Wellness

[Trinity11]

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@cherry wrote:

I think there is also more going on than just weight, with diabetes cases..@Trinity

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@cherry...sometimes I think the studies should be why we aren't finding a cure for this dreadful disease instead of claiming that fewer cases are being diagnosed. The emphasis should be on eradicating it from the face of the earth. After nearly 50 years of dealing with diabetes, I don't think there ever will be a cure with greedy Big Pharm coming up with more and more drugs with death as a side effect. And the enormous amount of money being made now from insulin is also a deterrent. Some of the newer Type 2 drugs have pancreatic cancer as a side effect. I really cannot understand how dying from diabetes is worse than that...

[cherry]

pt 2

The RISE pediatric medication study, presented at ADA last year, showed that in adolescents with impaired glucose tolerance (prediabetes) or recent-onset type 2 diabetes, early intervention with long-acting insulin followed by metformin or metformin alone — both given for a year — failed to prevent deterioration of beta-cell function.

"These are really critical studies for our understanding of what's happening in type 2 diabetes," Philipson emphasized.  

Kidney and Cardio: Latest Data from CREDENCE and CARMELINA

A single 2-hour session on Tuesday starting at 7:30 am will review data from the landmark Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial, which assessed progression of kidney disease and secondarily cardiovascular outcomes, and the Cardiovascular and Renal Microvascular Outcome Study with Linagliptin (CARMELINA), which assessed cardiovascular outcomes and secondarily kidney disease progression.

Primary findings from CREDENCE, presented in April at the International Society of Nephrology (ISN): 2019 World Congress, showed canagliflozin lowers the risk for progression to end-stage renal disease by 30% in patients with type 2 diabetes and chronic kidney disease, as well as lowers the risk for MACE. 

And data from CARMELINA, first presented in October 2018 at the EASD meeting, showed adding linagliptin to standard of care in patients with type 2 diabetes at high cardiovascular risk did not worsen cardiovascular, heart failure, or renal events, even in those who already had kidney disease.

Key findings from both trials will be reviewed and new analyses presented.  

"CREDENCE and CARMELINA are very big deals," Philipson underlined. "These are follow-up studies that will help affirm the original report. They're really exciting."

A Tough Subject: Type 2 Diabetes in Youth

On Saturday June 8 at 1:45 pm, a 2-hour session will be devoted to the latest findings from the follow-up to the multicenter, multi-ethnic, randomized Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study.

The post-intervention follow-up, TODAY2, is tracking the youth into young adulthood to investigate rates of renal, cardiac, eye, and nerve complications, as well as pregnancy outcomes and healthcare utilization.

Philipson commented, "If there's one ray of light that comes from this study it would be wonderful. But we have a strong feeling that children with type 2 diabetes actually do worse in some cases than children with type 1. It can be a profound disease that leads to early death, and in many cases we don't even have a good approach to treating it. These talks will give us some indication of the outcomes of the study and what we might learn."

Venture Outside Your Comfort Zone

Of course there's much, much more to the meeting. Other highlights include sessions on the rational use of opioids for treating painful diabetic neuropathy, learning from atypical diabetes, an ADA consensus paper on nutrition therapy for adults with diabetes, new artificial pancreas trial results, and two keynote award lectures on obesity that "will be more clinical than usual," Philipson observed.

Both Philipson and Florez urge delegates to attend sessions that may be outside their usual areas of focus. 

Referring to the nutrition session, held under the "Behavioral Medicine, Clinical Nutrition, Education, and Exercise" track, Florez said, "We tend to just go to sessions that are in our comfort zones. But if you're a clinician who takes care of people with diabetes you can't just leave it to the nutritionists and the [certified diabetes educators] to attend this track on behavioral medicine and clinical nutrition."

"I think it's incumbent on all of us who take care of diabetes…to be up to date on the latest in nutrition therapy...This disease requires a multidisciplinary, multipronged approach. Physicians need to go beyond drugs to other forms of therapy. Don't use the meeting to go over things you already know."

Indeed, said Philipson, "I encourage people to go to lectures and meetings they wouldn't normally go to...This meeting is really for everybody with an interest in diabetes, from basic scientists to practitioners, whether they're MDs or psychologists or exercise physiologists, ophthalmologists, etc. That breadth is unmatched by any other meeting that includes diabetes."

Florez has consulted for Janssen. Philipson has received research funding from Janssen, ADA, JDRF, Helmsley Foundation, and National Institutes of Health.

[cherry]

Pt 1

The Latest From CVOTs: REWIND, CAROLINA, and DECLARE-TIMI 58

As usual, the latest crop of CVOT results will each have their own 2-hour sessions. On Sunday June 9 at 2:15 pm, new data will be presented from the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) study, the first CVOT to enroll a much broader and healthier population of patients with type 2 diabetes — those without pre-existing cardiovascular disease but with multiple risk factors — as well as some patients with pre-existing cardiovascular disease.

Primary results from the trial were presented in November at the American Heart Association (AHA) Scientific Sessions 2018 and showed that dapagliflozin significantly reduced hospitalizations for heart failure and nonsignificantly reduced major adverse cardiovascular events (MACE).

At ADA, those results will be reviewed along with new subanalyses, renal endpoints, and safety data for the SGLT2 inhibitor.


Next, on Sunday June 9 at 4:30 pm, comes the Researching CV Events With a Weekly Incretin in Diabetes (REWIND) trial, with 5-year results for dulaglutide, a once-weekly injectable GLP-1 agonist, in a large population of lower-risk adults. This is the first such study with a GLP-1 agonist to include a majority of patients who did not have established cardiovascular disease at baseline. 

Top-line results from REWIND, announced in November 2018, showed dulaglutide significantly reduced the risk of MACE.

And on Monday June 10 at 4:30 pm, data will be presented from the Cardiovascular Safety of Linagliptin (CAROLINA) study, the longest CVOT so far (8 years) and the only one to include a head-to-head active comparator (the sulfonylurea glimepiride). In addition to the findings for linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, the results may also inform the longstanding debate about the cardiovascular safety of sulfonylureas.


Oral Semaglutide: A Game Changer?

A session on Tuesday morning at 9:45 am will cover the PIONEER program trials for oral semaglutide, the GLP-1 receptor agonist already approved as a once-weekly injectable.

Top-line results for PIONEER 6, announced in November 2018, showed reductions in cardiovascular and all-cause mortality but not the overall composite primary MACE endpoint.

Previously reported results from the PIONEER series of trials include PIONEER-1, which demonstrated the oral version's glucose-lowering and weight loss capabilities, while in PIONEER-3 the drug reduced HbA1c more than sitagliptin.


Philipson commented, "Semaglutide has been on the market for some time but we've never had an oral [GLP-1 agonist]...before...I think this is a very big deal and potentially game changing for people with type 2 diabetes, so I'm very excited about that."

"How much the oral semaglutide can recapitulate the benefits of the injected one is critical," he stressed. 

Proving Prevention: Vitamin D, Medications, and Lifestyle Interventions    

On Saturday June 8 at 4:00 pm, results from the Prevention of Diabetes in Europe and Around the World (PREVIEW) study, the largest-ever (N = 2326) to investigate diabetes prevention through lifestyle interventions, will be reviewed.

Data from PREVIEW, previously reported at the European Association for the Study of Diabetes (EASD) 2018 Annual Meeting, suggested a 2-month weight loss regimen using meal substitutes followed by long-term weight maintenance through diet and exercise may be an optimal approach to preventing type 2 diabetes through lifestyle.

Another prevention study, the multicenter Vitamin D and Type 2 Diabetes (D2d) clinical trial, supported by the National Institutes of Health, is the largest ever study specifically designed to determine whether vitamin D supplementation can reduce the risk of developing type 2 diabetes among people at risk. Final results will be presented on Friday at 11:30 am. 

"There's been a lot of epidemiological evidence that vitamin D is helpful for either beta-cell function or insulin action, but there's never been a real randomized prospective trial, particularly for type 2 diabetes  prevention," Florez explained.

And Philipson commented, "This is a hot topic in diabetes...Many of us are measuring vitamin D levels and supplementing, but should we be? It's not always reimbursed. Right now clinicians are deciding on their own."

On Sunday at noon, results will be presented from the Adult Medication study of the three-part Restoring Insulin Secretion (RISE) program looking at both prevention and early treatment of type 2 diabetes.

[cherry]

Research

Newly discovered hybrid immune cell linked to Type 1 diabetes

by Angus Liu |

May 30, 2019 11:00am

A peptide (blue) produced by the newly discovered "X lymphocyte" may help elicit a strong autoimmune response seen in Type 1 diabetes. (IBM Thomas J. Watson Research Center)

B and T cells are the two known lymphocytes of the immune system. But a team led by Johns Hopkins University researchers has identified a new cell type that looks like a hybrid of the two main immune cells. And the rare immune “X cell” may play a key role in the development of Type 1 diabetes, they found.

Scientists have long known that Type 1 diabetes happens when the immune system mistakenly attacks insulin-producing beta cells in the pancreas. However, the underlying mechanism at the cellular level was not clear.

The team believes the findings of what they call a dual expresser (DE) cell—and a protein that it produces—shed some light on the mechanism and lay the groundwork for developing immunotherapies against Type 1 diabetes. They published the findings in the journal Cell.  

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“What is unique about the entity we found is that it can act as both a B cell and a T cell,” the study’s senior author and Johns Hopkins pathologist Abdel-Rahim Hamad said in a statement. “This probably accentuates the autoimmune response because one lymphocyte is simultaneously performing the functions that normally require the concerted actions of two.”

Normally, bacteria, viruses and other foreign invaders are first processed by a white blood cell called the antigen presenting cell (APC). Antigenic proteins are exposed on the surface of APCs and then identified—and latched onto—by T-cell receptors and B-cell receptors that activate T cells and B cells, respectively.

In comparison, the DE cells express both receptors, the team found. To confirm their characteristics, the researchers made clones of DE cells and found that every clone possessed both receptors.

“It is well accepted that insulin is seen as an antigen by the T cells and that this occurs when the hormone is bound to a site on the APC known as HLA-DQ8,” Hamad explained. “However, our experiments indicate that it is a weak binding and not likely to trigger the strong immune reaction that leads to Type 1 diabetes.”

Hamad and colleagues noticed a protein encoded by the B-cell receptor present on the DE cell surface. Called the x-ld peptide, the protein could replace insulin and bind so tightly to DQ8 that it can elicit a CD4 T-cell response 10,000 times stronger, the team found, using computer simulations by Ruhong Zhou and his team at the IBM Thomas J. Watson Research Center.

RELATED: Reprogramming pancreatic cells into insulin makers to treat diabetes

Many different therapeutic methods are being examined to treat Type 1 diabetes. Within the regenerative medicine group, researchers at the University of Geneva recently converted other pancreatic cells into insulin-producing beta cells. Provention Bio is developing a vaccine based on the idea of a possible link between enterovirus infections and the autoimmune disorder. And Pfizer just licensed AnTolRx's nanoparticle therapeutics designed to induce immune tolerance to avoid attacks on beta cells.

Hamad’s team believes its findings could offer a biomarker that helps screen individuals at risk for developing Type 1 diabetes. “It also is possible that this study could lay the groundwork for developing immunotherapies that target DE cells for elimination or genetically alter the lymphocytes so that they cannot stimulate an immune response,” study co-author Thomas Donner said in a statement.

[cherry]

People with diabetes may have better brain function if they follow a Mediterranean diet rich in fruits, vegetables, legumes, whole grains, fish and healthy fats, a US study suggests.

Mediterranean diets have long been linked to better heart and brain health as well as a lower risk of developing diabetes. But research to date hasn't offered a clear picture of whether any cognitive benefits of eating this way might differ for people with and without diabetes, said lead study author Josiemer Mattei of the Harvard T.H. Chan School of Public Health in Boston.

"A healthy Mediterranean diet includes foods that are rich in fruit and vegetables, which has antioxidants, and in fish and oils, which include healthy fats," Mattei said by email. "These nutrients help sustain cognitive function by reducing inflammation and oxidation in the brain."

These benefits may help people whether or not they have diabetes. When people do have diabetes, however, the abundance of whole grains and legumes in a typical Mediterranean diet may help keep blood sugar well controlled and improve cognitive function, Mattei added.

As reported in Diabetes Care, researchers followed 913 participants in the Boston Puerto Rican Health Study over two years, assessing their eating habits, testing for type 2 diabetes, and administering a series of tests for cognitive function, memory, and executive function.

For diet evaluations, researchers scored participants' eating habits based on how much they consumed of the main foods that make up a Mediterranean diet, plus how much they ate of foods typically included in two other types of heart-healthy diets, including the DASH diet recommended by the American Heart Association.

Among people without diabetes, more closely following a Mediterranean diet was associated with memory improvements during the study period, but not with changes in other types of cognitive function. For these participants, the other two heart-healthy diets were both tied to better cognitive function.

For diabetics, however, the Mediterranean diet was associated with a wide range of improvements in brain health. People with diabetes who more closely followed a Mediterranean diet had bigger gains in cognitive function, word recognition, and clock drawing skills than their counterparts who didn't eat this way.

When people had diabetes, the brain health benefits of the Mediterranean diet were limited to individuals who had well-controlled blood sugar at the start of the study or experienced improvements in blood sugar control during the study. There wasn't a clear benefit for people who started out with poorly controlled blood sugar or individuals who got worse during the study.

The study wasn't a controlled experiment designed to prove whether or how a Mediterranean diet might directly improve brain health.

One limitation of the study is that its focus only on Puerto Rican people means the results might not apply to individuals from other racial or ethnic groups or with different dietary traditions. Researchers also relied on study participants to accurately recall and report what they ate and drank, which isn't always accurate.

Still, following a Mediterranean diet may make sense for many people with and without diabetes, said Allen Taylor of the Tufts University USDA Human Nutrition Research Center on Aging in Boston.

"There are many salutary effects of consuming a Mediterranean diet that is rich in fruits and vegetables, lower in simple sugars, lower in red and processed meats, with a few servings per week of fish," Taylor, who wasn't involved in the study, said by email.

SOURCE: Diabetes Care

[cherry]

NEW YORK (Reuters Health) - Different strains of bacteria in diabetic foot ulcers are associated with clinical outcomes and therapeutic efficacy, researchers report.

Microbial colonization, biofilm formation, and infection are thought to impair healing of diabetic foot ulcers and contribute to severe complications. But the significance of microbial load and diversity and the role of specific microorganisms in outcomes and complications remain unclear.

Dr. Elizabeth A. Grice of the Perelman School of Medicine at the University of Pennsylvania, in Philadelphia, and colleagues used shotgun metagenomics, the untargeted sequencing of bulk microbial genomes in a specimen, to identify strain-level diversity and profile the genomic content of ulcer microbiota and their association with outcomes in 100 patients with neuropathic, plantar diabetic foot ulcers.

Staphylococcus was the most abundant genus identified, followed by Corynebacterium, Pseudomonas and Streptococcus, the team reports in Cell Host and Microbe, online April 18.

Several strains of S. aureus were exclusively associated with unhealed wounds.

Nonhealing wounds also contained a microbiome associated with biofilm- and virulence-related genetic pathways.

Debridement was followed by reduced abundance of mixed anaerobic bacteria in healed wounds, but not in unhealed wounds.

"Our in-depth investigation of the diabetic foot ulcer microbiome, coupled with in vitro and in vivo functional modeling, enhances our understanding of microbial influences on tissue repair pathways, suggests diagnostic/prognostic and therapeutic targets, and has the potential to overcome challenges for improving patient outcomes," the researchers conclude.

Dr. Grice did not respond to a request for comments.

SOURCE: https://bit.ly/2Gyq5l6

Cell Host Microbe 2019.

[cherry]

Researchers believe they have found a way to "put a brake" on the immune system attacking itself in autoimmune conditions such as type 1 diabetes.

In autoimmune diseases the body mistakenly attacks itself, but this new research could indicate a way to prevent that from happening. The study team added though that any potential treatment would be a "long way off".

Using giant and powerful microscopes, a team from the University of Leeds and University of Pennsylvania, discovered an internal regulator which is responsible for controlling the body's reaction when fighting infections.

The regulator's structure was uncovered and shown to be made up of two proteins named BRISC and SHMT2, and the researchers believe they recognise how the proteins combine to work together within the cell: the proteins increase the immune response when an invading pathogen is detected.

The team speculate that this finding could one day lead to an effective treatment for autoimmune diseases including lupus and scleroderma.

Lead author Dr Elton Zeqiraj from the University of Leeds said: "We want to put a brake on the body's own immune system to stop it turning on itself.

"Our discovery has the potential to help us find a new drug to target this regulator, to suppress the immune system and stop the body destroying its own cells, even when there is no infection present."

On the back of the findings, the team believe they may be able to create genetically engineered versions of the proteins and then work out the processes which take place within the cells, which they describe as complex.

"We're a long way off being able to find a new effective treatment for autoimmune disease, but we're excited because this discovery could open the door to a new class of drugs," added Dr Zeqiraj.

"The next step is to find a way of targeting this protein to inhibit the process, to prevent our immune system from attacking healthy cells."

The study was published in the journal Nature.

[cherry]

pt 2

Assessing How Well the Body Deals with Types of Calories

The results of this Food Study showed a linear trend of an additional 52 calories burned for every 10% decrease in carbohydrate intake.1 Individuals who have the highest insulin secretion levels prior to efforts at weight loss achieve the greatest calorie expenditure, burning an average of 308 calories more daily when consuming a low carbohydrate/high-fat diet.1

However, among individuals who had normal insulin function at the outset, there was no difference in how the way their body metabolized calories from their carbohydrate intake.

These findings suggest that a carbohydrate-restricted diet is beneficial specifically for people who have type 2 diabetes and are known to be insulin insensitive.1 This makes sense if we think of insulin resistance and type 2 diabetes as a form of carbohydrate intolerance,1,3  as Dr. Ludwig believes we should. And there is support for this recommendation based on the hormone changes observed during the weight maintenance phase of the Framingham study.1

In fact, study participants in the moderate and low carbohydrate diet groups show decreases in the hormones—ghrelin and leptin—that regulate hunger. You can think of ghrelin as the short-term hunger regulator and leptin as the hormone in charge of satiety in the long-term. Leptin insensitivity is commonly seen in people with obesity and those who have metabolic syndrome.

Participants in the Framingham State Food Study had lower leptin levels in conjunction with decreased hunger and increased energy expenditure, suggesting that a lower carbohydrate, higher fat diet could help improve their glucose responsiveness.1

“The people who show the biggest declines in leptin are the most successful weight loss maintainers,” Dr. Ludwig tells EndocrineWeb.

Do You Need to Avoid Carbohydrates?

 “In my personal opinion, there is likely a major difference between people’s individual biology.  People who are insulin resistant, high insulin secretors, and especially people with diabetes, will benefit the most by restricting their carbohydrates,” Dr. Ludwig tells EndocrineWeb. 

Who will benefit?  The easiest way to determine which individuals are high insulin secretors is by an indirect measurement obtained by evaluating body composition; people who are more apple-shaped, with fat settling around their middle, are more likely to be high-insulin secretors, says Dr. Ludwig. 

In addition, clinical tests include an oral glucose tolerance test to assess insulin response and a fasting blood glucose test to assess insulin resistance. If you think you may be glucose intolerant, discuss the need for these testing options with your doctor.

Dr. Apovian also emphasizes, “for everybody, if you focus on the quality of your macronutrients, you’ll inherently have more metabolic flexibility. Focus on minimally processed, whole foods prepared simply and the ratio of carbohydrates to fats won’t matter as much for most people.”

 In the end, food quality matters—but to some more than others. Eating whole foods, and steering clear of processed, prepared foods, is a constant theme when seeking to improve your weight and overall health, the experts agree. It is worth noting that in Dr. Gardner’s DIETFITS study,4 participants were directed away from highly processed carbohydrates, and encouraged to choose vegetables and slow-release carbohydrates (eg, minimally processed, whole grains) that have a low glycemic index.

The lastest findings clarify that for insulin resisters, steering clear of low fiber, starchy, highly processed foods will give them a greater chance at keeping lost weight off.1

Do We Have the Answer to What’s the Best Diet?

Which types of foods are responsible for increasing your girth and what diet should you follow to achieve a healthier weight? What we know now is that it may depend on how your body responds to carbs, among other things. Therefore, the solution does not lie with one single food group, but in the best overall dietary pattern that works for you personally.

That said—there IS a lifestyle treatment for type 2 diabetes, heart disease, and obesity—the answer depends on how you react to different foods and diets. When you manage to lose weight quickly only to regain the lost weight, look at what you’ve been eating, and consider the findings presented by Dr. Ludwig’s research.

One thing that all of these nutrition specialists can agree on is this: stay away from processed foods and simple sugars, don’t be afraid of fat but do choose heart-healthy fats. Eat whole foods, just not too much.

[cherry]

pt 1

Low Carb or Low Fat Diet—The Best Way to Keep Off Weight Loss

Written by Jennifer Lutz
  
With David Ludwig, MD, PhD, Christopher Gardner, PhD, and Caroline Apovian, MD

Lose the weight any way you like but to avoid regaining the weight, you’ll need to know how your body responds to insulin. 

For individuals who are insulin resistant, eating more fats than carbs will help keep lost weight off. Photo: 123rf

You may be interested in these related articles:

• Paleo Diet for Disease Prevention, Weight Loss?

• What Does Obesity Mean for Your Health—Heart, Thyroid, Diabetes?

• Screen Light at Night—Distrupts Your Sleep, Worse for Your Health

• New Extreme Risk Category for Cardiovascular Disease & New, Lower LDL Target

Wondering About Your Diet? Carbs Versus Fats

The answer to which diet is better for weight-loss and maintenance: low fat or low carbohydrate is getting clearer. In the Framingham State Food Study, David Ludwig, MD, PhD, professor in the Department of Nutrition at Harvard T.H. Chan School of Public Health, and director of the New Balance Foundation Obesity Prevention Center at Boston Children’s Hospital, looks at the impact of decreasing carbohydrates and increasing fat on caloric expenditure and weight management.1

Rather than look at the impact of these foods, Dr. Ludwig and his research team considered the problem based on how the body metabolizes the macronutrients: carbohydrates and fat, by asking: Are all calories created equal? According to the study results,1 not always, or at least not for everyone.

“The type of calories being consumed have a clear effect on the number of calories being burned,” Dr. Ludwig told EndocrineWeb, summarizing the study findings in the journal, Science.2.  According to their findings, the key to glucose management is caloric expenditure in some individuals.  

Insulin Resistance Suggests Reducing Your Carbs

Researchers from the Framingham State Food Safety Study suggest that more fats and less carbohydrates could help people with insulin-insensitivity and type 2 diabetes maintain successful weight loss better.1 The study relies on the Carbohydrate Insulin Model (CIM) of obesity,3 which Dr. Ludwig and his team pioneered, to assess the total energy expenditure (TEE) of different food types.

The CIM demonstrates that high glycemic eating patterns— resulting from a diet high in processed carbohydrates (eg, white bread, white pasta, white rice, sugar)—directs the body to store more calories as  fat, rather than using the energy to support body functions.3 This switch from burning to storing calories occurs when the two metabolic hormones, insulin and glucagon become unbalanced, causing excess insulin, increased hunger, and a slowed metabolism.3 

Changing your eating pattern to one that is lower in processed carbohydrates and higher in heart-healthy fats—think avocados, Salmon, nuts, olive oil, and seeds—may correct this disrupted hormone pattern. 2 The result is an ability to burn more calories, and enabling you to more effectively regulate your weight.

The Framingham State Food Safety Study is a randomized control trial of young adults, 18-25 years, who had a body mass index (BMI) of 25 kg/m2 or more; their total energy expenditure (TEE) was monitored to measure how well they were able to burn calories during weight maintenance following a period of weight loss.1

For the first phase of the study, participants were put on a calorie-restricted diet for ten weeks to promote weight loss. During the twenty-week test phase, researchers measured the effect of decreased carbohydrates and increased fat intake on metabolic function and weight maintenance.1 Researchers adjusted caloric intake as needed to maintain weight loss.  Participants were randomly assigned to one of three diet groups:

• High carbohydrate (60% carbohydrate), low fat

• Moderate carbohydrate (40 % carbohydrate), moderate fat

• Low carbohydrate (20% carbohydrate), high fat

Individual insulin levels were tested before weight loss to determine the relationship between insulin secretion and diet, as predicted by the carbohydrate-insulin model.

[cherry]

The costs for certain widely used medicines continue to rise in the United States even amid competition from similar products, according to a new study. The results run contrary to normal expectations about market forces on prices.

"That was one of the more disheartening findings" of the study, lead author Nathan E. Wineinger, PhD, from Scripps Research in La Jolla, California, told Medscape Medical News.

In an article published today in JAMA Network Open, Wineinger and his coauthors said they found "highly synchronized" relative cost changes for blockbuster drugs in well-established categories: insulin for diabetes and tumor necrosis factor inhibitors for rheumatoid arthritis.

The median monthly cost of the rheumatoid arthritis drug adalimumab (Humira, AbbVie) rose 124%, from $1940 in January 2012 to $4338 in December 2017, while the cost of a similar drug etanercept (Enbrel, Pfizer), increased 133%, from $1862 to $4334 in the same period.


Meanwhile, the monthly cost of two fast-acting forms of insulin also more than doubled between 2012 and 2017. The median total monthly cost for Humalog from Eli Lilly rose from $126 to $274, while that of NovoLog from Novo Nordisk rose from $244 to $532.

"Such seeming coordination coinciding with high price increases is particularly worrisome," Wineinger and colleagues write.

These price increases continued well after the drugs reached the market.

Two of the initial Food and Drug Administration (FDA) approvals for these drugs date to the 20th century; Humalog in 1996 and Enbrel in 1998. The FDA then approved NovoLog in 2000 and Humira in 2002, according to the agency's website.


The pattern of persistently rising costs for well-established products was seen with other products in the study, the researchers said. Of the 36 drugs studied that have been available since 2012, 28 (78%) showed an increase in insurer and out-of-pocket costs of more than 50%. Sixteen (44%) of these medicines have more than doubled in price.

"[W]e did not find evidence that products that entered the market 3 to 6 years ago have different trends compared with other drugs in the first years of availability. This finding, along with the consistent, once- or twice-a-year price increases of most drugs we examined, implies that this cycle will persist throughout the lifetime of a drug in the current, private pharmaceutical insurance market," the authors write.

Wineinger and his coauthors focused on 49 top-selling branded drugs, restricting their analysis to drugs that exceeded $500 million in US sales or $1 billion in worldwide sales. They used Blue Cross Blue Shield pharmacy claims data from January 1, 2012, through December 31, 2017.

They note that a limitation of their analysis is the lack of information on how rebates affect net pharmaceutical prices. About 16% of spending by private insurers on branded drugs was returned as rebates in 2016, according to previous data. Yet there is variation in how these discounts are applied, depending on the drug and insurer. Moreover, the rebates cannot be linked to individual claims, Wineinger and colleagues write.


To address the lack of rebate data, they obtained third-party estimates of net price data of drugs. They said they observed high correlation between increases in the rates of insurer and out-of-pocket costs paid for each drug and the net prices.

"This association suggests that the offered supposition that higher list prices and greater reliance on rebates reduce costs may be untrue," Wineinger and colleagues write. "Instead, increases in list prices, and thus increases in insurer and out-of-pocket costs paid, may coincide with increases in net prices, which in turn make these drugs more expensive overall."

Complaints about the seeming murkiness of rebates are common in health policy discussions. Even members of Congress and their staffers are puzzled about the flow of discounts among middlemen known as pharmacy benefit managers, insurers, and patients who purchase medicines.


The Trump administration in January unveiled a plan to allow discounts on prescription medicines to flow more directly to patients in the Medicare Part D pharmacy program, while disrupting the flow of rebates that drug makers now pay to so-called middlemen.

More than 25,000 comments were submitted on the proposal. Drug makers were generally supportive. But opponents say it will be a windfall for the pharmaceutical industry and increase the cost of healthcare.

In a comment on the proposal, the trade group America's Health Insurance Plans said it would raise premiums paid for Medicare Part D plans, while allowing "a small percentage of Medicare patients may get some limited relief at the pharmacy counter."


The rebate proposal is part of the Trump administration's efforts to rein in rising drug prices. It remains uncertain how much of this rebate plan may eventually take effect.

Still, there's been bipartisan agreement in Congress about at least a need to consider ways to help more Americans afford their medicine.

In their new article, Wineinger and coauthors note a need to balance this affordability for consumers against the financial "incentives in the pharmaceutical industry to produce innovative drugs that improve and save lives."

They suggest looking toward methods that would peg payments to the level of benefits medicines bring to patients.

"Innovative solutions, such as the Institute for Clinical and Economic Review's value-based price benchmark, have the potential to find appropriate price points for patients while rewarding drug manufacturers that produce transformative products," Wineinger and colleagues write.

This study was funded by UL1 TR002550 Clinical and Translational Science Award from the National Institutes of Health National Center for Advancing Translational Sciences. One of the authors, Eric Topol, MD, reported personal fees from Blue Cross Blue Shield outside of the submitted work. Topol is editor-in-chief of Medscape.

JAMA Network Open. Published online May 31, 2019