CVD-REAL 2 demonstrates CV benefits of SGLT-2 inhibitors in Asia-Pacific, Middle East populations

Roshini Claire Anthony
20 Mar 2018
CVD-REAL 2 demonstrates CV benefits of SGLT-2 inhibitors in Asia-Pacific, Middle East populations
Professor Mikhail Kosiborod

Individuals with type 2 diabetes (T2D) who initiate therapy with sodium glucose cotransporter-2 (SGLT-2) inhibitors have lower risks of all-cause death and cardiovascular (CV) outcomes, specifically myocardial infarction (MI) and stroke, compared with those who initiate other glucose-lowering therapies, according to results from the CVD-REAL* 2 study.

“[This] large, international study across three major world regions, over 400,000 patients, and with a large number of events for each outcome shows that initiation of SGLT-2 inhibitors vs [other glucose-lowering agents] was associated with a lower risk of death, hospitalization for heart failure, and reassuringly, MI and stroke,” said study author Professor Mikhail Kosiborod from the Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, US, who presented the results at ACC.18.

Using registries from Australia, Canada, Israel, Japan, Singapore, and South Korea, researchers identified patients aged ≥18 years with T2D (mean age 57 years, 45 percent female, ~27 percent with established cardiovascular disease [CVD]) who were new users of SGLT-2 inhibitors and matched them to new users of other glucose-lowering drugs (n=235,064 in each group). Patients were followed up for a mean 374 and 392 days (for SGLT-2 inhibitor and other glucose-lowering drug users, respectively).

Of the patients on SGLT-2 inhibitors, exposure time was 75 percent for dapagliflozin, 9 percent for empagliflozin, 4 percent for canagliflozin, and 12 percent for other SGLT-2 inhibitors.

At baseline, about 65, 62, 54, and 74 percent of patients were on statins, anti-hypertensive therapies, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, and metformin, respectively.

Over the course of the study (~490,000 patient-years), 5,216 deaths, 5,997 cases of hospitalization for heart failure, 2,249 MIs, and 6,439 strokes occurred.

The high stroke incidence was put down to the predominantly Asian patient population in which strokes are a common occurrence, said the researchers.


Lower all-cause death, CV outcomes with SGLT-2 inhibitors

Patients on SGLT-2 inhibitors had a lower risk of all-cause death** compared with patients on other glucose-lowering drugs (hazard ratio [HR], 0.51, 95 percent confidence interval [CI], 0.37–0.70; p<0.001). [ACC.18, abstract 18-LB-18925-ACC; J Am Coll Cardiol 2018;doi:10.1016/j.jacc.2018.03.009]

Compared with other glucose-lowering therapies, initiation of SGLT-2 inhibitors was also associated with a lower risk of hospitalization due to heart failure (HR, 0.64, 95 percent CI, 0.50–0.82; p=0.001), a composite of death or hospitalization for heart failure (HR, 0.60, 95 percent CI, 0.47–0.76; p<0.001), MI (HR, 0.81, 95 percent CI, 0.74–0.88; p<0.001), and stroke (HR, 0.68, 95 percent CI, 0.55–0.84; p<0.001).

The positive all-cause death and CV outcomes with the use of SGLT-2 inhibitors over other glucose-lowering treatments were consistent across all countries and did not vary according to pre-existing CVD status.

“[T]he association between SGLT-2 inhibitors and lower risk of MI and stroke in our study should offer additional reassurance in regards to the effects of SGLT-2 inhibitors on atherothrombotic events,” said the authors.


Benefits extend beyond borders

According to Kosiborod, much of the previous research on the impact of SGLT-2 inhibitors on CV outcomes in T2D has focused on all-cause death and heart failure, primarily in Western populations, despite a majority of patients with T2D residing outside the US and Europe. Furthermore, patient characteristics, treatments, and CV events vary in patients in other regions.

“Collectively, findings [from CVD-REAL 2] suggest that the CV effects of SGLT-2 inhibitors may extend across patient ethnic and racial backgrounds, geographic regions, as well as the CV risk continuum,” he said.

“These findings … likely represent a class effect,” said Kosiborod and co-authors.

The authors acknowledged study limitations which included the potential for residual confounding, all-cause death data comprising only in-hospital deaths in Japan and Singapore, and the lack of information on comorbidities in the Australian data set. Nonetheless, excluding the data from these countries in the sensitivity analyses resulted in consistent findings. The study also did not focus on safety.

Nonetheless, the authors highlighted the importance of the CVD-REAL 2 study in assessing the effects of SGLT-2 inhibitors in a low-risk population, and called for further research into identifying the mechanisms behind the death, CV, and atherothrombotic effects of SGLT-2 inhibitors, as well as the long-term outcomes of this class of drugs.

According to cardiologist Dr Lim Chin Hock from the Mount Elizabeth Medical Centre in Singapore, heart failure and heart disease are common in diabetics, with SGLT-2 drugs helping to prevent heart failure.

“The data showed that the class of SGLT-2 inhibitors are able to cut deaths or heart failure by 40 percent, yet only one in 10 Singaporeans with T2D are treated using the SGLT-2 inhibitors. The reason for this is that many doctors, when they are introduced to a new drug, tend to be more concerned with the side effects than the benefits the drugs have for the patients. Unless there is a mindset change, then will these new class of drugs be adopted for the better treatment of diabetes patients,” said Lim.   

“The results of the CVD-REAL study were unexpected. Not only did [the study] show beneficial results for patients with existing CV disease that mirrored what had been seen in the only CV outcomes trial to that point [EMPA-REG***], but results suggested that SGLT-2 inhibitors might have potential for primary prevention. [The CVD-REAL 2 trial] presented early last month served to bolster the first results,” said endocrinologist Dr Loh Keh Chuan, also from Mount Elizabeth Medical Centre.

“The second study included findings from South Korea, Japan, and Singapore, where stroke is more common. This is good news for Asia. The current cornerstone drug therapy for T2D is metformin and with these results, SGLT-2 inhibitors would make a good second-line treatment for such patients. SGLT-2 inhibitors inhibit glucose absorption and do not cause gastrointestinal side effects, unlike [dipeptidyl peptidase-4 inhibitors]; however they do have their own side effects such as urinary tract infections and genital fungal infections in a small proportion of patients,” said Loh.  

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