An estimated 30 million Americans are living with diabetes. Additionally, 84 million have prediabetes, a condition that will result in type 2 diabetes within 5 years if not properly treated.

 Long regarded as one of the most prevalent chronic diseases in United States, diabetes is also a leading cause of disability and the seventh-leading cause of death.

 Less discussed is one of the most common complications of diabetes: diabetic foot ulcers (DFUs). If not properly treated with standard and adjunctive care, these chronic wounds can lead to permanent disability and premature death.

 Although DFUs are not an inevitable comorbidity of diabetes, it has been estimated that the annual risk of developing a DFU may be as high as 4% and the lifetime risk may be as high as 34%.

Without prompt intervention and proper treatment, DFUs will not heal, can cause soft tissue and/or bone infection, and may eventually require amputation of the affected limb or appendage. Unfortunately, this is not uncommon, as 1 in 6 patients with a DFU will undergo an amputation—making DFUs the leading cause of nontraumatic amputations in the country.

 Given the prevalence and risks associated with DFUs, it is imperative that clinicians understand, have access to, and use the best available science for the treatment of these hard- to-heal wounds.

In its recently released research compendium 

Diagnosis and Management of Diabetic Foot Complications

, the American Diabetes Association (ADA) provides a comprehensive overview of the latest approaches for the manage- ment and treatment of DFUs and their complications. Produced by leading international DFU authorities, the compendium includes information about the use of adjunctive therapies, such as hyperbaric oxygen and negative pressure wound therapy, in instances in which DFUs do not respond to standard treatment.

 Among the treatments highlighted in the compendium that garnered the most attention were advanced cellular tissue products (CTPs). These are bioengineered cell-based therapies that supply the wound with the cells, tissues, proteins, and growth factors needed to support the healing process.

In addition to being supported by a wide body of clinical evidence demonstrating their effectiveness in facilitating wound healing, advanced CTPs have also been shown to generate significant cost savings for payers and the US healthcare system overall. This article will review the clinical evidence highlighted in the compendium demonstrating the effectiveness of CTPs in wound healing. It will also review recent literature supplemented by my own experience suggesting there are long-term cost benefits associated with using these therapies.

Advanced CTPs: Clinically Effective DFU Treatment

Patients with DFUs who are not responding to standard care are at great risk of not having their wounds heal and can suffer dire consequences. In practice, we clinicians see this reality daily as patients whose DFUs are not properly treated face increased risk of limb amputation, which results in higher mortality rates. Despite the availability of new therapies, DFUs remain notoriously difficult to treat. As most patients first experience a loss of feeling in the foot due to neuropathy, it is common for patients and providers to fail to notice a DFU until weeks after it has developed. Therefore, it is often recommended that clinicians be aware that advanced care may be required to ensure complete healing.

 In my practice, the use of advanced therapies has undoubtedly saved many limbs and lives.

Though treatment approaches for DFUs vary according to wound severity, clinicians commonly use an intensive adjunctive therapy in instances in which standard treatment—which typically consists of debridement, infection control, off-loading, and appropriate dressing&mdash;is not sufficient to reduce wound size over the first few weeks of care and/or close the wound in a timely fashion. In recent years, several innovative, advanced therapies have been developed for the treatment of DFUs, presenting new opportunities to better treat patients and minimize common risky and costly complications.

The compendium highlights 2 types of advanced, bioengineered CTPs used in adjunctive treatment of DFUs: an allogeneic bilayered human skin equivalent (HSE) and a dermal skin substitute (DSS). Unlike other types of CTPs, these are unique because they are cellular constructs and are both FDA-approved class III medical devices indicated specifically for the treatment of DFUs. To date, these are the only such therapies in their product class approved for this purpose.

Like human skin, HSE consists of 2 layers, has living cells, and contains structural proteins. The underside, or dermal, layer comprises a protein matrix of bovine type 1 collagen and neonatal human fibroblasts, while the epidermal layer consists of a stratified epithelium containing neonatal keratinocytes. Other components normally found in human skin—such as melanocytes, Langerhans cells, macrophages, and lymphocytes, as well as structures such as blood vessels, hair follicles, and sweat glands&mdash;are absent.

Two randomized controlled trials cited in the compendium have confirmed that patients treated with HSE showed significantly higher rates of healing and a shorter time to full wound closure than patients receiving standard care, making HSE among the best studied of all CTP therapies.

 The results of these rigorous trials led to HSE’s premarket approval by the FDA. Results from other studies not included in the compendium show HSE to be effective compared with other types of therapies. For example, a comparison study in a real-world setting found that treatment with an HSE increased the probability of healing by 97% compared with treatment with a dehydrated human amnion/chorion membrane, suggesting added benefit or that it was used more appropriately in practice.

The dermal cellular CTP, DSS, is a single-layered construct of neonatal fibroblasts grown on absorbable mesh scaffold. The DSS delivers metabolically active human fibroblasts to a wound via a bioabsorable polyglactin mesh scaffold. Applying DSS imparts the benefits of human collagen, extracellular matrix proteins, and cytokines and other growth factors necessary for healing.

Among the studies cited by the ADA compendium, one large trial found that among patients with DFUs that have been present for more than 6 weeks, weekly application of the DSS resulted in significantly higher healing rates. Furthermore, treated patients were nearly twice as likely to have complete wound closure than those not treated with the DSS.

 Results of additional studies of patients treated with the DSS corroborate these findings. A study of patients with DFUs treated with the DSS found that 30% had achieved complete wound closure by week 12 compared with only 18.3% in the control group.

 Wounds treated with DSS—compared with other CTPs&mdash;were more likely to experience complete wound closure by week 12 (55% vs 32%) and week 24 (76% vs 50%) and had a significantly shorter mean time to full wound closure, evidence that DSS is perhaps among the most effective CTPs to date.

The cost of DFU treatment to the US health system is shockingly high—as much as $15 billion by some estimates.

 Another report found that treatment of DFUs may account for at least 33% of the direct medical costs associated with diabetes mellitus and that the cost to care for patients with DFUs is 5.4 times higher than the cost of care for those without them.

 The vast majority of these costs are related to patients with DFUs incurring higher emergency medical costs and being more likely overall to be admitted to the hospital. DFUs and related complications are one of the major reasons for hospitaliza- tions among patients with diabetes.

Considering that foot ulcer reoccurrence is quite common and roughly 50% of all patients have a reoccurrence within 1 year after ulcer healing,

 it is important for clinicians to be equipped with the means to most effectively treat DFUs to help minimize hospitalizations, infections, and other associated complications that contribute to long-term costs.

Results from research have shown that despite the substantially higher upfront cost, advanced care that includes CTPs leads to long-term cost savings in the context of total cost of care related to DFUs. A meta-analysis of several dozen economic evaluations of cell-based tissue products found that CTPs resulted in shorter wound treatment periods, which, in turn, led to fewer complications and inpatient episodes.

 In other words, the more quickly a DFU progresses to closure, the lower the risk is of infection or other complications that can stall wound healing and result in costly surgeries and hospitalizations.

A more recent analysis that exclusively examined patients treated with cellular CTPs found that although patients received more intensive physician office and outpatient care, those costs were more than offset by reductions in lower-limb amputations and hospitalizations.

 The investigators in that study examined administrative claims data from Medicare beneficiaries between 2006 and 2012 and found that patients treated with CTPs had significantly lower amputation rates, fewer days hospitalized, and fewer emergency department visits than the control group, who received only standard care. During the 18-month follow-up period after treatment, average per-patient costs for treatment with an HSE were $5253 lower than those of the matched control. Patients treated with a DSS had costs $6991 lower than those of the control. These findings appear to be consistent with previous research showing reductions in lower-limb amputations and other resource-intensive healthcare procedures.

In addition to improving healing, treatment of non—self-healing wounds with the products described above has the potential to lead to significant cost savings by reducing DFU-related complications such as osteomyelitis and amputation. An individual practitioner with a busy practice may reduce overall costs by tens or hundreds of thousands of dollars annually by using an advanced CTP in situations in which wound healing has not progressed using standard treatment.

Despite recent progress in the treatment of DFUs, these wounds remain a significant public health problem that will continue to require rigorous and evidence-based clinical practices. Proper use of evidence-based advanced adjunctive therapy is warranted. Advanced CTPs have shown promising scientific results for the treatment of DFUs,

in terms of both their clinical efficacy and the cost savings associated with shorter healing times and reduced risk of infection and related acute episodes and surgeries.

As clinicians, health systems, payers, and patient advocates grapple with how best to address this public health crisis, they would do well to consider the full suite of therapeutic options available and to use advanced interventions, when appropriate, that are clinically proved to help save limbs and lives.ABOUT THE AUTHOR:

Robert S. Kirsner, MD, PhD, is chairman of and holds the endowed Harvey Blank Chair in Dermatology in the Department of Dermatology and Cutaneous Surgery at the University of Miami Miller School of Medicine. He currently serves as director of the University of Miami Hospital and Clinics Wound Center and chief of Dermatology at the University of Miami Hospital and Jackson Memorial Hospital.

Dr Kirsner was a contributing author to Diagnosis and Management of Diabetic Foot Complications.

The author would like to acknowledge Schmidt Public Affairs of Alexandria, Virginia, for editorial support provided.REFERENCES:

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Kirsner RS, Bell D, Gibbons G, Ennis B, Masturzo A, Rothenberg G. Expert recommendations for optimizing outcomes utilizing Apligraf for diabetic foot ulcers. Podiatry Today website.podiatrytoday.com/files/ PT_orgo.pdf. Published 2012. Accessed November 8, 2018.

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Articles

Evidence-Based Diabetes Management

An estimated 30 million Americans are living with diabetes. Additionally, 84 million have prediabetes, a condition that will result in type 2 diabetes within 5 years if not properly treated. Long regarded as one of the most prevalent chronic diseases in United States, diabetes is also a leading cause of disability and the seventh-leading cause of death. Less discussed is one of the most common complications of diabetes: diabetic foot ulcers. If not properly treated with standard and adjunctive care, these chronic wounds can lead to permanent disability and premature death.

Clinical Evidence for and Cost-Effectiveness of Advanced Cellular Tissue Products for the Treatment of Diabetic Foot Ulcers

, 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).

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.

 The pathway outlined how cardiologists should use newer agents—specifically, sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide (GLP-1) receptor agonists&mdash;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 

). The concept of what can be done for T2D patients with medication has undergone a revolution, thanks to the 2008 FDA guidance

 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,

 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&mdash;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&mdash;looking not just at the laboratory values for type 2 diabetes control, but at what matters most to patients and clinicians&mdash;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 Care

 and a recent statement from the ADA and EASD

 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,

 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.”

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),

 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.

) 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.

. 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.

 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.

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.

“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

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).

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.

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? 

“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:

(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.

 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.

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

Medicare is now funding the Diabetes Prevention Program,

 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.

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.

 Similarly, Kosiborod said he is interested in results from a trial that treated patients with obesity and cardiovascular complications with GLP-1 receptor agonists.

 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&mdash;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.”

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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

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.

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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.

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

Large cardiovascular outcomes trials (CVOTs), which began a decade ago, will likely remain part of the drug approval process for companies that develop treatments for type 2 diabetes (T2D). But based on a 2-day hearing and the October 25, 2018, vote of an FDA panel, changes to the trials seem likely.

The question to the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee was “Should an unacceptable increase in cardiovascular risk be excluded for all new drugs to improve glycemic control in patients with type 2 diabetes, regardless of the presence or absence of a signal for cardiovascular risk in the development program?” Panelists voted 10-9 to keep the trials, but on both sides, there were calls to adjust the 2008 guidance that created the current system.

“We now have 8 clinical trials conducted under the guidance. All 8 have demonstrated no excess cardiovascular risk with any of the therapies studied,” wrote William Chong, MD, acting director of the FDA’s Division of Metabolism and Endocrinology Products, in an analysis presented to panel members ahead of the meeting. “Notably, [results of] some of the trials have shown a reduced risk for adverse cardiovascular events.”

It is not so simple, said Steven Nissen, MD, of the Cleveland Clinic, in an interview with 

) ahead of the meeting. Nissen’s 2007 meta-analysis of rosiglitazone in the 

 which suggested an increased risk of myocardial infarction and cardiovascular death, led to the 2-step process that

he recommended, which guides drug development for T2D to this day. At the time, he received backing from cardiologist Robert Califf, MD, who would go on to become FDA commissioner.

Conducting CVOTs would lead to more than their expressed purpose of informing physicians and the FDA about whether drugs for T2D increased the risk of major adverse cardiovascular events (MACEs), Nissen predicted. “We also knew that if you did outcomes trials, you would learn things you didn’t otherwise know,” he said.

For example, he said, CVOTs have caused the FDA to add information about heart failure risk to the label of saxagliptin (Onglyza),

and the trial for canagliflozin (Invokana), the

sodium-glucose cotransporter 2 (SGLT2) inhibitor, showed an increased risk for lower-limb amputations.

At the same time, results of other trials have shown that SGLT2 inhibitors appear to have cardiovascular benefits,

 as does the glucagon-like peptide-1 (GLP-1) receptor agonist (RA) liraglutide (Victoza).

 Novo Nordisk, which makes liraglutide, announced in late November that top-line results of the PIONEER 6 trial showed that another GLP-1 RA, oral semaglutide, reduces cardiovascular and all-cause mortality risk but not the overall number of cardiovascular events.9 Nissen noted that results of CVOTs have shown that GLP-1 RAs do not cause pancreatitis, which had been a concern.

The FDA’s guidance sets standards that allow drugs for T2D to reach the market, while these giant randomized controlled trials often continue in a postmarketing phase, depending on the phase 2 and 3 results (see 

). The trials are huge, involving thousands of patients and laboratories around the world to ensure the studies are adequately powered. As a result, some stakeholders argue that the trials have become too expensive and stifle innovation while driving up the cost of drugs currently on the market.

Nissen said using claims data and other “real-world” observational sources just would not do, and 2 of the 3 experts who testified before the FDA—cardiologist Marc Sabatine, MD, MPH, of Harvard Medical School and the TIMI Study Group, and Jennifer Green, MD, of the Duke Clinical Research Institute&mdash;agreed.

“Adequately powered and randomized CVOTs of individual agents should continue,” Green said. “There is no substitute.”

“I don’t think loosening regulatory standards is good public policy,” Nissen said in the interview with 

. He added that it was “unlikely” that doing so would make drugs for T2D

But Robert Ratner, MD, former chief scientific and medical officer at the American Diabetes Association (ADA) and now with Georgetown University, and several panelists said the knowledge gained from the first decade of CVOTs could allow the FDA to recommend adjustments, which would make premarket trials stronger and more streamlined. Nissen agrees there are approaches that can achieve this goal without going back to pre-2008 standards. Among the ideas offered during the meeting:

• Strengthen the phase 2 and 3 trial requirements and require CVOTs only if a signal is detected.

• Tighten premarket requirements, and use registry or observational data to detect safety signals post approval.

• Add premarket requirements beyond MACE for other safety issues, based on findings in the first decade of CVOTs. CVOTs have prompted major professional

societies, including the ADA and the American College of Cardiology (ACC), to update their clinical guidelines based on findings about newer classes of therapy, especially SGLT2 inhibitors GLP-1 RAs (see 

). And pharmaceutical companies have gone back to the FDA to add cardiovascular indications after their initial drug approvals to gain a

The ADA published a paper in January 2018 that discussed the issues surrounding CVOTs; the authors rejected the idea that the trials were discouraging drug development but acknowledged their contribution to drug costs.

 ACC Vice President Richard Kovacs, MD, FACC, similarly cited the FDA panel’s effort to balance competing concerns in

“Over the course of the last decade, our awareness of the connection between diabetes treatments and cardiovascular outcomes has increased tremendously. Outcomes trials performed since publication of the guidance provided us with a great deal of additional information, but they also raised many new questions. The Committee has appropriately highlighted the need for pausing to consider whether we have the correct information or whether we should be asking different questions and/or using different types of trials. The information generated by the guidance has forced clinicians to face the realities of cost and value consideration, generating winners and losers among the drugs

 authors led by William T. Cefalu, MD, the ADA’s current chief scientific, medical, and mission officer, offered several ways in which “the next generation of diabetes trials should be smarter, simpler, and innovatively designed to make more efficient use of resources and produce more generalizable results while still addressing safety issues.” Suggested areas for improvement included:

. Because the FDA sought to show that new therapies for diabetes were safe, the guidance called for studying patients with

higher levels of cardiovascular risk. But some trial designs have included only those with advanced cardiovascular disease and failed to measure whether a therapy could stop it

from advancing. Larger, longer trials would tell investigators more about the value of therapies in prevention.

. The ADA authors suggested innovative trial designs that include lifelong follow-up through electronic health records (EHRs), along with FDA approval of methods to track clinical outcomes in this manner. Such trials would give more information about cost-effectiveness, they wrote.

. The authors noted the need for trials with other therapies as a control, including tests of combinations of drugs known to be cardioprotective. Cost

sharing between pharmaceutical companies should be encouraged to free up resources for innovation.

. Methods that use big data, or factorial designs that test multiple interventions at once, are more efficient. Pragmatic trials that make use of health systems’ EHRs can boost treatment persistence. Data from earlier trials can help investigators modify how the analysis is conducted, especially if they are exploring new end points.

 Patient-reported outcomes should be included in future studies, and digital reporting tools can increase these abilities. Although some have cited the cost of CVOTs to pharmaceutical companies, the trials have also helped drugs like empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly) stand apart from competitors; the SGLT2 inhibitor was the first to demonstrate a cardiovascular benefit in the EMPA-REG OUTCOME trial, according to results released in September 2015.

Thomas Seck, MD, vice president of US clinical development and medical affairs, primary care, at Boehringer Ingelheim, said in an interview with 

 that the FDA guidance changed the discussion about glucose-lowering agents. “To say [an] agent should not increase the risk of cardiovascular events was not only appropriate, [but] it was something

that society in general should expect,” he said.

Seck shares the view that broader use of real-world evidence would be useful, and he would like to see more flexibility to allow more attention to other end points, including heart failure. “This would add more information for patients and for the healthcare system overall,” he noted.

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

2. 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/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM623913.pdf. Accessed December 4, 2018.

3. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457-2471. doi: 10.1056/NEJMoa072761.

4. Herper M. The great drug debate. Forbes website. forbes.com/2008/07/03/fda-nissan-diabetes-biz-healthcare_mh_0703diabetes.html#5cd838774355. Published July 3, 2008. Accessed December 3, 2018.

5. FDA drug safety communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin [news release]. Silver Spring, MD: FDA; April 5, 2016. www.fda.gov/drugs/drugsafety/ucm486096.htm. Accessed December 3, 2018.

6. 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.

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

9. 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 3, 2018.

10. FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes [news release]. Silver Spring, MD: FDA; December 2, 2016. www.fda.gov/newsevents/newsroom/pressannouncements/ucm531517.htm. Accessed November 27, 2018.

11. FDA approves Invokana (canagliflozin) to reduce the risk of heart attack, stroke or cardiovascular death [news release]. Titusville, NJ: Janssen; October 30, 2018. janssen.com/us-fda-approves-invokanar-canagliflozin-reduce-risk-heart-attack-stroke-or-cardiovascular-death. Accessed November 27, 2018.

12. Mattina C. Liraglutide gains new indication for reducing CV event risk. The American Journal of Managed Care® website. ajmc.com/newsroom/liraglutide-gains-new-indication-for-reducing-cv-event-risk. Published August 25, 2017. Accessed November 27, 2018.

13. Cefalu WT, Kaul S, Gerstein HC, et al. Cardiovascular outcomes trials in type 2 diabetes: where do we go from here? Reflections from a Diabetes Care editors’ expert forum. Diabetes Care. 2018;41(1):14-31. doi: 10.2337/dci17-0057.

Concerns over cost should lead FDA to recommend adjustments to these trials, which many say have led to unexpected knowledge and changed the field of diabetes care.

After FDA Panel Vote, Some See Next Generation of Cardiovascular Safety Trials for Diabetes Drugs

It is of paramount importance to a health plan that any therapy result in an improved clinical outcome. In addition, therapy should be priced in a way to keep healthcare and insurance costs as low as possible. Rising medication costs contribute to higher premium costs, making coverage less affordable.

Payers are keenly interested in outcomes data. From their perspective, the goal of treatment for any disease state is not the treatment itself but rather an improvement in the outcome experienced by the member. In this way, the goal of the payer is aligned with the goal of the member. In the case of type 2 diabetes, before 2008 control would result in better outcomes, including cardiovascular outcomes. The recognition that improved glycated hemoglobin did not necessarily lead to a guaranteed improvement in cardiovascular

A perspective on the current FDA guidance for diabetes therapies.

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