Patricia Salber, MD, MBA, and Joseph Kvedar, MD, discuss the growth of telehealth during COVID-19 and its future beyond the pandemic.

The Growth of Telehealth During COVID-19 and Its Future After

The value of biosimilars in terms of reducing the financial burden on employers and fostering competition, and the need for employer education on these value points is discussed.

Value of Biosimilars to Employers

Higher levels of the omega-3 fatty acid eicosapentaenoic acid (EPA) found in the blood appear to explain why icosapent ethyl drives down the risk of a cardiovascular (CV) event.

REDUCE-IT: Serum EPA Levels Hold Key to Vascepa's Dramatic CV Benefits

The Mediterranean diet, which is known to have health benefits, may help prevent rheumatoid arthritis in current or previous smoker.

Mediterranean Diet May Prevent RA in Current or Previous Smokers

 disease, results from a multicenter, double-blind trial show that treatment with ertugliflozin is noninferior to placebo with respect to major adverse cardiovascular events (MACE). Results of the study were published in the

Ertugliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor originally approved by the FDA for the improvement of glycemic control in adults with T2D. Recent studies have demonstrated that the 

 as a whole is effective in treating certain forms of 

In patients with T2D, cardiovascular disease is the leading cause of illness and death, while T2D is also a major risk factor for developing HF and progression of renal disease. However, the specific cardiovascular (CV) effects of ertugliflozin in this population have not been established.

While continuing standard care, eligible patients were randomly assigned 1:1:1 to receive 5 mg or 15 mg of ertugliflozin or matching placebo once daily for 18 weeks. Primary outcomes included a composite of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke (all were considered MACE). Secondary outcomes consisted of a composite of death from CV causes or hospitalization for HF, death from CV causes, and a composite of death from renal causes, renal replacement therapy, or doubling of the serum creatinine level.

Between December 2013 and July 2015 and from June 2016 through April 2017, a total of 8246 participants were enrolled in 2 cohorts (cohort 1, n = 4023; cohort 2, n = 4223). Patients were followed for a mean of 3.5 years, and a total of 8238 patients received at least 1 dose of ertugliflozin or placebo.

 in the ertugliflozin arm and in 327 of 2745 patients 

in the placebo arm (HR, 0.97; 95.6% CI, 0.85-1.11; 

Death from CV causes or hospitalization for HF occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (HR, 0.88; 95.8% CI, 0.75-1.03; 

HR (ertugliflozin vs placebo) for death from CV causes was 0.92 (95.8% CI, 0.77-1.11).

HR for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63-1.04).

Amputations were performed in 54 patients who received a 5-mg dose of ertugliflozin (2%), 57 patients who received a 15-mg dose (2.1%), and 45 patients who received placebo (1.6%).

At week 18, least-squares mean difference from baseline in glycated hemoglobin (A1C) level was –0.7% (95% CI, –0.7% to –0.69%) among those who received 15 mg of ertugliflozin and –0.22% (95% CI, –0.25% to –0.19%) among those who received placebo.

“We do not have a clear explanation about why our results did not reach significance, whereas significance was reached for many (but not all) end points in previous CV outcomes trials of SGLT-2 inhibitors,” researchers wrote.

Pharmacologically similar doses of ertugliflozin were used in the present trial compared with 

, a trial that tested the efficacy of ertugliflozin in CV outcomes. However, authors note that secular trends of more intensive preventive therapies over recent years may have had a greater impact on the current trial.

When it comes to adverse events, results from the trial are consistent with the known risks of the SGLT-2 inhibitor class. In addition to amputation, genital mycotic infections occurred more frequently among individuals in patients who received ertugliflozin compared with placebo. The percentage of patients who experienced diabetic ketoacidosis was higher in either ertugliflozin group than in the placebo group, although statistical testing was not performed.

The study was funded by Merck Sharp & Dohme and Pfizer.

Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. 

 Published online September 23, 2020. doi:10.1056/NEJMoa2004967

Articles

In patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease, results from a multicenter, double-blind trial show that treatment with ertugliflozin is noninferior to placebo with respect to major adverse cardiovascular events.

Ertugliflozin CV Outcomes in T2D Population Are Similar to Placebo

Based on findings of the Business Group on Health’s 2021 Large Employers' Health Care Strategy and Plan Design Survey, employers have increased funding in virtual care and behavioral health amid the coronavirus disease 2019 (COVID-19) pandemic, said Ellen Kelsay, president and CEO of the Business Group on Health.

: Hello, I'm Matthew Gavidia. Today on MJH Life Sciences’ Medical World News, 

® is pleased to welcome Ellen Kelsay, president and CEO of the Business Group on Health. Can you just introduce yourself and tell us a little bit about your work?


: Sure, thanks so much for having me! Yes, I am president and CEO of Business Group on Health, and we are a nonprofit representing the largest employers in the world: Fortune 500 employers on a variety of health and well-being

So, we work with them and on their behalf, and alongside industry stakeholders to discuss and address and hopefully make progress and advance on some of the more challenging health and well-being

related issues that are present in the American and global workforce today.


: Can you speak on Business Group on Health’s 

Large Employers' Health Care Strategy and Plan Design Survey

: I'd be happy to. Yeah, it’s a piece of work that we're very proud of. We have been launching this and fielding it every year now for a number of years, and it is an insight into the perspectives of those large employers on health and well-being strategies–their perspective on the changing landscape of health care within the United States, but then also foreshadowing some of their strategies for the upcoming year and beyond.

This year's survey was fielded in May and June, and it represents the perspectives of over 122 large employers that represent over 9 million covered lives.


: Just to build off on that, were there any trends you were especially interested in learning more on?

: There were a number of trends. At the beginning of each year before we field the survey, we forecast what we anticipate the trends to be for the upcoming year, and when we fielded the survey, we were interested in seeing if those trends were validated, if they were underscored, or certainly in light of the pandemic this year, if new trends and strategies really emerged to the forefront.


What we found in the survey was really nothing but an underscoring of the trends that we anticipated at the outset of the year, namely, in a few areas. First, certainly around mental health and emotional well-being. We know that is an issue that our members and many employers around the world have been keenly focused on for a number of years. Second to that issue was certainly the expansion of virtual and digital health solutions. We're also focused on the pandemic itself and the impact the pandemic had on employer strategies, new offerings, as well as what the pandemic meant in terms of their overall plan costs.

Then, lastly, one trend that we were very interested in observing through these survey findings was what impact does the pandemic have on employers’ efforts to move towards delivery system and payment transformation. That has certainly been an effort and a focus area for many of our employers, and certainly for us organizationally for a number of years. And we wanted to see what impact the pandemic had on both employers’ desires to move forward in that area, but then also their partner's ability, whether that be providers, health systems, or health plans, to continue moving forward in that focus area as well.


So, many key findings and trends that we were tracking prior to the survey, and the survey certainly gave us some good, robust data and some nuanced perspectives on those issues, as well.


: As something you just referred to, increased funding of virtual care, as well as behavioral health, is a major takeaway from this survey. Can you first speak on why greater need for these services are warranted and how they can benefit overall health care cost?

: Sure, I'll start first with virtual. We have seen, certainly in health care, a massive amount of innovation for many, many years now and an explosion of new start-ups and new solutions coming to market.

Many employers have been implementing these solutions for a number of reasons. First, they do address cares, or gaps, in their current ecosystem of solutions that they offer to their employees. Then, certainly they meet the need from a consumer perspective. Consumers like the ease and convenience of these solutions, and from a care delivery perspective, they're more apt to seek care in a virtual environment in many instances.

Sometimes going to the actual doctor, going to an office, is prohibitive from a work schedule perspective or for other reasons. So, when you can make services available at a much more convenient forum and different modality, employees are more apt to pursue care that way.


Certainly with the pandemic, we have seen, because of shutdowns and stay-at-home orders, many people simply could not see their physician in person even if they wanted to. So, these virtual solutions have really emerged to be, out of necessity, a very optimal way to deliver care at a time when care could not be delivered in person. It would have been many, many years ago that if your doctor's office was closed, you just simply didn't talk to the doctor, see the doctor, until they open the office again.


In the pandemic environment, many physicians have deployed telehealth and virtual models, and so their comfort and receptivity has increased, and certainly, as I said before, we know that consumers prefer it in many ways. We also see that virtual solutions are sometimes more effective in many ways, such as for musculoskeletal treatments. Many people used to go see surgeons when they had back and spine issues, and we know that most of many musculoskeletal issues can be effectively addressed, at least in the early stages, via physical therapy, and that in some instances physical therapy can be delivered effectively through a virtual solution.


So, there are some conditions like that for which virtual is a really viable alternative, and it is a much more cost-effective alternative to seeing an in-person physician or surgeon for some of those services.


When it comes to mental and emotional health, we know that those have been issues for a long time coming in society. There has been a lot of stigma associated with individuals seeking out care for those solutions. So, employers have been long on the path to do what they can to both break down some of the cultural and stigma issues associated with mental health, but then also to make solutions available to their employees that are more accessible and perhaps a little less intimidating quite honestly.


So, if an employee can access therapy or coaching and counseling via an app, via video, versus going into a counselor or therapist office, they might be more willing to do that. Then certainly with, again, the pandemic, there are very many people. You'd be hard pressed to find anybody who has not felt some period of stress, isolation, or anxiety in this pandemic environment. So, the number of people who are accessing services for mental and emotional well-being has certainly grown exponentially in the past many months as well, making again those virtual services even more desirable for more people within the population.

Videos

Based on findings of the Business Group on Health’s 2021 Large Employers' Health Care Strategy and Plan Design Survey, employers have increased funding in virtual care and behavioral health amid the coronavirus disease pandemic.

Employers Increasing Virtual, Behavioral Health Coverage Amid Pandemic

 (ALL) who had an ABL-class fusion had superior outcomes when they received adjuvant therapy with a tyrosine kinase inhibitor (TKI) in first remission, according to a new study.

Corresponding author Anthony V. Moorman, PhD, of Newcastle University, in the United Kingdom, and colleagues explained that patients with ALL who have BCR-ABL1-like or Philadelphia chromosome-like gene expression profiles tend to have poor outcomes. ABL-class gene fusions are a network of chimeric gene fusions that functionally result in constitutive activation of the ABL pathway. This response mimics BCR-ABL1 fusion.

“A subset of patients with BCR-ABL1-like ALL harbor an ABL-class fusion defined as a fusion between ABL1, ABL2, PDGFRB/A or CSF1R and a variable partner gene,” they said. “Patients harboring ABL-class fusions have high levels of minimal residual disease (MRD) at the end of induction (EOI) and a high risk of relapse.”

Preclinical evidence has suggested that TKIs can be effective against ABL-class fusions, but the research to date is limited. In an effort to bolster the data around the question, Moorman and colleagues identified 191 patients from the UKALL2011 trial who had ALL and at least 1% MRD following induction therapy.

Of those, 126 patients were screened for ABL-class fusions, and 21 were found to harbor an ABL-class fusion. The patients, who had a median age of 9 years, had a median MRD level of 32%, driven largely by 10 patients who harbored EBF1‐PDGFRB.

Some of the patients (13), were identified prospectively, and were given the TKI imatinib (Gleevec) in their first remission. The other 8 patients were identified retrospectively and thus were given standard EOI therapy without a TKI. The latter group was treated as the control group.

The TKI group and the control group had similar demographics, white cell counts, and post-induction MRD. Eight patients in the TKI group had EBF1-PDGFRB, compared to 2 in the control group.

At a median follow up of 3.9 years, none of the patients in the TKI group suffered a leukemia-related event. Conversely, 6 of 8 patients in the control group either relapsed or died from primary refractory disease. That translated into a 4-year relapse/refractory rate of 0% for the TKI group and 62.5% for the control group. Event-free survival and overall survival rates similarly were superior among those receiving TKI.

Three patients in the control group were eventually treated with TKI following relapse, but 2 of the 3 died due to respiratory/multi-organ failure. Two patients in the TKI group died of transplant complications. Overall, 2 of 13 patients in the TKI group died; half of the 8 control-group patients died.

Moorman and colleagues noted that because the patient population considered in this study is so small, it is highly unlikely that a randomized clinical trial will be possible. Instead, they said retrospective studies like this one will likely be among the best evidence for treating these patients.

“We have demonstrated a reduced risk of relapse for ABL-class fusion patients with EOI MRD ≥1% treated with adjuvant TKI without a significant increased risk of severe toxicity,” they said.

Moorman AV, Schwab C, Winterman E, et al. Adjuvant tyrosine kinase inhibitor therapy improves outcome for children and adolescents with acute lymphoblastic leukaemia who have an ABL-class fusion. 

Patients with acute lymphoblastic leukemia (ALL) who have an ABL-class fusion had better outcomes than a control group when treated with tyrosine kinase inhibitors at their first relapse, according to a new study.

TKI Leads to Superior Outcomes in ALL With an ABL-Class Fusion, Study Says

Drug resistance continues to be a major problem in proteasome inhibitor (PI) therapy for patients with multiple myeloma (MM).

In a new review article, investigators outlined some of the latest findings related to the mechanisms of PI resistance, and stressed the importance of overcoming the problem.

Asia-Pacific Journal of Clinical Oncology

, coauthors Yang Bai, PhD, and Xing Su, PhD, explained that since the approval of the first PI, bortezomib (Velcade) in 2003, outcomes for patients with MM have improved significantly.

“Interestingly, it has been reported that the 5-year relative survival rate of MM increased by 49% from 2005 to 2011,” Bai and Su reported. Both authors are affiliated with the First Hospital of Jilin University, in China.

PIs target the 26S proteasome. Bortezomib works primarily by inhibiting the chymotrypsin-like site of the 20S proteolytic core, explained Su and Bai, which in turn induces cell-cycle arrest and apoptosis by suppressing NF‐κB signaling. MM cells express a higher level of NF‐κB activation signature molecules, compared to normal hematopoietic cells, they said.


“IκB, the inhibitory factor of NF‐κB, is the substrate of 26S proteasome,” they wrote. “PI causes the accumulation of IκB which results in blocking nuclear translocation of NF‐κB and displayed antitumor activity against MM cells.”

The authors said several mechanisms are suspected to be involved in drug resistance. Specific target mutations and genetic changes in the target gene or other signaling genes of signal transduction have been implicated in primary resistance, they said.

“Though culturing TH1 cells in escalating concentrations of bortezomib, the first reported point mutation in PI resistance is a single point mutation to the binding pocket of the β5 subunit (PSMB5) which mapped to the cluster region in the catalytic site (Ala49Val),” they said. “The mutation was found to interfere with the spatial construction of the bortezomib binding pocket, resulting in drug resistance.”

Other mutations, such as in the binding pocket of the β5 subunit, have been identified in MM patients.

Other mechanisms believed to play a role in resistance include key stress signaling pathways, apoptosis failure and autophagy activation, and aberrant expression of proteasomal subunits, among other processes.

Bai and Su said there is an “urgent need” to overcome PI resistance. They said a number of drugs have been developed that could the problem, either as single-agent therapies or in combination with other agents..

Among them are venetoclax (Venclexta), a BCL-2 inhibitor.

“Combined autophagy inhibitors bafilomycin A [and] chloroquine with the p62 inhibitor verteporfin increased cytotoxicity and synergistic activity with bortezomib,” they said. “Selinexor, a reversible inhibitor of XPO1, overcomes acquired PI resistance associated with bortezomib or carfilzomib in MM patients.”

New research also suggests miR-126b is a negative regulator of p53, which could be a meaningful agent because overexpression of miR-125b leads to suppression of the endogenous level of p53.

Bai and Su concluded that drug resistance is currently inevitable after long-term treatment with PIs.

“It is necessary to unravel the mechanism of drug resistance in MM in order to improve novel therapeutic strategies for refractory and relapsed patients,” they said. “In addition, more extensive basic research and clinical trials are required for combination therapy regimens, the development of newer PIs, and reduction of drug toxicity.”

Bai Y, Su X. Updates to the drug-resistant mechanism of proteasome inhibitors in multiple myeloma. 

Proteasome inhibitors have brought major advances in the treatment of multiple myeloma (MM), but eventual drug resistance remains a serious hurdle.



Review Updates Mechanisms Underlying Proteasome Inhibitor Resistance in MM

Data from the EMPOWER-Lung 1 trial of cemiplimab (Libtayo) monotherapy vs platinum-based doublet chemotherapy show why the fully-human monoclonal antibody could become a new treatment option for first-line locally advanced or metastatic non–small cell 

specially for tumors with PD-L1 expression of at least 50%, 

 presented at this year’s virtual European Society for Medical Oncology (ESMO) meeting. 

“In new analyses presented at ESMO, Libtayo reduced the risk of death by 43% in patients whose cancer had confirmed PD-L1 expression of 50% or greater. This is notable given that nearly three-quarters of patients crossed over from chemotherapy following disease progression and 12% of patients had pretreated and stable brain metastases,” Ahmet Sezer, MD, associate professor in the Department of Medical Oncology at Başkent University in Adana, Turkey, and a trial investigator, 

In the open-label, multicenter, phase 3 trial, the 710 study participants were almost equally randomized into 2 groups: cemiplimab (n = 356) and investigator’s choice of chemotherapy (n = 354). Both groups had the same median follow-up of 13 months and range of follow-up, at <1 to 32 months. Overall survival (OS) and progression-free survival (PFS) were the primary end points, with overall response rate, duration of response, and quality of life being the secondary end points.

The overall results demonstrate cemiplimab’s superiority on several fronts compared with chemotherapy:

Risk of death decreased 32% (HR, 0.68; 95% CI, 0.53-0.87; 

Median OS of 22.1 months (95% CI, 17.7 months-not evaluable) vs 14.3 months (95% CI, 11.7-19.2)

Risk of disease progression dropped 41% (HR, 0.59; 95% CI, 0.49-0.72; 

< .0001), equating to a PFS of 6.2 months (95% CI, 4.5-8.3) vs 5.6 months (95% CI, 4.5-6.1).

Objective response rate of 37% (3% had a complete response [CR], 33% had a partial response [PR]; 95% CI, 32%-42%) vs 21% (1% had a CR, 20% had a PR; 95% CI, 17%-25%)

Cemiplimab’s benefit carried over into the 563 patients (cemiplimab group, n = 283; chemotherapy group, n = 280) with confirmed PD-L1 expression of at least 

50%. Both groups again had the same 11-month median follow-up, with almost equal ranges: <1 to 32 months and <1 to 30 months, respectively. Results in this group demonstrated the following:

Risk of death decreased 43% (HR, 0.57; 95% CI, 0.42-0.77; 

Median OS not reached (95% CI, 17.9 months-not evaluable) vs 14.2 months (95% CI, 11.2-17.5).

Risk of disease progression dropped 46% (HR, 0.54; 95% CI, 0.43-0.68; 

<. 0001), equating to a PFS of 8.2 months (95% CI, 6.1-8.8) vs 5.7 months (95% CI, 4.5-6.2).

Objective response rate of 39% (2% had a CR, 37% had a PR; 95% CI, 34%-45%) vs 20% (1% had a CR, 19% had a PR; 95% CI, 16%-26%)

The PD-L1 IHC 22C3 pharmDx was used to confirm PD-L1 expression.

Treatment in the trial consisted of 350-mg intravenous (IV) cemiplimab every 3 weeks, for a maximum of 108 weeks, or investigator’s choice of standard-of-care chemotherapy for 4 to 6 cycles (with or without histology-relevant maintenance pemetrexed chemotherapy).

Importantly, objective response rate to cemiplimab was highest in tumors with at least 90% PD-L1 expression: 46% (range, 36%-56%). These tumors shrunk more than 40% after an average 6 months of treatment. Similar findings were not seen with chemotherapy.

The cemiplimab-treated patients also experienced 32% fewer grade 3 adverse events (AEs) overall: 37% vs 49% of patients receiving chemotherapy. The most common immune-mediated AEs, which occurred in 17% of patients receiving cemiplimab, were hypothyroidism (6%), hyperthyroidism (4%), pneumonitis (2%), hepatitis (2%), skin adverse reaction (2%), and arthritis, increased blood thyroid stimulating hormone, thyroiditis, colitis, nephritis, and peripheral neuropathy (each 1%).

Crossover was allowed from the chemotherapy to the cemiplimab arm, and occurred with 73.9%, and those receiving cemiplimab could combine it with 4 to 6 cycles of chemotherapy.

Cemiplimab already holds indications in the United States, European Union, and other countries for metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC in adults for whom curative surgery or radiation are not treatment options.

Sezer A, Kilickap S, Gümüş M, et al. EMPOWER-Lung 1: phase III first-line (1L) cemiplimab monotherapy vs platinum-doublet chemotherapy (chemo) in advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%. Presented at: European Society for Medical Oncology Virtual Congress 2020; September 19-21, 2020. Abstract LBA-52.

Data from the EMPOWER-Lung 1 trial of cemiplimab (Libtayo) monotherapy vs chemotherapy show why the fully-human monoclonal antibody could become a new treatment option for non–small cell lung cancer (NSCLC).

Phase 3 Trial Results Highlight Cemiplimab’s Potential in NSCLC

In assessing the relationship between obstructive sleep apnea (OSA) and cardiovascular disease (CVD), researchers of a review published in 

highlight that it remains unclear how OSA induces changes in those with the disease.

As researchers note, OSA is a common yet underdiagnosed condition known to cause brief episodes of partial or total upper airway obstruction during sleep, which leads to apnea or hypopnea. These intermittent and recurrent episodes of hypoxia could have extensive implications for those with CVD.

injury and other mechanisms seen in OSA lead to changes in the CV system,” explain researchers.

Examining 31 published articles from the PubMed database, researchers conducted a literature review to address existing gaps in knowledge about the relationship between OSA and its effect on CV changes. “Only those publications that explained the mechanism by which OSA itself poses a risk to CV health, rather than just the impact of obesity or metabolic syndrome on it, were selected.”

In the review of selected data for 21,763 subjects, researchers uncovered a myriad of CVDs associated with OSA, as well as the mechanism behind how OSA influences CV events.

Focusing on pathological changes reported in OSA, recurrent hypoxia was found to trigger systemic inflammation, causing an alteration in transmural, intrathoracic, and cardiac pressures. As referenced previously, VEC injury is then caused by this change in the human body, which causes damage to coronary arteries. This can then lead to coronary artery diseases or cardiac ischemia, noted the researchers.

As a potentially preventive discovery, they found several proteins that are released by repeated hypoxia due to OSA that then lead to VEC injury. This could assist in making diagnoses of comorbid OSA and CVD, as these proteins could serve as biomarkers for identifying even asymptomatic patients with OSA.

So, for those diagnosed with comorbid OSA and CVD, what therapies may enhance long-term health?

Exercise is often associated with significant effects on both 

, particularly moderate to vigorous exercise. Authors of a study published yesterday in the 

 sought to determine the effects of continuous positive airway pressure (CPAP) treatment on improving adherence to moderate to vigorous physical activity among those with comorbid OSA and CVD.

In the study, titled the Sleep Apnea cardioVascular Endpoints (SAVE) trial, researchers recruited 2687 participants with confirmed CV disease history and OSA aged 45 to 75 years. The study cohort was randomly split into 2 groups, with the intervention group receiving CPAP plus usual care (n = 1346) and the control group receiving usual care alone (n = 1341).

Participants were followed for a mean of 3.7 years, with self-reported physical activity recorded at baseline, 6 months, 24 months, and 48 months via the Godin-Shepard Leisure Time Exercise Questionnaire (LTEQ).

“We also determined effects on any limitation of physical activity reported on the physical functioning subscale (PFS) of the 36-item short form questionnaire (SF-36) and proportions of participants reaching guideline recommended physical activity levels,” added researchers.

Comparing both groups, the intervention group that received CPAP reported significantly more physical activity (adjusted mean, 8.7; 95% CI, 7.5–9.9) than the control group (adjusted mean, 7.3; 95% CI, 6.1–8.5), attributed to approximately 20% higher moderate activity on the LTEQ during follow-up (

Additionally, the intervention group reported more sufficient levels of physical activity to meet recommendations, with less limitation in physical activity (adjusted between-group difference in SF-36 PFS score, 1.66; 95% CI, 0.87–2.45; 

“CPAP has positive effects on improving physical activity levels, consistent with long-term health benefits,” concluded the study authors.

1. Rana D, Torrilus C, Ahmad W, et al. Obstructive sleep apnea and cardiovascular morbidities: a review article. 

. Published online September 13, 2020. doi:10.7759/cureus.10424

2. Stevens D, Loffler KA, Human MP, et al. CPAP increases physical activity in obstructive sleep apnea with cardiovascular disease. 

. Published online September 21, 2020. doi:10.5664/jcsm.8792

In 2 separate articles, researchers review the relationship between obstructive sleep apnea (OSA) and cardiovascular disease, as well as the effects of continuous positive airway pressure treatment on level of physical activity in patients with these comorbid conditions.

What Is the Relationship Between OSA, Cardiovascular Disease? 

Prevalence of restless legs syndrome (RLS) is elevated among individuals with 

Migraine is classified as a type of brain disturbance of the subcortical aminergic sensory modulatory systems and can be triggered by a variety of causes such as food, barometric pressure changes, and stress. However, the exact underlying cause of migraine is unknown.

RLS is a movement disorder in which there is a feeling of distress and a tendency to move one’s legs, and in some cases, one’s arms and neck. Similarly, an underlying cause of RLS has not been established, although the syndrome is thought to be associated with iron deficiency in the brain. Kidney failure, pregnancy, anemia, and genetics are also associated with secondary RLS, the researchers wrote. It is estimated RLS affects 2% to 15 % of the population, and that prevalence increases with age.

Both migraine and RLS can negatively impact individuals’ quality of life. Using the databases  ScienceDirect, Embase, Scopus, SID, IranDoc, Medline (PubMed), and Google Scholar, the researchers aimed to quantify the overall prevalence of RLS in migraineurs.

Only related cross-sectional studies published between January 2000 and December 2019 in Persian or English were included in the review. To assess the quality of the studies, researchers used the STROBE checklist. The final analysis included 12 articles with a total sample size of 15,196. A meta-analysis found the overall prevalence of RLS in migraineurs was 16.3% (95% CI, 12.6%-20.8%).

The prevalence of RLS in patients with migraine was higher in patients ≥65 years in Turkey (33.8%; 95% CI, 23.4%-64.1%) but lower (8.7%; 95% CI, 7.7%-9.8%) in France

As sample size increased, the prevalence of RLS in patients with migraine decreased (

As years went on, the prevalence of RLS in patients with migraine increased (

The researchers hypothesized that as sample sizes increased, and thus more health individuals entered studies, the incidence of RLS decreased. Similarly, increases and improvements in diagnostic testing may contribute to increased incidence of RLS in more recent studies.

Dopamine chemicals are believed to be involved in the development of RLS while dopaminergic treatments may alleviate symptoms. However, migraine treated with certain therapies such as antiepileptic agents, like topiramate, may also induce RLS.

Studies have also shown that the prevalence of RLS in patients with migraine in Western countries is higher than those in Asian nations, potentially pointing to a genetic factor.

“This study provides a context for further studies on the treatment and impact of different therapies in the RLS population,” the authors concluded. “Future studies may focus on the comparison of the effects of dopaminergic treatments in patients with RLS and migraine.”

Ghasemi H, Khaledi-Paveh B, Abdi A, et al. The prevalence of restless legs syndrome in patients with migraine: a systematic review and meta-analysis.

. Published online August 29, 2020. doi:10.1155/2020/2763808

Prevalence of restless legs syndrome is elevated among individuals with migraine according to a systematic review and meta-analysis published in Pain Research and Management. 


Review Highlights Prevalence of Restless Legs Syndrome Among Migraineurs

 sequence (HXB2 position 2550-3356) data from 1397 

-1 infected patients at diagnosis in Germany shows they are increasingly demonstrating drug resistance mutations (DRMs) to certain classes of drugs used as antiretroviral therapy (ART), 

The drug classes are nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), and the most common shared mutation was K103N (47.4%). Coupled with the lack of data on the dynamics and patterns of HIV transmission in these areas is the public health concern around DRMs, which prompted the investigators’ analysis.

Patients from the study were receiving routine care at 7 university hospitals in 6 metropolitan areas in Germany between 2001 and 2018: Boon, Cologne, Frankfurt, Hamburg, Hannover, and Munich. Most were men (82.9%; n = 1158), from Germany (69.6%), infected with HIV-1 subtype B (72.9%), and men having sex with men (MSM; 56.7%). All had to be ART-naïve with a newly diagnosed case of HIV-1.

“This conservative approach excluded participants for whom the exact start date of ART or history of prior ART was not accurately documented,” the report noted.

Using blood samples collected before ART began, the investigators found that at diagnosis, an overall 17.8% (95% CI, 15.7%-19.8%) had any DRM. Per region analyzed (

 < .001), Hannover had the highest individual rate, at 31.4% (95% CI, 24%-38%), and Munich the lowest, at 9.1% (95% CI, 5%-13%).

Of the DRMs noted, the most common were associated with NRTIs (12.3%) and NNRTIs (8.9%). Within these classes, the most common mutations were K103N (25%) and G190A (6.5%) for NNRTIs and M41L (14.5%) and T215S (10.5%) for NRTIs.

Further analysis revealed there were 102 transmission clusters. Among these clusters, the following were identified:

Bonn, Cologne, Munich, and Frankfurt combined had the largest cluster: 12 patients.

Likely ages of clustering were younger than 25 years (adjusted OR [aOR], 4.38; 95% CI, 2.55-7.52; 

< .001) and 25 to 45 years (aOR, 1.91; 95% CI, 1.36-2.678; 

Among patients younger than 25 years, a higher proportion shared DRMs (3.5%) compared with older patients, both those 24 to 45 years (1.5%) and those older than 45 years (0.5%).

Clustering was more common among cases of HIV-1 subtype B vs non-B subtype (aOR, 4.05; 95% CI, 2.37-6.90; 

Despite the cities’ proximity, Bonn participants were genetically linked more often than Cologne participants (aOR, 1.63; 95% CI, 1.06-2.49; 

Cologne patients shared 16 of the 47 sequences with a DRM.

The second most common shared DRM was D67N (31.6%).

Of the cities investigated, Munich, Cologne, and Frankfurt had the top 3 highest rated of new HIV-1 infections, as of 2017, at 17.3, 13.3, and 12.3 cases per 100,000 population, respectively.

“Such resistance might be an upcoming challenge as PrEP use increases,” the report concluded. “Monitoring for HIV infections with these mutations is of utmost importance for preventing an epidemic among high-risk PrEP users; one mitigation is to consider alternative PrEP regimens in regions with high resistance.”

Stecher M, Chaillon A, Stephan C, et al. Drug resistance spread in 6 metropolitan regions, Germany, 2001-2018. 

. 2020;26(10):2439-2443. doi:10.3201/eid2610.191506

Despite the known benefits of antiretroviral therapy, the treatment may prove more difficult to use among clusters of patients with HIV exhibiting resistance to certain drug classes.

Drug Resistance Mutations Increasingly Showing Up in Germany Among HIV-Positive Individuals

 (T2D) with no previous insulin treatment, once-weekly injections of insulin icodec resulted in glucose-lowering efficacy and a safety profile similar to individuals who took once-daily insulin glargine U100. 

 of the randomized double-blind trial were published in the 

Although the American Diabetes Association and the European Association for the Study of Diabetes recommend treatment escalation when individualized glycemic targets are not met, clinical delays in insulin initiation can take place.

“Previous data have indicated that patients with T2D would generally prefer fewer injections and greater flexibility than is typical of the current once-daily treatment option,” researchers wrote. “Therefore, reducing the number of injections could potentially increase acceptance of and adherence to insulin treatment among patients with T2D, thereby potentially improving glycemic control.”

In a phase 2 trial testing insulin icodec, a basal insulin analogue administered once-weekly, investigators compared glycemic profiles of individuals who received weekly or daily insulin injections. All patients included had poorly controlled diabetes at baseline while randomization was stratified according to dipeptidyl peptidase 4 inhibitor use.

A total of 125 patients were assigned to receive icodec plus a once-daily placebo and 122 patients were assigned to receive glargine plus a once-weekly placebo. The 26-week trial included patients with a baseline glycated hemoglobin level (A1C) of 7.0 to 9.5%.

The starting dose of icodec was 70 U once weekly, and the starting dose of glargine was 10 U once daily. Insulin doses were adjusted weekly to achieve a pre-breakfast patient-measured blood glucose target of 70 to 108 mg per deciliter (3.9 to 6.0 mmol per liter), researchers explained.

Around 97% of the icodec arm completed the trial compared with 94.3% of the glargine group.

Mean (SD) A1C level in the icodec group decreased from 8.09% (0.70) at baseline to an estimated mean of 6.69% at week 26; in the glargine group, A1C level decreased from 7.96% (0.65) to 6.87%

Estimated mean change in A1C level from baseline at week 26 was −1.33 percentage points for icodec and −1.15 percentage points for glargine, for an estimated mean treatment difference of −0.18 percentage points (95% confidence interval [CI], −0.38 to 0.02;

Estimated percentages of patients reaching an A1C level of less than 7% at week 26 were 72% in the icodec group and 68% in the glargine group (estimated odds ratio [OR], 1.20; 95% CI, 0.98 to 2.13)

Percentages of patients reaching an A1C level of 6.5% or less were 49% in the icodec arm and 39% in the glargine group (OR, 1.47; 95% CI, 0.85 to 2.52)

The observed incidence of level 1 hypoglycemia alerts was 53.6% in the icodec group and 37.7% in the glargine group

For both icodec and glargine, the observed incidence of combined level 2 or level 3 hypoglycemia was 16.0% and 9.8%, respectively; the observed event rates were 0.53 and 0.46 events per patient-year of exposure, respectively, with an estimated rate ratio of 1.09 (95% CI, 0.45 to 2.65)

In addition, the icodec group exhibited a lower mean patient measured A1C level at all time points compared with the glargine group. Approximately half of patients in each treatment arm experienced an adverse event (AE) throughout the trial, including reports of 2 serious AEs in 2 patients receiving icodec and 12 serious AEs in 3 patients who received glargine. However, none of the AEs were considered by investigators to be possibly or probably related to trial medications.

Rosenstock J, Bajaj HS, Janež A, et al. Once-weekly insulin for type 2 diabetes without previous insulin treatment. 

Published online September 22, 2020. doi:10.1056/NEJMoa2022474

In individuals with type 2 diabetes with no previous insulin treatment, once-weekly injections of insulin icodec resulted in glucose-lowering efficacy and a safety profile similar to individuals who took once-daily insulin glargine U100. 