas canagliflozin was predominant in the United States (76% of patients), and the remaining 5% to 6% of patients in Europe or the United States received empagliflozin.

During the 8-month follow-up, patients with established CVD had higher rates of death and/or hospitalization for heart failure than patients without established CVD.

Patients with or without cardiac disease had lower rates of these outcomes if they were treated with an SGLT2 inhibitor vs another glucose-lowering drug.

Study limitations include potential confounders that were not taken into account and no assessment of other outcomes or safety, Dr Cavender acknowledged.

However, "the fact that we saw no geographic heterogeneity suggests that an SGLT2 inhibitor in general would be effective," he said.

"Ongoing randomized clinical trials will provide further evidence regarding the cardiovascular benefits of different SGLT2 inhibitors, including [in] patients with established CVD," he added.

"There is at least a pooled appearance of benefit, and...we need to figure out why" and see if there really is a class effect, Dr Shubrook agreed.

More Data Needed for Primary Prevention

Although SGLT2 inhibitors have proven benefits on HbA1c reduction, weight, and blood pressure, with a low risk of hypoglycemia, Dr Bajaj insists the CVD REAL study findings should not affect clinical practice

"These benefits will need to...be balanced against the expanding adverse-effect profile of this class — including the relatively recent amputation and fracture risk with canagliflozin demonstrated in CANVAS — as well as the relative risk/benefit profiles of other antihyperglycemic agent options," he added.

Evidence-based Canadian guidelines for treating patients with type 2 diabetes "correctly suggest a preference for either empagliflozin or liraglutide only in those patients with a history of established CVD," according to Dr Bajaj.

Empagliflozin is the only SGLT2 inhibitor and indeed the only type 2 diabetes agent to have a claim for reducing CVD mortality on the US label [based on EMPA-REG results]. An FDA advisory committee is today considering a similar claim for liraglutide, a glucagonlike peptide-1 (GLP-1) agonist, based on the results of the LEADER trial.

The "list of cardioprotective agents in secondary prevention can now be expanded to include canagliflozin based on the CANVAS program results," with the caveats noted by the investigators and others, Dr Bajaj added.

"However, more compelling [randomized controlled trial] data in primary prevention are needed," he concludes.

The study was funded by AstraZeneca. Dr Cavender is a consultant and author for AstraZeneca, and he is on the advisory panel and is an author for Merck. He receives research support and is an author for the Medicines Company, GlaxoSmithKline, Novartis, Takeda, Abbott, and AstraZeneca. Disclosures for the coauthors are listed in the abstract. Dr Shubrook reports receiving a research grant from Sanofi and income from Eli Lilly, Novo Nordisk, GlaxoSmithKline, and AstraZeneca. Dr Bajaj reports research support from and/or being on speakers' bureaus for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi.

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American Diabetes Association 2017 Scientific Sessions. June 13, 2016; San Diego, California. Abstract 377-OR

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