The CVD-Real Trial: What Can Real-World Evidence Tell Us About Primary Prevention?

IN MARCH 2017, when the first results of the CVD-REAL trial were presented at the American College of Cardiology Scientific Sessions, there was a buzz in the room: This wasn’t a randomized clinical trial (RCT), but this could be interesting.

All 3 FDA-approved sodium glucose co-transporter-2 (SGLT2) inhibitors would be compared as a group with other type 2 diabetes (T2D) drugs in a single study, using patient registries or claims data involving over 300,000 patients from 6 di erent countries. AstraZeneca, maker of the SGLT2 inhibitor dapagliflozin (Farxiga), funded the CVD-REAL study.¹

The findings, later published in Circulation,² showed evidence that investigators had wondered about for more than a year: In patients with T2D who were mostly free of established cardiovascular disease (CVD), initiation of an SGLT2 inhibitor was associated with a 51% lower risk of death and a 39% lower risk of hospitalization for heart failure, compared with those initiating another glucose-lowering drug. What’s more, despite considerable differences in which SGLT2 inhibitor was predominant in different countries, the results were consistent across the continents—raising the possibility of a class effect.

Although the EMPA-REG OUTCOME trial had surprised clinicians and investigators in 2015 by showing that empagliflozin (Jardiance, Eli Lilly/Boehringer Ingelheim) produced a 38% relative risk reduction in cardiovascular (CV ) death,³ all patients in this study had T2D with established CVD; thus, no conclusions could be made about patients without established cardiovascular disease. But cardiovascular outcomes trials (CVOTs) in the queue at the time CVD-REAL was presented—including CANVAS,⁴ for the SGLT2 inhibitor canagliflozin (Invokana, Janssen)—included some of these patients, who have CV risk factors but have not suffered a heart attack or stroke.

Thus, the CVD-REAL study increased the excitement about those trials—and new clinical trials for heart failure just getting under way—because it suggested SGLT2 inhibitors might be useful for patients in earlier stages of T2D.

To understand what this bounty of real-world evidence tells us, and what to expect as CVD-REAL continues, Evidence-Based Diabetes Management^TM spoke with Matthew A. Cavender, MD, MPH, FACC, an interventional cardiologist at the University of North Carolina and a coauthor of the study who presented additional results during the American Diabetes Association meeting in June.

At that same meeting, the CANVAS investigators reported a 14% reduction in major CV events, including CV death, and said there was no reason to believe the drug behaved any differently between primary prevention patients, who accounted for a third of the study population, and the others.⁴ Researchers, payers, and clinicians alike are now looking ahead to DECLARE-TIMI-58, the CVOT for dapagliflozin,⁵ as well as new clinical trials that will examine how empagliflozin affects heart failure in patients with and without diabetes.^6,7

Real-world versus clinical trial data.

CVD-REAL is an observational study based on real-world data, and Cavender is very clear on what CVD-REAL says and what it does not say. “The randomized controlled trial is still the gold standard for establishing a clear benefit for establishing definitive evidence of benefit,” he said. “However, observational studies are important and play a role in our understanding of the clinical effectiveness of therapies. Observational studies such as CVD-REAL help us ll in holes to understand the potential benefit in patients who were not part of the randomized trials and help us understand whether the benefits seen in randomized trials are translating to clinical practice.”

Cavender added, “These benefits, which we see in RCTs, are also being seen in patients in clinical practice, providing evidence that the benefits seen in clinical trials are translating into clinical practice.”

Timing and geography.

Another important aspect of CVD-REAL, Cavender said, is its timing. It comes between 2 large clinical trials that both studied SGLT2 inhibitors but had different study populations. “Overall, the ndings from CVD-REAL are pretty consistent with what was seen in CANVAS,” he said. “In CANVAS, two-thirds of the population had established cardiovascular disease, and one-third did not have established cardiovascular disease. In CVD-REAL, the majority of the patients (87%) do not have established cardiovascular disease.”

And yet the reductions in hospitalization for heart failure and death are consistent across the 2 study populations, Cavender said.

CVD-REAL is a compilation of studies performed in different countries, with the data merged into a meta-analysis, Cavender explained. The first phase included sites in the United States, the United Kingdom, Sweden, Denmark, Norway, and Germany. Cavender pointed out that consistency in the results between the United States and the European countries is noteworthy.

“The majority of the time evaluated in our first pass of CVD-REAL occurred either immediately before or in the period immediately after the [results of] EMPA-REG OUTCOME [were] released,” he said. “One of the things this allowed us to do was look at whether there were variations across geography, since in the United States the majority of the SGTL2 inhibitor use was canagliflozin, and in the European countries the majority of the use was dapagliflozin.”

“And what we found was there were no differences [between] the United States or the countries that predominantly used dapagliflozin. While not definitive, this does provide evidence that the associations we’re seeing—and the effects we’re seeing with canagliflozin in CANVAS, and the effects we’re seeing in empagliflozin in EMPA-REG—may not be specific to those drugs, but rather specific to the inhibition of SGLT2. Thus, these associations were seen across the different medications.”

Changes over time.

Overall, 52.8% of the patients were taking canagliflozin during the study period, while 41.7% were taking dapagliflozin. Because empagliflozin did not reach the market until the end of the initial study period, it accounts for only 5.5% of the patients in the study, but Cavender said this share will increase the next time CVD-REAL reports results, based on Truven Health Analytics data he has seen.¹

“That’s one of the reasons we’re interested in continuing to pursue analyses of CVD-REAL. We’re looking to see how these associations change over time,” Cavender said. Not only will the mix within the SGLT2 class change, he noted, but the drugs in the comparator arm will, too—as more patients take glucagon-like peptide-1 receptor agonists.

Cavender said there’s great interest in whether the SGLT2 inhibitor class can prevent heart failure, which remains one of the primary causes of 30-day hospital readmission in the United States.⁸ Besides the 3 approved SGLT2 inhibitors, he said, there’s interest in sotagliflozin, a dual SGLT1 and SGLT2 inhibitor. Trial data presented this fall showed the drug helped patients with diabetes lower glycated hemoglobin while using less insulin; patients also experienced improved time in range.⁹

Payers in other countries are interested in real- world data, Cavender said. “I have meetings with regulatory agencies and payers in Asian countries later this year. They are interested in hearing about these results and how they fit into their overall treatment strategies and priorities,” he said.

Investigators are currently trying to expand the number of countries that contribute data to CVD- REAL, although they have not been announced. And there’s no end date for the research, Cavender said. “As long as we’re able to get high-quality clinical data, and as long as we’re able to do high-quality analysis, there will be interest,” he said.References

1. Caffrey M. Can SGLT2 inhibitors prevent heart failure in a broad population? results from a real-world study. The American Journal of Managed Care. ajmc.com/conferences/acc-2017/can-sglt2-inhibitors-prevent-heart-failure-in-a-broad-population-results-from-a-real-world-study. Published March 19, 2017. Accessed November 24, 2017.

2. Kosiborod M, Cavender MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation. 2017;136(3):249-259. doi: 10.1161/CIRCULATIONAHA.117.029190.

3. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720.

4. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi: 10.1056/NEJMoa1611925.

5. DECLARE TIMI 58. TIMI Study Group website. timi.org/index.php?page=declare-timi-58. Accessed November 24, 2017.

6. Empagliflozin outcomE tRial in Patients With chrOnic HeaRt Failure With Reduced Ejection Fraction) EMPEROR-Reduced. clinicaltrials.gov/ct2/show/NCT03057977. Updated October 4, 2017. Accessed October 15, 2017.

7. EMPagliflozin outcomE tRial in Patients With chrOnic HeaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved). clinicaltrials.gov/ct2/show/NCT03057951. Updated October 4, 2017. Accessed October 15, 2017.

8. O’Connor CM. High heart failure readmission rates: is it the health system’s fault? JACC Heart Fail. 2017;5(5):393. doi: 10.1016/j.jchf.2017.03.011.

9. Garg SK, Henry RR, Banks P, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes [published online September 13, 2017]. N Engl J Med. doi: 10.1056/NEJMoa1708337.

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