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

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, The American Journal of Managed Care^® 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—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—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),^1,2 “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—basically every situation where a treat-to-target trial has been done—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”—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 Evidence-Based Diabetes Management™ that discussed the complexity of the debate over prices.³ “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 » until they move through the “donut hole.” (Starting in 2017, changes to the law will allow Medicare patients to close the gap more quickly.⁴)

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.⁵ 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.⁶

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.

1. Examine the evidence for what offers a benefit versus what is questionable.
2. Negotiate to give patients options to improve cost.
3. Hold costs down while keeping an array of options for a particular member.
4. 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.

A Marriage Made in Heaven

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).⁷

“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—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—but a very important convenience issue if they’re not adherent [with separate injections].”

All stakeholders—managed care, pharmaceutical companies, physicians, and patients—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 the issue,” Gabbay said. “Medicine only works if people are adherent to it.”

Selecting the Right Therapy

“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—for the patient, affordable; accessible per the payer and the mail order pharmacies; and appropriate—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.” 

1. American Diabetes Association. Standards of medical care in diabetes—2017, glycemic targets. Diabetes Care. 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. Endocr Pract. 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. Am J Manag Care. 2016;22(SP13)SP472.

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. The American Journal of Managed Care^® 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. The American Journal of Managed Care^® website. http://www.ajmc.com/newsroom/soliqua-sanofis-entrant-in-insulin-combo-battle-gets-fda-approval. Published November 22, 2016. Accessed June 23, 2017.

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