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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“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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Coffee Could Be the Secret Weapon Against NAFLD

Treatment of obesity through exercise and diet is unquestionably the foundation of care for patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). But drinking at least several cups of coffee a day makes for additional powerful medicine, said Manal F. Abdelmalek, MD, MPH, at the Gastroenterology Updates, IBD, Liver Disease Conference.

“I do recommend at least two to three cups of coffee per day for my patients with NAFLD,” said Abdelmalek, professor of medicine and a gastroenterologist at Duke University, Durham, N.C.

Her thinking on this recommendation has been influenced by a meta-analysis of 16 studies including more than 3,000 coffee drinkers and 132,000 nonconsumers; the meta-analysis concluded that coffee drinkers were 39% less likely to develop cirrhosis. There was evidence of a dose-response effect: Consumers of two or more cups daily had a 47% reduction in the risk of cirrhosis, compared with the nondrinkers, while more modest consumption was associated with a 34% reduction. Moreover, the investigators found that coffee consumption was also associated with a 27% reduction in the likelihood of developing advanced hepatic fibrosis, compared with that of non–coffee drinkers.

“What’s even more provocative is the evidence that coffee decreases risk of hepatocellular carcinoma,” the gastroenterologist said.

She highlighted a U.K. meta-analysis of 18 cohort studies with 2.27 million participants and 2,905 cases, along with 8 case-control studies featuring a collective 1,825 cases and 4,652 controls. The investigators reported that drinking at least two cups of coffee per day was associated with a 35% reduction in the risk of hepatocellular carcinoma independent of a patient’s stage of liver disease or the presence or absence of high alcohol consumption, smoking, obesity, type 2 diabetes, or hepatitis B or C infection.

“This is very impressive data and certainly not something you should ignore,” according to Abdelmalek.

There is also “fairly strong” data that coffee reduces the risk of developing type 2 diabetes, she continued. The mechanism of these benefits is unclear.

“It’s not known if it’s caffeine or some other constituent of the bean; a phenol, for example. The story behind tea is not as compelling as for coffee, so it may be something beyond caffeine,” according to Abdelmalek.

Session moderator Norah A. Terrault, MD, MPH, noted that drinking at least two cups of coffee per day has also been associated with reduced risk of cirrhosis in patients with hepatitis B or hepatitis C infection. So she too is on board the coffee express.

“I’m also a big proponent of recommending coffee. We take so much away from the patients, it’s nice to give them back something, right?” said Terrault, professor of medicine and chief of gastroenterology and liver diseases at the University of Southern California, Los Angeles.

Diet and Exercise

Most of the major gastroenterology professional societies emphasize in their practice guidelines for NAFLD that diet and routine physical activity are mandatory. If sustained, these lifestyle modifications can improve NASH and hepatic fibrosis, as well as reduce the risk of portal hypertension and liver cancer. Abdelmalek counsels her patients to aim for at least 150 minutes per week of moderate or vigorous aerobic and/or resistance exercise. She doesn’t care about the exercise intensity or type, noting that what she considers to be “a beautifully done intervention trial” in 220 patients over the course of 12 months concluded that both moderate and vigorous exercise achieved a significant reduction in intrahepatic triglyceride content.

“Tailor exercise to what patients can do, what they enjoy, and what they can sustain,” she advised.

She identifies and addresses all modifiable risk factors for NAFLD, including hypertension, diabetes, abdominal obesity, smoking, excessive alcohol intake, obstructive sleep apnea, and an unhealthy diet high in fat, red meat, and fructose.

“The primary message I tell my patients interested in dieting is: I want you to find the right approach for you. There is no right or wrong answer. For some of my patients, it’s intermittent fasting and having their first meal at 2 or 3 o’clock in the afternoon. For others it’s a Weight Watchers approach, or a Mediterranean diet, or it’s high protein. The bottom line of my approach is a gravitation away from excess carbohydrates and fats, and beyond that if I can achieve weight loss through caloric restriction or intermittent fasting, I try to tailor that to my patients’ preferences. I do send them to nutritionists,” the gastroenterologist said.

A 7%-10% weight loss has been shown to result in resolution of NASH in 64%-90% of patients. However, only about 10% of patients who achieve clinically meaningful weight loss short term are able to maintain it at 1 year, so ongoing follow-up is essential.

At present there is no FDA-approved therapy for NAFLD/NASH. Beyond diet and exercise – and coffee – there is the option of antiobesity weight-loss drug therapy, which is about as effective as successful lifestyle modification, and bariatric surgery, which is dramatically effective. French surgeons recently reported in a prospective single-center study of 180 severely obese patients with NASH who underwent bariatric surgery that, at 5 years’ follow-up, 84% of them had resolution of NASH with no worsening of liver fibrosis. Indeed, 63% of patients with mild fibrosis at baseline experienced complete resolution of their fibrosis at follow-up, as did 46% of those with more severe baseline bridging fibrosis.

Abdelmalek reported having no financial conflicts of interest regarding her presentation.

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

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Aflibercept Won’t Help Vision in Early Diabetic Retinopathy

Intravitreal injections with aflibercept (Eylea) don’t improve the visual acuity of people with nonproliferative diabetic retinopathy (NPDR), researchers say.

The treatments do reduce the risk for center-involved diabetic macular edema and proliferative diabetic retinopathy, however, said Adam R. Glassman, MS, principal investigator of the DRCR Retina Network Coordinating Center, Tampa, Florida.

“Some clinicians may decide to initiate preventative Eylea treatment for eyes with severe NPDR based on the reduction in anatomic complications, but some clinicians may choose to wait until disease worsens before initiating anti-VEGF [vascular endothelial growth factor] treatment,” Glassman told Medscape Medical News in an email.

The DRCR Retina Network Protocol W trial was published online March 30 in JAMA Ophthalmology.

Previously large randomized clinical trials showed that treatments with anti-VEGF intravitreal injections are effective in protecting and restoring vision for patients with diabetic macular edema and proliferative diabetic retinopathy.

But it was uncertain whether these treatments would benefit patients in whose diabetic retinopathy had not led to such complications.

To address that question, Glassman and colleagues recruited adults with diabetes and moderate to severe NPDR. They randomly assigned 200 of them to receive intravitreal aflibercept 2 mg and 199 to receive sham injections at baseline and at 1, 2, and 4 months, and then every 4 months for 2 years.

The patients in both groups also received aflibercept injections if they developed center-involved diabetic macular edema with vision loss or high-risk proliferative diabetic retinopathy.

After 2 years, the mean number of aflibercept injections in the aflibercept group was 8.0; 7.7 of those were given for prevention alone. In the sham group, the mean number of aflibercept injections was 1.1, and the mean number of sham injections was 7.4.

After 2 years, significantly more patients in the sham group than in the aflibercept group developed sight-threatening complications. The difference in the change in visual acuity was not significant between the two groups.

Table. Complications and Visual Acuity

Outcome Aflibercept group Sham group P value
Center-involved diabetic macular, % edema 4.1 14.8 .002
Proliferative diabetic retinopathy, % 13.5 33.2 .001
One or both of these complications, % 16.3 43.5 .001
Mean change in visual acuity, ETDRS letters –.09 –2.0 .47

There were three cases of endophthalmitis in the aflibercept group and none in the sham group. There was no difference between the groups in cardiovascular or cerebrovascular adverse events.

On the basis of these results, Jayanth Sridhar, MD, associate professor of clinical ophthalmology at the Bascom Palmer Eye Institute in Miami, Florida, said he doesn’t see a need to administer anti-VEGF treatments as prophylaxis for his patients with NPDR.

The burden of frequent intravitreal injections outweighs the benefit of preventing complications, he said. That could change if longer-term treatments, such as drug-eluting implants or gene therapy, become available, he said.

For now, Sridhar closely monitors his patients with NPDR for complications, he told Medscape Medical News. “If they do develop a complication, treat them early with anti-VEGF, and you will not lose any sort of visual acuity benefit by waiting to treat them.”

Protocol W is continuing for 2 more years, and it is possible that a difference in visual acuity will emerge between the two groups over that time because it can take that long for diabetic macular edema and proliferative diabetic retinopathy to affect vision, Glassman said.

But Sridhar doesn’t expect that to happen because the design of the trial calls for the treatment of complications, and it appears possible to restore visual acuity once complications develop.

“It’s reassuring, and it really gives providers a lot of options to kind of tailor treatment depending on the patient,” Sridhar said.

The findings of Protocol W confirm those of the PANORAMA trial, which had a similar design but was sponsored by Regeneron, the maker of Eylea, said Sridhar. “It’s great to see the pharmaceutical-sponsored study sort of matched by the nonaffiliated study,” he said.

While completing the 4-year results of Protocol W, the DRCR Retina Network is also studying the cholesterol-lowering drug fenofibrate to see whether it can slow the progression of diabetic retinopathy, said Glassman.

JAMA Ophthalmol. Published online March 30, 2021. Full text

Sridhar is a consultant for Regeneron. Glassman reported grants from Regeneron and Genentech.

Laird Harrison writes about science, health and culture. His work has appeared in magazines, newspapers , and online publications. He is at work on a novel about alternate realities in physics. Harrison has taught writing at San Francisco State University, UC Berkeley Extension and the Writers Grotto. Visit him at lairdharrison.com or follow him on Twitter: @LairdH.

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