Time for a "New Goalpost" in Cardiovascular Outcomes Trials, Kosiborod Suggests

Evidence-Based Diabetes Management, December 2018, Volume 24, Issue 14

Leading cardiologist Mikhail N. Kosiborod, MD, FACC, FAHA, discusses how the FDA's 2008 guidance requiring cardiovascular outcomes trials has changed the treatment landscape in diabetes care and what expectations might look like going forward.

In a July editorial in Circulation, Mikhail Kosiborod, MD, FACC, FAHA, and coauthor Michael E. Nassif, MD, issued a call to their fellow cardiologists: The specialty is “well-poised to take the lead” in using newer classes of therapies that can lower cardiovascular risk among patients with type 2 diabetes (T2D).1

In November, Kosiborod was a coauthor on a much-anticipated consensus pathway from the American College of Cardiology (ACC) on treating patients with both T2D and atherosclerotic cardiovascular disease.2 The pathway outlined how cardiologists should use newer agents—specifically, sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide (GLP-1) receptor agonists—with the goal of preventing heart attacks, strokes, heart failure hospitalizations and/or early cardiovascular death.

A decade ago, this would have been difficult to fathom, Kosiborod said in an interview with Evidence-Based Diabetes Management™ (EBDM). The concept of what can be done for T2D patients with medication has undergone a revolution, thanks to the 2008 FDA guidance3 that launched a new staple of annual meetings for the ACC, the American Heart Association, the American Diabetes Association (ADA), and the European Association for the Study of Diabetes (EASD): the dedicated cardiovascular outcomes trial (CVOT).

After an FDA advisory panel voted 10-9 on October 25, 2018,4 to retain the trials, EBDM asked Kosiborod about the fresh look that regulators are taking at these practice-changing studies. While he acknowledged the criticisms about the restrictions and high costs of CVOTs, Kosiborod said that the FDA requirement has done much to advance the care for people with type 2 diabetes (T2D).

“The guidance, and the clinical trials and the data we learned from the trials—and we learned a tremendous amount over the past decade—were the catalysts for this complete, fundamental paradigm shift in how we approach type 2 diabetes management,” he said. The narrow focus on lowering glycated hemoglobin (A1C) has been replaced with an emphasis on comprehensive risk reduction—looking not just at the laboratory values for type 2 diabetes control, but at what matters most to patients and clinicians—prevention of its deadly complications, “of which cardiovascular disease is number 1 in terms of impact.”

Kosiborod, a cardiologist and clinical researcher at Saint Luke’s Mid America Heart Institute and a professor of medicine at the University of Missouri —Kansas City School of Medicine, said both the ADA Standards of Care5 and a recent statement from the ADA and EASD6 now recommend “a completely separate approach for treatment of patients who have T2D and established cardiovascular disease.”

“The only reason this has occurred is because of the large cardiovascular outcomes trials—the majority of which were done as a direct result of this guidance,” he said.

The 10-9 vote obscured the consensus among members of the FDA Endocrinologic and Metabolic Drugs Advisory Committee that the trials have had a “huge [and] positive impact,” Kosiborod said. “I don’t think any of the panel members wanted to completely abandon the FDA guidance,” he said. Rather, the discussion pointed toward updating CVOTs to reflect knowledge gained over the past decade.

“The overarching message is that the guidance has produced a lot of good. It has come at a [financial] cost, but it has dramatically changed how we think about diabetes management. Patients are clearly going to benefit from all the things we have learned,” he said.

Like other experts, Kosiborod foresees a regulatory paradigm with different end points, more flexibility, and greater use of real-world evidence. CVOTs were designed primarily to prove that T2D drugs did not harm patients, not to show which drugs were superior to others. With multiple T2D therapies now demonstrating a cardiovascular benefit,7-10 Kosiborod said that perhaps this is the new baseline. “That doesn’t mean you don’t do safety trials if you’re just trying to prove that [a drug] is safe,” he explained. “But for many of the compounds in development, the new goalpost should be that they are superior to whatever the comparator is, rather than noninferior.”

What Would Updated CVOTs Look Like?

Kosiborod had several suggestions on where the large outcomes trials could go from here:

Less rigidity in the way CVOTs are constructed. The 8 trials the FDA reviewed did not show increases in major adverse cardiovascular events (MACE),11 so future trials may need to prove that novel compounds are better than the alternatives. “If you have a compound you believe will provide a benefit, doing a cardiovascular superiority trial, rather than

one for safety, may be a better construct,” he said.

Redefining the primary end point. FDA’s guidance focuses on MACE (see Cover) but Kosiborod notes that many other cardiovascular outcomes also matter in diabetes. “Heart failure is emerging as one of the most common cardiovascular complications, if not the most common in people with diabetes and the one associated with the worst prognosis of all known fatal cardiovascular events,” he said. Having heart failure as primary end point is entirely appropriate, and Kosiborod praised investigators of the DECLARE trial for adding a coprimary end point of cardiovascular death or hospitalization for heart failure (HF). Shortly after the interview, DECLARE showed a reduction in this second end point, driven by the HF benefits.12

Mechanics of trial operations. Kosiborod said the term “pragmatic trial” is discussed as a successor to the current format; this generally refers to simplifying the trial mechanics and even integrating the trial into clinical practice, but the field needs consensus on what that means. “I think that in some cases it’s not easy to do pragmatic trials; there are always compromises that come with any relaxation of restrictions in which these clinical trials operate. But, if we are to really consider lowering the cost, we have to look at some ways in which they can be made more pragmatic,” he said. Randomized registry trials, which don’t require researchers to repeatedly construct “the machinery” of the trial, are 1 option, but there are limits here, too. “It’s a very elegant concept,” Kosiborod said. “The problem is that appropriate registries that provide high-quality data are limited to certain countries; not all that many countries can do it.” Using patients from just a few countries is a problem if the results are to be generalizable.

Adjudicating end points. FDA requires independent adjudication of end points, but Kosiborod said studies show investigator adjudication may produce the similar results without the added costs. “You need to look at it on a case-by-case basis,” he said.

What Is the Role of Real-World Evidence?

Kosiborod is the lead investigator for CVD-REAL, which has used claims and registry data from multiple countries to show that SGLT2 inhibitors are associated with significantly lower risks of hospitalization for HF and death in patients with T2D, compared with patients who took other glucose-lowering therapies. Recent results published in June, based on data from South Korea, Japan, Singapore, Israel, Australia, and Canada, for example, found a 49% reduction in all-cause mortality and a 36% reduction in hospitalization for HF.13

“You have to evaluate real-word evidence just like you would evaluate any other piece of evidence,” Kosiborod said, noting that as with a clinical trial, not all real-world evidence studies are of the same quality. Both real-world evidence studies and clinical trials have their own limitations. “Sometimes patients with the highest risk and the lowest risk are underrepresented in clinical trials,” he said.

With event-driven trials, “very low-risk patients are typically not included,” because it would take too long for the trial to conclude. long for the trial to conclude. In addition, he said, real world data may matter when evaluating health resource utilization and costs, and regulators are starting to pay more attention to it. “It will be interesting to see how the regulators incorporate real-world data into their decision making. I suspect that it’s going to have a bigger role over time. But it will need to be used as a complement to clincial trial data, not a

replacement for it.”

New Therapies and Heart Failure

Kosiborod and other investigators recently published a research letter that examined an unanswered question from the EMPA-REG OUTCOME trial, the first to show a cardiovascular benefit in a T2D therapy, empagliflozin (Jardiance; Eli Lilly/Boehringer Ingelheim).14 The letter asked whether the benefits seen in reducing cardiovascular death and hospitalization for HF were tied to a patient’s baseline A1C, or, alternately to A1C reduction during the trial. Kosiborod explained that several hundred patients in EMPA REG OUTCOME screened at 7% A1C to meet the trial criteria but were below that level at the time of randomization. Kosiborod and his colleagues were able to show that the cardiovascular benefits seen in this trial were independent of a patient’s baseline A1C or a to A1C reduction during the course of the trial.15

This adds to the growing body of data that the benefits of SGLT2 inhibitors, including prevention of heart failure, are likely to be independent of their glucose-lowering effects. Does these results add to the sense that SGLT2 inhibitors have a future role in prevention of heart failure? And if so, could patients benefit even if they don’t have diabetes?

Not so fast, said Kosiborod.

“We can speculate that maybe that’s the case, but of course, we don’t know,” he said, warning that discussing broader use of SGLT2 inhibitors is premature because all the published studies to date involve patients with diabetes. “We will have to wait for those answers, but they will be coming.”

He mentioned several trials that will examine these questions:

• The EMPEROR trials (EMPEROR Preserved, for HF patients with preserved ejection fraction, and EMPEROR Reduced, for HF patients with reduced ejection fraction) are

studying the safety and efficacy of 10 mg per day of empagliflozin in patients with heart failure both with and without diabetes.16

• The DAPA-HF and DELIVER trials are evaluating the effects of dapagliflozin (Farxiga, AstraZeneca) in patients with heart failure with reduced and preserved ejection fraction, respectively, in patients both with and without T2D.17,18

• The SOLOIST trial will examine the effect of sotagliflozin, a dual SGLT1/2 inhibitor, (Zynquista; Sanofi) in patients with T2D and worsening HF.19

Looking Toward Earlier Intervention

Medicare is now funding the Diabetes Prevention Program,20 which has shown that lifestyle interventions can be effective in the near term: The landmark study found a 58% reduction in progression to T2D, compared with metformin. While 15-year results have shown that over the long haul, the percentage of patients who progress to T2D is about the same, the patients in the lifestyle intervention at least took much longer to get there.21

The simple fact is, it’s hard to stick with a healthy diet and exercise. Should clinicians be doing more early on? “We know that people with prediabetes are also at elevated risk of cardiovascular complications—probably not as much as people with manifest diabetes, but certainly higher than people with normoglycemia. It’s so important to understand what we can do to lower that risk,” Kosiborod said. “Lifestyle changes are the foundational therapy for people with diabetes, and I believe for people with prediabetes, and this is where we should start. However, I don’t think it’s where we should end.”

Lifestyle modification is probably not enough for most people with prediabetes, because sticking with regimens long-term is so difficult. There’s a lot to learn in the coming years, Kosiborod said, about whether SGLT2 inhibitors and GLP-1 receptor agonists have a role for those who have not progressed to T2D. The DISCOVER study across 38 countries just reported how widespread the microvascular and macrovascular complications are for people with T2D, and how early these problems develop.22 Similarly, Kosiborod said he is interested in results from a trial that treated patients with obesity and cardiovascular complications with GLP-1 receptor agonists.23 Such a trial may help convince payers to treat obesity more aggressively, as some have been reluctant to pay for therapies.

“When it comes to cost, we really need to keep a holistic view,” Kosiborod said. While medications have a cost, events like heart failure, heart attacks, and strokes, progression of kidney disease, etc.— which bring high costs to the healthcare system and can leave patients disabled—have a cost to society as well, he said. Both HF and chronic kidney disease, 2 long-term cardiovascular complications, are not only expensive but reduce quality of life for patients.

Kosiborod is excited about the results that will be reported over the next 5 years. “It’s an incredibly exciting time in the field,” he said, comparing today’s choices for people with T2D with those available in 2008, when there were fears that medications were causing patients harm. “It’s a real milestone, something that is extremely exciting to see. The field is evolving to where we have multiple evidence-based treatments with really tangible benefits to patients.”References

1. Nassif ME, Kosiborod M. Are we ready to bell the cat? a call for cardiologists to embrace glucose-lowering therapies proven to improve cardiovascular outcomes. Circulation. 2018;138(1):4-6. doi: 10.1161/CIRCULATIONAHA.117.022680.

2. Das SR, Everett BM; Members of the Writing Committee. 2018 ACC Expert Consensus Decision Pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease [published online November 26, 2018]. J Am Coll Cardiol. doi: 10.1016/j.jacc.2018.09.020.

3. FDA Center for Drug Evaluation and Research. Guidance for industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. fda.gov/downloads/Drugs/Guidances/ucm071627.pdf. Published December 2008. Accessed December 4, 2018.

4. Caffrey M. Narrow vote calls for keeping drug safety trials, but many see changes. The American Journal of Managed Care® website. ajmc.com/focus-of-the-week/narrow-vote-calls-for-keeping-drug-safetytrials-but-many-see-changes. Published October 29, 2018. Accessed December 14, 2018.

5. American Diabetes Association. Cardiovascular disease and risk management: standards of medical care in diabetes—2018. Diabetes Care. 2018;41(suppl 1):S86-S104. doi: 10.2337/dc18-S009.

6. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2018;61(12):2461-2498. doi: 10.1007/s00125-018-4729-5.

7. 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.

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

9. Marso SP, Daniels GH, Brown-Frandsen K; LEADER investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. doi: 10.1056/NEJMoa160382.

10. Caffrey M. Oral semaglutide shows reduction in cardiovascular death, all-cause mortality in type 2 diabetes. The American Journal of Managed Care® website. ajmc.com/newsroom/oral-semaglutide-shows-reduction-in-cardiovascular-death-allcause-mortality-in-type-2-diabetes. Published November 24, 2018. Accessed December 14, 2018.

11. FDA Center for Drug Evaluation and Research. FDA background document: Endocrinologic and Metabolic Drugs Advisory Committee Meeting, October 24-25, 2018. www.fda.gov/downloads/Advisory-Committees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM623913.pdf. Accessed

December 4, 2018.

12. Wiviott SD, Raz I, Bonaca MP, et al; DECLARE—TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes [published online November 10, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1812389.

13. Kosiborod M, Lam CSP, Kohsaka S, et al; CVD-REAL Investigators and Study Group. Cardiovascular events associated with SGLT2 inhibitors versus other glucose-lowering drugs: the CVD-REAL 2 study. J Am Coll Cardiol. 2018;71(23):2628-2639. doi: 10.1016/j.jacc.2018.03.009.

14. Inzucchi SE, Kosiborod M, Kitchett D, et al. Improvement in cardiovascular outcomes with empagliflozin is independent of glycemic control. Circulation. 2018;138(17):1904-1907. doi: 10.1161/CIRCULATIONAHA. 118.035759.

15. EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved). clinicaltrials.gov/ct2/show/NCT03057951. Updated December 11, 2018. Accessed December 10, 2018.

16. EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced). clinicaltrials.gov/ct2/show/NCT03057977. Updated December 11, 2018. Accessed December 10, 2018.

17. Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPA-HF). clinicaltrials.gov/ct2/show/NCT03036124. Updated October 15, 2018. Accessed December 10, 2018.

18. Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure. (DELIVER). clinicaltrials.gov/ct2/show/NCT03619213. Updated November 29, 2018. Accessed December 10, 2018.

19. Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF Trial). clinicaltrials.gov/ct2/show/NCT03521934. Updated December 10, 2018. Accessed December 10, 2018.

20. Medicare Diabetes Prevention Program Expanded Model. CMS website. innovation.cms.gov/initiatives/medicare-diabetes-prevention-program/. Updated December 11, 2018. Accessed December 14, 2018.

21. Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol. 2015;3(11):866-875. doi: 10.1016/S2213-8587(15)00291-0.

22. Kosiborod M, Gomes MB, Nicolucci A, et al. Vascular complications in patients with type 2 diabetes: prevalence and associated factors in 38 countries (the DISCOVER study program). Cardiovasc Diabetol. 2018;17(1):150. doi: 10.1186/s12933-018-0787-8.

23. Htike ZZ, Yates T, Brady EM, et al. Rationale and design of the randomised controlled trial to assess the impact of liraglutide on cardiac function and structure in young adults with type 2 diabetes (the LYDIA study). Cardiovasc Diabetol. 2016;15(1):102. doi: 10.1186/s12933-016-0421-6.