SGLT-2 Inhibitors Tied to Less Death, HF, MI, Stroke: CVD REAL 2

Marlene Busko

March 20, 2018

ORLANDO — The CVD REAL 2 observational study extends the cardiovascular (CV) benefit seen with sodium glucose co-transporter 2 (SGLT-2) inhibitors in North America and Europe in the previously reported CVD REAL study to outcomes in a more diverse, largely Asian population.

In CVD REAL 2, patients with type 2 diabetes from clinical practices in six countries in the Asia Pacific region, Israel, and Canada who started treatment with an SGLT-2 inhibitor vs another glucose-lowering drug had a lower risk for death, hospitalization for heart failure (HF), or having a myocardial infarction (MI) or stroke, with a year or less of follow-up.  

Mikhail Kosiborod, MD, Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, presented these findings from the Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors 2 (CVD-REAL 2) study here at the American College of Cardiology (ACC) 2018 Annual Scientific Sessions. The study was simultaneously published online March 11 in the Journal of the American College of Cardiology.

"What we observed for [lower risk of] heart failure and death were very consistent with the CVD REAL study, despite a very different patient population," Kosiborod told | Medscape Cardiology.  

The lower risk for stroke, especially, in patients started on SGLT-2 inhibitors, was "quite reassuring," said Kosiborod, because this was in a predominantly Asian population who are more prone to stroke, and there were almost 6500 stroke events in this study.

"We continue to see this data indicating that using SGLT-2 inhibitors in clinical practice is associated with a lower risk of essentially all cardiovascular events across the board," Kosiborod summarized, which is "very complementary to the data that we had from clinical trials and should be quite reassuring to treating physicians."

"What was impressive was presentation of data from patients in routine practice, representing the clinical practice pattern in countries that we don't often see data on," session panelist Elliott M Antman, MD, Brigham and Women's Hospital, Boston, Massachusetts, added in an interview with | Medscape Cardiology.

Kosiborod and Antman both say that these growing data about lower cardiovascular risks associated with SGLT-2 inhibitors have important implications for cardiologists as well as diabetologists and family practitioners.

Beyond the United States and Europe

Previous studies on the new glucose-lowering drugs enrolled patients who were mostly all in Europe or the United States, the researchers note.

CVD REAL 2 aimed to examine the risk for all-cause death, HF hospitalization, MI, and stroke in patients initiated on an SGLT-2 inhibitor vs another glucose-lowering drug.

From claims data, medical records, and national registries, the researchers identified 3.9 million adults (age 18 years or older) in these countries who were new users of these drugs, starting in 2013 to 2015.

Most patients were from South Korea (72%), followed by Japan (14%), Australia (6%), Israel (4%), Canada (3%), and Singapore (<1%). A small proportion, 249,348 patients, had been initiated on an SGLT-2 inhibitor. 

The researchers developed a country-specific propensity score for the likelihood of being prescribed an SGLT-2 inhibitor.

They matched 235,064 patients who were initiated on an SGLT-2 inhibitor with the same number of patients who were initiated on another glucose-lowering drug,

After propensity matching, patient baseline characteristics were well balanced in both groups.

The patients had a mean age of 57 years, and 45% were women. About 27% had established CVD, including stroke (10%), HF (7%), and MI (3%).

About two thirds were receiving an antihypertensive — including an angiotensin receptor blocker (47%) or an angiotensin-converting enzyme inhibitor (9%) — and a similar number were receiving a statin.

Three quarters were receiving metformin, more than half were receiving a sulfonylurea (52%) or a dipeptidyl peptidase-4 inhibitor (55%), and 20% were receiving insulin.

Different SGLT-2 inhibitors were prescribed in the various countries, reflecting different regulatory approvals and practice patterns.

Overall, 70% of patients who were prescribed an SGLT-2 inhibitor, and most patients in Japan, Australia, and Singapore, received dapagliflozin (Farxiga/Forxiga, AstraZeneca).

Another 14% of patients, and more than half of patients in Israel, received empagliflozin (Jardiance, Boehringer Ingelheim).

A further 9% of patients received ipragliflozin (Suglat, Astellas). These patients lived in Japan and South Korea, where this drug is approved.

Another 4% of patients received canagliflozin (Invokana, Janssen).

The remaining 3% and 1% of patients received tofogliflozin (Chugai Pharmaceuticals) and luseogliflozin (Lusefi, Taisho Pharmaceuticals), respectively. These patients lived in Japan, where these drugs are approved.

Survival and Cardiac Outcomes

In pooled data from all 470,128 patients, 5216 patients died during a mean follow-up of 374 days in the SGLT-2 inhibitor group and 392 days in the other group.

During this approximately 1-year follow-up, the risk for death was significantly lower in the patients initiated on an SGLT-2 inhibitor than in those starting another glucose-lowering drug.

Table. Risk for Outcome, SGLT-2 inhibitor vs Other Glucose-Lowering Drug

Outcome Patients (n) Events (n) Hazard Ratio (95% CI) P Value
All-cause deatha 470,128 5216 0.51 (0.37 - 0.70) <.001
Hospitalization for HF 442,686 5997 0.64 (0.50 - 0.82) .001
MI 442,686 2249 0.81 (0.74 - 0.88) <.001
Stroke 442,686 6439 0.68 (0.55 - 0.84) <.001
aDuring 374 days in the SGLT-2 inhibitor group and 392 days in the other group.


The cardiovascular outcome data did not include Australia. In the 442,685 patients in the other five countries, 5997 patients were hospitalized for HF, during 441,357 person-years of follow-up, and initiation of an SGLT-2 inhibitor was associated with a significantly lower risk for this outcome.

During a similar follow-up, initiation of an SGLT-2 inhibitor was also associated with a significantly lower risk for MI or stroke.

The findings were generally consistent across countries.

The researchers acknowledge that study limitations include possible residual confounding and no examination of safety outcomes, which include the risk for amputation reported with canagliflozin in the CANVAS trial, as well as diabetic ketoacidosis and genitourinary infections associated with this drug class.   

Real-world clinical experience with SGLT-2 inhibitors is still relatively short, they add, so studies with longer follow-up are needed to see whether the effects are sustained.

Further research is needed to unravel the potential mechanisms by which SGLT-2 inhibitors may affect death, HF, and atherothrombotic events, they note.

Ongoing clinical trials, such as the Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE) trial with dapagliflozin, will provide further evidence of the potential benefits of SGLT-2 inhibitors in patients with and without CV disease.

In the meantime, "collectively, these findings suggest that CV benefits of SGLT-2 [inhibitors] may extend both across various patient ethnic and racial backgrounds, as well as across the CV risk continuum," the researchers write.

Beyond Lowering Hemoglobin A1c, a Role for Cardiologists?

According to Kosiborod, the clinical implications of these findings extend beyond lowering glucose and hemoglobin A1c (HbA1c) levels.

"You did not see me show any HbA1c data," he pointed out, "and the reason for that is that we know from clinical trials...that HbA1c does not appear to be significantly modified," he said.

For diabetologists, that doesn't discount the importance of lowering HbA1c in preventing microvascular outcomes, he added, "but from a cardiologist standpoint we really should think about this class as a class that lowers cardiovascular risk regardless of HbA1c."

Similarly, Antman said that these results and the benefits for HF with canagliflozin in the CANVAS study, which were presented in the same session of the meeting, provide cardiologists with "very impressive results for a class of drugs that we don't usually prescribe."

"We are seeing," Antman said, "a slower uptake of the prescription of drugs in this class by endocrinologists and primary care physicians in many hospitals for reasons that aren't clear yet, and as cardiologists we're going to have to make a decision."

"Are we going to take on the role of managing a patient's diabetes and all the potential implications of that?" he asked rhetorically.

"Or are we going to increase our level of advocacy on behalf of patients to the other physicians who are caring for them about the importance of considering a class of drugs which have mounting impressive data [starting with the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME)] trial in terms of benefitting, from a cardiovascular perspective?" 

The study was funded by AstraZeneca. Kosiborod has received research grants from AstraZeneca and Boehringer Ingelheim and been on advisory boards for AstraZeneca, Boehringer Ingelheim, Sanofi, Glytec, Novo Nordisk, ZS Pharma, Janssen, Merck (Diabetes), and Novartis. He has been a consultant for AstraZeneca, Boehringer Ingelheim, Sanofi, GSK, Janssen, Intarcia, Merck (Diabetes), Novo Nordisk, Glytec, and ZS Pharma. Antman has received research grants from Daiichi Sankyo and Eli Lilly.

American College of Cardiology (ACC) 2018 Annual Scientific Session. Abstract 407-08.  Presented March 11, 2018.

J Am Coll Cardiol. Published online March 11, 2018. Abstract

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