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 Key to Vascepa's CV Benefits

We interview experts on investigational treatments such as liso-cel, and ask how to bring them to community practice.

Spotlight on CAR T-Cell Therapy

The American Journal of Accountable Care® features research and commentary on new payment models.

New Members for AJAC Board

's parent company, MJH Life Sciences, since 2011. She has an MA in business and economic reporting from New York University.

Triple oral combination therapy with macitentan, riociguat, and selexipag may be a promising strategy to treat patients with low/intermediate-risk pulmonary arterial hypertension (PAH), and possibly even patients with high-risk PAH, according to a study 

Therapeutic Advances in Respiratory Disease

PAH is a lethal disease, and there is currently a scarcity of evidence of the efficacy and safety of triple oral combination therapy. There are 3 pathways that are targeted in PAH treatment: the endothelin pathway, nitric oxide pathway, and prostacyclin pathway.

Research has shown the effectiveness of triple therapy, but the studies analyze the use of 2 oral therapies and an infusion. However, there are 3 oral therapies targeting each of the pathways: macitentan targets the endothelin pathway; riociguat targets the nitric oxide pathway; and selexipag targets the prostacyclin therapy.

The researchers conducted a retrospective study in Keio University Hospital in Japan evaluating patients with PAH who received the triple oral combination therapy of macitentan, riociguat, and selexipag. The patients in the study were divided into 2 groups based on the REVEAL 2.0 risk score: high risk, defined as patients with a predicted 1-year survival rate of less than 90%; and low/intermediate-risk, defined as patients with a predicted 1-year survival rate of 90% or greater.

In addition, patients who were treatment-naïve when they were enrolled were independently assessed. Most of the patients (65.4%) in the study were treatment-naïve.

In total, 26 patients were enrolled in the study. Of these, 4 (15%) discontinued the oral triple combination therapy due to adverse events. “Among these four patients, one had diarrhea with selexipag, one had suspected myelosuppression with macitentan, one had nausea with riociguat, and one had hypotension with riociguat,” the authors wrote. “These patients changed their drug to another drug targeting the same pathway.”

The study found that the combination therapy improved the hemodynamics, right ventricular function, and clinical function for patients. The median follow-up period for the hemodynamic analysis was 293 days and there was a 29% decrease in the mean pulmonary arterial pressure and a 66% decrease in the pulmonary arterial resistance. Cardiac output increased by 90% over the course of the study. The median follow-up period for echocardiography was 385 days and the findings indicated right ventricular function increased significantly.

The authors concluded that most of the low/intermediate-risk patients and about half of the high-risk patients could be treated sufficiently with this combination. However, they noted that “it is difficult to generalize these findings.” The small, single-center, retrospective nature of the study was one of the limitations the authors highlighted. Additional limitations were that some patients were not treatment-naïve at baseline and the unknown nature of how each etiology of PAH may have affected the results of the study.

“In particular, this triple oral combination therapy can be a promising therapeutic strategy in patients with low/intermediate risk and possibly even in half of patients with high risk,” the authors concluded. “Further investigation is required to validate these findings.”

Momoi M, Hiraide T, Shinya Y, et al. Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension. 

. Jan-Dec 2021;15:1753466621995048. doi:10.1177/1753466621995048

Articles

Triple oral combination therapy with macitentan, riociguat, and selexipag may be a promising strategy to treat patients with low/intermediate-risk pulmonary arterial hypertension (PAH), and possibly even patients with high-risk PAH.

Real-World Study Finds Oral Combination Therapy of Macitentan, Riociguat, and Selexipag Effective in PAH

® since 2019 after receiving his Bachelor's degree at Rutgers University–New Brunswick in journalism and economics.

Early-career physicians with an irregular 

 schedule were found to be at an increased risk for depression over the long term, with short-term consequences shown to affect mood the next day, according to study findings published in 

Although several factors play a distinct role in evaluating sleep health, the researchers highlight that studies often focus solely on 

 in their analyses. Moreover, 24-hour total sleep time (TST), an established critical driver of major depression, remains poorly understood due to reliance “on either self-report assessments or traditional objective sleep measurements restricted to cross-sectional time frames and small cohorts.”


Seeking to build on emerging evidence that has identified the sleep-wake schedule as a particularly important and stable contributor to health over time, they assessed 2115 early-career physicians (mean [SD] age, 27.5 [2.4] years; 56% female) who were all in their first year of residency training after medical school. Participants were analyzed in the 2 weeks prior to the study and then for 1 year during residency, which was characterized by long, intense work days and irregular work schedules that contributed to day-to-day variance in sleep.

Delineate the changes in objective, longitudinally monitored sleep with the transition into internship

Identify the specific objective sleep characteristics, including variability, associated with depression over the course of the intern year

Evaluate the impact of day-to-day changes in objective sleep duration and sleep-wake timing on mood the next day

They evaluated sleep via wearable device, daily mood with a smartphone application, and depression through the 

"The advanced wearable technology allows us to study the behavioral and physiological factors of mental health, including sleep, at a much larger scale and more accurately than before, opening up an exciting field for us to explore," said lead study author Yu Fang, MSE, research specialist at the Michigan Neuroscience Institute, in a 

. "Our findings aim not only to guide self-management on sleep habits but also to inform institutional scheduling structures."

Among the study cohort, several factors were associated with more depressive symptoms:

In comparing the aggregated impact of sleep variability and mean sleep parameters, both were found to be similar in magnitude on PHQ-9 scores (both: 

Furthermore, after evaluating objective sleep duration and sleep-wake timing on mood the next day, improved next-day mood was associated with:

  < .001) and lower day-to-day shifts in TST (

“Variability in sleep parameters substantially impacted mood and depression, similar in magnitude to the mean levels of sleep parameters,” concluded the study authors. “Interventions that target sleep consistency, along with sleep duration, hold promise to improve mental health.”

Due to the young patient cohort, authors note that study findings are not representative of the general population.

Fang Y, Forger DB, Frank E, Sen S, Goldstein C. Day-to-day variability in sleep parameters and depression risk: a prospective cohort study of training physicians. 

. Published online February 18, 2021. doi:10.1038/s41746-021-00400-z

An irregular sleeping schedule is associated with a greater risk of depression in the long term, with consequences similar to results seen among persons who sleep fewer hours overall or stay up late most nights.

Irregular Sleep Schedule Linked With Depression, Worse Mood

A systematic review and meta-analysis of studies of patients with 

 (MS) found that mindfulness- and acceptance-based interventions (MABIs) did not have a significant effect on mindfulness among these patients. Quality of life (QOL), coping skills, cognition, and mindfulness were shown to have just moderate gains.

The author searched PubMed (1966-2020), CINAHL (1981-2020), PsycINFO (1935-2000), and SCOPUS (1966-2020) from their inception through July 3, 2020, including 18 randomized controlled trials in her final analysis. Search terms used included 

. Among qualifying criteria, the 18 trials had to be written in English, provide a comparison of before and after results, and test sole or multicomponent interventions “involving MABIs at least 50% of the whole intervention time.”

Of the 18 studies included, in-person interventions were tested in 15 and web- or phone-based interventions in 3, among a mean (SD) cohort size of 61.2 (37.5) patients, with the smallest trial including 24 individuals and the largest, 150. The mean (SD) patient age was 42.4 (8.6) years, and 78.7% of patients were female.

“Interventions involving mindfulness training have shown growing evidence for improving cognitive functions, including attention and memory,” said Areum Han, PhD, the study’s author. “But the scientific investigation regarding effects of mindfulness training on cognition is still relatively new with a limited number of studies.”

Her analysis revealed these findings of the MABIs tested:

They had a moderate effect on QOL in 12 of the trials, which covered 547 participants (standardized mean difference [SMD], 0.56; 95% CI, 0.15-0.97). This was seen immediately following the interventions.

QOL improved more with follow-up in 7 of the trials, which covered 390 participants (SMD, 0.81; 95% CI, 0.21-1.40).

Coping skills had slight improvements in 4 of the trials, of 214 participants (SMD, 0.45; 95% CI, 0.02-0.87), immediately following the interventions.

Coping skills did not have statistically significant increases in 3 of the trials, among 170 participants (SMD, 0.63; 95% CI, –0.15 to 1.42), at follow-up.

Cognition (memory) moderately improved in just 4 trials, covering 170 participants (SMD, 0.49; 95% CI, 0.19-0.80), a finding seen right after the MABIs concluded.

Memory was shown to greatly improve in 3 of the trials, covering 137 participants (SMD, 1.12; 95% CI, 0.06-2.17), but this was only seen at follow-up.

No statistically significant improvements from MABIs were noticed for mindfulness, both immediately following interventions (SMD, 0.22; 95% CI, –0.34 to 0.77) and at a more distanced follow-up (SMD, 0.59; 95% CI, –0.26 to 1.44).

“The present meta-analysis paper found new information by conducting meta-analyses regarding effects on coping, attention, memory, and mindfulness,” Han noted. “Previous meta-analyses for people with MS were not conducted in these outcomes.”

These previous studies, she added, have primarily focused on symptom reduction for depression, anxiety, stress, fatigue, and pain.

Because the present meta-analysis did not include subgroup analyses on individual MABI features and only studies written in English were included, these findings may be limited in their generalizability.

Future studies on the effects of MABIs on QOL, coping, cognition, and mindfulness should include subgroup analyses for contributions of mindfulness-based cognitive therapy, acceptance and commitment therapy, and dialectical behavior therapy among patients with MS, Han concluded.

“High-quality studies with follow-up evaluations are needed to support effects of MABIs on QOL, coping, cognition, and mindfulness in people with MS and examine intervention features that increase and maintain effects,” she emphasized.

Han A. Effects of mindfulness-and acceptance-based interventions on quality of life, coping, cognition, and mindfulness of people with multiple sclerosis: a systematic review and meta-analysis. 

2021;1-18. doi:10.1080/13548506.2021.1894345

A systematic review and meta-analysis of studies of patients with multiple sclerosis (MS) found that mindfulness- and acceptance-based interventions did not have a significant effect on mindfulness among these patients.

Mixed Improvements Seen Among Patients With MS Practicing Mindfulness

 since 2019 and has a BA in philosophy and journalism & professional writing from The College of New Jersey. 

Timing of bout-related moderate-to-vigorous physical activity (MVPA) is associated with cardiorespiratory fitness and cardiovascular risk among men with type 2 

 (T2D), independent of bout-related MVPA volume and intensity, according to 

Although regular physical activity (PA) is an important component of blood glucose management and overall cardiovascular health in individuals with prediabetes and diabetes, few studies have examined the role that time of day of bout-related MVPA plays in this population.

Using baseline data from the Look AHEAD Study, investigators aimed to characterize the temporal distribution of bout-related MVPA in adults with overweight/obesity and T2D, define whether the timing varies according to sociodemographic or anthropometric factors, and determine associations of timing of bout-related MVPA with baseline cardiorespiratory fitness and risk for coronary heart disease (CHD).

The Look AHEAD Study randomized adults (n = 5145) with overweight/obesity and T2D to an intensive lifestyle intervention or diabetes support and education program. All participants in the current analysis (n = 2035) completed baseline testing prior to randomization, had been diagnosed with T2D, had a body mass index (BMI) of at least 25 kg/m

 when taking insulin), and were between the ages of 45 and 76 years.

Throughout the study period (1 week), “participants were instructed to wear the hip-mounted RT3 triaxial accelerometer for 7 consecutive days during waking hours, removing it only for periods of sleep, bathing, showering, or other water-based activities,” and they were instructed not to alter their habitual PA patterns while wearing the device.

To determine intensity of physical activity (expressed in metabolic equivalent tasks [METs]), researchers divided the estimated energy expenditure per minute by estimated resting energy expenditure per minute, computed using the software.

“Periods of MVPA were defined as ≥3 METs. Bout-related MVPA was defined as any activity ≥3 METs and ≥10 minutes in duration, allowing for a 1-2 minutes interruption in MVPA,” the authors wrote. In addition, “Participants were categorized into 6 groups based on the time of day with the majority of bout-related MVPA (MET× min): ≥50% of bout-related MVPA during the same time window (morning, midday, afternoon, or evening), <50% bout-related MVPA in any time category (mixed; the reference group), and ≤1 day with bout-related MVPA per week (inactive).”

Cardiorespiratory fitness was highly associated with timing of bout-related MVPA (

= .0005), independent of weekly bout-related MVPA volume and intensity, while the association varied by sex (

In men, the midday group had the lowest fitness (β = –0.46; 95% CI, –0.87 to –0.06), while the mixed group in women was the least fit.

Framingham risk score (FRS) was associated with timing of bout-related MVPA (

The male morning group had highest 4-year FRS (2.18%; 95% CI, 0.70%-3.65%), but no association was observed in women.

Overall, men who performed the majority of bout-related MVPA in the midday had the lowest cardiorespiratory fitness, the authors wrote. In comparison, men who were the most active in the morning hours tended to have the highest cardiorespiratory fitness. Additionally, “men who performed the majority of bout-related MVPA in the morning hours had higher 4-year FRS indicating a higher chance of developing CHD in the next 4 years, independent of their overall levels of bout-related MVPA, MVPA bout intensity, and their cardiorespiratory fitness,” the researchers noted.

This finding could be due to the fact that men with higher risk were more likely to perform MVPA in mornings. Other factors such as timing of food intake, sleep duration, or types of occupation may have contributed to this finding but were not measured in the current analysis.

“The general message for our patient population remains that you should exercise whenever you can as regular exercise provides significant benefits for health," 

 study author Jingyi Qian, PhD. “But researchers studying the effects of physical activity should take into account timing as an additional consideration so that we can give better recommendations to the general public about how time of day may affect the relationship between exercise and cardiovascular health.”

Findings do align with evidence on the link between circadian system and exercise physiology. However, it is unclear why time-specific activity could be associated with different levels of health.

“Interest in the interaction between physical activity and the circadian system is still just emerging," said Qian. "We formed a methodology for quantifying and characterizing participants based on the clock-time of their physical activity, which allows researchers to carry out other studies on other cohorts."

Future longitudinal studies are warranted to further investigate the association between timing of bout-related MVPA and improvement of cardiorespiratory fitness and potential mechanisms, authors concluded.

Qian J, Walkup MP, Chen S, et al. Association of objectively-measured timing of physical activity bouts with cardiovascular health in type 2 diabetes. 

. Published online February 17, 2021. doi:10.2337/dc20-2178

Timing of bout-related moderate-to-vigorous physical activity (MVPA) is associated with cardiorespiratory fitness and cardiovascular risk among men with type 2 diabetes (T2D), independent of bout-related MVPA volume and intensity, according to research published in Diabetes Care. 

Exercise Timing Linked to Cardiorespiratory Fitness in Men With T2D

The FDA approved the first therapy for an 

 genetic metabolic disorder that affects infants, who don’t normally live past the age of 4.

The disorder is known as molybdenum cofactor deficiency (MoCD) Type A, which presents shortly after birth, often with severe encephalopathy and intractable seizures.

The approval for the injection, fosdenopterin (Nulibry), was granted to BridgeBio Pharma and its affiliate, Origin Biosciences.

A progressive disease, MoCD Type A affects fewer than 150 patients across the globe. It is characterized by an inability to produce cyclic pyranopterin monophosphate (cPMP). The injection replaces missing cPMP in treated patients.

"Today's action marks the first FDA approval for a therapy to treat this devastating disease," Hylton V. Joffe, MD, MMSc, director of the Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine in the FDA's Center for Drug Evaluation and Research, 

. "The FDA remains committed to facilitating the development and approval of safe and effective therapies for patients affected by rare diseases—an area of critical need."

BridgeBio’s Origin submitted a new drug application with the FDA for in December 2019. The FDA reviewed the injection under Priority Review, and the therapy received Orphan Drug Designation, Breakthrough Therapy Designation and Rare Pediatric Disease Designation. In addition, the agency issued a Rare Pediatric Disease Priority Review Voucher (PRV) to Origin.

The FDA said efficacy was established in 13 patients administered fosdenopterin, compared with 19 matched, untreated patients. The therapy was linked with a survival rate of 84% at 3 years, compared with 55% among untreated patients.

The most common side effects included complications related to the intravenous line, fever, respiratory infections, vomiting, gastroenteritis, and diarrhea.

 with fosdenopterin in 3 studies was also associated with a marked reduction in urine concentrations of S-sulfocysteine (SSC), a toxic substance that is associated with neurological damage in patients with MoCD Type A. The studies show that the reduction in SSC was sustained over 48 months with long-term use of fosdenopterin.

The disorder known as molybdenum cofactor deficiency (MoCD) Type A presents shortly after birth, often with severe encephalopathy and intractable seizures.

FDA Approves First Treatment for Rare Genetic Metabolic Pediatric Disorder 

As the COVID-19 pandemic has led to a nation-wide boom in 

, new questions are emerging regarding reimbursement, accessibility, data protection, and quality measurement. Although the practice has greatly aided in maintaining care for many Americans throughout the past year, several 

To create a measurement framework linking quality of care delivered by telehealth, health care system readiness, and health outcomes in rural areas specifically, the National Quality Forum (NQF) recently announced a committee of 

 to discuss, update, and enhance NQF’s 

, first released in 2017. Currently, there are no nationally endorsed telehealth quality measures.

On this episode of Managed Care Cast, we speak with Sheri Winsper, RN, MSN, MHA, the senior vice president for quality measurement at NQF. For the past 20 years, the forum has worked to advance health care quality across the nation by endorsing measures that assess quality of care and value. It also develops specific measurement frameworks for gap areas.

Listen above or through one of these podcast services:

Podcasts

On this episode of Managed Care Cast, we speak with Sheri Winsper, the senior vice president for quality measurement at the National Quality Forum, to discuss how the forum plans to devise national telehealth quality metrics. 

How the National Quality Forum Plans to Measure Telehealth Quality, Value

FDA has sent Athenex a complete response letter (CRL) regarding the company’s new drug application (NDA) for oral paclitaxel plus encequidar for the treatment of metastatic breast cancer. The company announced the CRL early Monday and 

 along with other developments as part of its financial update for 2020.

Regulators called for a new “adequate and well-conducted clinical trial,” marking an about-face from the course Athenex seemed to be on when the company’s NDA was accepted for 

 in September 2020. The targeted action date was February 28, 2021.

FDA cited concerns about the risk to patients of increased neutropenia-related adverse events in the oral paclitaxel arm compared with the intravenous (IV) paclitaxel arm. Regulators also said they were concerned about the uncertainty over results of the primary end point of the objective response rate (ORR) at week 19 conducted by a blinded independent central review (BICR).

In its statement, Athenex said, “The agency stated that the BICR reconciliation and re-read process may have introduced unmeasured bias and influence on the BICR.”

Athenex officials expressed their surprise at the turn of events, and said they would request a meeting with FDA to discuss the response and a plan to move forward.

“Our clinical and regulatory teams are disappointed by the complete response letter,”  Rudolf Kwan, MD, chief medical officer of Athenex, said in the statement. “We plan to work with the agency to resolve the issues raised in the CRL and to obtain approval for oral paclitaxel plus encequidar in metastatic breast cancer.”

The application was supported by data from a 

 that showed oral paclitaxel plus encequidar improved ORR compared with IV paclitaxel in patients with metastatic breast cancer; the ORR for the study drug was 36% compared with 24% for the control arm. Duration of response among those who responded to treatment was long as well, at 150 days or 2.5 times longer in those given oral paclitaxel with encequidar compared with IV paclitaxel.

Rates of neutropenia were comparable between the 2 arms, but more patients who took the study drug had grade 4 neutropenia and were more likely to have gastrointestinal side effects.

During the conference call, Athenex officials said the issue of whether the study population was representative of a US population also came up during the review process. The 

 of patients taking the combination drug was 90% Hispanic, 1% Black, and 7% White. According to the US Census Bureau, the nation’s 

 is 18.5% Hispanic, 13.4% Black, and 60% White.

Johnson Lau, MBBS, MD, FRCP, CEO of Athenex, said, “We remain committed to the breast cancer community and will explore the best path forward to obtain regulatory approval. In the interim, we will identify and undertake the appropriate internal organizational adjustments accordingly.”

FDA's action marks an abrupt change of course from the Priority Review granted September 2020.

Athenex Receives CRL on Oral Paclitaxel Plus Encequidar for Treatment of Metastatic Breast Cancer

Today, President Joe Biden will announce that competitors Merck and Johnson & Johnson (J&J) will form a partnership to produce more doses of the J&J COVID-19vaccine. Reported by 

 granted by the FDA to J&J’s vaccine this past weekend that will bring 3.9 million doses into circulation this week, although no doses are set to come next week due to production delays. This is the latest of several partnerships aiming to accelerate delivery of COVID-19 vaccines, with 

GlaxoSmithKline having partnered with CureVac

Fauci: US to Stick to 2-Dose Vaccine Plan

Speaking on the possibility of administering 1 shot of the approved 2-shot COVID-19 vaccines to provide protection to more people, the nation’s top infectious disease expert Anthony Fauci, MD, 

 yesterday that the United States will stick to the plan of inoculating tens of millions of Americans with 2 doses. He warned that shifting to a single-dose strategy may leave people less protected and at higher risk for emerging variants. 

, Public Health England said that 1 shot of the 2-shot vaccine manufactured by Pfizer/BioNTech was 57% to 61% effective in preventing symptomatic COVID-19 after 4 weeks in patients over the age of 70.

Medtronic announced it is recalling the HVAD Pump Implant Kit because the device may fail to initially start, restart, or have a delay in restarting after the pump has stopped, potentially causing serious patient harm, including heart attack, worsening 

 as a Class 1 recall, the most serious type of recall, the HVAD system is used as a bridge to cardiac transplants in patients who are at risk of death from end-stage left ventricular heart failure. So far, there have been 29 complaints about the device, with 19 serious injuries and 8 life-threatening events reported.

Merck and Johnson & Johnson (J&J) partner to produce J&J's COVID-19 vaccine; Anthony Fauci, MD, warns against shifting to a single-dose strategy for approved 2-shot vaccines; Medtronic recalls its HVAD Pump Implant Kits. 

What We're Reading: Merck to Produce J&J Vaccine; Fauci on Shifting Vaccine Strategies; HVAD Pump Implant Kits Recalled

 To compare use of diabetes medications between beneficiaries enrolled in Medicare Advantage (MA) and traditional Medicare (TM).

 Retrospective cohort analysis of Medicare enrollment and Part D event claims during 2015-2016.

 Data came from 1,027,884 TM and 838,420 MA beneficiaries who received at least 1 prescription for an oral or injectable diabetes medication. After matching MA and TM enrollees by demographic characteristics and geography, we analyzed use of medication overall, choices of first diabetes medication for those new to medication, and patterns of adding medications.

Overall and for patients on 1, 2, or 3 diabetes medications, use of metformin was higher in MA by about 3 percentage points, but use of newer medication classes was 5.1 percentage points higher in TM overall (21.3% vs 16.2%). Use of guideline-recommended first-line agents was higher in MA. For those who started metformin first, use of a sulfonylurea as a second medication was 7.8 percentage points higher in MA than TM (61.5% vs 53.7%), whereas use of medications from newer classes was 7.7 percentage points lower (22.0% vs 29.7%). Mean total spending was $149 higher in TM for those taking 1 medication and $298 higher for those taking 2 medications. Differences in spending among MA plans were of similar magnitude to the MA-TM differences.

 MA enrollees are more likely to be treated with metformin and sulfonylureas and less likely to receive costly newer medications than those in TM, but there also is substantial variation within MA. A limitation of the study is that we could not assess glucose control using glycated hemoglobin levels.

Medicare Advantage (MA) is associated with decreased utilization and higher quality relative to traditional Medicare (TM), but little is known about differences in medication management of chronic medical conditions such as diabetes. Using retrospective analyses of Medicare claims, we find that:

MA enrollees were more likely to use metformin and sulfonylureas and less likely to receive newer medications.

Mean plan and patient out-of-pocket spending for patients on 1, 2, or 3 medications was substantially higher for patients in TM.

There is substantial variation in the approaches to medication management across MA health plans.

Enrollment in Medicare Advantage (MA), Medicare’s managed care program, continues to expand, with more than one-third of Medicare beneficiaries currently enrolled in an MA plan.

 Relative to traditional Medicare (TM), care management by MA plans may enable them to treat patients at lower costs while attaining equal or superior quality through their control of enrollee benefits, network contracting, and coordination of care.

 This may be of particular relevance for patients with chronic medical conditions, for whom plans may employ a variety of care management approaches and financial incentives to promote the delivery of appropriate services and influence the quantity of services delivered.

 Prior research has demonstrated higher quality of ambulatory care for those enrolled in MA for process measures such as preventive care and monitoring of chronic diseases, as well as lower utilization of emergency department and inpatient services and of some elective services such as joint replacements.

 Differences in choices of medication might be another method by which MA plans achieve savings compared with TM. Most MA enrollment is in plans that include Part D coverage in an integrated product. TM enrollees generally enroll in stand-alone Part D prescription drug plans, although some have non-CMS coverage (retiree or other private plans) or none. However, no prior research that we are aware of has compared patterns of medication management in the 2 programs.

Diabetes is a prototypical example of a chronic and often progressive medical condition that may be affected by managed care approaches. Diabetes currently affects more than one-fourth of Medicare beneficiaries and is among the most common and costly chronic medical conditions affecting elderly Medicare enrollees.

 The principal medical treatment for diabetes is pharmacologic therapy aimed at controlling blood glucose levels and thereby preventing downstream cardiovascular, renal, and retinal complications that may arise from poorly controlled diabetes. The American Diabetes Association estimated that in 2017, almost $50 billion was spent on prescription diabetes medications and testing.

 Consensus recommendations uniformly support lifestyle modification plus metformin as the preferred initial treatment strategy for type 2 diabetes, but many classes of medication compete for use as second- or third-line therapy, including those new in the past decade.

 More recently, some emerging data suggest improved outcomes with several new agents in high-risk populations with cardiovascular or chronic kidney disease, but health plans and patients who use these newer medications, which have no generic alternatives, also face higher plan and out-of-pocket costs, respectively.

 For instance, according to GoodRx.com, mean monthly costs of glucagon-like peptide-1 (GLP-1) receptor agonists are approximately $800/month or higher compared with less than $100 for even the most costly dose of metformin. In addition, recommendations specifically for elderly patients include avoidance of long-acting sulfonylureas, which are associated with increased rates of hypoglycemia, and application of less stringent treatment goals for glucose control, particularly for those with limited life expectancy or multiple coexisting comorbid conditions.

 The large number of treatment options and potential intensity of treatment, as well as the wide range in prices of medications used to treat diabetes, present an opportunity for MA plans to improve the care of diabetes using approaches that are less expensive but similarly effective. Moreover, lower out-of-pocket costs to patients are associated with improved adherence to treatment recommendations, which ultimately can influence patient outcomes, as well.

Previous research indicates that diabetes is among the clinical areas in which MA plans achieve their highest rates of savings for medical services,

 but little research has examined how choices of medications for enrollees with diabetes differ for those enrolled in MA vs TM. Given the high cost of medical treatment of diabetes, we therefore used comprehensive data on beneficiaries being treated for diabetes in TM and MA to compare patterns of drug use in the 2 programs, as well as total pharmaceutical spending and adherence. We hypothesized that, relative to TM, MA plans would promote higher rates of use of medications that are recommended by consensus guidelines and that they also would promote use of less expensive generic medications when more expensive alternatives have not demonstrated clear benefits.

We analyzed Medicare claims and enrollment data provided by CMS for the period 2015-2016, the 2 most recent years available to us. Demographic and enrollment characteristics drawn from the Beneficiary Summary File were available for all enrollees. Data on prescription medication use from the Part D prescription drug event files were available for the subset (more than 67.8% in the study years) of the 20% random sample of TM beneficiaries enrolled in a Part D plan, and for a substantially higher percentage (94.6%) of those enrolled in MA plans, which typically are bundled with Part D coverage.

Our sample included all persons who were continuously enrolled in Medicare parts A and B throughout the year and were at least 65 years old on January 1. We excluded residents of long-stay nursing homes, whom we identified using a validated algorithm,

 because these beneficiaries rarely enroll in MA plans other than the dedicated special needs plans aimed at this population,

 and Medicare beneficiaries with end-stage renal disease. We also excluded MA enrollees in special needs plans that most commonly are restricted to low-income enrollees and have different rules related to enrollee cost sharing. We restricted some analyses focused on initiation or up-titration of prescription drugs to beneficiaries 66 years or older who had at least 1 year of continuous Part D enrollment prior to the respective study year.

Because medical claims data are not available for enrollees in MA plans, we restricted our analyses to those with diabetes who had received at least 1 prescription for a diabetes medication during the year of study.

 Thus, our study sample focuses on enrollees with diabetes being treated with medication and excludes those who received a diagnosis of diabetes but were being treated conservatively through lifestyle modification and diet.

Beneficiary and Health Plan Characteristics

The Medicare Master Beneficiary Summary Files provided data on age, sex, race/ethnicity, region of the country, and, when applicable, Medicaid coverage and disability as the original reason for Medicare eligibility.

Using CMS data, we categorized health plans (defined based on Medicare contracts) as large (> 25,000 enrollees) vs small, and we identified health plans new to MA since 2006.

Characterizing Medication Use and Guideline Concordance

We lacked data on clinical indicators, such as glycated hemoglobin levels, that typically drive decisions regarding use of medication; therefore, in addition to analyzing medication use overall, we focused on prespecified cohorts that we defined for this study to identify those with diabetes at a similar level of disease control for whom a clinician had decided that initiation or escalation of medical therapy was warranted. Medications were identified through drug or product names (see 

] for a full list and how they were classified).

For patients who received a new prescription for any diabetes medication in the year of interest and had received no diabetes medications in the prior year, we categorized the 

by class. These enrollees are likely those who previously had been treated with diet and lifestyle modification and who a physician now thought needed to start medication treatment. We considered metformin to be the only guideline-concordant initial choice of medication.

For those treated with a single drug in the prior year, we then characterized the 

 for those started on the 2 most commonly prescribed initial drug classes (metformin and sulfonylureas). Although guidelines regarding second medications allow for individualized use of medications from any of multiple classes, the guidelines also suggest that cost could be a consideration.

 Because of their less frequent use, we grouped into 1 category all relatively newly available medications without a generic alternative, such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and GLP-1 receptor agonists.

Finally, we examined whether those patients who were 

 received short-/rapid-acting, intermediate-acting, long-acting, or combination insulin, counting patients filling prescriptions for 2 types of insulin within 30 days as receiving combination therapy. When insulin therapy is necessary, guidelines consistently recommend beginning with basal or long-acting insulin. We did not differentiate between human and analogue insulin.

We based our classifications on largely consistent recommendations from the American College of Physicians, the American Diabetes Association, and the American Geriatrics Society for the treatment of elderly adults with diabetes during the time period of our study.

 Finally, we considered long-acting sulfonylureas to be guideline discordant at any stage of treatment because of increased risks of hypoglycemia in the elderly population.

These analyses included all patients taking any diabetes medication in a year. We calculated each beneficiary’s total, out-of-pocket, and Part D plan monthly diabetes drug spending over the year. Finally, for each medication taken, we calculated the medication possession ratio as a measure of adherence.

 This measure counts the number of days of supply that a patient had starting from the date of the first prescription fill to the date of the last prescription filled during the year plus the days supplied from that last prescription. Higher numbers indicate greater adherence.

We first compared the characteristics of enrollees in TM and MA who were identified as users of diabetes medications by available Part D prescription claims. As in previous studies, for all comparisons between the MA and TM samples, we first reweighted the TM sample to match the MA sample distribution by geography and demographic characteristics (age [in 5-year ranges], sex, race/ethnicity) and then aggregated these results to obtain national estimates that were weighted by the enrollment of MA plans.

 Matching on geography controlled for variation in practice patterns within Medicare across regions.

 By matching at the zip code level where possible (73% of the prevalent cohort), we also controlled for unmeasured socioeconomic characteristics associated with residence at this level of geography, as well as the proportion who were dually eligible for Medicaid. Of note, excluding those dually enrolled in Medicaid did not substantively affect our results, so dual-eligible enrollees were included in the study.

We tabulated characteristics of all enrollees with diabetes on medication as well as those initiating any drug treatment and those initiating treatment with insulin, testing differences between MA and TM proportions or means using χ

 tests as appropriate. We calculated the unadjusted and adjusted MA mean, the matched TM mean, the difference, and their respective standard errors, and we performed χ

 tests as appropriate to assess significance. Because of the size of our sample, most overall MA-TM differences that we report were statistically significant at the 

 < .001 level unless otherwise noted in the tables. Therefore, comparisons were not adjusted for multiple comparisons.

Lastly, as an illustrative example to examine variation in spending among MA plans, we modeled total spending for beneficiaries on 2 medications, using hierarchical linear regression models that included a random effect for each MA contract, as well as random effects for MA and TM at the state and hospital referral region levels. The random effects variance parameters quantify the variation across plans of savings relative to matched TM enrollees in its same service area after accounting for market- and state-level variation and sampling error.

All analyses were conducted using SAS software version 9.2 (SAS Institute). Our study protocol was approved by the Harvard Medical School Human Studies Committee. This work was funded by the National Institute on Aging, which had no role in the design of the study or in the collection, analysis, and interpretation of the data.

During 2015 and 2016, we studied 1,027,884 enrollees in TM and 838,420 enrollees in MA who were enrolled for the full year in Medicare and had available Part D pharmaceutical claims. Their respective characteristics are shown in 

. Among these enrollees, 62,265 from TM and 49,089 from MA initiated treatment with an initial diabetes drug (including all oral medications or insulin) during this time period, and, of these, 24,530 in TM and 16,635 in MA first started using insulin (including as an initial medication). In each treatment category, White enrollees were overrepresented in TM (near 75%) relative to MA (60%), and Hispanic enrollees were underrepresented in TM (7%-9%) relative to MA (21%-23%). More TM enrollees were eligible for Medicaid (25.7% vs 21.2% overall). After weighting, there were no observable demographic differences between the MA and TM populations.

Overall, use of metformin was lower in TM by about 3 percentage points (

Medicare Advantage enrollees are more likely to be treated with metformin and sulfonylureas and less likely to receive costly newer medications than those in traditional Medicare.