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Saturday, November 10, 2018

Pedal desks could address health risks of sedentary workplace


A recent pilot study by kinesiologists at UMass Amherst found that pedaling at a self-selected light-intensity pace while at work improved insulin responses to a test meal.
Credit: UMass Amherst/Catrine Tudor-Locke
A recent pilot study by kinesiologists at the University of Massachusetts Amherst found that pedaling while conducting work tasks improved insulin responses to a test meal. Investigators led by Dr. Stuart Chipkin found that insulin levels following the meal were lower when sedentary workers used a pedal desk compared to a standard desk. In addition, work skills were not decreased in the pedaling condition.
Chipkin and colleagues conclude that pedal desks “could have the potential to achieve public and occupational health goals in sedentary work environments.” They point out that physical inactivity and sedentary work environments have been linked to higher rates of obesity, diabetes and heart disease through insulin resistance and other mechanisms. Results appear in the October issue of Medicine & Science in Sports & Exercise.
Chipkin, an endocrinologist who studies the impact of physical activity and medications on insulin sensitivity and skeletal muscle metabolism at UMass Amherst’s School of Public Health and Health Sciences, explains that instead of approaching the problem by trying to squeeze intermittent activity into a largely sedentary work routine, “we chose to consider integrating physical activity into the workday.”
He and colleagues felt that the alternatives now available for office workers — standing desks and treadmill desks — are not feasible to use for whole shifts and may even pose some barriers, such as standing too long. By contrast, a pedal desk can be used in a seated position at the user’s own pace for as little or as much time as the worker chooses.
Though there are currently no commercial pedal desks on the market, Chipkin and colleagues were able to use a prototype Pennington Pedal Desk co-invented by UMass Amherst kinesiology researcher Catrine Tudor-Locke, a co-author who did not determine study design or have any contact with participants or study data.
For this work, the researchers recruited 12 overweight/obese full-time sedentary office workers, six men and six women, and tested them in two conditions, pedaling at self-selected light-intensity pace for two hours, and working while seated for two hours at a conventional desk. In both conditions, participants performed computer-based tasks and were tested on mouse proficiency, typing speed and accuracy, reading comprehension and concentration/attention.
The participants also provided blood samples after eating a light meal for analysis of metabolic responses of glucose, insulin and free fatty acids, a link between obesity, insulin resistance and type 2 diabetes.
Chipkin and colleagues report that pedal desk use required significantly less insulin to maintain glucose concentrations compared with using the standard desk. He notes, “It took much less insulin to keep their blood sugars the same. This means that the body doesn’t work so hard to maintain blood glucose and fatty acid levels with use of the pedal desk compared to a standard desk. From the metabolic point of view, the pedal desk seems to be helpful and the from the work point of view, work tasks were not impaired.”
“While there were no changes in blood glucose or free fatty acids, none would be expected in a group of subjects without diabetes,” he notes. In future studies, Chipkin plans to explore the impact of the pedal desk on people with diabetes.
Story Source:
Materials provided by University of Massachusetts at Amherst. Note: Content may be edited for style and length.
Journal Reference:
  1. Ho Han, Jongil Lim, Richard Viskochil, Elroy J. Aguiar, Catrine Tudor-Locke, Stuart R. Chipkin. Pilot Study of Impact of a Pedal Desk on Postprandial Responses in Sedentary Workers. Medicine & Science in Sports & Exercise, 2018; 50 (10): 2156 DOI: 10.1249/MSS.0000000000001679
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Link between autoimmune, heart disease


People with autoimmune diseases such as psoriasis, lupus and rheumatoid arthritis are at high risk of developing cardiovascular disease, even though none of these conditions seem to target the cardiovascular system directly. Now, researchers at Washington University School of Medicine in St. Louis believe they have begun to understand the link between the two.
Researchers studying mice with a psoriasis-like condition found that the mice’s blood vessels were stiff. Cholesterol normally circulates freely between the blood and the tissues, but in these mice the inflexible vessel walls trapped cholesterol in their walls, promoting plaques that can cause heart attacks and strokes.
“For decades it’s been known that the trapping of cholesterol drives disease, and now we have a mechanism for how certain immune responses typical of autoimmune diseases might make that worse,” said senior author Gwendalyn Randolph, PhD, the Emil R. Unanue Distinguished Professor of Immunology and a professor of medicine. “In the mouse, the signs of cardiovascular disease scarcely arose when we neutralized these immune components. In people, it’s hard to be sure, but we would predict it would be preventable, too.”
The findings are published Nov. 8 in Cell Metabolism.
People with psoriasis and lupus are two to eight times more likely to suffer a heart attack than people without these diseases. For young and middle-aged adults with rheumatoid arthritis, cardiovascular disease is the top cause of death.
Psoriasis is characterized by patches of red, thickened, scaly skin. The thickening is partly due to an excess of collagen, the main protein in connective tissues such as skin and blood vessels — and also the key ingredient in some beauty products designed to plump lips and erase wrinkles. In people with psoriasis, the excess collagen isn’t confined to the rash area; it can be found in seemingly normal, healthy skin, too.
Randolph and first author Li-Hao “Paul” Huang, PhD, an instructor in pathology, suspected that the walls of blood vessels also might be webbed with too much collagen. They created a light-sensitive form of high-density lipoprotein (HDL) — the molecular carrying case for cholesterol — that fluoresces when hit with a laser beam, and inserted it into mice. The researchers then induced a psoriasis-like disease in the mice by painting their ears with imiquimod, an inflammatory compound that activates the same kinds of immune cells that play a role in human psoriasis.
By following the fluorescent cholesterol carrier, the researchers could see that HDL cholesterol was delayed in getting out of the bloodstream in the mice that received the compound. This was true not only in the skin, but in internal arteries near the heart. In addition, the skin and blood vessels were more densely interlaced with collagen and more resistant to stretching.
Further, when the researchers fed mice a high-cholesterol diet for three weeks while also painting their ears, the mice in the experimental psoriasis group developed significantly larger cholesterol deposits in their blood vessels.
“The skin-driven immune response can drive systemic changes,” Randolph said. “Once immune cells are programmed by reactions to the inflamed skin, they move around the body to other skin sites and arteries to be ready for the next insult, enhancing the collagen density wherever they go.”
An immune cell type called Th17 cells multiplies robustly in autoimmune diseases such as psoriasis, lupus and rheumatoid arthritis, releasing copious amounts of the immune molecule IL-17. When the researchers neutralized IL-17 in mice with psoriasis-like disease, using an antibody, collagen density went down and cholesterol deposits shrank.
Drugs that target IL-17 already are approved to treat psoriasis, marketed under brand names such as Cosentyx and Taltz, and other anti-IL-17 therapies are in the pipeline.
“It’ll take a few years before we know for sure, but we predict that the anti-IL-17 antibodies that already are being used to treat autoimmune diseases will be effective at reducing risk of cardiovascular disease,” Randolph said. “This would be important because some other drugs on the market seem to improve the skin disease but not reduce cardiovascular risk.”
Story Source:
Materials provided by Washington University School of Medicine. Original written by Tamara Bhandari. Note: Content may be edited for style and length.
Journal Reference:
  1. Li-Hao Huang, Bernd H. Zinselmeyer, Chih-Hao Chang, Brian T. Saunders, Andrew Elvington, Osamu Baba, Thomas J. Broekelmann, Lina Qi, Joseph S. Rueve, Melody A. Swartz, Brian S. Kim, Robert P. Mecham, Helge Wiig, Michael J. Thomas, Mary G. Sorci-Thomas, Gwendalyn J. Randolph. Interleukin-17 Drives Interstitial Entrapment of Tissue Lipoproteins in Experimental Psoriasis. Cell Metabolism, 2018; DOI: 10.1016/j.cmet.2018.10.006
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Glaxo Once-Daily Trelegy Ellipta Gains Expanded COPD Indication in Europe


First single inhaler triple therapy to be specifically indicated for COPD patients not adequately treated with dual bronchodilation.
GlaxoSmithKline plc (LSE/NYSE: GSK) and Innoviva, Inc. (NASDAQ: INVA) today announced that the European Commission has authorised an expanded label for once-daily Trelegy Ellipta (fluticasone furoate/umeclidinium/vilanterol ‘FF/UMEC/VI’), recognising its effect on exacerbations and making it the first single inhaler triple therapy indicated for patients with moderate to severe chronic obstructive pulmonary disease (COPD) not adequately treated with dual bronchodilation or with an inhaled corticosteroid (ICS) and a long-acting 2-agonist (LABA).
Dr. Hal Barron, Chief Scientific Officer and President, R&D, GSK, said, “We are pleased that the European Commission has approved the expanded use of Trelegy Ellipta as this will enable even more COPD patients to benefit from this important medicine.”
While bronchodilation is recognised as the foundation of COPD therapy, many patients may continue to struggle with symptoms and exacerbations over time. The expanded indication for Trelegy Ellipta reflects the evidence supporting its potential benefits in a broader group of patients than originally indicated, giving them the option of taking a once-daily single inhaler triple therapy for the first time.
Dr. Paul Meunier, VP, Respiratory Medicine at Innoviva, added, “We are delighted that once-daily single inhaler triple therapy will now be available for COPD patients requiring a step up from dual bronchodilation, giving them a new option to help manage their disease.”
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Esperion Late-Breaking Final Study 3 Results at American Heart Association


Esperion (NASDAQ:ESPR), today announced that the final Phase 3 results from Study 3 (1002-046, also known as CLEAR Serenity) were presented at the American Heart Association (AHA) Scientific Sessions in Chicago. The late-breaking oral presentation was delivered by Professor Dr. med Ulrich Laufs, Director of the Department of Cardiology at Leipzig University, Leipzig, Germany. This study evaluated the LDL-C lowering efficacy and the safety and tolerability of bempedoic acid 180 mg versus placebo in high-risk patients with atherosclerotic cardiovascular disease (ASCVD), or at high risk for ASCVD with hypercholesterolemia, inadequately treated with maximally tolerated background LDL-C lowering therapy who are only able to tolerate less than the approved daily starting dose of a statin and considered statin intolerant. Topline results were previously announced in May 2018.
Details on the presentations are as follows:
Title: Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia and Statin Intolerance
Date: November 10, 2018
Time: 8:15 a.m. ET
Location: McCormick Place Convention Center
“In Esperion’s CLEAR Serenity trial, bempedoic acid was shown to significantly lower both LDL-cholesterol and high-sensitivity C-reactive protein (hsCRP) in statin-intolerant patients.  There is a significant need for additional treatments for the large number of patients with hypercholesterolemia who are not at their LDL-cholesterol treatment goals despite using maximally tolerated statins.  This is particularly true for patients who cannot tolerate statins and have limited options available,” said Professor Laufs.
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AHA: Lipid Guidelines to Headline Meeting


Big guideline updates will bookend the American Heart Association’s annual Scientific Sessions in Chicago.
The meeting will kick off Saturday with release of AHA/American College of Cardiology lipid guidelines that revise the 2013 recommendations for both primary and secondary prevention as well as management of familial hypercholesterolemia.
One notable change will be specific recommendations on when and for whom to use the two PCSK9 inhibitors approved in 2015, said Donald Lloyd-Jones, MD, of Northwestern University in Chicago and co-chair of the meeting program committee as well as an author on the guidelines, in speaking at a media telebriefing preview of the program.
“We spent a lot of time thinking of what is the appropriate use of those medications,” given the significant cost, Lloyd-Jones noted. “I think the clear recommendations will be helpful to clinicians.”
Another key facet to the update will be how to better select primary prevention patients for cholesterol-lowering therapy — which risk scores to use and when to focus on strategies beyond risk scores, he added. Even with these changes, he said the document is substantially shorter than in the past and is modular.
However, the guidelines will not be returning to a threshold number for starting lipid-lowering therapy, Lloyd-Jones noted. “It will never be as simple as a single cholesterol number because that has to be interpreted in the context of the patient’s other risk factors, the likelihood that they will benefit from drug therapy and not just lifestyle therapy, and a number of other things.”
Another set of important guidelines come out Monday, the last day of the now 3-day meeting: national physical activity recommendations from the Department of Health and Human Services.
The first such guidelines were published in 2008, “so this is really only the second time we’ve had national guidelines for physical activity in 10 years,” Lloyd-Jones noted. “In addition to our long standing understanding that doing something is better than doing nothing, and doing more is better than doing something, I think we’ve in the past 10 years seen some really interesting data on the intensity of exercise, duration of bouts of exercise, and how those can potentially affect health outcomes.”
A draft of the document has not been released, but a scientific report meant to support the update was published in February.
Among the important late-breaking clinical trials slated for presentation at the meeting, Eric Peterson, MD, of the Duke Clinical Research Institute in Durham, North Carolina, and chairman of AHA’s Committee on Scientific Sessions Programming, highlighted the following:
  • VITAL: A huge, NIH-funded, two-by-two trial of vitamin D and omega-3 fatty acid supplements for primary prevention of cardiovascular disease and cancer.
  • REDUCE-IT: Prescription fish oil (Vascepa) worked for primary prevention in this large trial, based on top-line results, but just how big a win remains to be seen. The good news is it was done on top of statins and in a broad population with relatively low triglycerides, Peterson said. “It has the potential to be a drug we would think about in using in up to half of the patients we treat currently with statins.”
  • EWTOPIA75: A trial of ezetimibe (Zetia) for cerebro- and cardiovascular event prevention in people 75 and older — a population in which there has been less evidence from clinical trials, Peterson noted.
  • DECLARE: The cardiovascular outcomes trial for diabetes drug dapagliflozin (Farxiga) was recently announced to have met one primary endpoint for heart failure hospitalization or cardiovascular death but not the other primary composite of major adverse cardiovascular events. Full results will be presented.
  • PIONEER-HF: Sacubitril/valsartan (Entresto) has been shown effective in chronic heart failure; this trial is testing it in the acute setting.
  • TRED-HF: This trial looks at what Peterson called a seldom-addressed but important issue for clinicians and patients: the safety of withdrawing heart failure medication after heart function recovers in dilated cardiomyopathy.
  • REGROUP: A long-term outcomes trial of endoscopic harvesting of vein grafts for coronary bypass.
Another notable trial is CIRT, which tested low-dose methotrexate for prevention of atherosclerotic events as a conceptual follow-on to the CANTOS trial’s demonstration that cutting inflammation with immunotherapy reduced cardiovascular events.
However, the high cost of canakinumab (Ilaris) used in CANTOS and the counterbalancing risk of infections made it impractical for prevention in clinical practice, Peterson suggested, even if the FDA hadn’t rejected a cardiovascular prevention label last month. Methotrexate, in contrast, is a relatively inexpensive drug with a well-known safety profile.
Generic low-dose methotrexate, too, is known to reduce inflammatory marker C-reactive protein, he pointed out. “Given its low cost and its potentially relative safety from other prior studies, this has the potential to think about a new therapeutic paradigm.”
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Age Just a Number for Older, Fit Limited-Stage Small Cell Lung Cancer Patients


Select elderly patients given standard of care concurrent chemoradiotherapy for limited-stage small cell lung cancer (SCLC) achieved rates of survival and toxicity comparable to younger patients, an age-group analysis of the CONVERT trial found.
Median overall survival was 29 months among patients ages 70 and older compared with 30 months in younger patients (HR 1.15, P=0.38), according to Corinne Faivre-Finn, MD, PhD, of the University of Manchester in England, and colleagues.
Median time to local or distal disease progression between the older (n=67) and younger group (n=423) was also comparable (18 versus 16 months, HR 1.04, P=0.81), as reported in the Journal of Thoracic Oncology.
Although elderly patients had significantly more grade 3/4 neutropenia (84% versus 70%, P=0.02) and thrombocytopenia (28% versus 18%, P=0.05) than younger patients, no significant differences were seen for rates of neutropenic sepsis (4% versus 7%, P=0.07).
“Our results are particularly relevant as robust evidence to guide treatment decisions in elderly [limited-stage] SCLC patients is lacking,” the researchers wrote. “Certainly, up to the age of 80, chronological age as a sole factor should not be a barrier to this treatment being offered. Future work should concentrate on establishing elderly-specific clinical trials incorporating functional assessment tools.”
The investigators noted that the current standard of care for fit patients with limited-stage SCLC is thoracic radiotherapy delivered concurrently with platinum doublet chemotherapy. This is followed by prophylactic cranial irradiation in patients without progressive disease.
The CONVERT (Concurrent Once-daily versus Twice-daily Radiotherapy) trial, published in 2017, established twice-daily radiotherapy as the standard of care in good performance status (ECOG 0-2) limited-stage SCLC. The trial showed that there was no significant difference in survival and toxicity between patients randomized to once-daily or twice-daily concurrent chemoradiotherapy.
Survival rates in both treatment arms of CONVERT were higher than previously reported, and the incidence of severe toxicity, particularly of radiation esophagitis, was lower.
“The improved outcomes were thought to reflect advances in staging and supportive management of [limited-stage] SCLC in the last two decades, alongside the use of modern radiotherapy techniques,” Faivre-Finn’s group explained.
Charles B. Simone, II, MD, of the Maryland Proton Treatment Center in Baltimore, told MedPage Today that these new findings will help guide treatment decisions for select elderly patients with limited-stage SCLC.
The analysis also supports results from a 2015 population-based analysis showing that modern chemoradiation can improve survival over single modality treatment in elderly patients expected to tolerate the toxicities of the combined approach, he noted.
“Oncologists should not let chronological age alone be the sole determinant of which patients receive standard of care treatment,” said Simone, who was not affiliated with the study.
Currently, the best screening method to assess a patient’s fitness for a particular intervention remains “an active area of research,” Simone pointed out. In clinical practice, however, performance status evaluation “is often the primary driver of deciding between a more palliative approach or a more aggressive, potentially curative approach in elderly patients,” he said.
Of note, all but two of the elderly patients in the current study were ECOG 0-1.
For the analysis, the investigators looked at 490 patients randomized to the CONVERT trial protocol: 45 Gy in 30 twice-daily fractions over 19 days or 66 Gy in 33 once-daily fractions over 45 days, each given concurrently with platinum-based chemotherapy. Three-dimensional conformal radiotherapy began on day 22 of the first cycle.
Patients in the elderly group had a median age of 73. This included 21 patients ages 75 and older and 4 patients who were 80 and above. There were 29 (43%) randomized to the twice-daily radiotherapy group and 38 (57%) in the once-daily group.
Fewer older patients received the optimal number of radiotherapy fractions (73% versus 85% in younger patients, P=0.03), but both groups had similar chemotherapy compliance, with most patients receiving four cycles.
Between the elderly and younger patients, respectively, rates of grade 3/4 radiation pneumonitis (3% versus 2%, P=0.31) and esophagitis (19% versus 20%, P=0.870) were similar. This indicates that “radiotherapy, even when administered in a twice-daily schedule, is well tolerated by older patients,” the investigators said.
There were eight treatment-related deaths: two in the elderly group and six in the younger group (3% versus 1.4%, P=0.67). There were seven cardiovascular deaths in the younger group but none in the elderly group.
The results of this analysis should be interpreted with caution since their generalizability to elderly patients treated in routine clinical practice is limited, the study authors said.
“These criteria only apply to a small proportion of elderly patients with [limited-stage] SCLC, which highlights the need for adequately powered, elderly-specific clinical trials or for population-based studies which may be more representative of the patients seen in the routine setting,” they pointed out.
The study was funded by Cancer Research U.K., the French Ministry of Health, the Canadian Cancer Society Research Institute, and the European Organisation for Research and Treatment of Cancer (EORTC).
Faivre-Finn reported no potential conflicts of interest. One co-author disclosed that her spouse is an employee of Sirtex Medical. No other relationships with industry were reported.
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Reporting harms more transparently in trials of cancer drugs


Studies of cancer drugs often use terms that downplay the seriousness of adverse events. Bishal Gyawali and colleagues call for greater clarity and transparency

The clinical trial report of ribociclib, a drug for breast cancer, mentions in its discussion that “Most patients had an acceptable adverse-event profile.”1 A report of a trial of liposomal irinotecan in pancreatic cancer states in the concluding paragraph that it “has a manageable and mostly reversible safety profile.”2 And a trial of tasquinimod in patients with prostate cancer reports “the tolerability was good overall.”3
All three of these studies were published in top medical journals. Naturally, readers would take these statements to be true. However, a look at the data for adverse events doesn’t paint as good a picture. In the first study, more than twice as many patients in the ribociclib arm as in the control arm experienced severe (grade 3 or higher) adverse events (271/334 v 108/330).1 The difference in treatment related serious adverse events (leading to death, life threatening condition, hospital admission or prolonged admission, disability or permanent damage, congenital anomaly or birth defect, or that required medical or surgical intervention to prevent one of the other outcomes4) was nearly five times higher (25 v 5). The trial of liposomal irinotecan that mentioned “manageable and mostly reversible” toxicities in fact shows that five patients in the intervention arm died from drug toxicities versus none in the control.2 In the trial reporting overall good tolerability of tasquinimod, the incidences of severe and serious adverse events compared with control were 42.8% v 33.6% and 36.0% v 23.6%, respectively.3
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