Nearly 100 years ago, the discovery of insulin forever changed the lives of people with diabetes. Today, insulin continues to extend lives and improve health for those with both type 1 (T1D) or type 2 diabetes (T2D), as drug companies create improved versions of this metabolism-regulating hormone.

The insulin available today lasts longer and gives patients more dosing flexibility, but it must be balanced with therapy prices and changes in benefit design, which may require higher out-of-pocket (OOP) costs. In April, 

 convened its second Diabetes Stakeholders Summit to discuss how to evaluate value in modern insulins and therapies that combine insulin with a glucagon-like peptide-1 (GLP-1) receptor agonist.

Moderator Dennis P. Scanlon, PhD, professor of health policy and administration and director of the Center for Health Care Policy and Research in the College of Health and Human Development at Pennsylvania State University, in University Park, Pennsylvania, led the Peer Exchange™ panel discussion “Finding Value in Today’s Insulin Therapies.” Joining him were Zachary Bloomgarden, MD, clinical professor in the Division of Endocrinology, Diabetes, and Bone Disease of the Department of Medicine at Mount Sinai Health System, New York, New York; Robert A. Gabbay, MD, PhD, FACP, senior vice president and chief medical officer, Joslin Diabetes Center, Boston, Massachusetts; Mary Ann Hodorowicz, RDN, MBA, CDE, CEC, a Chicago, Illinois—based consultant, dietitian, and trainer; and Kenneth Snow, MD, MBA, medical director, Aetna.

Scanlon called on the panel to describe the changes in the treatment landscape in recent years. Bloomgarden noted there certainly are more choices—up from a pair of medication classes to more than 10&mdash;allowing clinicians to individualize therapy (including GLP-1s and sodium glucose co-transporter-2 [SGLT2] inhibitors). While metformin is still considered the starting point, Bloomgarden said, “many people do have advanced renal disease and should not be treated with metformin.”

Gabbay outlined a host of considerations: potential for weight gain, adverse effect profile, costs, patient coverage, and the suitability of injections for a particular patient. Hodorowicz pointed to the need for considering the challenges of diabetes: Is the patient struggling with preprandial blood glucose, postprandial blood glucose, or both?

“We are aiming for excellent glycemic control in as many of our patients as possible, recognizing that we want to avoid hypoglycemia, weight gain, gastrointestinal side effects—all of these issues that plague us,” Bloomgarden said. “And we want to avoid undue expense while recognizing that some of the less expensive medicines with more side effects may ultimately be less desirable.”

 The panelists noted disagreement among professional societies on when to start patients on insulin, which Gabbay said creates challenges for the primary care physician. In general, providers probably wait too long, Snow said. “Part of that clearly reflects the patients’ concern about starting insulin, but part of it reflects the providers’ concerns—or at least some providers’ concerns&mdash;with using insulin in their patients,” he said.

Gabbay reiterated the need for individualization: “Unfortunately, there haven’t been a lot of randomized trials to be able to say, ‘Second-line drug—what’s the best choice?’ It really ends up being based on logic.” For example, if a patient is at high risk of cardiovascular disease and a drug has been shown to lower that risk, that “makes that choice better,” he said.

Once it’s clear a patient needs therapy beyond metformin, it’s “extraordinarily complex with a lot of nuance,” Snow said. “What we prefer to look for [as payers] is whether it makes reasonable sense and whether folks are achieving good control.” There may be disagreement between a target of 7% or 8% for glycated hemoglobin (A1C),

 “but everyone agrees it should never be 9%,” he said.

Today’s Insulins versus Older Formulations

Prescribing habits for patients with T2D changed with the introduction of U100 insulin glargine (Lantus), because most patients could achieve good glycemic control with 1 dose a day, Bloomgarden said. He described the “unique advantages” of recently introduced ultra—long-acting insulins (U300 insulin glargine, sold as Toujeo, and insulin degludec, sold as Tresiba). “With both of these products, there may be a little bit less variability of action. These may [provide] a little bit of a smoother insulin curve,” he said. “These are these treat-to-target studies against U100 insulin glargine. And in both cases with both insulins, and in people with type 1 diabetes and type 2 diabetes on basal insulin alone and type 2 diabetes on basal bolus&mdash;basically every situation where a treat-to-target trial has been done&mdash;they’ve shown less nocturnal hypoglycemia, which is certainly good. Insulin degludec has the additional advantage that it really can be given at a different time of day on different days,” Bloomgarden continued. “So, if the person takes it one day in the morning, and then the next day forgets to take it in the morning but takes it in the afternoon, it actually works fine. And the flatness of it is such that you get fairly stable blood insulin levels without causing hypoglycemia”&mdash;helpful with older patients for whom family members are caregivers. This flexibility could lead to better adherence, Gabbay added.

When it comes to coverage decisions, Snow said, ideally, there should be no dramatic difference in cost. “What you hope for is that as there are additional insulin options available…[so] that the price doesn’t become the driving force, but, rather, that the appropriateness for a particular patient becomes the driving force,” he said.

Bloomgarden agreed: “I would just absolutely echo that.”

Health plans, providers, and patients must balance the advantages with the costs of the newer insulins. Gabbay recently wrote an editorial in 

™ that discussed the complexity of the debate over prices.

 “There isn’t 1 bad guy or 1 bad player in all of this—it’s sort of a series of difference pieces,” he said.

Greater transparency would help, Gabbay said, and Hodorowicz agreed that it’s difficult when an endocrinologist takes time to match an insulin with a patient’s needs, only to learn that the drug is not covered.

Because of changing benefit designs, OOP costs are an issue and can affect patient behavior. “I have, unfortunately, seen people who simply say, ‘I won’t use more than 1 syringe worth of insulin.’ It really is a dilemma,” Bloomgarden said. When Medicare patients reach the point in the year when they have a coverage gap, cost sharing temporarily becomes a big problem&ensp;

 until they move through the “donut hole.” (Starting in 2017, changes to the law will allow Medicare patients to close the gap more quickly.

The DEVOTE Study, Formulary Decisions, and Busy Clinicians

The Peer Exchange™ took place shortly before Novo Nordisk submitted data to the FDA asking that the label of insulin degludec be updated to reflect data from the DEVOTE trial, a head-to-head cardiovascular (CV) outcomes trial that found that 27% of patients experience severe hypoglycemia compared with those taking insulin glargine.

Full results from DEVOTE, presented in June at the American Diabetes Association 77th Scientific Sessions, showed that insulin degludec offers the same level of CV safety as insulin glargine, as well as a 40% overall reduction in hypoglycemia.

From these data, which involve patients at high risk of CV events, payers look at the evidence to make formulary decisions. Snow outlined the steps involved.

		Examine the evidence for what offers a benefit versus what is questionable.

		Negotiate to give patients options to improve cost.

		Hold costs down while keeping an array of options for a particular member.

		Make exceptions for members who are allergic or have a failure on a therapy.

 The process is very fluid. Even within a plan, there are different levels of pharmacy benefits, Snow said. “You could have 5 patients in a row with the same insurance, and yet they have 5 different drug plans,” he said. “It’s something that computers should be aiding the busy clinician with.”

Advance knowledge about a patient’s coverage options would help, Bloomgarden said. Gabbay agreed. “It’s a solvable problem, and it’s mind-boggling that it hasn’t happened,” he said.

Scanlon introduced a discussion of combination therapies: insulin with GLP-1 receptor agonists, which have been approved for patients with T2D. The FDA approved both drugs on the same day: Xultophy, which combines insulin degludec and liraglutide (from Novo Nordisk), and Soliqua, which combines insulin glargine and lixisenatide (from Sanofi).

“It’s like a marriage made in heaven,” said Hodorowicz. “The GLP-1 [agonists] have 3 main mechanisms of action: they increase glucose-dependent insulin secretion, which is wonderful;  decrease glucagon secretion (so the liver is not generating glucose); and decrease gastric emptying (for better postprandial, postmeal blood sugar control). So, you combine those 3 mechanisms of action from the GLP-1 [agonist] with the insulin’s ability to lower pre- and postprandial blood glucose. It’s like a 4-way marriage made in heaven—these 3 functions of GLP and then the insulin.”

Bloomgarden explained it another way: “We have known for a long time that after basal insulin, you often go to basal bolus, where you give insulin before meals…but there’s an entirely different way of achieving this, which is basal insulin plus a GLP-1 receptor activator. And that essentially gives you a better version of basal bolus insulin.”

Patients can delay gastric emptying and achieve good glycemic control, with less weight gain and less hypoglycemia, Bloomgarden said. The combination allows the patient to take less of the GLP-1 therapy, which can reduce the gastrointestinal adverse effects, the Achilles’ heel of this class.

Payers must consider a balance when offering the 2 therapies in a single injection, Snow said. “The opportunity to combine them into 1 syringe—of course it’s better for the patient. It’s easier&mdash;it’s only 1 injection versus 2,” he said. In similar situations, this has improved adherence. “It’s not medically going to be any better, so in a way it’s a convenience issue&mdash;but a very important convenience issue if they’re not adherent [with separate injections].”

All stakeholders—managed care, pharmaceutical companies, physicians, and patients&mdash;must be on the same page, Bloomgarden said. “If it exists as 1 shot, and it’s so much easier for the human being with diabetes to accept 1 injection than 2, let’s all strive to make that 1 injection available because it will pay off,” he said.

“Framing in terms of adherence, as you did, I think really is 

 issue,” Gabbay said. “Medicine only works if people are adherent to it.”

“So, with all these medication improvements, what are the key challenges?” Scanlon asked.

Hodorowicz framed her answer in terms of the AADE7: 7 evidence-based behaviors identified by the American Association of Diabetes Educators, which include medication. A challenge with newer therapies is that patients are not referred for education on proper use, and physicians often do not have time to teach them in a 10- to 15-minute appointment. “It’s not a good situation,” she said.

Gabbay agreed that diabetes educators are underutilized. “I think it’s a big issue, and it’s more than just reimbursement, because even in places where there is reimbursement, they’re still underutilized,” he said. “Providers may not realize the benefit, and also, I think patients probably don’t like the term ‘education.’ ”

Each panelist offered final thoughts, starting with Bloomgarden. “Every one of us who tries to treat people with diabetes feels that this is a human being who’s struggling with this disease,” he said. “We really can help people by using these newer treatments. And, of course, the managed care companies have helped us to make it available. Even though we grumble a lot, without the insurance companies supporting the patients’ use of this, we could never do it. So it’s a challenge.”

“We can individualize care much more effectively based on what the needs of the patient are,” Gabbay said. “We talked about a number of factors to consider: hypoglycemia, weight gain, and other comorbidities.” In terms of cost, transparency would be an important first step. “That said, I think there’s so much improvement that can be made in diabetes care, and we have so many more tools to be able to do it now than ever,” he said.

“Insulin has to be—in all its forms, in all its devices to inject it&mdash;for the patient, affordable; accessible per the payer and the mail order pharmacies; and appropriate&mdash;individualized for patients’ unique lifestyle needs, metabolic needs, [and] complication needs,” Hodorowicz said.

“We need to be sure that it’s being utilized as frequently as it needs to be,” Snow said. “For type 1, that’s easy, in a way, because it’s absolutely essential for life. But, for so many folks with type 2 who clearly have a need to move beyond the therapy they’re on to achieve the level of control that they should, insulin is still almost 100 years later a wonderful drug—and needs to be available for those folks, so they can achieve that control and stay healthy.”&ensp;

1. American Diabetes Association. Standards of medical care in diabetes—2017, glycemic targets. 

. 2017;40(suppl 1):S48-S56. doi: 10.2337/dc17-S009.

2. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2017 executive summary. 

. 2017;23(2):207-237. doi: 10.4158/EP161682.CS. 

3. Gabbay RA. Discussions of high costs for new therapies raise questions about an old one: insulin. 

4. Costs in the coverage gap. Medicare website. www.medicare.gov/part-d/costs/coverage-gap/part-d-coverage-gap.html. Accessed June 23, 2017.

5. Caffrey M. Novo Nordisk asks FDA to update Tresiba label on hypoglycemia.

 website. www.ajmc.com/newsroom/novo-nordisk-asks-fda-to-update-tresiba-label-on-hypoglycemia. Published May 31, 2017. Accessed June 23, 2017.

6. Marso SP, McGuire DK, Zinman B, Pratley R, Buse J. Cardiovascular safety of insulin degludec versus insulin glargine in patients with type 2 diabetes at high risk of cardiovascular events (DEVOTE) trial results. Presented at: American Diabetes Association’s 77th Scientific Sessions; June 9-13, 2017; San Diego, California. https://professional.diabetes.org/webcasts/browsebyname?title=DEVOTE. (Subscription required.)

7. Caffrey M. Rival Sanofi, Novo Nordisk insulin combinations gain FDA approval. 

 website. http://www.ajmc.com/newsroom/soliqua-sanofis-entrant-in-insulin-combo-battle-gets-fda-approval. Published November 22, 2016. Accessed June 23, 2017.

Articles

Evidence-Based Diabetes Management

Coverage from the first of 3 Peer Exchangeâ„¢ discussions from the Diabetes Stakeholders Summit.

Finding Value in Today's New Insulins,  GLP-1 Combinations

In September 2015, results from the EMPA-REG OUTCOME trial stunned the medical world: for the first time, a treatment for type 2 diabetes (T2D), empagliflozin, was found to have cardiovascular (CV) benefits.

 The good news about the sodium glucose co-transporter-2 (SGLT2) inhibitor did not end there, however. Researchers have continued to pore over data, finding evidence of additional benefits.

 convened its second Diabetes Stakeholders Summit. Moderator Dennis P. Scanlon, PhD, professor of health policy and administration and director of the Center for Health Care Policy and Research in the College of Health and Human Development at Pennsylvania State University, University Park, Pennsylvania, led the Peer Exchange™ panel discussion, “Diabetes Therapy and Cardiovascular Outcomes: An Update.” Joining him were Silvio Inzucchi, MD, medical director for Yale Diabetes Center, New Haven, Connecticut; Zachary Bloomgarden, MD, clinical professor in the Division of Endocrinology, Diabetes, and Bone Disease of the Department of Medicine at Mount Sinai, New York, New York; Robert A. Gabbay, MD, PhD, FACP, senior vice president and chief medical officer, Joslin Diabetes Center, Boston, Massachusetts; and Kenneth Snow, MD, MBA, medical director, Aetna.

Inzucchi explained that for years, diabetes providers had been frustrated by the fact that correcting a fundamental feature of the disease—hyperglycemia&mdash;had little or no effect on CV outcomes. “We can reduce retinopathy, and nephropathy, and probably neuropathy,” he said. “But when you look at studies over many decades, it’s been very difficult to demonstrate that lowering glucose with a specific strategy or any drug actually benefits the heart.”&ensp;

EMPA-REG OUTCOME didn’t set out to find a CV benefit. The trial’s purpose was to show that empagliflozin was safe, in the wake of events in the mid-2000s that suggested rosiglitazone caused heart attacks. While the FDA ultimately cleared rosiglitazone, the saga paved the way for new protocols that require diabetes and obesity therapies to demonstrate safety for those at high risk of heart attack or stroke.

Inzucchi made an important distinction about what the trial did and did not find. “I think what EMPA-REG OUCOME showed us is that you can improve cardiovascular outcomes, perhaps not through lowering glucose, but through using a glucose-lowering therapy,” he said. This was the first time a diabetes drug was shown to have a benefit for CV mortality, and it was associated with a 38% reduction.

“I must say, when I saw these results—and I was on the steering committee for the trial&mdash;I almost fell out of my chair,” Inzucchi shared with the panel. He was struck that a diabetes therapy that was effective, but not hugely powerful, in lowering blood glucose, could bring such a result in reducing CV death.

It’s important, he said, not to overinterpret the results, as EMPA-REG OUTCOME involved patients at high risk or established CV disease (CVD). “Primary prevention, in terms of patients without prior history of CVD, has not been demonstrated,” he said.

As much as researchers are still gleaning information from EMPA-REG OUTCOME—and still learning about SGLT2 inhibitors generally&mdash;the trial is a breakthrough and has changed the thinking about treating diabetes in many ways, Gabbay said.

Snow agreed. “Certainly, one of the major driving forces for why we treat diabetes to begin with, and why payers pay for the treatment of diabetes is not so much because we want to see lower blood sugar, but because we want folks to live longer, healthier lives,” he said. “And ultimately, these types of outcomes trials, particularly if we are seeing reductions in major cardiovascular events, are exciting.”

The SGLT2 inhibitor drug class has a completely different mechanism from other antidiabetic therapies. The drugs target a protein that normally reabsorbs glucose in the kidney, and instead blocks this function and causes excess glucose to be expelled in the urine. Scanlon asked Gabbay what researchers have learned about the mechanism of action of SGLT2 inhibitors that explains the results found in EMPA-REG OUTCOME.

“It’s a great question,” Gabbay said, adding that the results surprised many. There’s been a lot of “thinking backward,” to truly understand how SGLT2 inhibitors work, and therefore, how they achieve what they do. “What we do know about SGLT2 inhibitors is that they result in a little bit of diuresis and volume contraction, and that, certainly, could be one of the factors [particularly in terms of congestive heart failure incidences and hospitalizations for congestive heart failure], for which they saw a benefit. There’s also a small amount of weight loss, which could also be a factor.”

As he explained, regression models using data from the EMPA-REG OUTCOME trial estimated that about half the effects could be related to volume. Another correlation that merits further study involves uric acid levels.

“There’s another finding of the empagliflozin trial, which is fascinating and may shed light on this—the effect on renal disease,” said Bloomgarden. EMPA-REG OUTCOME showed that empagliflozin was not simply a diuretic, but also acted on sodium secretion; it worked in the kidney “in a lovely way with angiotensin blocking agents,” Bloomgarden said.

“So, at the level of the macula densa, delivering more sodium to that part of the kidney seems to then potentiate the benefit of not having so much angiotensin action on board,” he said. “Well, this fits very nicely into a lot of our clinical knowledge of what’s good for heart failure and our theoretical ideas of what’s good for the heart and what’s good for the kidneys.”

Scanlon asked the panel to discuss an FDA decision to add a new indication to empagliflozin, to reduce CV death in patients with T2D.

What, he asked, are the clinical decision-making implications?

Payers face challenges, Snow said, in deciding whether the effect is just for empagliflozin or a class effect that applies to other SGLT2 inhibitors. “Is it in all patients or only those with preexisting heart disease?” Snow asked. “These are research questions that are still in the process of being answered, and somehow, in the process, there needs to be a decision on coverage.”

Bloomgarden said that if other trials do not show benefits, it would be difficult for any payer to not provide empagliflozin to patients with known heart disease, “of which there are so many.”

“At the very least, there are now data out there about the population of folks who clearly got a benefit with a particular agent,” Snow said. “And now, really the question is, is it unique and is it unique to that population?”

Scanlon asked Bloomgarden to comment on the LEADER trial, which found that liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, also had cardioprotective benefit: results presented at the 76th Scientifiic Sessions of the American Diabetes Association (ADA) in June 2016 showed it reduced CV death in high-risk patients by 22%.

 Results presented at ADA the year prior for another GLP-1, lixisenatide, had shown only that the drug was safe, not that it had demonstrated any CV benefit.

“LEADER was fascinating, coming as it did, immediately after the EMPA-REG OUTCOME trial,” Bloomgarden said. “The strategy was a little bit different. The centers were asked to try to achieve good glycemic control in the patients in the control group and the patients in the liraglutide group, so that there was an up-titration of nonliraglutide, non-GLP-1 receptor agonist therapies in the control group.” From his vantage point, liraglutide’s benefit was that it allowed clinicians to avoid the harms of older medications like sulfonylureas.

Inzucchi agreed. He discussed results for SUSTAIN-6, which found a CV benefit for semaglutide, a once-weekly GLP-1 that is not yet available.

 “It seemed that the most potent effect was actually on stroke, which was surprising because that’s not what you see with atherosclerosis trials,” Inzucchi said. “You typically see it on nonfatal (myocardial infarction) and, maybe, cardiovascular mortality.”

For Inzucchi, the differences point up the importance of not assuming anything. “It leads us to understand that you cannot appreciate the effects of these individual drug categories until you get at least 3 or 4 trials under your belt so you can see the overall effect of the class,” he said.

Recently, increased attention has been given to the idea that SGLT2 inhibitors could have a role in primary prevention of heart failure (HF) for the broader population with diabetes, not just patients at high risk for CV events. The presentation of results for the CVD-REAL trial in March 2017 at the American College of Cardiology

 (which were followed by a paper presented in June at the 77th Scientific Sessions of the ADA

), involved the use of more than 300,000 patient records from 6 countries to study the effect of SGLT2 inhibitors. Researchers found a 39% reduction in rate of hospitalization for HF and a 51% reduction in death for any cause.

Bloomgarden explained the relationship between diabetes and HF. “Diabetes is associated with increased likelihood of atherscrotic cardiovascular disease,” he said. “And certainly, individuals who have myocardial damage have decreased heart function and are at risk of heart failure.”

What is less appreciated, he explained, is how diabetes leads to fibrosis and decreased heart function, and endocrinologists are aware of 2 types of HF in these patients: HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). “These are extremely important causes of morbidity and mortality,” Bloomgarden said. “People with heart failure feel tired. They have less energy, and then, eventually they progress to peripheral edema, dyspnea, and all the classic things we learned.

When more and more patients with diabetes come in with these symptoms, he said, “it becomes very attractive to say, we may have a specific drug that could be useful.”

Inzucchi noted that a secondary endpoint in EMPA-REG OUTCOME showed a 35% risk reduction for hospitalization for HF among patients with T2D with known coronary artery disease.

The number of people with high-risk T2D and existing heart disease is “a real epidemic,” Inzucchi said. “I think our cardiology colleagues are getting so good at saving people during their acute coronary syndromes that many patients are now living with somewhat damaged ventricles. So, the 35% risk reduction, we saw that and we wondered whether this was something that occurred in patients with established heart failure or whether it was preventing heart failure episodes. And I think the answer is both.”

As a result, the EMPEROR studies are now under way for empagliflozin, which will examine the effect of the SGLT2 inhibitor specifically on patients with HFpEF and HFrEF.

 Results will come in 3 to 4 years. “These are heart failure trials being driven by heart failure experts,” Inzucchi said. “The heart failure community is very interested in this class because of the EMPA-REG signal,&ensp;

but the question is, will the benefits be seen again in the diabetic population?”

“Or in prediabetes?” Bloomgarden asked.

Of course, clues to what the EMPEROR results may reveal were contained in CVD-REAL. Scanlon asked Gabbay to discuss these findings, as well as the importance of using data to gain these insights.

“It’s the beginning of what we’ll see a lot more of—using big data to try to answer some of these questions,” Gabbay said. “There are a lot of hypotheses. Is it a class effect? What’s the effect on congestive heart failure? We have some data, but not all the questions are answered. There are a number of studies that are ongoing. Some, we’ll get results soon, but some will still take several years. What do we do in the meantime?”

Gabbay explained that while CVD-REAL seemed to suggest a signal for reducing congestive heart failure across all SGLT2 inhibitors, the “challenge with a retrospective analysis is you’re not randomizing people to therapy.” Gabbay and Inzucchi agreed there was some value in observational studies—as statisticians can use propensity matching to make up for the loss of randomization&mdash;but Inzucchi said these studies should be taken “with a grain of salt.”

Bloomgarden, too, noted the need to watch for “channeling bias,” in observational studies—when patients ask to be put on the “new drug.” But he said that even the largest clinical trials have event rates that are so low there are questions that can’t be answered. Inzucchi said the question is whether patients in trials are different from those in the real world. “I think it’s great when the randomized clinical trials and the observational data sets point in the same direction, but when they don’t, I think it’s really confusing.”

CV outcomes trials started with one idea, “First, do no harm.” But, Scanlon asked, is it time for a redesign? Are they powered sufficiently? As large as they are, are they large enough? How long should patients be followed? Can data be collected retrospectively, and if so, for how long?

Bloomgarden said as “hugely expensive” as it would be to follow large numbers of patients for a decade or more, this must be balanced against the 650 million individuals worldwide who will develop diabetes by 2040. And trials shouldn’t just examine the effect of therapies or strategies on the highest-risk patients. “Let’s try to figure out how all people developing diabetes should be treated going forward,” he said.

Long term, the progression of diabetes makes it impractical to study a single therapy for an extended period, Inzucchi said. “It’s not clean like that,” he said, using an example of a study conducted in 2004 based on the approaches that were common at the time that resulted in “cross contamination” as patients needed additional therapies.

Snow, the payer, said there’s no chance that an analysis of big data will ever replace the role of the randomized clinical trial, “no matter how good it is.” However, he said, “we do know that there are certain situations where a randomized clinical trial just doesn’t work because the population is relatively homogenous. So, you’re stuck with the question of, ‘Well, can’t I expand this into other populations? Do I need a full, other randomized controlled trial to answer that question or not?’ ”

Observational studies can help with questions that would take a long time to answer, that would require studies of great complexity, or in cases in which there is great risk of patients dropping out of the study, Snow said.

“I totally agree,” Gabbay said. There are many questions

that need answers, and not every question will get a randomized controlled trial that collects data for 5 to 10 years. Practically speaking, there are patients who need treatment today.

“As big data [analysis] becomes more sophisticated,…and studies are done more accurately, we’re going to have to rely on that kind of data to answer some of the questions that there are unlikely to be clinical trials on,” Gabbay said. The challenge is that some will be well done and others will be poorly done, and the average provider reading an abstract won’t know the difference. The danger is that kind of data sways clinical care. I think a better arbitration of study technique for big data analysis will really help move the field forward.”

Clinical Decision Making and Cost—Effectiveness

From Unexpected CV Benefits to Potential in Heart  Failure: Insights and Outlook for SGLT2 Inhibitors

 A study of nearly 365,000 patients taking medication for type 2 diabetes (T2D) has found that sodium glucose co-transporter-2 (SGLT2) inhibitors outperform other treatments for the disease in key ways—and may help prevent heart failure (HF) in patients with T2D not yet diagnosed.

Results from the study, called CVD-REAL, were first presented March 19, 2017, at the 66th Scientific Session of the American College of Cardiology (ACC).

 (A related paper was published in May in 

) The study, which covered patients from the United States and 5 European countries, examined some questions left unanswered by the EMPA-REG OUTCOME study, which was the first cardiovascular outcomes trial (CVOT) that did not merely find that a T2D therapy was safe, but that it could offer cardioprotective benefits and reduce deaths.

But because EMPA-REG OUTCOME was a safety trial required by the FDA, it studied high-risk patients, and it only examined 1 drug, empagliflozin (Jardiance). In an interview at ACC prior to presentation of the results, AstraZeneca’s Jim McDermott, vice president for medical affairs, Diabetes, said CVD-REAL was designed to ask whether the effects on HF are a class effect for all SGLT2 inhibitors, if these effects could be applied to a broad population, and “if they can be demonstrated in a real-world environment.” AstraZeneca funded the study.

Researchers in the CVD-REAL study gathered data from patients 1 of 3 approved SGLT2 inhibitors: dapagliflozin (Farxiga) from AstraZeneca; canagliflozin (Invokana) from Janssen; and empagliflozin from Boehringer-Ingelheim and Eli Lilly. They also matched data from patients taking other glucose-lowering therapies. Compared with other T2D drugs, the SGLT2 inhibitor class:

		Reduced the rate of hospitalization for HF by 39%

		Reduced the rate of death from any cause by 51%

Researchers also computed a composite endpoint of hospitalization for HF and death from any cause and found that SGLT2s inhibitors reduced this by 46% compared with other T2D therapies.

SGLT2 inhibitors work through a unique mechanism of action, which causes excess blood glucose to be expelled through urine. McDermott said this mechanism has been shown to have a diuretic effect that positively affects blood pressure (and has been shown to help patients lose weight), although this effect is not well understood.

EMPA-REG OUTCOME raised the curtain on potential new benefits that CVD-REAL sought to explore. Could SGLT2 inhibitors not only treat diabetes, but also prevent HF in these patients?

Mikhail Kosiborod, MD, the study’s lead author and a cardiologist at St. Luke’s Health System in Kansas City, Missouri, said in his presentation at ACC that the results suggest a “heart failure prevention signal,” because so few of the study participants had been diagnosed with cardiovascular disease at baseline.

McDermott agreed. “Eighty-seven percent of the patients did not have predefined cardiovascular disease,” he said. “This tells me we can apply the results to a much broader population.”

The study did not include results by individual drug. Of the data reviewed for the HF analysis, 41.8% of patients were on dapagliflozin, 52.7% on canagliflozin, and 5.5% on empagliflozin. The US population was more heavily weighted with canagliflozin users, where it was approved first, while the European data had more dapagliflozin users. Because the results were so consistent across different countries, McDermott said, they point to a class effect.

CVD-REAL will continue with more countries participating, McDermott said. Besides the United States, the first study included Denmark, Norway, Sweden, the United Kingdom and Germany; future studies may include data from Canada, Mexico, and Japan.

The expense of CVOTs has raised the question whether data-driven studies, such as CVD-REAL, could be the wave of the future. But both McDermott, in the interview, and Kosiborod, in his presentation, said CVOTs remain extremely important. “We need more and more data from various sources,” Kosiborod said.1. Kosiborod M, Cavender MA, Norhammar A. Lower rates of hospitalization for heart failure and all-cause death in new users of SGLT2 inhibitors: the CVD-REAL study. Presented March 17-19, 2017, at the 66th Scientific Session of the American College of Cardiology, Washington, DC. Abstract 415-14. acc.org/latest-in-cardiology/articles/2017/03/13/17/58/sun-2pm-cvd-real-study-lower-rates-of-hospitalization-for-hf-in-new-users-of-sglt-2-inhibitors-vs-other-glucose-lowering-drugs-acc-2017.

2. Kosiborod M, Cavender MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on SGLT2 inhibitors versus other glucose lowering drugs: the CVD-REAL study [published online May 18, 2017].

2017. doi: 10.1161/CIRCULATIONAHA.117.029190.

3. Zinman B, Wanner C, Lachin JM, for the EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. 

. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720.

A study presented at the 2017 Scientific Session of the American College of Cardiology uses claims data to examine whether SGLT2 inhibitors offer a protective benefit against heart failure.

Can SGLT2 Inhibitors Prevent Heart Failure in a Broad Population?

Wth seemingly everyone having a smartphone and carrying it everywhere, it was only a matter of time before apps took center stage in efforts to prevent and manage diabetes.

But figuring out how to connect health plans with this technology is proving complicated. Medicare’s efforts to launch the Diabetes Prevention Program (DPP) by early 2018 have slowed as it works to include digital providers, which are needed to scale DPP to all who will need the program.

Even paying for more conventional devices isn’t always straightforward. As diabetes technology evolves, patients want more choices, whereas payers want to hold down costs.

 hosted the discussion “Technology in Diabetes Care: From Prevention to Disease Management” during its April Diabetes Stakeholders Summit, a Peer Exchange

Moderator Dennis P. Scanlon, PhD, professor of health policy and administration and director for the Center for Health Care Policy and Research in the College of Health and Human Development at Pennsylvania State University, in University Park, Pennsylvania, led the discussion. Joining him were Robert A. Gabbay, MD, PhD, FACP, senior vice president and chief medical officer, Joslin Diabetes Center, Boston, Massachusetts; Mary Ann Hodorowicz, RDN, MBA, CDE, CEC, a Chicago, Illinois—based consultant, dietitian, and trainer; Kenneth Snow, MD, MBA, medical director, Aetna; and Neal Kaufman, MD, MPH, founder and CMO of Canary Health.

The April discussion foreshadowed an important development when Snow said that “without a doubt” the diabetes device world would be moving toward value-based payment models. On June 26, 2017, as this special issue of 

™ went to press, Aetna and Medtronic announced a risk-sharing agreement for patients transitioning from multiple daily insulin injections to Medtronic’s insulin pumps, including the new Medtronic MiniMed 670G. The agreement covers patients with types 1 and type 2 diabetes (T1D and T2D). Medtronic’s reimbursement will be partly based on outcomes-based measures for patient experience, clinical outcomes, and total cost of care.

Technology and the Diabetes Prevention Program

As the discussion began, Gabbay explained that results from a landmark National Institutes of Health study show that a lifestyle intervention under “very controlled, rigorous conditions” could produce better results than medication (metformin) for preventing diabetes.

“The challenge of that study [is that] it was done in a very resource-intensive way to ensure that people adhered to their lifestyle,” Gabbay said. “Now, how do you apply that to the broader population?”

That was the early concern for payers, Snow said, even though they were excited about the DPP. Kaufman, who was very involved in the early years of the DPP, weighed in, pointing out that a single trainer could help 30 to 40 people a year because the program required 16 weekly sessions at the start, followed by monthly in-person sessions. Training was done one-on-one.

“The CDC recognized that that was not a scalable or sustainable model and began looking at how to provide it in other ways,” Kaufman said, and then described 2 “threads” of approaches. The first, most common approach involves training to 10 to 15 people at once, with highly trained educators leading the groups. The best example is the YMCA pilot study funded by the Center for Medicare & Medicaid Innovation (CMMI), which provided the evidence to scale the program across Medicare.

The second approach is to use technology. The question here, Kaufman said, is whether a program offered in person would translate in a digital format, using a cell phone. “I was very much involved back in 2006 to create a digital version of that program,” he said. “At that time, we didn’t know if it was going to work. We didn’t know if people would accept it, but we recognized that people need choice …

“And so, we, and now a number of other companies, have been able to demonstrate that you can take an in-person program, use great design and great approaches to make technology work, and have individuals use it effectively.”

Scanlon asked the panelists to elaborate more on the YMCA study, because it formed the basis for Medicare’s decision to fund DPP, a decision that will bring diabetes prevention to seniors on a widespread basis in 2018. Many DPP providers believe that once commercial payers that administer Medicare Advantage see the value of the program, DPP will become even more embedded in health plans.

 Hodorowicz said that the dynamic of self-monitoring—tracking weight and exercise and keeping a food diary&mdash;and having to report to a lifestyle coach increases motivation more than taking these steps alone does.

Scanlon asked if the number of sessions patients must attend helps, as well. Kaufman replied that based on the YMCA study results, it does. The study contributed to the regulations CDC uses for program recognition: 16 weekly sessions, followed by less frequent attendance for a total of 26 sessions.

What about evidence? “This was a big decision for CMS to decide they were going to go ahead and pay for this,” Scanlon said, adding that it has not been without controversy. “Will other payers follow?”

Snow noted the enormous impact: “Any decision by CMS, whatever cost there is has to be multiplied by millions.” But one difference with Medicare, he said, is that beneficiaries don’t leave, so Medicare reaps the rewards of its investment. For other payers, a preventive service may or may not pay dividends if enrollees switch insurers. Still, “some payers have already made decisions regarding continuing coverage similar to CMS,” and Aetna is among them, he said. “Some will be looking at the type of data that comes out in the real world and real-life experience to see if the results that are hoped for are actually achieved.”

Thanks to the YMCA pilot, Gabbay said, it’s no longer theoretical that the DPP saves money. “That, in essence, was exactly what CMMI was set up to do—to be able to do pilot studies that show cost savings or high value, and then spread that more broadly,” he said.

When asked by Scanlon to address the role of diabetes educators in offering the DPP, Hodorowicz said that for years, patients with prediabetes were referred to educators but did not quality for coverage, even though a certified diabetes educator was perhaps the best person to help that patient avoid progressing to diabetes. But now, with some commercial payers offering coverage and&ensp;

 CMS poised to do so, the American Association of Diabetes Educators is training DPP coaches. “It’s an easy fit to include prevention with an existing self-management program run by diabetes educators,” Hodorowicz said. “It’s a perfect marriage.”

Kaufman agreed. If a person is at risk for diabetes, he said, “we need to help them improve their life’s trajectory, to help them so that they don’t add a new chronic condition every 3 to 5 years, as many people do.” That starts with lifestyle intervention. Focusing on the glucocentric requirements of eligibility for the DPP that will help people lose weight and become active is too restrictive, he said.

Once payers have the data, Snow said, they will look beyond the issue of diabetes: Does helping at-risk patients lose weight also help avoid issues such as joint damage or back problems? “[These] are clearly not glucocentric but still related to the same population,” he said.

“The real secret sauce is, how do you get people to sign up and show up?” Kaufman asked. “Once you can get them to the program, we can almost predict for 1000 people or 10,000 people what’s going to happen. But how do you get the right person to the right program at the right time to engage them, to activate them, to get them to see that there is a benefit?”

Gabbay agreed that for some patients, in-person programs such as the YMCA will be best, but for others, digital solutions will work well. Hodorowicz said she believes that for the younger generation, digital solutions will be more popular, and Snow noted that Medicare enrollees are more accepting of technology than people realize.

It’s important to distinguish between a digital tool, such as a text, which acts as a reminder, Kaufman said, and an intervention, which is a full program of health improvement. Gabbay said he regularly uses the smartphone, such as to show patients that they are walking less than they think. By contrast, he said, “if you want to do something to prevent diabetes, you need a whole intervention, based not only on counting steps but also [on] dietary changes and other behavior change approaches.”

The Clinical Rationale for Continuous Glucose Monitoring

Scanlon moved the discussion to the importance of continuous glucose monitoring (CGM), now considered the standard of care for those with T1D and becoming more common for those with advanced T2D. A 2011 study

 was the first to quantify the cost of a hypoglycemic admission to the hospital and was cited by JDRF and others in their successful effort to convince the FDA and Medicare to change policies that will ultimately allow beneficiaries to have coverage for the Dexcom G5, although there have been some implementation issues.

There’s evidence that—particularly for patients with T1D willing to use CGM technology&mdash;it shows a benefit, Snow said, both in terms of improving glycemic control and lowering hypoglycemia risk. “Once you get outside of that, causation data becomes very thin,” he said, “so you see observational data, where there’s clearly a relationship between hypoglycemia and…if you can give them the message that prevents the hypoglycemia event, well, then that is optimal.”

The challenge is to make sure that patients have access to both the CGM and the right education, which Hodorowicz said is key, because when patients know how to use the data the device provides, educators can more easily instruct them on how to “embed lifestyle changes.”  “The good news is that Medicare is starting to cover [CGM],” despite strict criteria, she said.

“It’s fantastic news,” Gabbay agreed. “At Joslin, we have a large type 1 population, and for them, they reach Medicare age and they have to go off their continuous glucose monitor, which is a big problem,” he said. “But I think you’ll see, in the not-too-distant future, this spreading to more use in the type 2 [population] based on the kind of evidence that people who are on multidose insulin can clearly benefit.”

From a payer perspective, Snow said, the fact that the FDA approved the Dexcom G5 for dosing was reassuring—this was a key step in Medicare’s reversal of its longstanding refusal to pay for CGM. “Once you have that FDA stamp of approval, there’s significant advantage, not the least of which is it usually means that there’s legitimate scientific evidence,” he said. “And that scientific evidence is what supports the use.”

CGM data will be more reliable than patient logs, which could be helpful with older patients. “That helps diabetes educators and physicians with medication adjustments and lifestyle changes,” Hodorowicz said. “With the pediatric population, it’s wonderful because parents are so involved with their children’s control, especially of type 1.”

Audible alerts can help patients or caregivers avert an approaching hypoglycemic event. “Payers are starting to recognize that,” Hodorowicz said, “and it’s not just for the type 1s, it’s also for the type 2s on multiple daily insulin doses.”

Devices help, but it’s essential that patients already be engaged in their own care, Kaufman said. He pointed to a program developed by Stanford University, the Chronic Disease Management Program, which is decades old and has been highly successful with patients with T2D.

 “If your A1C was above 9%, it went down by 0.93% at 6 months, and 1.27% at 12 months with a 6-week intervention,” he said. “How does it work a year later? Because people change their lives, change their emotions; they change their sense of well-being, and, therefore, they were able to follow doctor’s orders better, follow nurse’s orders better.”

“And that becomes crucial in anything that has to do with self-management,” Kaufman added. Scanlon noted that this was work pioneered by Katie Lorig, DrPH, and remains foundational in chronic disease management.

Scanlon and Kaufman discussed the need for peer-to-peer support, either in person or in digital formats. Gabbay noted that vast potential for the latter is “just beginning to be tapped.” “Continuous glucose monitoring certainly helps, and even the simple ability of downloading blood glucose meter data and looking at that with the patient is really helpful,” he said. Providers don’t want too much data, however, and decision support tools help manage it all, which he called the next revolution.

“The next revolution after that,” Kaufman said, “is being able to assess it in the moment and give feedback to the individual in the moment.” The challenge, he noted, is that managing diabetes requires patients to constantly make micro decisions. No single decision is hugely important; it’s the sum of them that determines the outcome. The perfect device would require no interaction.

It’s hard to balance the desire for tools without overloading patients to the point of “alarm fatigue,” when they tune out the efforts to help them, Snow said, “because it just gets in the way of living.”

Payer Coverage, Patient Choice in Insulin Pumps

In this rapidly evolving area, Gabbay said, the FDA appears to be open to approving devices more quickly that it had been. “The floodgates are about to open because there are a whole series of iterative changes that can be made to push forward semiautomated insulin delivery,” he said.

As Scanlon noted, however, the issue is figuring out for whom is the device appropriate. “And how do we determine appropriateness?” he asked.

“That’s one of the great challenges, because there’s not a lot of good data that identifies who makes a good pump user,” Snow said. “We can extrapolate [whom] we believe that might be, but there’s not really a lot of data that [are] going to predict for the person sitting in front of you, whether they are likely to succeed or fail.”

Gabbay said that this is changing with the movement toward semiautomatic delivery; the bar is no longer as high for patients’ carb-counting and insulin-adjustment skills. “You could take patients with poor glycemic control and maybe not terribly adherent and [put them] on semiautomated insulin delivery, and that would at least improve their blood sugars overnight, and they would benefit,” Gabbay said.

CMS approved external insulin pumps for T1D and T2D Medicare patients who had been on multiple daily injections (and who have less control as they learn to use the pump in the first year), Hodorowicz noted. “The cost benefit has to be there for CMS to approve coverage for such an expensive item,” she said.

When asked about the differences between models and patient preferences, Hodorowicz said that a waterproof device is important to many patients. Some devices are disposable; some offer wireless infusion versus manual control. Different types of alarms matter to patients, as does ease of calibration. “I think the ease factor is critical,” she said.

CGM devices are on the verge of becoming much smaller and cheaper, Gabbay said, although pumps may remain relatively expensive and complex. Snow noted a possible disconnect between what makes sense from an individual’s point of view versus the population perspective. Giving an expensive device to a patient with a high glycated hemoglobin who seems unmotivated and unengaged may not make sense, but if a person’s A1C of 10% drops by 1.5%, then the population has become healthier overall.

A person with T2D with poor control could benefit from a continuous glucose monitor, Kaufman said, by identifying personal patterns and seeing the connection between certain foods and spikes in blood glucose. “The question becomes, can it become a behavior-change incentive to allow you to become even better at managing your own condition?” he said.

The panel discussed an agreement that will require most adult UnitedHealth patients with diabetes to transition to Medtronic pumps and CGM devices as warranties expire.

 “Sadly,” Gabbay said, “it’s somewhat inevitable because there will be competition around price, the same kind of things that happen in the pharmacy world—I don’t see why it won’t happen in the device world.”

Snow said that historically, if 2 drugs have equal efficacy but 1 is cheaper, the savings are passed down the line and ultimately result in lower premiums. “Clearly, there can be a benefit without a detriment of care,” he said.

Scanlon asked if payment models would change in this area, too. “Without a doubt,” Snow said. “It is the direction of the payer industry.” Many pharmaceutical companies have entered these agreements, “and the device companies are looking that way, as well,” he said.

“The idea of just paying for your treatment is one that was there in the past, but more and more the question is: is there a value from your drug, from your device? Regardless of what it is, is it adding value in terms of either less expensive care or better care? And it doesn’t have to be both.”

Gabbay added that A1C is no longer the only measure of success. “If you reduce hypoglycemic episodes, well, that’s probably a good thing, and that should be a metric, as well.”

The field of diabetes technology has entered an exciting era, Kaufman said. “A paradigm shift is happening,” he said. “We’ve got consumerism, where individuals are taking more control and responsibility for many things, including their health and health care. We’ve got technology being able to deliver something in the moment. You have it in your pocket at all times.

Peer Exchange: Diabetes Stakeholders Summit

Finding Value in Today's New Insulins, GLP-1 Combinations

From Unexpected CV Benefits to Potential in Heart Failure: Insights and Outlook for SGLT2 Inhibitors

Can SGLT2 Inhibitors Prevent Heart Failure in a Broad Population?

With Rise of Diabetes Technology Comes Value-Based Payment