A pair of experts in the management of diabetes review the role of insulin therapy and review the approval process for biosimilars, including the FDA's approval of the first interchangeable insulin biosimilar.

Interchangeable Insulin Biosimilars: A Game Changer in Diabetes Management

Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES: 

I’d love to hear about these clinical studies that were done to support that Semglee [insulin glargine-yfgn] can be interchanged with the reference product.

Thomas C. Blevins, MD, ECNU, FACE, FNLA: 

I’m going to ask the audience a question. Diana, you said earlier this insulin is called glargine-yfgn, and that’s Semglee [insulin glargine-yfgn]. So I’m going to ask the audience, what does YFGN mean? What does it stand for? I’m going to go ahead and answer. It means nothing—4 lowercase letters and any biosimilar now just has to have a dash from the reference. Instead of glargine-yfgn, you could choose, zzzz or something.

You’re right. Remember, you have to study these biosimilars in humans with diabetes. There’s an INSTRIDE 1, guess what, that’s type 1; INSTRIDE 2, for type 2; and INSTRIDE 3, which is the study that helps get the interchangeability. I’ll talk about each 1. Let me just give you a brief. In INSTRIDE 1, there were 558 people with type 1 diabetes. This is a study in which 1 group is going to be put on reference—the originator—and 1 is going to be put on the biosimilar. They’re going to be followed for a period of time—24, 52 weeks. As it turns out, the different end points are going to be looked at at those times. They’re going to be looked at for [hemoglobin] A1C changes, hypoglycemia. We’ll talk about it in a minute. In INSTRIDE 2, there were 560 people with type 2 diabetes. These are people who need basal insulin. The reference is compared with the biosimilar. We’ll talk about the INSTRIDE 3 separately.

Let’s talk about INSTRIDE 1. It turns out that if you look at the A1C data—I wish I could show it to you, but I’ll summarize it—they’re the same. There was no difference between the start and finish of the study and between the 2 groups, Lantus [insulin glargine] and biosimilar insulin glargine. We’re talking about -yfgn insulin. The A1Cs were the same from start to finish in this group of people with type 1 diabetes. If you look at the fasting plasma glucose, it’s the same. There’s no significant difference, and that goes for the A1C. The bottom line is noninferiority in A1C results. The doses of the insulin were similar. The A1C results were close to the same. As I mentioned, the fasting glucose, incidence of adverse events, serious adverse events are all very similar. Incidence of hypoglycemia is also similar. No clinically meaningful differences between treatment groups. That’s the type 1 study.

The type 2 study can summarize easily too if you look at the A1C changes at week 12 and 24, between the 2 insulins. It’s very close—no significance there, and no significant difference. If you look at safety—and the same thing goes for serious adverse events, hypoglycemia—if you look at the glargine dose over time, it’s very similar in terms of dosing over time. There are no significant differences. There are no clinically significant or meaningful differences between the 2. There were immunogenicity studies—the INSTRIDE 1 and INSTRIDE 2 studies—looking at antidrug antibodies studies—antibodies to insulin. Does 1 type of insulin cause more antibody production than another? That’s a big deal in terms of safety. The answer is, long story short, the INSTRIDE 1 and INSTRIDE 2 studies over the time period looked at—we have 50-week data in the type 1 study and 24-week data in type 2 and no significant cross-reactive, antidrug antibody presence between the 2—were very similar. Those are the data on the core studies.

INSTRIDE 3 is the switching study. The way this study worked is that people were taken from the INSTRIDE 1 study and were offered to continue into this switch study. One group is left on references in glargine throughout the study, and we’re looking at 36 weeks. Another group is given the biosimilar for 12 weeks, then given the reference insulin for 12 weeks, then given the biosimilar for 12 weeks. It’s a switch study, and their results are looked at. The results again showed that there was no significant difference between the treatment groups when it came to A1C during the different treatment periods. There was no difference in fasting glucose and monitor glucose, and immunogenicity looked very similar too. Those data show us that we can have the confidence, and the FDA has the confidence, that a pharmacist can change without us saying it’s OK because we have an insulin extremely similar in every way that we talked about. That’s a big deal.

Thank you. That was such a good summary of the different studies. That should be reassuring that the clinical outcomes are almost the same between the 2 products, and it should give people peace of mind that if they’re switching between insulins, they can expect the same clinical effect.

Videos

Experts in diabetes management discuss data from key clinical trials—INSTRIDE 1, INSTRIDE 2, and INSTRIDE 3—and evaluate the use of insulin glargine-yfgn as an interchangeable product with biologics.

Results of INSTRIDE Studies for Diabetes Management

I want to switch gears and talk about biosimilars. We have insulin glargine-yfgn. The brand name is Semglee. This is the first interchangeable biosimilar approved by the FDA. Tom, I know you have so much expertise in this area. Can you define for our audience what a biosimilar is? Maybe talk through how the FDA approves biosimilars and how these compare with the original reference product.

Diana, I’d be happy to talk about out that. This is important to understand. Let me throw out a couple definitions. No. 1, a biologic is essentially a pharmaceutical agent created in living cells. That’s what we’re dealing with here. Insulin is a biologic. This is a very complicated process. Making a biologic is not like making a generic statin or a generic other kind of medicine; this is complicated. A biosimilar is a biologic medicine that’s highly similar to the reference biologic with no clinically meaningful or notable or significant differences in terms of the safety, purity, and potency. We’re talking about insulin. We’re talking about glargine. The reference biologic, the reference glargine, will always be the Sanofi Lantus insulin. Anytime somebody wants to do a biosimilar glargine, they’re going to reference to the original, essentially Lantus.

Another point is that a biosimilar is an approved version of a biologic medicine with identical amino acid structure sequencing to the originator, which would again be the reference. The intent is to make it as close as possible in every way to the reference biologic. Biologics are complex; therefore, biosimilars are complex proteins. If you look at a small molecules—things that are generics, that are pills—they’re very different from a biologic. I won’t dwell on that, but the biologics are much larger and complicated. There are quite a few biologics available.

The approval process for a biosimilar requires the person who wants approval of their biosimilar to go to the FDA with data that show that the pharmacokinetic/pharmacodynamic data are very similar. Also, they have to show mitogenicity. They have to look at things that are from the bench to the clinic. Then they need to do large, but not terribly large, studies with people who have type 1 or type 2 diabetes and show that the insulin is highly similar in terms of efficacy, safety, and immunogenicity. Those are the standards set by the FDA. The Semglee [insulin glargine-yfgn] people and the Viatris people had to do that. That’s what Eli Lilly had to do when they got Basaglar [insulin glargine] approved. It had to show that all those things, from the bench to the clinic, were highly similar. Then they get approved if their insulin was highly similar. We can talk more about that in a minute, as far as the studies that were done.

Thanks. That’s so informative and helpful. What exactly is an interchangeable product? Are there any other biosimilars that also have this status of being interchangeable?

Everyone may be surprised to hear that there was no insulin, until now, approved as an interchangeable insulin. Now Semglee [insulin glargine-yfgn] has that approval. The FDA requires that a company does studies that show that you get the same clinical result as the reference product, with no diminished efficacy, no sign of safety issues, and no sign of difference in immunogenicity. What the FDA requires can change, and this is an evolution. The FDA encourages switching studies. That’s a study where you take people with type 1 or 2 diabetes, and you put 1 group on the reference product—the originator, like Lantus [insulin glargine]—and other people on the biosimilar. Then you treat them for periods like 3 months at a time. Then you switch them to the other side to see if there’s any difference, then you switch them back. The question is, how many switching periods will there be? As long as the safety, efficacy, and all that are highly similar, you have a chance of getting approved. You have to show that to get interchangeability. This is the bottom line, and it’s surprising to everyone I think. Interchangeability has not been approved until now, and I suspect there will be others down the road. This is a big deal. I wanted to talk more about the design. We can in a bit or anytime you’d like about the advantage of having an interchangeable insulin.

I’ll just add that 1 of the big things about interchangeable insulin is it means if a prescription is sent to the pharmacy for insulin glargine or for Lantus [insulin glargine], the pharmacist can change it to Semglee [insulin glargine-yfgn] and not have to contact the prescriber to be able to do that. That’s a big deal, and we’ll definitely talk more about that in a bit.

Thomas C. Blevins, MD, ECNU, FACE, FNLA, provides an overview of biosimilars and discusses interchangeability status among biosimilars such as for insulin glargine-yfgn for the management of diabetes.

Role of Interchangeable Biosimilars in the Management of Diabetes

 presentation titled “Interchangeable Insulin Biosimilars: A Game Changer in Diabetes Management.” I’m Diana Isaac from Cleveland Clinic in Cleveland, Ohio. I’m joined today by Dr. Thomas Blevins from Texas Diabetes and Endocrinology in Austin, Texas. Our discussion will focus on insulin therapy and approval of the first interchangeable insulin biosimilar. We’ll also discuss the role of biosimilars in endocrinology. Welcome, and let’s begin. Tom, I want to start by asking you to just briefly describe the pathophysiology of diabetes and the whole rationale for insulin therapy.

Thank you for asking, and thanks everyone for listening. This is interchangeability, which we’re going to get to; it’s a big deal. Pathophysiology in type 1 diabetes is straightforward. People don’t make insulin; therefore, they need insulin replacement and a hormone replacement treatment. We use basals and bolus, and we use insulin pumps and things like that. They have to have insulin. If they’re using multiple daily injection, then they’re going to need to have a basal insulin. We’ll talk more about those in a minute. For type 2 diabetes, many people don’t need insulin at all. They don’t make enough insulin, as you all know. We do use insulin in those who can’t control with other means. We use basal, and we use the bolus pre-meal. Sometimes we need basal alone to give them that supplemental amount, to give them just enough to get the control we want. So they are 2 different pathophysiologies. Both need insulin, but not everyone with type 2 needs insulin.

All great points. People with type 1 diabetes are always going to need kind of a basal and a bolus. As we see, people with type 2 diabetes are being diagnosed earlier in life. Through the natural progression of diabetes, even though we have a lot of great noninsulin medications, it’s very natural that over time people do need to supplement with insulin. Very commonly, we start with a basal insulin. Many people progress to needing a bolus insulin with type 2 diabetes as well. With that, I’m hoping that you might be able to provide us with maybe a brief historical overview of the FDA-approved basal insulins.

You may be saying I’m a little historic. But you’re probably right. I was in training in the 1980s and medical school starting in the 1970s. I’ve seen, as many of us have, quite a bit of evolution. We had long-acting insulins, like Ultralente—most people don’t even know what that is nowadays. Don’t even try to know by the way—let me give you that advice. It was once a day. For the most part, though, we used an insulin, the Neutral Protamine Hagedorn, the NPH, which was the protamine-based insulin that was more of an intermediate acting. We called it basal. The way we used it back then—diabetes management was an art and a science. A little more art than science sometimes because with NPH you had to use multiple doses to get any a leveling in the background. NPH was a true mess. It would peak in 6 to 8 hours, and then it dropped off after 14 to 16 to 18 hours depending on the dose. I’d have some patients use NPH in the morning, some at dinner, and some at bedtime to try to spread out the effect.

Then, about 20 years ago, came detemir, which is a once a day. It’s an insulin that we use now. I’ll say the drug name Levemir [insulin detemir] because people are familiar with that name. It lasts for about 24 hours. Then along came insulin glargine. You add a glycine to the A chain of insulin and 2 arginines to the B chain, and voilà—you have an insulin that lasts longer, and you get into this manipulation of the molecule to make it work better and longer and to suit our needs better.

Glargine came along; it’s once a day. That was a huge change. We had much more predictable usage of basal. glargine is probably the most commonly used basal around the world at this point. I think that’s true. Later, around 2005 or so, we got degludec, which is Tresiba [insulin degludec]. Then we got the U300 glargine, and we got that 10 or 15 years ago. So we’ve had this nice evolution of where we’re going with basal insulin.

We use these in people with type 1. We try to simulate physiology as best we can. That’s what we try to do. We use them in type 1, and we use them in type 2 to get our basal effect. We’re not going to talk about bolus much here, but we’re talking basal. We’ll get into this as we talk more about these in a minute. Now we’ll get into the biosimilars that will offer some better access and affordability.

Thanks. Those are all great points. Having an insulin that truly can last 24 hours a day has been a big game changer in diabetes because back with the NPH, patients had to dose it twice a day, and it’s challenging to remember to take something that many times. Unfortunately, it would wear off before 24 hours, and then your glucose levels go up. So it was much more challenging. It’s so nice to have basal insulins that can truly last 24 hours or even longer than 24 hours that we see with degludec and with glargine U300, the more concentrated version.

Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES, and Thomas C. Blevins, MD, ECNU, FACE, FNLA, review FDA-approved basal insulins for the management of diabetes.

Basal Insulin Therapies for Diabetes Management

Patrick Campbell is the senior editor of Endocrinology Network, as well as its sister publication Practical Cardiology. Prior to joining these brands, he led coverage of cardiology and diabetes with HCPLive. Before joining parent company MJH Life Sciences in 2019, he spent time as a beat reporter with the Pocono Record in Stroudsburg, PA and Star News Group in Manasquan, NJ. He also touts experience in multimedia, having spent time as a freelance multimedia specialist with NJ Advance Media and multimedia coordinator at the Pocono Record. In his free time, he enjoys traveling, sports, and exploring the great outdoors. Follow him on Twitter @RealPatCampbell or reach him via email at PCampbell@mjhlifesciences.com.

A recent analysis suggests transfeminine individuals were at a 40% greater risk of developing diabetes than their cisgender counterparts, but this increase in risk was not attributable to gender-affirming hormone therapy.

A retrospective look at electronic medical record data from more than more than 50,000 patients, results of the study provide insight into the increase in risk among transfeminine patients and the apparent lack of influence undergoing gender-affirming hormone therapy had on the risk of developing 

“Our study findings provide some reassurance that gender-affirming therapy does not increase the risk of type 2 diabetes, but our analysis was not designed to evaluate more subtle subclinical changes,” said Noreen Islam, MD, MPH, of Emory University School of Medicine, 

. “For this reason, health care providers should continue monitoring the metabolic status of individuals receiving gender-affirming therapy.”

As the incidence of type 2 diabetes and use of gender-affirming hormone therapy both increasing in recent years, Islam and a team of colleagues sought to assess the occurrence of type 2 diabetes among transgender persons and compare this to the rate among cisgender reference groups. To do so, they designed their study as an analysis of data from the Study of Transition Outcomes and Gender (STRONG) study and electronic medical record data from a trio of Kaiser Permanente health systems in Northern California, Southern California, and Georgia from 2006-2014.

For the purpose of analysis, up to 10 male and 10 female cisgender Kaiser Permanente patients were matched to transgender individuals in the final cohort based on race/ethnicity, year of birth, study site, and calendar year of membership based on index date. Overall, 5002 transgender individuals were identified for inclusion in the study, including 2869 trans feminine and 2133 transmasculine individuals. The patients in the transfeminine cohort were then matched to 28,300 cisgender females and 28,258 cisgender males while the transmasculine cohort were matched to 20,997 cisgender females and 20,964 cisgender males.

Investigators used Cox proportional hazards and logistic regression models to assess the incidence and prevalence of type 2 diabetes among these patient cohorts. Investigators pointed out all analyses performed were controlled for BMI.

Upon analysis, 94 incident cases of type 2 diabetes were identified among the trans feminine cohort and 44 incident cases were identified among the transmasculine cohort. Of the 94, 17 were diagnosed after initiation of gender-affirming hormone therapy. Of the 44, 12 were diagnosed after initiation of gender-affirming hormone therapy. The incidence of type 2 diabetes per 1000 person-years was 9.3 (95% CI, 7.6–11.3) among all transfeminine patients and 5.9 (95% CI, 3.6-9.4) among those who underwent gender-affirming hormone therapy. Among transmasculine individuals, the incidence rate was 6.2 (95% CI, 4.6-8.4) overall and 5.5 (95% CI, 3.1-9.7) among those who underwent gender-affirming hormone therapy after the index date.

Further analysis indicated those in the overall trans feminine cohort had a moderately greater rate of type 2 diabetes compared to the cisgender female reference group (HR, 1.4; 95% CI, 1.1-1.8), but not in comparison with the cisgender male reference group (HR, 1.2; 95% CI, 0.9-1.5). For the transmasculine cohort, the corresponding hazard ratios were 1.3 (95% CI, 0.9-1.8) compared to the cisgender female cohort and 1.2 (95% CI, 0.9-1.7) for the cisgender male cohort.

“Although more research is needed, there is little evidence that type 2 diabetes occurrence in either transgender women or transgender men is attributable to gender-affirming hormone therapy, at least in the short term,” Islam said.

Is There a Link Between Hormone Use and Diabetes Incidence in Transgender People? Data from the STRONG Cohort

Journal of Clinical Endocrinology & Metabolism.

Articles

A study from Emory University details the risk of developing type 2 diabetes among transgender individuals compared to their cisgender counterparts and takes a deeper dive into the influence of gender-affirming hormone therapy on this risk

Transgender Individuals at Increased Risk of Type 2 Diabetes, Not Linked to Hormone Therapy

This article was originally published on 

New data suggests a cell-infusion grown from stem cells similar to insulin-producing pancreas cells could one day become a solution for restoring insulin production in patients with type 1 diabetes.

Back in June 2021, Brian Shelton received the infusion in a clinical trial by Vertex Pharmaceuticals, Inc. They were testing a decade-in-the-making treatment started by a scientist, Doug Melton, PhD, Xander University Professor at Harvard and Investigator of the Howard Hughes Medical Institute, whose own family was impacted by the disease.

Today, Shelton’s body automatically controls insulin and blood sugar levels, representing a huge leap forward in the treatment of T1D. Previously, the only cure that has been known to work is a pancreas transplant or a transplant of islet cells from an organ donor’s pancreas.

Similar to patients who get pancreas transplants, Shelton is required to take immunosuppressants so his body will not reject the infused cells, which he claims give him no side effects.

Some experts urged caution, as the research is not yet published in a peer-reviewed journal and is based on a single result and needs to be replicated further. The study will continue for 5 years and include 17 patients with severe T1D.

The positive 90 day results were announced by Vertex Pharmaceuticals, Inc. from the Phase ½ clinical trial of VX-880.

VX-880 is the investigational stem cell-derived, fully differentiated pancreatic islet cell replacement therapy for people with T1D. The patient was treated with a single infusion of VX-880 at half the target dose through a hepatic portal vein infusion, together with immunosuppressive therapy.

It was noted that in the year prior to treatment, the patient experienced a total of 5 severe, potentially life-threatening hypoglycemic episodes.

Before VX-880 treatment, the patient’s insulin dose was 34 units per day, while fasting and stimulated C-peptide levels could not be detected, showing the patient was not making insulin.

At various intervals, through Day 90, fasting C-peptide, HbA1c, and 7-day average insulin daily dose was measured. Data show fasting C-peptide was detected early into the treatment course and increased rapidly to Day 90. On the other hand, HbA1c and daily insulin dose decreased over time.

They evaluated islet cell function at baseline and then, at Day 90 using a Mixed Meal Tolerance Test (MMTT) with quantification of C-peptide levels.

Data show at day 90 after VX-880, fasting C-peptide was 280 pmol/L and increased after MMTT stimulation to a peak of 560 pmol/Lm indicating the agent restored glucose-responsive insulin production

Additionally, at day 90, HbA1c improved from 8.6% at baseline to 7.2%, while daily insulin dose decreased from 34 units per day prior to an average of 2.9 units per day over a week at the day 90 visit. This reflected a 91% decrease in daily exogenous insulin use.

No serious adverse events (SAE) were considered related to VX-880.

, James Markmann, MD, Professor of Surgery and Chief of the Division of Transplant Surgery at Massachusetts General Hospital, noted his excitement to progress the potential of transformative medicine through clinical trials.

“As a surgeon who has worked in the field of islet cell transplantation for decades, this approach, which obviates the need for an organ donor, could be a game changer,” Markmann said.

Additionally, Melton discussed the hope he feels stemming from these results.

​​“More than a decade ago our lab had a vision for developing an islet cell replacement therapy to provide a functional cure to people suffering from T1D,” Melton said. “These promising results bring great hope that stem cell-derived, fully differentiated islet cells could deliver a life-changing therapy for people who suffer from the relentless life-long burden of T1D.”

The company will continue the phase ½ program for VX-880, with multiple active sites in the United States and an approval of the Clinical Trial Application in Canada.

Results from a recent clinical trial indicate VX-880 stem cell-derived therapy demonstrated restoration of insulin production and was generally well-tolerated in T1D treatment.

Stem Cell Infusion Shows Promise for Restoring Insulin Production in Type 1 Diabetes

Data from a cohort study of 525 individuals with youth-onset 

 is providing clinicians with insight into the risk of developing diabetes-associated 

Results of the Mayo Clinic-led study, which was a retrospective analysis of individuals from Olmsted County, Minnesota, suggest patients with type 2 diabetes had an 88% greater risk of developing any diabetic retinopathy within the first 15 years of diagnosis compared to their counterparts with type 1 diabetes. Results also demonstrated risk of visually significant cataracts and requiring pars plan vitrectomy were more than doubled for patients with type 2 diabetes compared to type 1 diabetes.

“In this population-based cohort of children diagnosed with diabetes during a 50-year period, patients with T2D developed vision-threatening retinopathy after a shorter diabetes duration and at a higher rate than children with T1D. These findings suggest that to prevent serious ocular complications, children with T2D may require ophthalmoscopic evaluations at least as frequently as or more frequently than children with T1D,” wrote investigators.

As the prevalence of type 2 diabetes in younger populations continues to increase, a greater understanding of the natural history of ocular sequelae could result in improvements in standards of care and quality of life for patients. With this in mind, a group of Mayo Clinic clinicians and medical students sought to provide an overview of the risk of diabetes-associated ocular complications through a retrospective review of electronic medical record data from all residents within Olmsted County, Minnesota diagnosed with diabetes before the age of 22 between 1970-2019.

Using diagnostic codes, investigators identified 1362 individuals for potential inclusion in their analysis. From this cohort, investigators were able to confirm a diagnosis of type 1 or type 2 diabetes among 606 children, including 525 who underwent at least 1 eye examination and were included in the final analysis. Of the 525, 461 (87.8%) had type 1 diabetes and 64 (12.2%) had type 2 diabetes. This cohort had a mean age at diagnosis of 12.1 (SD, 5.4) years and 50.3% were male.

Upon analysis, diabetes-associated ocular complications were identified among 147 individuals with type 1 diabetes and 17 with type 2 diabetes. When assessing risk between type 2 diabetes and type 1 diabetes, results suggested those with type 2 diabetes had an 88% greater risk for developing any diabetic retinopathy (HR, 1.88 [95% CI, , a 49% increase in risk of diabetic macular edema (HR, 1.49 [95% CI, 0.46-4.89]; 

=.50), and a more than doubling in risk for proliferative diabetic retinopathy (HR, 2.33 [95% CI, 0.99-5.50]; 

=.048), visually significant cataract (HR, 2.43 [95% CI, 0.54-11.07]; 

=.24), and for requiring pars plana vitrectomy (HR, 4.06 [95% CI, 1.34-12.33]; 

=.007) in the first 15 years following diagnosis.

, Jennifer Sun, MD, MPH, vitreoretinal surgeon and chief of the Center for Clinical Eye Research and Trials of the Beetham Eye Institute, commends the investigators for the additions of their study to the current knowledge base and points out how results underline the need for further research into differences in patients with type 1 and type 2 diabetes.

“These results emphasize the need to explore potential differences between ocular outcomes in patients with T1D vs T2D and to elucidate the mechanisms behind any differences that do exist. Although the pathophysiology of diabetic retinopathy in T1D and T2D appears largely similar, characteristics such as body mass index, lipid profiles, and presence of hypertension differ substantially between cohorts with these 2 forms of diabetes, and it is important to understand how and whether they contribute to onset or worsening of diabetic retinopathy in youth and adults,” Sun wrote.

Ocular Sequelae in a Population-Based Cohort of Youth Diagnosed With Diabetes During a 50-Year Period

A Mayo Clinic-led retrospective analysis suggests patients with T2D had an 88% greater risk of developing any diabetic retinopathy within the first 15 years of diagnosis compared to those with T1D. 

Type 2 Diabetes Carries Greater Risk of Ophthalmic Complications Than Type 1 Diabetes

New research from an international team of investigators suggests insufficient sleep and later bedtime routines could play a role in the dysregulation of 

among a population of healthy adult patients.

Conducted by investigators from Massachusetts General Hospital and Harvard Medical School, Kings College London, and Lund University in Sweden, results of the study, which was a secondary analysis of data from the PREDICT 1 trial, demonstrate poor sleep efficiency and later bedtime routines were associated with higher blood glucose levels and poorer control of blood sugar following meals.

“This study’s findings may inform lifestyle strategies to improve postprandial blood glucose levels, focusing on earlier bedtime routines and maximizing high-quality uninterrupted sleep. A combination of both generalized and more personalized sleep guidelines is likely required to ensure optimal metabolic health 

 and maximize the effectiveness of guidelines for diabetes prevention,” wrote investigators.

As knowledge of the role of sleep in metabolic regulation becoming more recognized in the care of patients, a team of investigators sought to assess whether night-to-night fluctuations in sleep duration, efficiency, or timing might influence postprandial glucose response to a breakfast meal the following morning. With this in mind, the current study was designed as a secondary analysis of data from the Predicting Inter-individual Differences in Biochemical and Behavioral Response to Meals With Different Nutritional Compositions Using Metabolomic and Microbiome Profiling (PREDICT 1) trial.

Conducted from June 2018-May 2019, PREDICT 1 was a single-arm, multiple-test-meal challenge study conducted over 14 consecutive days that included 1002 healthy participants aged 18-65 years from the UK and the US. Data from 953 of the 1002 participants were included in the trial, which provided investigators with data related to 8395 sleep and postprandial responses for inclusion in their analysis.

Investigators pointed out postprandial glucose was assessed using a Freestyle Libre Pro, which measured interstitial glucose every 15 minutes. Activity and sleep were monitored using a wearable device with a triaxial accelerometer.

Upon analysis, results suggested sleep variables were significantly associated with postprandial glycemic control, which was measured as 2-hour incremental AUC, at both between- and within-person levels. Specifically results indicated sleep period time interacted with meal type, with a smaller effect observed for poor sleep on postprandial glucose levels when high-carbohydrate (

=.03) breakfasts were consumed compared with a reference 75 g OGGT. a similar interaction was observed when assessing the effects of within-person sleep period time (high carbohydrate: 

Further analysis suggested within- and between-person sleep efficiency was significantly associated with lower postprandial blood glucose levels, irrespective of meal type (

 for both <.03). When assessing those with a later sleep midpoint, which was defined as time deviation from midnight, results indicated a later sleep midpoint was significantly associated with a higher postprandial glucose in comparisons in between-person (

“These findings underscore the importance of sleep in regulating metabolic health, and a combination of both general and more personalized sleep guidelines is likely to be necessary to enable patients to minimize their risk of metabolic disease,” investigators added.

Impact of insufficient sleep on dysregulated blood glucose control under standardized meal conditions,

Data from a secondary analysis of the PREDICT 1 trial provides insight into the effects of sleep habits on postprandial glucose control among a cohort of healthy individuals. 

Study Details Impact of Sleep on Postprandial Glucose Control 

This is exciting because this is interchangeable. I feel like this is the beginning of a new era. Can you comment a little on what you think the future is with biosimilars?

In terms of biosimilars around everywhere, we’ll see. You’re talking about biosimilar insulin of course, I think.

You can comment on all biosimilars, but yes, specifically insulin. I’m curious what’s going to be in the future? We have so many types of insulin. Probably many of them are going to be coming off a patent eventually.

They are. There are biosimilar insulin asparts, the NovoLog biosimilars that have been approved by the European group. Sanofi has the biosimilar of Eli Lily’s Humalog [insulin lispro], and that’s Admelog [insulin lispro]. We have that available. It’s in Europe in tier 2. There’s another aspart that’s going to be approved from Sanofi biosimilar before long. The 1 I referred to earlier is going to be Beatrice or Mylan, and then we already have Basaglar [insulin glargine]. As soon as I go off, patent people are going to rush and biosimilar themselves to the reference.

Semglee [insulin glargine-yfgn] is going to be the leader of the interchangeability. That will become the standard, I believe. Every biosimilar will go after interchangeability, as it should. The FDA is defining what a company needs to do to get approval. It’s going to continue to refine its requirement. Remember I mentioned INSTRIDE 3? There were 3 switch periods. It might have to be more than that in the future. Who knows? But biosimilar is going to be the way of the future, and we’ll have choices. Fortunately, we have choices between them, and this biosimilar thing will lead to a lot price competition.

You mentioned that Semglee [insulin glargine-yfgn] is cheaper by 50%, and when you’re looking at numbers, perhaps 1 of the reference product manufacturers will decide to drop their price. Of course, their formulary and prices are sometimes different from what we’re talking about in terms of retail. There’s a gigantic future for biosimilars, which is a good thing. We’re talking about treating diabetes and making the lives of people with diabetes better. More affordability of good treatments makes things better and more accessible. You’ve said this already, but price can stop treatment. If good treatments aren’t affordable, then it’s not going to happen. It’s not going to happen regularly. This is all a big deal for people with diabetes.

Unfortunately, I’ve had patients rationing their insulin. It’s a much more common thing than we realized. Cutting off a few units here and there because they’re trying to conserve their insulin—that’s the saddest thing, that people feel they have to do that. We need to get the price down so people can afford these medications.

We’re wrapping up here, but you mentioned how these are not generics, right? This is a different approval process. Yet I know insulin lispro and insulin aspart have generics, I believe, made by the same exact company. It’s confusing for a lot of people. Why are those considered generics, but then these are biosimilars? How are people supposed to navigate all that?

You’re asking me to refine the definition of that. Any insulin is going to be made from a living cell. It’s a biologic, and those are biosimilars. They’re not approved under the biosimilars pathway because of the approval process change in 2020. They’re approved under what was called a follow-on biologic, which is the same thing. It’s semantics, but it’s the way the approval changes.

There’s 1 lispro, a refined lispro, that has additives. That’s the Lyumjev [insulin lispro-aabc]. That has an -aabc category after it. The Admelog doesn’t have that because it’s approved under somewhat different pathways. Those are biologics and those are biosimilars; they’re not generic. We talk about them. Generic is this concept of something that’s less expensive than the originators but really descriptive. I still talk to patients about this with what would be a biosimilar, and I say it’s like a generic because it’s descriptive. It makes people understand it better. Being strict to terms, those are biosimilars, and they’re not approved as a biosimilar. They’re biosimilars. Generics could be like aspirin, salicylic acids, and statins. Those are small molecules, and they’re easy to make. These are derived from either yeast, bacteria, or living organisms.

I bring it up because there’s a ReliOn insulin aspart that’s available at Wal-Mart. Sometimes patients may get that instead of their usual branded NovoLog [insulin aspart]. We’re seeing things substituted, and it’s important to highlight that it’s all similar. It’s expected to have the same effect, and people should not be alarmed. In fact, they should be happy because they’re going to save the cost. It’s going to be more accessible. Hopefully, that will lead to better clinical outcome.

We’ve talked about a lot of great information. Tom do you have a closing remark that you want to leave the audience with?

I enjoyed the discussion. Our job is to make the lives of people with diabetes better—controlling their diabetes, preventing complications. We want to use meds that we’re familiar with, and we want to get control of the diabetes effectively. In the insulin world, hormonal replacement, we want to simulate the physiology. Having a product—the basal, in particular—that’s less expensive, perhaps more available for our patients and conceptually for anyone, anywhere. That’s a big deal, so this interchangeability is a big deal. I’ll leave you with that final comment.

I love it. I totally agree. This is great news for diabetes. What I want to leave everyone with is, please educate your colleagues and your patients about it. Let people know this is a good thing for diabetes. Hopefully it will help people feel better and lead to the best-possible clinical outcomes by helping remove a barrier, which is cost. With that, I want to thank you all for watching this 

 presentation. We hope you found this presentation to be rich an informative. I wish you all a wonderful day. Thank you.

Drs Thomas C. Blevins and Diana Isaacs share insight on unmet needs and the future treatment landscape of biosimilars in the treatment of patients with diabetes.

Future Directions for the Use of Biosimilars in Diabetes

I want to talk about some challenges institutions might face in trying to adopt biosimilars like Semglee [insulin glargine-yfgn]? What strategies can we use to try to overcome these challenges?

I was going to ask you that, but let me take a stab at it. How do we get people to use a biosimilar? You already said it. Some patients may say, “It’s a generic.” Well, it’s not a generic, but that’s what they’ll understand it as. It’s a biosimilar. They might think it’s inferior. That means educating ourselves and the practitioners to understand the data in a general way. People aren’t going to want to know all about those studies—INSTRIDE 1, INSTRIDE 2, and INSTRIDE 3. We need to talk to practitioners and educate them more about interchangeability and what it means. It needs to be repeated over and over. This is the first insulin that’s going to be interchangeable, and that should give everyone a lot of confidence. If the practitioners are able to educate themselves and educate the patient about—so utilization—the challenge will be educating people about the similar effect and highly similar molecule. It’s not some inferior thing. Then educate them about the potential for cost saving, which is important to all of us. It’s going to be a big education effort.

Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES:

 I totally agree. I just had an email the other day from 1 of our diabetes educators asking, “What’s this new thing, this interchangeable insulin?” There will need to be a big education effort, especially because people may have never heard of the name Semglee [insulin glargine-yfgn]. Or they see those insulin glargine with those additional letters—what does that mean? Why are there these extra letters there? It’s different. Education for the health care team and the patient—we’ve all got to be on board. The other thing, what’s important, is that prescribers always have a choice. When a prescription is put in, they can put “Do not substitute.” Of course, patients have a choice. Prescribers have a choice. That being said, we want to educate. But the outcomes are expected to be similar, other than the potential inactive ingredients, which can be slightly different. Other than that, everything is essentially identical. We want to just make sure everyone is on the same page with that and everyone really knows that so they’re ready.

I’m curious. Do you have any ideas, any strategies for how we get this education? Hopefully educational programs. Any strategies or something you do in your in your office to help educate all those staff so they’re prepared with this new information?

We’re still using a lot of this video approach. That’s what we’re doing with the staff. We have education meetings—getting everyone on and defining these terms are important. Interchangeability—what does it mean and how do you get it? Biosimilar vs generic. There’s a lot of blurring of terms. Understanding the quality of the agent is important. Then we need to talk to our staff and, as you were talking about, educate patients about this. If you go to the pharmacy, you might get another medication. It’s not like you’ve been taken advantage of. You’re getting a really good medication. It’s right on target, so why would I write “Do not substitute”? I don’t think I would. We’re going to get feedback from patients and doctors about those things, and some people will have strong opinions.

We just have to educate—you’re right, we have to. It’s a big effort, and maybe some information bulletins, maybe people talking on some of the education channels like we’re doing. Everyone in the country should hear this show. That’s what I think. There’s a lot of work. A lot of information dissemination. The pharmacist will be a very big part of this, perhaps the biggest part. Having the pharmacist understand this is important, and we can be proactive in terms of education. The last thing is that the guidelines need to say something about this to us. The guidelines speak to us, and all the diabetes treatment guidelines—the ADA [American Diabetes Association], the American Association of Clinical Endocrinology, the European group, the Indian Medical Association, Asian, and everybody around the world—need to say something about this.

I agree. The guidelines need to mention this so people know that this is an option that can help with cost saving. With insulin, which is really a lifesaving, life-needing medication, there’s a lot of interest in what we can do to reduce the cost. This is a mechanism to do that, and it’s a really important 1. We’ve got to get the word out. I agree with you that pharmacists have an important role with this. Because pharmacists now can directly interchange this insulin, it’s going to be important that they educate patients. That may be the first time the patients hear about it. They may go to the pharmacy, and they’re ready to fill their usual Lantus [insulin glargine] prescriptions and then they open their bag and have Semglee [insulin glargine-yfgn]. It’s essential that the pharmacist spend some time explaining the difference. I don’t think it takes much time. You’re just explaining that this is expected to work exactly the same. The doses are going to be the same. If you’re taking 10 units of Lantus [insulin glargine], you’re going to take 10 units of Semglee [insulin glargine-yfgn]. Understanding that is so important. Perhaps it’s putting leaflets into the bag explaining, but we need to let patients know. Otherwise, there are going to be a lot of phone calls to the pharmacies or doctor’s offices saying, “What happened? Did I get the wrong drug? Was this is a mix up?” We owe it to our patients to be transparent with everything and explain that this is truly what’s best for everyone. This is in everyone’s best interests.

Thomas C. Blevins, MD, ECNU, FACE, FNLA, leads the discussion on potential challenges to the adoption of biosimilars in clinical practice, such as for insulin glargine-yfgn in diabetes management, and discusses the importance of patient and provider education.

Challenges to Biosimilar Adoption of Insulin Glargine-yfgn

There’s some additional competition in the marketplace with similar products. I’m curious how you think this may affect things in terms of formulary and price considerations in the marketplace with insulin.

It’s interesting. The biologics are never going to be as cheap as generics because even though they’re biosimilars, they’re still very complicated. The way to make a generic—it’s not inexpensive—is you just crunch out a pill of a statin or something, apparently fairly inexpensively. That’s a generic. This is a biosimilar, and that’s different. Look at some of the pricing strategies. Let’s talk about Semglee [insulin glargine-yfgn]. Basaglar [insulin glargine] is out already as a biosimilar—it’s a follow-on biologic because it was approved under a different pathway. Now we have Semglee [insulin glargine-yfgn] out, and there are others around the world. The pricing can be quite a bit lower potentially. I’m not going to give numbers—they change all the time, and I’m not sure they’re totally accurate every time—but they’re a considerably lower cost. Then comes the complexity of the formularies. Sometimes the formularies have different pricing that they can offer, or they can get from pharmaceutical companies.

Then comes the idea of translating data into practice. Will doctors feel comfortable? In general, it’s safe to say biosimilars are less expensive, making them more affordable, making access better, which is huge in the United States and around the world too. Making a good basal insulin available, to everyone who needs it, is very important. Lots of people have diabetes, and the number of people with diabetes is not going to get smaller. It’s going to be greater everywhere. There’s a real potential for cost saving with a product that’s highly similar—so similar that the FDA says it’s interchangeable. From a practitioner standpoint, I’m pretty happy about that because every time somebody switches from 1 type of insulin to another based on formulary, even though it’s the same insulin almost—sometimes not, sometimes the rapid acting might be a little different from the other rapid acting—I have to prove it. Because the formulary says, “we prefer 1 over the other,” I have to approve it, or my staff does. It costs us a ton of time. If someone could just change it up at the pharmacy, I’ll say yes, go for the 1 that has the best price. I’m very confident that the quality is good. They’re highly similar, they’re interchangeable based on the data, and the FDA agrees. So interchangeability things a big deal.

I totally agree. I can also commiserate with some of the challenges of when you send a prescription in for Lantus [insulin glargine] and it ends up being Basaglar [insulin glargine]. The follow-on biologic is preferred, but the pharmacist can’t make that automatic substitution. Then that requires either unnecessarily trying to submit prior authorization for Lantus [insulin glargine] or going back and forth having to change it. It does add a lot of time to everyone, but it can end up being a delay in the patient being able to get insulin, which is a huge problem. In terms of cost, it’s interesting because our cost structure for insulin is very complicated. Just because 1 product has a lower cost, doesn’t mean it’s going to be preferred by the insurance plan because there are a lot of other dynamics going on with the pharmacy benefit managers and rebates.

Each person’s insurance plan might be a little different, and some may prefer the reference product. They may prefer Lantus [insulin glargine]. In some case, they may prefer Basaglar [insulin glargine]. In some cases, they may prefer Semglee [insulin glargine-yfgn]. It’s very complicated. For sure, for someone who’s paying out of pocket, who didn’t have insurance but now has this interchangeable insurance, it will be less. I recently had to look up all these drug costs. You’re right—they change month to month. I’m updating the standards-of-care table for the ADA [American Diabetes Association], so I had to look all this up. I can tell you Semglee [insulin glargine-yfgn] is about half the price of the reference. It’s a cost savings, and we hope that will translate to everyone—to patient insurance plans, health systems, and across the board. That would be great.

Thomas C. Blevins, MD, ECNU, FACE, FNLA, and Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES, discuss the impact of interchangeable insulin biosimilars on biologic products in the marketplace for diabetes management.

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