FDA OKs Extended-Release Exenatide for Children With T2D

The Food and Drug Administration has approved exenatide extended release (Bydureon/Bydureon BCise, AstraZeneca) for use in children with type 2 diabetes down to 10 years of age, the agency announced July 22.

Previously approved in adults, the injectable is now the second glucagon-like peptide-1 receptor agonist approved for use in pediatric type 2 diabetes, after liraglutide (Victoza, Novo Nordisk) in 2019, and the first with once-weekly administration.

The two extended-release Bydureon products – which differ in delivery device and mixing procedure – are now indicated for use in addition to diet and exercise to improve glycemic control in pediatric patients 10 years of age or older with type 2 diabetes.

Exenatide extended release is not recommended as first-line treatment following diet and exercise.

The approval was based on a 24-week, double-blind, placebo-controlled study in 82 children with type 2 diabetes aged 10 and older. They were randomized to 2 mg once-weekly exenatide extended release or placebo. At week 24, hemoglobin A1c in those randomized to the drug had dropped by 0.25 percentage points, compared with a 0.45 percentage point increase in the placebo group.

Side effects were similar to those seen in adults, including injection site reactions, headaches, and gastrointestinal discomfort.

Currently, metformin is the only oral medication approved for treating pediatric type 2 diabetes, while the injectables also include insulin in addition to the two GLP-1 receptor agonists. During a symposium held in June 2021 at the annual scientific sessions of the American Diabetes Association, speakers expressed alarm about the rise in youth developing type 2 diabetes, noting that the condition typically progresses more rapidly and is less likely to respond well to metformin, compared with adults.

But, the panelists were also optimistic about extended-release exenatide as well as several other therapies for pediatric patients with type 2 diabetes in ongoing phase 3 trials, including the sodium-glucose cotransporter 2 inhibitors dapagliflozin and empagliflozin, and the dipeptidyl peptidase-4 inhibitors alogliptin and linagliptin. Results are expected in the next 1-2 years.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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Walmart to Sell Cheaper Insulin; Advocates Say It’s Still Expensive

The retail giant Walmart has launched its first private brand of analog insulin in the United States called ReliOn Novolog (insulin aspart).

The new product will cost $72.88 per vial and $85.88 for a package of FlexPens. This represents savings of 58% to 75% off the cash price of branded analog products, or up to $101 per branded vial and $251 per FlexPens package, according to the company.

The products will be available at Walmart pharmacies across the United States this week and at Walmart subsidiary Sam’s Club pharmacies in mid-July. Like the brand-name Novolog, they will also be manufactured by Novo Nordisk and require a prescription. The products are intended for use by patients with type 1 or type 2 diabetes.

Walmart’s other ReliOn insulins — NPH, Regular, and 70/30 mix — are all human rather than analog insulin and sell for about $25 a vial.

Analog insulin tends to be more effective and easier to administer than the older human insulin.

The biosimilar rapid-acting lispro analog insulin (Admelog, Sanofi) retails for about $150 a vial.

Organizations React Positively, Yet Caution More Work Is Needed

In a Walmart statement, Tracey D. Brown, chief executive officer of the American Diabetes Association, said: “Diabetes often comes with high medical costs, estimated around $9,601 per person per year. We welcome all affordable solutions that make diabetes management more accessible to millions of Americans living with diabetes. We encourage everyone to ask their healthcare provider questions to better understand what the right and affordable treatment is for their unique medical needs.”

(Prior to becoming ADA CEO in 2018, Brown was chief membership & marketing officer and also senior vice president of operations and chief experience officer for Sam’s Club.)

The type 1 diabetes research and advocacy organization JDRF stated: “JDRF welcomes Walmart’s announcement regarding their plan to offer lower-cost insulin…For people with type 1 diabetes, insulin is a lifesaving drug that no one should ever have to ration or go without. No one should die because they can’t afford their insulin. JDRF has long advocated for affordable and predictable out-of-pocket costs of insulin. The rising cost of insulin is a fundamental issue faced by those living with diabetes, and JDRF applauds this new effort.”

However, JDRF also noted, “While today’s announcement is a step toward making insulin affordable for everyone, more needs to be done. JDRF will continue to urgently drive long-term efforts and push for action from manufacturers, health plans, employers, and the government to remove accessibility barriers.”

And in a statement from Beyond Type 1, an advocacy group that partners with Novo Nordisk, chief advocacy officer Christel Marchand Aprigliano said: “The launch of Walmart’s private-label ReliOn analog insulin is one step closer to ensuring that no one rations or dies from lack of affordable access to insulin in the United States, but longer-term systemic change is needed. We look forward to the elimination of more barriers through both commercial innovation and legislative policy efforts.”

Some Advocates Say the Cost Is Still Too High

On Twitter, however, some people disputed Walmart’s claim that the new products “will revolutionize the access and affordability to diabetes care,” pointing out that the $73/vial price tag is still too steep for many and far more than the price of analog insulin in other Westernized countries.  

Long-time diabetes advocate Kelly Rawlings (@KellyRawlings) tweeted: “Rapid-acting insulin analog (for mealtime dosing): Walmart’s private label insulin brand pen or vial, for diabetes. Vial $72.88. Why not $7.30?”

And Hilary Koch (@HilaryKochME), policy manager for T1International, an advocacy organization that does not take pharma funding, tweeted: “Walmart insulin for $75? Even my 15yo figured out that this was a smokescreen to keep lawmakers from taking real action. $75 x 3 = $225…Hey, Pharma. We see through you. We need a federal price cap. #insulin4all”

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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“Overbasalization” Common in Type 2 Diabetes Management

Overuse of basal insulin rather than adding therapies that target mealtime glucose levels is a common problem in primary care management of type 2 diabetes that impedes achievement of optimal glycemic control, new research suggests.

Such ‘overbasalization,’ defined as a hemoglobin A1c of greater than 8% despite use of more than 0.5 units/kg per day of basal insulin, was identified in about 40% of patients seen in a Florida primary care clinic during 2015-2018. The findings were published in the April 2021 issue of Clinical Diabetes by Kevin Cowart, PharmD, a diabetes care and education specialist at the University of South Florida, Tampa, and colleagues.

The literature suggests that once people with type 2 diabetes start basal insulin, the chance that they’ll achieve a given hemoglobin A1c target, i.e., less than 7%, diminishes significantly if that goal isn’t achieved within the first year of starting insulin, Cowart said in an interview.

“Our analysis suggests that overbasalization plays a role in patients with type 2 diabetes on basal insulin not achieving optimal glycemic control. Basal insulin is not designed to address postprandial hyperglycemia. I think there’s a clear need to address hesitancy in therapeutic progression beyond basal insulin. A lot of factors underlie the delays, with therapeutic inertia being one of them. It’s complex,” he said.

Overbasalization Seen in Large Proportion of Patients

The study comprised 655 adults diagnosed with type 2 diabetes for at least a year who received a prescription for a basal insulin (glargine U-100, glargine U-300, detemir, degludec U-100, degludec U-200, regular U-500, or NPH insulin).

The patients had a mean hemoglobin A1c of 8.4% and a mean basal insulin dose 0.4 units/kg per day. The prevalence of overbasalization was 38.1% for those with hemoglobin A1c above 8%, 42.7% for those with A1c of 9% or above, and 42% with A1c of 10% or greater.

Patient characteristics independently associated with overbasalization were age 35-54 years (odds ratio 1.89), age 65-80 years (0.44), A1c 9% or greater (13.97), and A1c 10% or greater (6.04). Having a prescription for insulin glargine U-100 was associated with a lower overbasalization risk (0.62). In multivariate analysis, only an A1c of 9% or greater remained significant.

Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic, Rochester, Minn., said in an interview that she sees [overbasalization] frequently in patients who are referred to her. “It’s kind of that wall that patients with type 2 diabetes hit because their A1c is high but their fasting blood sugars are normal. Sometimes it’s assumed that there’s a discrepancy, because people don’t always think about postprandial hyperglycemia.”

She also noted that there has been a push in recent years to simplify regimens, particularly in older patients.

“We really want to avoid rapid-acting insulin in older patients because we’re afraid of hypoglycemia, so we start them on basal and keep the noninsulins like metformin and sulfonylureas around. Initially those control the postprandial blood sugar but over time they’re no longer enough.”

Options Exist for Addressing Postmeal Blood Sugar Highs While Minimizing Lows

While in the past adding premeal insulin was the only option, today there are alternatives for addressing postmeal hyperglycemia, at least in the short term.

Cowart advised that the first step is to have patients self-monitor their blood glucose and titrate their basal insulin to address fasting hyperglycemia first. Once that appropriate dose is reached, if the patient’s hemoglobin A1c is still above target, the next step is to evaluate the need for postmeal control.

For patients who are at high cardiovascular risk, the next step might involve adding a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) instead of premeal insulin. But for patients in whom overbasalization is the main concern, a GLP-1RA might be the better choice since it will have a greater impact on postprandial glucose levels, while an SGLT2i will have more effect on fasting blood sugar, he said.

Another option is to use a fixed-dose combination of basal insulin and a glucagon-like peptide 1 receptor agonist (GLP-1RA), provided there aren’t cost or formulary barriers. “We want to use the right combination of drugs and not use too much of one to lead to hypoglycemia,” Cowart said.

McCoy doesn’t use fixed-dose combinations because they don’t allow as much flexibility in dosing. To correct overbasalization, she also recommends adding either a GLP-1RA or SGLT2i instead of premeal insulin. However, she cautions, “you still have to monitor those patients because after a few years it still won’t be enough and you’ll have to add mealtime insulin.”

If cost or lack of coverage prevents a patient’s use of SLGT2i/GLP-1RAs, McCoy said that adding just one premeal injection of rapid-acting insulin before the largest meal of the day is one option. Another is to use twice-daily NPH insulin instead of analog basal insulin, since that does offer some postprandial coverage.

Cowart said his approach in cost barrier situations is to try to use patient assistance programs and to look into the patient’s formulary to see if there is step therapy or tier considerations, and maybe have a discussion with the insurance company. “We often have to navigate that, and it does take a significant amount of time and could potentially delay patients getting the right therapy when it’s warranted. That is an area where there is a particular role for pharmacists in helping to overcome that and get patients on the right drugs,” he explained.

Problem May Be Even More Common; Testing Is Key

McCoy said that the A1c cutoff of 8% used to define overbasalization in the study probably resulted in an underestimation of the problem, since many patients are experiencing nighttime hypoglycemia from the basal insulin. The lows bring down their A1c level, but they’re still experiencing postmeal highs.

“I think they’re missing a lot of people, to be honest. I see a lot of patients with A1cs that aren’t that bad, say 7.5%, and their fasting blood sugars are okay, but if you were to put a [continuous glucose monitor] on those patients, invariably there’s hypoglycemia at night that no one knew about.”

Of course, for insurance reasons, most people with type 2 diabetes don’t currently have access to continuous glucose monitors. And often those who are not taking multiple daily injections are limited to one fingerstick test strip a day.

McCoy says that if hypoglycemia is a concern she will write a prior authorization justifying more test strips.

“I state explicitly in my notes why I recommend frequent monitoring. If they’re on a sulfonylurea, they should be able to check more frequently because they can have hypoglycemia. Same thing with basal insulin.”

McCoy advises that patients test their blood sugar 2 hours after the largest meal on one day, and at other times on different days. “Blood glucose after a meal shouldn’t be more than 200 [mg/dL]. If it is, that’s not a failure of basal insulin. It’s doing its job. You just need a different agent.”

Cowart has no disclosures. McCoy receives funding from the National Institutes of Health.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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Daily Cup of Coffee Linked to Lower Risk for Type 2 Diabetes

Drinking one cup of coffee each day lowered individual risk for developing type 2 diabetes 4%–6%, according to data from a pair of large, population-based cohorts.

Coffee had previously been associated with a lower risk of type 2 diabetes, said Carolina Ochoa-Rosales, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands. However, the potential impact of coffee consumption on the subclinical inflammation associated with type 2 diabetes has not been well studied, she said.

In a study presented at the American Heart Association’s virtual Epidemiology and Prevention/Lifestyle & Cardiometabolic Health meeting, Ochoa-Rosales and colleagues reviewed information for men and women who were enrolled in the UK Biobank Study (145,368) and in the Rotterdam Study (7,172).

Coffee consumption assessment was based on interviews, while diabetes incidence was based on fasting glucose measures, general medical records, and pharmacy records of type 2 diabetes drugs.


The researchers used a Cox proportional hazard model to determine the association between coffee and type 2 diabetes, controlling for sociodemographic, health, and lifestyle factors.

Overall, an increase of one coffee cup a day was associated with a 4%-6% reduced risk of type 2 diabetes (hazard ratios, 0.94 for the Rotterdam Study and 0.96 for the UK Biobank study). The effects appeared strongest in drinkers of filtered or ground coffee vs. those who reported drinking mainly instant coffee, she added.

Also, an increase in coffee consumption of one cup a day was linked to lower levels of longitudinally assessed homeostatic model assessment of insulin resistance (HOMA-IR), with lower C reactive protein (CRP) and higher levels of adiponectin, Ochoa-Rosales said.

Levels of CRP and adiponectin may contribute to the association between coffee consumption and diabetes risk, she said. In a mediation analysis, CRP levels mediated roughly 3%-9% of the effect of coffee on type 2 diabetes risk; some effect was observed for adiponectin, but did not reach statistical significance, she added.

The study findings were limited by the lack of control for all potential confounding variables, and the results must be interpreted cautiously, Ochoa-Rosales said. However, the results were strengthened by the large sample size and suggest that coffee’s beneficial effects on lowering type 2 diabetes risk are partially mediated by improvements in systemic inflammation, she concluded. “Other mediators that we did not investigate may also play a role,” she said.

Large Cohort Adds Credibility

Although the associations between coffee and type 2 diabetes have been previously reported, “this study offers important findings due to the carefully standardized analyses on these two major data sources,” Linda Van Horn, PhD, RD, said in an interview.

But what makes this study different is that “these investigators hypothesized that this association could be due to an anti-inflammatory benefit,” she said.

The take-home message for clinicians is that drinking moderate amounts of filtered coffee offers a potentially reduced risk of developing type 2 diabetes, said Van Horn, of Northwestern University, Chicago. However, additional research is needed to account for the total amount of coffee per day, and whether additions such as cream or sugar or other additives make a difference in outcomes, she added.

“Also, the risk vs. benefit of drinking coffee over the life course, including childhood, pregnancy, and older age, with possible adverse drug-nutrient interactions, remain unexplored,” she noted.

Ochoa-Rosales disclosed study funding from the Institute for Scientific Information on Coffee but had no other financial conflicts to disclose. Van Horn had no financial conflicts to disclose.

This article originally appeared on MDEdge.com.

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Ancient people had far different microorganisms in their guts than modern humans

Only an anthropologist would treasure millennia-old human feces found in dry caves. Just ask Dr. Meradeth Snow, a University of Montana researcher and co-chair of UM's Department of Anthropology.

She is part of an international team, led by the Harvard Medical School-affiliated Joslin Diabetes Center, that used human "paleofeces" to discover that ancient people had far different microorganisms living in their guts than we do in modern times.

Snow said studying the gut microbes found in the ancient fecal material may offer clues to combat diseases like diabetes that afflict people living in today's industrialized societies.

We need to have some specific microorganisms in the right ratios for our bodies to operate effectively. It's a symbiotic relationship. But when we study people today – anywhere on the planet – we know that their gut microbiomes have been influenced by our modern world, either through diet, chemicals, antibiotics or a host of other things. So understanding what the gut microbiome looked like before industrialization happened helps us understand what's different in today's guts."

Dr. Meradeth Snow, Researcher, University of Montana

This new research was published May 12 in the prestigious journal Nature. The article is titled "Reconstruction of ancient microbial genomes from the human gut." Snow and UM graduate student Tre Blohm are among the 28 authors of the piece, who hail from institutions around the globe.

Snow said the feces they studied came from dry caves in Utah and northern Mexico. So what does the 1,000-year-old human excrement look like?

"The caves these paleofeces came from are known for their amazing preservation," she said. "Things that would normally degrade over time look almost brand new. So the paleofeces looked like, well, feces that are very dried out."

Snow and Blohm worked hands-on with the precious specimens, suiting up in a clean-room laboratory at UM to avoid contamination from the environment or any other microorganisms – not an easy task when the tiny creatures are literally in and on everything. They would carefully collect a small portion that allowed them to separate out the DNA from the rest of the material. Blohm then used the sequenced DNA to confirm the paleofeces came from ancient people.

The senior author of the Nature paper is Aleksandar Kostic of the Joslin Diabetes Center. In previous studies of children living in Finland and Russia, he and his partners revealed that kids living in industrialized areas – who are much more likely to develop Type 1 diabetes than those in non-industrialized areas – have very different gut microbiomes.

"We were able to identify specific microbes and microbial products that we believe hampered a proper immune education in early life," Kostic said. "And this leads later on to higher incidents of not just Type 1 diabetes, but other autoimmune and allergic diseases."

Kostic wanted to find a healthy human microbiome without the effects of modern industrialization, but he became convinced that couldn't happen with any modern living people, pointing out that even tribes in the remote Amazon are contracting COVID-19.

So that's when the researchers turned to samples collected from arid environments in the North American Southwest. The DNA from eight well-preserved ancient gut samples were compared with the DNA of 789 modern samples. Half the modern samples came from people eating diets where most food comes from grocery stores, and the remainder came from people consuming non-industrialized foods mostly grown in their own communities.

The differences between microbiome populations were striking. For instance, a bacterium known as Treponema succinifaciens wasn't in a single "industrialized" population's microbiome the team analyzed, but it was in every single one of the eight ancient microbiomes. But researchers found the ancient microbiomes did match up more closely with modern non-industrialized population's microbiomes.

The scientists found that almost 40% of the ancient microbial species had never been seen before. Kostic speculated on what caused the high genetic variability:

"In ancient cultures, the foods you're eating are very diverse and can support a more eclectic collection of microbes," Kostic said. "But as you move toward industrialization and more of a grocery-store diet, you lose a lot of nutrients that help to support a more diverse microbiome."

Moreover, the ancient microbial populations incorporated fewer genes related to antibiotic resistance. The ancient samples also featured lower numbers of genes that produce proteins that degrade the intestinal mucus layer, which then can produce inflammation that is linked with various diseases.

Snow and several coauthors and museum collection managers also led a project to ensure the inclusion of Indigenous perspectives in the research.

"This was a really vital part of the work that had to accompany this kind of research," she said. "Initially, we sent out multiple letters and emails and called the tribal historic preservation officers of the all the recognized tribes in the Southwest region. Then we met with anyone who was interested, doing short presentations and answering questions and following up with interested parties.

"The feedback we received was noteworthy, in that we needed to keep in mind that these paleofeces have to ties their ancestors, and we needed to be – and hopefully have been – as respectful as possible about them," she said.

"There is a long history of misuse of genetic data from Indigenous communities, and we strove to be mindful of this by meeting and speaking with as many people as possible to obtain their insights and perspectives. We hope that this will set a precedent for us as scientists and others working with genetic material from Indigenous communities past and present."

Snow said the research overall revealed some fascinating things.

"The biggest finding is that the gut microbiome in the past was far more diverse than today – and this loss of diversity is something we are seeing in humans around the world," she said. "It's really important that we learn more about these little microorganisms and what they do for us in our symbiotic relationships.

"In the end, it could make us all healthier."


The University of Montana

Posted in: Microbiology | Genomics

Tags: Anthropologist, Antibiotic, Antibiotic Resistance, Children, Contamination, Diabetes, Diet, DNA, Education, Genes, Genetic, Inflammation, Laboratory, Medical School, Microbiome, Nutrients, Research, Type 1 Diabetes

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