Diabetes

Patients with type 2 diabetes who were part of a health care plan and used a computer and/or app on a mobile device to access a portal (website) with tools for managing diabetes were more adherent with prescription refills and had improved hemoglobin A_1c levels, according to findings from a 33-month study published online in JAMA Network Open.

The improvements were greater in patients without prior portal usage, who began accessing the portal via a mobile device (smartphone or tablet) app as well as computer, compared with those who used only a computer.

Moreover, the improvements were greatest in patients with poorly controlled diabetes (HbA_1c greater than 8%) who began accessing the portal by both means.

“Patients with greater clinical need were able to benefit even more from mobile portal access, both in taking their medications more often and in actually improving blood sugar levels,” lead author Ilana Graetz, PhD, an associate professor at the Rollins School of Health Policy and Management, Emory University, Atlanta, observed in a statement from Kaiser Permanente.

The results show that “patients can use technology to better manage their own care, their medications, and their diabetes,” added senior author Mary Reed, DrPH, a research scientist at the Kaiser Permanente Division of Research, Oakland, California. “This is an example of how the health care system, by offering patients access to their own information and the ability to manage their health care online, can improve their health.”

“Offering this in a mobile-friendly way can give even more patients the ability to engage with their health care,” Dr. Reed noted. “It literally puts the access to these tools in the patient’s own pocket wherever they go.”

Checking refills and lab results

Dr. Graetz and colleagues performed a retrospective analysis of data from 111,463 adults with type 2 diabetes who were not receiving insulin but were taking oral diabetes medications and were covered by a health care plan with Kaiser Permanente Northern California from April 1, 2015 to December 31, 2017. The patients were a mean age of 64 years, and 54% were men.

Patients could register online for free access to a portal that allowed them to get general health information and see their laboratory test results, as well as securely send and receive messages to and from their health care providers, make medical appointments, and request prescription refills.

Study outcomes were change in oral diabetes medication adherence and HbA_1c levels at 33 months.

At baseline, 28% of patients had poor medication adherence (monthly days covered, less than 80%), and 20% had poor glycemic control.

After 33 months, the proportion of patients who never accessed the diabetes management portal dropped from 35% to 25%, and the proportion who accessed it from both a computer and an app increased from 34% to 62%.

Among patients with no prior portal access and who began accessing the portal by computer only, medication adherence increased by 1.16% and A_1c dropped by 0.06%.

However, among patients with no prior portal access who began to access it using both a computer and an app, diabetes management improvement was greater: medication adherence increased by 1.67% and HbA_1c levels dropped by 0.13%.

And among patients with no prior portal usage who had an initial HbA_1c level of more than 8.0% and began to access the website by both means, medication adherence increased by 5.09%, equivalent to an added 1.5 medication-adherent days per month, and HbA_1c levels fell by 0.19%.

There was also “a more modest, but still statistically significant increase,” of about 0.5 added medication-adherent days per month in patients with lower initial A_1c levels who began accessing the portal both ways.

“Although medication adherence measured by medication dispensed cannot guarantee which medications were actually used by patients,” the authors wrote, “our findings of concurrent improvements in [HbA_1c] levels confirm physiological improvements in diabetes control.”

“Convenient access to portal self-management tools through a mobile device could significantly improve diabetes management,” they conclude.

The study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases. The authors reported no relevant financial relationships.

This article first appeared on Medscape.com.

Patients with type 2 diabetes who were part of a health care plan and used a computer and/or app on a mobile device to access a portal (website) with tools for managing diabetes were more adherent with prescription refills and had improved hemoglobin A_1c levels, according to findings from a 33-month study published online in JAMA Network Open.

The improvements were greater in patients without prior portal usage, who began accessing the portal via a mobile device (smartphone or tablet) app as well as computer, compared with those who used only a computer.

Moreover, the improvements were greatest in patients with poorly controlled diabetes (HbA_1c greater than 8%) who began accessing the portal by both means.

“Patients with greater clinical need were able to benefit even more from mobile portal access, both in taking their medications more often and in actually improving blood sugar levels,” lead author Ilana Graetz, PhD, an associate professor at the Rollins School of Health Policy and Management, Emory University, Atlanta, observed in a statement from Kaiser Permanente.

The results show that “patients can use technology to better manage their own care, their medications, and their diabetes,” added senior author Mary Reed, DrPH, a research scientist at the Kaiser Permanente Division of Research, Oakland, California. “This is an example of how the health care system, by offering patients access to their own information and the ability to manage their health care online, can improve their health.”

“Offering this in a mobile-friendly way can give even more patients the ability to engage with their health care,” Dr. Reed noted. “It literally puts the access to these tools in the patient’s own pocket wherever they go.”

Checking refills and lab results

Dr. Graetz and colleagues performed a retrospective analysis of data from 111,463 adults with type 2 diabetes who were not receiving insulin but were taking oral diabetes medications and were covered by a health care plan with Kaiser Permanente Northern California from April 1, 2015 to December 31, 2017. The patients were a mean age of 64 years, and 54% were men.

Patients could register online for free access to a portal that allowed them to get general health information and see their laboratory test results, as well as securely send and receive messages to and from their health care providers, make medical appointments, and request prescription refills.

Study outcomes were change in oral diabetes medication adherence and HbA_1c levels at 33 months.

At baseline, 28% of patients had poor medication adherence (monthly days covered, less than 80%), and 20% had poor glycemic control.

After 33 months, the proportion of patients who never accessed the diabetes management portal dropped from 35% to 25%, and the proportion who accessed it from both a computer and an app increased from 34% to 62%.

Among patients with no prior portal access and who began accessing the portal by computer only, medication adherence increased by 1.16% and A_1c dropped by 0.06%.

However, among patients with no prior portal access who began to access it using both a computer and an app, diabetes management improvement was greater: medication adherence increased by 1.67% and HbA_1c levels dropped by 0.13%.

And among patients with no prior portal usage who had an initial HbA_1c level of more than 8.0% and began to access the website by both means, medication adherence increased by 5.09%, equivalent to an added 1.5 medication-adherent days per month, and HbA_1c levels fell by 0.19%.

There was also “a more modest, but still statistically significant increase,” of about 0.5 added medication-adherent days per month in patients with lower initial A_1c levels who began accessing the portal both ways.

“Although medication adherence measured by medication dispensed cannot guarantee which medications were actually used by patients,” the authors wrote, “our findings of concurrent improvements in [HbA_1c] levels confirm physiological improvements in diabetes control.”

“Convenient access to portal self-management tools through a mobile device could significantly improve diabetes management,” they conclude.

The study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases. The authors reported no relevant financial relationships.

This article first appeared on Medscape.com.

Patients with type 2 diabetes who were part of a health care plan and used a computer and/or app on a mobile device to access a portal (website) with tools for managing diabetes were more adherent with prescription refills and had improved hemoglobin A_1c levels, according to findings from a 33-month study published online in JAMA Network Open.

The improvements were greater in patients without prior portal usage, who began accessing the portal via a mobile device (smartphone or tablet) app as well as computer, compared with those who used only a computer.

Moreover, the improvements were greatest in patients with poorly controlled diabetes (HbA_1c greater than 8%) who began accessing the portal by both means.

“Patients with greater clinical need were able to benefit even more from mobile portal access, both in taking their medications more often and in actually improving blood sugar levels,” lead author Ilana Graetz, PhD, an associate professor at the Rollins School of Health Policy and Management, Emory University, Atlanta, observed in a statement from Kaiser Permanente.

The results show that “patients can use technology to better manage their own care, their medications, and their diabetes,” added senior author Mary Reed, DrPH, a research scientist at the Kaiser Permanente Division of Research, Oakland, California. “This is an example of how the health care system, by offering patients access to their own information and the ability to manage their health care online, can improve their health.”

“Offering this in a mobile-friendly way can give even more patients the ability to engage with their health care,” Dr. Reed noted. “It literally puts the access to these tools in the patient’s own pocket wherever they go.”

Checking refills and lab results

Dr. Graetz and colleagues performed a retrospective analysis of data from 111,463 adults with type 2 diabetes who were not receiving insulin but were taking oral diabetes medications and were covered by a health care plan with Kaiser Permanente Northern California from April 1, 2015 to December 31, 2017. The patients were a mean age of 64 years, and 54% were men.

Patients could register online for free access to a portal that allowed them to get general health information and see their laboratory test results, as well as securely send and receive messages to and from their health care providers, make medical appointments, and request prescription refills.

Study outcomes were change in oral diabetes medication adherence and HbA_1c levels at 33 months.

At baseline, 28% of patients had poor medication adherence (monthly days covered, less than 80%), and 20% had poor glycemic control.

After 33 months, the proportion of patients who never accessed the diabetes management portal dropped from 35% to 25%, and the proportion who accessed it from both a computer and an app increased from 34% to 62%.

Among patients with no prior portal access and who began accessing the portal by computer only, medication adherence increased by 1.16% and A_1c dropped by 0.06%.

However, among patients with no prior portal access who began to access it using both a computer and an app, diabetes management improvement was greater: medication adherence increased by 1.67% and HbA_1c levels dropped by 0.13%.

And among patients with no prior portal usage who had an initial HbA_1c level of more than 8.0% and began to access the website by both means, medication adherence increased by 5.09%, equivalent to an added 1.5 medication-adherent days per month, and HbA_1c levels fell by 0.19%.

There was also “a more modest, but still statistically significant increase,” of about 0.5 added medication-adherent days per month in patients with lower initial A_1c levels who began accessing the portal both ways.

“Although medication adherence measured by medication dispensed cannot guarantee which medications were actually used by patients,” the authors wrote, “our findings of concurrent improvements in [HbA_1c] levels confirm physiological improvements in diabetes control.”

“Convenient access to portal self-management tools through a mobile device could significantly improve diabetes management,” they conclude.

The study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases. The authors reported no relevant financial relationships.

This article first appeared on Medscape.com.

Oral hygiene may be a key factor in diabetes risk, new data from a Korean national health database suggest.

“Frequent tooth brushing may be an attenuating factor for the risk of new-onset diabetes, and the presence of periodontal disease and increased number of missing teeth may be augmenting factors,” wrote Yoonkyung Chang, MD, of the Department of Neurology, Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, South Korea, and colleagues.

“Improving oral hygiene may be associated with a decreased risk of occurrence of new-onset diabetes,” they continued in an article published online in Diabetologia.

Periodontal disease involves inflammatory reactions that affect the surrounding tissues of the teeth. Inflammation, in turn, is an important cause of diabetes because it increases insulin resistance and endothelial dysfunction, Dr. Chang and colleagues explained.

They analyzed data gathered during 2003-2006 from 188,013 individuals from the Korean National Health Insurance System – Health Screening Cohort who had complete data and did not have diabetes at baseline. Oral hygiene behaviors, including frequency of tooth brushing, and dental visits or cleanings, were collected by self-report.

Over a median follow-up of 10 years, there were 31,545 new cases of diabetes, with an estimated overall 10-year event rate of 16.1%. The rate was 17.2% for those with periodontal disease at baseline, compared with 15.8% for those without, which was a significant difference even after adjustments for multiple confounders (hazard ratio, 1.09; P less than .001).

Compared with patients who had no missing teeth, the event rate for new-onset diabetes rose from 15.4% for patients with 1 missing tooth (HR, 1.08; P less than .001) to 21.4% for those with 15 or more missing teeth (HR, 1.21; P less than .001).

Professional dental cleaning did not have a significant effect after multivariate analysis. However, the number of daily tooth brushings by the individual did. Compared with brushing 0-1 times/day, those who brushed 3 or more times/day had a significantly lower risk for new-onset diabetes (HR, 0.92; P less than .001).

In subgroup analyses, periodontal disease was more strongly associated with new-onset diabetes in adults aged 51 years and younger (HR, 1.14), compared with those who were 52 years or older (HR, 1.06).

The study was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education. The authors reported no relevant financial relationships.
 

This article first appeared on Medscape.com.

Oral hygiene may be a key factor in diabetes risk, new data from a Korean national health database suggest.

“Frequent tooth brushing may be an attenuating factor for the risk of new-onset diabetes, and the presence of periodontal disease and increased number of missing teeth may be augmenting factors,” wrote Yoonkyung Chang, MD, of the Department of Neurology, Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, South Korea, and colleagues.

“Improving oral hygiene may be associated with a decreased risk of occurrence of new-onset diabetes,” they continued in an article published online in Diabetologia.

Periodontal disease involves inflammatory reactions that affect the surrounding tissues of the teeth. Inflammation, in turn, is an important cause of diabetes because it increases insulin resistance and endothelial dysfunction, Dr. Chang and colleagues explained.

They analyzed data gathered during 2003-2006 from 188,013 individuals from the Korean National Health Insurance System – Health Screening Cohort who had complete data and did not have diabetes at baseline. Oral hygiene behaviors, including frequency of tooth brushing, and dental visits or cleanings, were collected by self-report.

Over a median follow-up of 10 years, there were 31,545 new cases of diabetes, with an estimated overall 10-year event rate of 16.1%. The rate was 17.2% for those with periodontal disease at baseline, compared with 15.8% for those without, which was a significant difference even after adjustments for multiple confounders (hazard ratio, 1.09; P less than .001).

Compared with patients who had no missing teeth, the event rate for new-onset diabetes rose from 15.4% for patients with 1 missing tooth (HR, 1.08; P less than .001) to 21.4% for those with 15 or more missing teeth (HR, 1.21; P less than .001).

Professional dental cleaning did not have a significant effect after multivariate analysis. However, the number of daily tooth brushings by the individual did. Compared with brushing 0-1 times/day, those who brushed 3 or more times/day had a significantly lower risk for new-onset diabetes (HR, 0.92; P less than .001).

In subgroup analyses, periodontal disease was more strongly associated with new-onset diabetes in adults aged 51 years and younger (HR, 1.14), compared with those who were 52 years or older (HR, 1.06).

The study was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education. The authors reported no relevant financial relationships.
 

This article first appeared on Medscape.com.

Oral hygiene may be a key factor in diabetes risk, new data from a Korean national health database suggest.

“Frequent tooth brushing may be an attenuating factor for the risk of new-onset diabetes, and the presence of periodontal disease and increased number of missing teeth may be augmenting factors,” wrote Yoonkyung Chang, MD, of the Department of Neurology, Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, South Korea, and colleagues.

“Improving oral hygiene may be associated with a decreased risk of occurrence of new-onset diabetes,” they continued in an article published online in Diabetologia.

Periodontal disease involves inflammatory reactions that affect the surrounding tissues of the teeth. Inflammation, in turn, is an important cause of diabetes because it increases insulin resistance and endothelial dysfunction, Dr. Chang and colleagues explained.

They analyzed data gathered during 2003-2006 from 188,013 individuals from the Korean National Health Insurance System – Health Screening Cohort who had complete data and did not have diabetes at baseline. Oral hygiene behaviors, including frequency of tooth brushing, and dental visits or cleanings, were collected by self-report.

Over a median follow-up of 10 years, there were 31,545 new cases of diabetes, with an estimated overall 10-year event rate of 16.1%. The rate was 17.2% for those with periodontal disease at baseline, compared with 15.8% for those without, which was a significant difference even after adjustments for multiple confounders (hazard ratio, 1.09; P less than .001).

Compared with patients who had no missing teeth, the event rate for new-onset diabetes rose from 15.4% for patients with 1 missing tooth (HR, 1.08; P less than .001) to 21.4% for those with 15 or more missing teeth (HR, 1.21; P less than .001).

Professional dental cleaning did not have a significant effect after multivariate analysis. However, the number of daily tooth brushings by the individual did. Compared with brushing 0-1 times/day, those who brushed 3 or more times/day had a significantly lower risk for new-onset diabetes (HR, 0.92; P less than .001).

In subgroup analyses, periodontal disease was more strongly associated with new-onset diabetes in adults aged 51 years and younger (HR, 1.14), compared with those who were 52 years or older (HR, 1.06).

The study was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education. The authors reported no relevant financial relationships.
 

This article first appeared on Medscape.com.

Infant rice cereal contains lower levels of arsenic than it did in 2014, according to test results released by the Food and Drug Administration.

In April 2016, the FDA issued draft guidance calling for manufacturers of the product to reduce the level of arsenic in their cereals by establishing an action level of arsenic of 100 mcg/kg or 100 parts per billion.

Seventy-six percent of samples of infant rice cereal tested in 2018 had levels of arsenic at or below 100 parts per billion versus 47% of samples tested in 2014, according to a statement from the FDA. In 2011-2013, an even lower percentage of samples tested contained amounts of inorganic arsenic at or below the FDA’s current action level for this element, whose consumption has been associated with cancer, skin lesions, cardiovascular diseases, and diabetes.

The 2018 data is based on the testing of 149 samples of infant white and brown rice cereal samples.

“Results from our tests show that manufacturers have made significant progress in ensuring lower levels of inorganic arsenic in infant rice cereal,” Susan Mayne, PhD, director of the Center for Food Safety and Applied Nutrition, said in the FDA statement.

“Both white rice and brown rice cereals showed improvement in meeting the FDA’s 100 ppb proposed action level, but the improvement was greatest for white rice cereals, which tend to have lower levels of inorganic arsenic overall,” according to the statement.

[email protected]

Infant rice cereal contains lower levels of arsenic than it did in 2014, according to test results released by the Food and Drug Administration.

In April 2016, the FDA issued draft guidance calling for manufacturers of the product to reduce the level of arsenic in their cereals by establishing an action level of arsenic of 100 mcg/kg or 100 parts per billion.

Seventy-six percent of samples of infant rice cereal tested in 2018 had levels of arsenic at or below 100 parts per billion versus 47% of samples tested in 2014, according to a statement from the FDA. In 2011-2013, an even lower percentage of samples tested contained amounts of inorganic arsenic at or below the FDA’s current action level for this element, whose consumption has been associated with cancer, skin lesions, cardiovascular diseases, and diabetes.

The 2018 data is based on the testing of 149 samples of infant white and brown rice cereal samples.

“Results from our tests show that manufacturers have made significant progress in ensuring lower levels of inorganic arsenic in infant rice cereal,” Susan Mayne, PhD, director of the Center for Food Safety and Applied Nutrition, said in the FDA statement.

“Both white rice and brown rice cereals showed improvement in meeting the FDA’s 100 ppb proposed action level, but the improvement was greatest for white rice cereals, which tend to have lower levels of inorganic arsenic overall,” according to the statement.

[email protected]

Infant rice cereal contains lower levels of arsenic than it did in 2014, according to test results released by the Food and Drug Administration.

In April 2016, the FDA issued draft guidance calling for manufacturers of the product to reduce the level of arsenic in their cereals by establishing an action level of arsenic of 100 mcg/kg or 100 parts per billion.

Seventy-six percent of samples of infant rice cereal tested in 2018 had levels of arsenic at or below 100 parts per billion versus 47% of samples tested in 2014, according to a statement from the FDA. In 2011-2013, an even lower percentage of samples tested contained amounts of inorganic arsenic at or below the FDA’s current action level for this element, whose consumption has been associated with cancer, skin lesions, cardiovascular diseases, and diabetes.

The 2018 data is based on the testing of 149 samples of infant white and brown rice cereal samples.

“Results from our tests show that manufacturers have made significant progress in ensuring lower levels of inorganic arsenic in infant rice cereal,” Susan Mayne, PhD, director of the Center for Food Safety and Applied Nutrition, said in the FDA statement.

“Both white rice and brown rice cereals showed improvement in meeting the FDA’s 100 ppb proposed action level, but the improvement was greatest for white rice cereals, which tend to have lower levels of inorganic arsenic overall,” according to the statement.

[email protected]

Diabetic foot ulcers (DFUs) are devastating, common, and costly. This burden is borne disproportionately by veterans who have high prevalence of type 2 diabetes mellitus (T2DM) and other precipitating risk factors.¹ The mortality of veterans following a DFU is sobering, and ulceration is recognized as a significant marker of disease severity.

A 2017 study by Brennan and colleagues reported a 19% mortality rate within 1 year, and only 29% survive past 5 years.² DFUs are often complicated by peripheral arterial disease (PAD) and diabetic immune dysfunction, contributing to chronic wounds and infection.^3,4 About 60% of all foot ulcers become infected, and > 20% of patients with a diabetic foot infection require amputation.^5,6

A 2010 retrospective study reports that > 3,400 veterans have a diabetes-related lower extremity amputation annually, vastly surpassing the rate of amputation secondary to trauma in the Veterans Health Administration (VHA).^7,8 The inpatient costs for each amputation exceeded $60,000 in fiscal year 2010, and these amputation-related costs represent only 1 component of the total expense to the VHA attributable to diabetic foot complications.⁷ A recent systematic review by Chan and colleagues estimated mean annual costs in the year following a foot ulcer to be $44,200 to the public payer.⁹ This implies that direct expenditures for treatment of DFUs within the VHA exceeds $3 billion annually.

Diabetic Foot Ulcer Prevention

Given the dramatic impact of diabetic foot complications to the veteran and the US health care system, the VHA has long recognized the importance of preventive care for those at risk. In 2017 US Department of Veterans Affairs (VA) and Department of Defense issued a clinical practice guideline for the management of T2DM that recommended prophylactic foot care for early identification of any deformity or skin breakdown.¹⁰ The guidelines note that a “person who has had a foot ulcer is at lifelong risk of further ulceration,” reflecting the high rate of recurrence among all patients, including veterans. Multiple studies suggest that as many as 40% of patients experience recidivism in the first year after healing from a wound.^11-16

The VA is well equipped to deliver quality preventive care because of its innovative and long-standing PAVE (Prevention of Amputations for Veterans Everywhere) program.¹⁷ PAVE provides screening, education, appropriate footwear, and stratified care guidelines for veterans at risk for diabetes-related foot complications (Table 1). The practices encouraged by PAVE are evidence-based and synergistic with the objectives of the VA’s patient aligned care team (PACT) delivery approach.¹⁸ The granular data collected through PAVE are used to guide best practices and provide benchmarks for diabetic foot outcomes.

Unfortunately, despite PAVE guidelines requiring annual specialist foot care for at-risk veterans, a 2013 report by the VA Office of the Inspector General (OIG) found that one-third of all patients had no documentation of this minimal requirement of preventive foot care.¹⁹ Although the VA has worked to address this issue, the data hint at the missed opportunities for prevention of complications and the challenges of ensuring that a large at-risk veteran population has systematic and routine screening with access to specialist foot care.

Given the large proportion of veterans at high risk of chronic wound formation and the challenges of ensuring that this cohort receives good preventive foot care, expanding telemedicine has been suggested. Telemedicine solutions have the potential to reduce the impact of chronic wounds on overburdened clinic resources, schedules, and local and federal budgets.²⁰ Interestingly, the only preventive practice for the diabetic foot that has been proven effective through multiple randomized controlled trials and national and international clinical guidance documents is once-daily foot temperature monitoring.^21-26 Daily monitoring has the potential to reduce the burden of DFUs to veterans, improve veteran access to needed preventive care, and reduce costs incurred by the VHA treating diabetic foot complications. Yet despite a recent national guidance document detailing its appropriate use in PAVE 3 veterans, it remains underutilized.²⁷

The purpose of this review is to: (1) discuss the evidence supporting once-daily remote temperature monitoring (RTM), a telemedicine approach critical to improving both veteran access to care and diabetic foot outcomes; (2) summarize a 2017 study that presented an advanced clinical understanding of RTM use among veterans; (3) provide previously unpublished data from this study comparing high-risk VA and non-VA cohorts, highlighting the opportunity for additional focus on foot ulcer prevention within the VA; and (4) report on recent VA utilization of a RTM technology based on this research, emphasizing lessons learned and best practices.

Remote Temperature Monitoring

The objective of daily foot temperature monitoring is to identify impending inflammatory foot conditions, such as DFUs, infection, and acute Charcot neuroarthropathy episodes. The patient and care team then act to resolve the cause of detected inflammation before clinical presentation (prevention) and begin treatment earlier than would otherwise be possible to avoid expensive complications, such as infection (early detection). Preventive therapies are low risk to the patient and inexpensive.

RTM is recommended by multiple clinical practice guidelines, including those of the International Working Group on the Diabetic Foot, the American College of Foot and Ankle Surgeons, and the Wound Healing Society.^24-26 Its use is supported by evidence from 3 National Institutes of Health-funded and well-designed randomized controlled trials, 1 of which was additionally supported by a VA Health Services Research and Development Service Merit Award.^21-23,28 Conducted between 2004 and 2007, these studies demonstrated the potential to reduce foot ulcer incidence by as much as 85% using a dermal thermometer to identify inflammation and prompt decreased ambulation. Investigators established a clinical monitoring protocol comparing the temperatures between 6 matched locations on the left and right feet. Persistent differences in contralateral temperatures exceeding 2.2°C (4.0°F) were used as a marker for elevated risk and to initiate preventive care. Based on the encouraging results from these studies, a 2017 effectiveness review prepared for the Agency for Healthcare Research and Quality concluded that “home monitoring of foot skin temperature is effective for reducing foot ulcer incidence and recurrence.”²⁹

Accuracy of RTM

A 2017 longitudinal study (NCT02647346) has provided novel data to advance understanding of RTM for the prediction and prevention of DFUs.³⁰ This study was the first to systematically analyze the accuracy of RTM over different monitoring thresholds. The results enable practitioners to deliver risk-stratified preventive care. Policy makers can use the data from this study to weigh the cost and benefits of RTM for population health.

The multicenter trials had 129 participants from 4 VA health care systems: VA Long Beach Healthcare System in California, Miami VA Healthcare System in Florida, Phoenix VA Healthcare System in Arizona, and VA West Los Angeles Healthcare System in California. Each participant was followed for 34 weeks under standard preventive foot care and was instructed to step on a telemedicine SmartMat (Podimetrics, Inc) RTM mat for 20 seconds daily. Participants and investigators were blinded to the temperature data so that the accuracy of temperature monitoring could be assessed. All participants had a history of T2DM and healed DFU. Principal exclusion criteria included unhealed plantar wound, history of proximal lower extremity amputation (ie, above ankle), active Charcot foot disease, and comorbidities that could potentially inhibit an inflammatory response, such as end-stage renal disease, active malignancy, and immunosuppressive diseases.

The investigators reported that RTM with the study mat detected 97% of nonacute plantar DFUs using the most commonly studied threshold (sustained 2.2°C temperature difference). The lead time averaged 37 days before clinical identification of the wound under standard care. Although the false-positive rate of 57% was high, corresponding to approximately 3.0 notifications per patient per year on average in the research setting, it is important to note that this study only considered the prediction of plantar DFUs. Thus, detection of foot inflammation secondary to other conditions, such as preulcerative lesion, dorsal wound, Charcot neuroarthropathy, or foot infection, were reported as a false positive per the study’s definitions. Further, Crisologo and Lavery noted in a translational medicine summary of this research, because the intervention is noninvasive and minimally impactful to the patient and the health care system, “the potential to arrest re-ulceration is worth the perceived inconvenience to the patient.”³¹

Secondary outcomes related to adherence and ease of use were encouraging. Eighty-eight percent of participants reported that the mat was “very easy to use,” the highest possible score, and 98% were able to set up the mat for home use without difficulty. At the end of the 34-week study, more than 74% of participants remained engaged in routine use of the mat under a per-protocol assessment of adherence. These results are especially impressive given the documented poor adherence of at-risk patients to routine use of therapeutic footwear, which has been reported to be as low as 15%.³²

New Research

The data collected during this study has led to new research and advancements in RTM. A recent publication by Gordon and colleagues investigated whether RTM is less accurate in cohorts with perceived challenges.³³ They include patients with recently healed wounds and those with a history of partial foot amputation. There was no difference in the accuracy or lead time for either cohort relative to the entire cohort, suggesting that RTM is appropriate for monitoring patients with recently healed DFUs or partial foot amputations.

In another recent study, the data were used to derive a novel approach to monitor a single at-risk foot.³⁴ The practice of RTM has traditionally required comparing temperatures between contralaterally matched plantar locations on the feet, thus limiting its use in patients with a history of major lower extremity amputation and patients being treated for a wound, which may be bandaged or in an off-loading cast or boot. Because the risk factors for DFUs exist in both limbs, these patients are at high risk for developing complications to the contralateral foot and may benefit from preventive once-daily foot temperature monitoring. The investigators empirically derived a novel monitoring approach for patients without a contralateral control. This approach was found to predict 91% of impending plantar DFUs on average 41 days before clinical presentation with a false positive rate of 54%.

Additional Focus on Prevention

Table 2 shows previously unpublished data from a subgroup analysis between veteran and nonveteran participants in the study.²⁵ These descriptive statistics reinforce some widely held assumptions regarding the high-risk veteran population and challenge others. For example, compared with the nonveteran participants, the veteran cohort unsurprisingly had a larger ratio of male participants (P < .01), had a higher rate of cigarette use (P < .01), and was more likely to live alone (although not at a statistically significant level). Veterans in the study had body mass index, rates of alcohol use, frequency of exercise, and glucose control comparable to that of nonveterans.

The potential impact of the PAVE program is clear in several of these comparisons. Although as few as 15% of patients use therapeutic shoes routinely, PAVE ensures that the majority of veterans receive them. Nearly 95% of veterans have therapeutic shoes compared with about 80% of nonveteran participants (P < .05). Veterans also had higher ankle-brachial index results (P < .05), although on average both cohorts were within normal clinical parameters. Veterans had a significantly longer duration since healing from the most recent wound, and fewer veteran participants had a wound that healed in the 3 months prior to the study. Despite this, during the study veterans had annualized DFU incidence equal to that of nonveterans. Furthermore, veterans also had significantly higher rates of amputation prior to participation. That these critical outcomes for veterans are no better than those observed in other care environments despite PAVE suggests that approaches recommended via PAVE alone are insufficient to significantly arrest DFU recurrence, and even more focus on prevention in the VA may be warranted.

From Research to Practice

Since the publication of the 2017 study, the VHA has been at the vanguard of translating the evidence and research underlying RTM into clinical practice. A clinical guidance document governing appropriate use of RTM with the study mat was recently published by the VA Prosthetic and Sensory Aids Service in collaboration with the National Podiatry Program office.²⁷ This guidance document recommends once-daily RTM for at-risk veterans designated PAVE level 3. It defines roles and responsibilities required for the successful implementation of a RTM program with the study device. The document additionally presents various clinical monitoring protocols for veterans, although the protocol and thresholds used are at the discretion of the prescribing clinician and should reflect the risk profile of the veteran in question.

A staged response to inflammation has proven popular, whereby an initial high-sensitivity threshold is chosen for monitoring. The initial response is telephone outreach by a designee supplied by the clinic or device manufacturer, typically a trained registered nurse, to the veteran to collect subjective history and instruct off-loading and reduced ambulation, with a target of 50% baseline reduction in step count. Should the inflammation persist despite off-loading, an examination may be necessary to identify and resolve its cause. For recalcitrant inflammation, more targeted pressure off-loading of the affected area may be accomplished with custom orthotics, accommodative insoles, removable cast walkers, and total contact casting. After 2 to 4 weeks without signs of inflammation, the cause is deemed to have been resolved and lowered the acute risk for developing further diabetic foot complications.

More than 600 veterans have been monitored for > 1,000 patient-years—13 VA medical centers are practicing RTM with the study mat as of this writing. The monitoring program has been integrated into many veteran daily routines as evidenced by > 70% retaining full engagement after having been monitored for > 1 year. The total number of alerts/patient-years across these veterans has been 1.4, significantly lower than the 3.0 alerts/patient-year observed in the study. This is potentially due to successful interventions in response to detected inflammation, resolving inflammation, and avoiding unnecessary alerts occurring in the research setting, which did not employ interventions that resolved inflammation episodes. In the past 6 months, 68% of all inflammation detected resolved via off-loading alone without requiring further clinical intervention. In the cases that required an examination, 76% of patients reported clinically meaningful preventive care (eg, preulcerative callus was debrided, a subungual hemorrhage was treated, a foot ulcer was identified).

Organizational Best Practices

Several best practices have been cultivated related to initiating a RTM program at a new site, for promoting the success of a RTM program, and provisioning excellent preventive care to support the RTM program. Although we advise adhering to the recommendations in the VA guidance document,²⁷ the authors have observed several additional organizational best practices that are not explicitly addressed.

Partnering with PACT. Collaboration between PAVE and PACT has the potential not only to improve outcomes for patients at risk for diabetic foot complications, but also can help identify appropriate high-risk veteran candidates for preventive care with RTM who may not be followed for routine care from a specialty provider, such as a podiatrist, as highlighted by the 2013 OIG report.

Prescreening eligible patients. Several programs have used PAVE data or appointment schedules to identify and target high-risk veterans proactively. This approach has several benefits. It simplifies clinical coordination and streamlines workflow for patient identification and onboarding. It also allows those veterans at highest risk to receive needed and recommended preventive care at their next scheduled appointment. Finally, if PAVE data are used to identify eligible patients, it has the added benefit of ensuring a baseline level of telemedicine preventive foot care for veterans who have become lost to follow-up and have not been seen recently for a routine foot examination.

Implementing foot monitoring during wound treatment. Recent research has expanded the reach of once-daily RTM with the mat to patients being treated for a wound to only 1 foot. This practice has 2 benefits: The patient is able to establish a preventive routine before healing, an important advantage because research strongly suggests that recurrence is most likely in the first months after healing. Second, 48% of patients with a history of DFUs will develop new wounds to the contralateral foot because risk factors, such as neuropathy and peripheral arterial disease, exist in both limbs.³⁵ Furthermore, ongoing treatment for a wound to 1 foot may result in gait deviation and elevated pressure to the sound foot, additionally predisposing the veteran to complications, resulting in a high rate of wounds occurring to the unwounded foot during treatment (0.2 DFU/DFU-year).³⁴ Thus, there is potential benefit in monitoring the sound foot while undergoing treatment for a wound; further, the patient will have immediate access to the device for prevention of recurrence once the wound has resolved.

Utilizing foot monitoring as an extension of telemedicine. Many VA facilities have large geographic catchment areas, making routine follow-up difficult for veterans living in rural areas. RTM serves as an extension of the patient’s daily self-examination and the clinician’s ability to monitor patients with objective information daily. The veterans using the system become more invested and feel as though they are taking an active role in their health care.

Investing in ongoing medical education. Multidisciplinary education sessions reviewing supporting clinical data and resultant clinical practice guidelines raise awareness for those providers and trainees unaware of preventive best practices for the diabetic foot, including those related to foot RTM. These sessions also are helpful for those familiar with foot temperature monitoring or who are responsible for administration of an ongoing program to remain current with contemporary best practices and to discuss improvements for patient care. Familiarity also can help address clinical inertia when benefits and evidence are clearly communicated with health care providers (HCPs).

Clinical Best Practices

Treating preulcerative lesions urgently and aggressively. Callus and other preulcerative lesions often cause progressive tissue damage and poor outcomes. When identified, these lesions should be promptly treated to ensure best outcomes.²⁴

Recognizing the limits of patient self-examinations. Comorbidities such as visual impairment and reduced joint mobility often preclude patients from completing rigorous self-examinations of the foot, which is especially critical while collecting subjective history from the patient during triage of inflammation. A caregiver or spouse can help inspect the foot during outreach and provide additional context.³⁶

Interpreting a benign foot on examination. Because RTM has been demonstrated to detect inflammation preceding a foot ulcer as many as 5 weeks before presentation to the clinic, some veterans may have few signs or symptoms of acute risk during examination. Often, the damage is to subcutaneous tissue resulting from repetitive microtrauma. Research suggests that clinical examination in these cases is often unreliable for identifying the earliest signs of risk, such as palpation to identify subtle temperature changes secondary to inflammation.³⁷ If a patient has refractory inflammation requiring examination and presents with an otherwise unremarkable foot, it is an opportunity to evaluate whether the patient’s shoewear remains appropriate or has worn out, to communicate the veteran’s ongoing elevated risk, and to educate on the importance of diligence in daily foot self-examinations, daily use of the foot temperature monitoring, and continued off-loading until the inflammation resolves.

Communicating the distinction between healing and remission. Although healing is the goal of wound care, patients should be educated that the underlying disease remains after epithelialization. In some cases, tissue deep to the skin has not completed remodeling, and the patient is at acute risk of recurrence. Remission is a powerful metaphor that better describes the patient’s ongoing risk to encourage continued healthy routines and diligent self-care.³⁸Considering the entirety of both feet for recurrence. Critical risk factors for diabetic foot complications, such as peripheral neuropathy and PAD, exist in both limbs, and patients with a history of wounds often develop new complications to different ipsilateral locations, or in as many as 48% of cases, to the contralateral foot.³⁵ For best outcomes, detected inflammation should be treated aggressively independent of whether the location coincides with an area of previous concern.

Encouraging adherence, routine, and empowerment. Advanced diabetes mellitus and neuropathy may impact a patient’s executive function, and multiple studies have reported that patients at risk for inflammatory foot diseases exhibit fatalism toward their foot care and outcomes.^39-41 Consistent education, encouragement, empowerment, and establishment of positive routines are needed to ensure high adherence with all preventive care regimens, including RTM.

Case Presentations

The following case series illustrates many of these clinical best practices and characterizes the potential benefits of RTM to veterans within the VA.

Case 1: Prevention After Healing

A veteran underwent a Chopart amputation and was recommended to use the mat after healing was perceived. Immediately on use of the study mat, the patient was found to have inflammation to the surgical incision (Figure 1). Clinical staff was alerted to the findings, and the patient was instructed to limit further walking and continue off-loading in his removable cast walker, per protocol. The inflammation of the operative foot quickly reduced, and the patient continued healing successfully, potentially avoiding incisional dehiscence and possible postoperative infection.

This case illustrates that patients’ wounds or surgical incisions may not be completely healed on epithelialization. In the immediate phase after closure, HCPs should consider additional protection to avoid complications. This case demonstrates that RTM can provide objective data to help guide care in that critical period.

Case 2: Identifying Preulcerative Lesions

An 88-year-old veteran had a chronic callus under the second metatarsal head. In addition to routine foot care and therapeutic shoes, he was followed with once-daily RTM. Inflammation was noted, and the veteran was seen in the podiatry clinic where debridement of the callus was performed. The difference in temperatures between feet detected by thermography prior to the clinic visits rapidly resolved after callus debridement, indicating that the underlying inflammation had subsided. RTM was used by the clinical staff to determine the appropriate time interval between clinic visits to avoid callus breakdown and subsequent ulceration.

Case 3: Extending the Clinic Into the Home

An 80-year-old veteran with T2DM and neuropathy was deemed a high-risk patient due to recurrent ulcerations to the left great toe. He was issued a RTM mat and was adherent with routine use. After nearly a year without hot-spot development, inflammation was noted (Figure 2).

Unfortunately, the patient had missed several routine foot care visits and likely that was the reason for the noted inflammation. The patient was called and became reengaged in regular visits for routine foot care. On debridement of his callus, a superficial, noninfected ulceration was discovered. Had remote monitoring not detected the inflammation and impending ulceration, the patient likely would not have been seen in the regular clinic and may have developed a wound infection, potentially resulting in a worse and more costly outcome.

Paradigm Shift to Prevention

Given the exceedingly high burden of diabetic foot complications in the VA, a paradigm shift is needed among HCPs from a culture of treatment to one of prevention. Bus and colleagues reported that in Europe, for every euro spent on ulcer prevention, 10 are spent on ulcer healing, and for every randomized clinical trial conducted on prevention, 10 are conducted on treatment.^42-44 Hicks and colleagues showed that the cost of curative care for DFUs is 5 to 30 times greater than the cost of preventive care.⁴⁵ For RTM in high-risk cohorts (ie, PAVE level 3), the number-needed-to-treat for DFU prevention may be as low as 6, assuming that a 70% reduction in incidence is possible, consistent with previous research. In the year following a DFU, costs exceed $44,000.⁹ Thus, it seems natural that future direction in diabetic foot care should emphasize prevention strategies.

Foot ulcers that become infected often lead to hospitalization and result in an increased burden to an already overburdened VA health care system. Research suggests that about two-thirds of all diabetic foot costs are attributable to inpatient management.⁴⁶ The impact of diabetic foot complications on hospital resource utilization is staggering. A 2017 study by Skrepnik analyzed the risk of hospitalization for various diseases.⁴⁷ The investigators found that the inpatient admission odds ratio (OR) for congestive heart failure was 2.6, surpassed only by DFUs (OR, 3.4) and diabetic foot infection (OR, 6.7). A 2019 point-prevalence study found that > 10% of hospital admissions have a foot-related condition as the primary or secondary reason, and the majority of these are due to foot diseases, such as ulcers, infections, and Charcot neuroarthropathy.⁴⁸

It is therefore incumbent on VA HCPs to avert wound recurrence in the interest of avoiding veteran hospitalizations and for administrators to encourage and incentivize best practices for managing the diabetic foot, with an emphasis on prevention therapies. In evaluating the financial impact of prevention with foot RTM, administrators should consider that the cost benefit is likely to be realized across the medical center, with budgets related to inpatient management likely to receive the largest returns.

Prevention has the potential to rein in costs as well as reduce strain on the hospital and clinic by preventing outcomes that require frequent visits for treatment or hospitalization. Wound treatment is very burdensome to the clinic; patients require frequent (in many cases, weekly) examinations, and chronic wounds often require hospitalization, necessitating rounding and additional coordination in care. Thus, preventing wounds or reducing their severity at presentation substantially reduces burden on the clinic, even after accounting for the modest clinical resources needed to administer preventative care. For example, a brief examination may be necessary if the inflammation detected by the study mat is secondary to a callus that must be debrided. However, if the patient was not seen until the callus had progressed to a wound, weekly follow-up and substantial clinical and budgetary resources may be required to heal the wound. Preventive care allows for substantially better patient outcomes, and the minimal time invested prevents the clinical burden of extensive wound treatment.

The success of preventive efforts relies on multidisciplinary management of this high-risk patient cohort. Often, it is the responsibility of the primary care provider to follow diabetic foot clinical reminders and appropriately refer to specialty care. Successful, open communication between PACT, PAVE, and the Podiatry Service has been shown to reduce poor outcomes, including lower extremity amputations. Traditionally, the model of preventive care has included podiatrist-driven interventions, including integrated routine foot care and comprehensive diabetic foot education. Collaboration between routine evaluation and prompt referral of at-risk patients for specialist foot care, therapeutic footwear recommendations, daily self-foot examinations, and in-home temperature monitoring are critically effective when performed consistently.

When trying to translate research science to effective clinical practice for preventing lower extremity complication, there are several important concepts. First, given the frequency of examination for patients being treated for a wound, provision of good preventive care, such as RTM, can reduce overall burden to resource-constrained clinics and improve access for patients needing to be seen. Additionally, preventive efforts extend clinical practice into the home and may reduce the need for in-clinic examinations and routine follow-up visits. Finally, there may be a sense of trust established between the clinician and patient with a positive record of adherence with preventive practices. This may translate into more productive communication and less frequent routine visits to better accommodate urgent visits and ensure podiatric care is accessible to veterans.

Conclusions

There is a significant opportunity to shift diabetic foot care from treatment to prevention, improving veteran outcomes and reducing resource utilization. RTM is an evidence-based and recommended but underused telemedicine solution that can catalyze this needed paradigm shift. The VA has been at the forefront of preventive foot care through the PAVE program and more recently through research and clinical application of RTM for veterans. However, as the data presented suggest, more can be done to improve veteran outcomes. More widespread adoption of evidence-based preventive technologies for the diabetic foot, such as RTM, has the potential to dramatically improve the quality of and access to care and reduce costs and burden on resource-constrained clinics.

Diabetic foot ulcers (DFUs) are devastating, common, and costly. This burden is borne disproportionately by veterans who have high prevalence of type 2 diabetes mellitus (T2DM) and other precipitating risk factors.¹ The mortality of veterans following a DFU is sobering, and ulceration is recognized as a significant marker of disease severity.

A 2017 study by Brennan and colleagues reported a 19% mortality rate within 1 year, and only 29% survive past 5 years.² DFUs are often complicated by peripheral arterial disease (PAD) and diabetic immune dysfunction, contributing to chronic wounds and infection.^3,4 About 60% of all foot ulcers become infected, and > 20% of patients with a diabetic foot infection require amputation.^5,6

A 2010 retrospective study reports that > 3,400 veterans have a diabetes-related lower extremity amputation annually, vastly surpassing the rate of amputation secondary to trauma in the Veterans Health Administration (VHA).^7,8 The inpatient costs for each amputation exceeded $60,000 in fiscal year 2010, and these amputation-related costs represent only 1 component of the total expense to the VHA attributable to diabetic foot complications.⁷ A recent systematic review by Chan and colleagues estimated mean annual costs in the year following a foot ulcer to be $44,200 to the public payer.⁹ This implies that direct expenditures for treatment of DFUs within the VHA exceeds $3 billion annually.

Diabetic Foot Ulcer Prevention

Given the dramatic impact of diabetic foot complications to the veteran and the US health care system, the VHA has long recognized the importance of preventive care for those at risk. In 2017 US Department of Veterans Affairs (VA) and Department of Defense issued a clinical practice guideline for the management of T2DM that recommended prophylactic foot care for early identification of any deformity or skin breakdown.¹⁰ The guidelines note that a “person who has had a foot ulcer is at lifelong risk of further ulceration,” reflecting the high rate of recurrence among all patients, including veterans. Multiple studies suggest that as many as 40% of patients experience recidivism in the first year after healing from a wound.^11-16

The VA is well equipped to deliver quality preventive care because of its innovative and long-standing PAVE (Prevention of Amputations for Veterans Everywhere) program.¹⁷ PAVE provides screening, education, appropriate footwear, and stratified care guidelines for veterans at risk for diabetes-related foot complications (Table 1). The practices encouraged by PAVE are evidence-based and synergistic with the objectives of the VA’s patient aligned care team (PACT) delivery approach.¹⁸ The granular data collected through PAVE are used to guide best practices and provide benchmarks for diabetic foot outcomes.

Unfortunately, despite PAVE guidelines requiring annual specialist foot care for at-risk veterans, a 2013 report by the VA Office of the Inspector General (OIG) found that one-third of all patients had no documentation of this minimal requirement of preventive foot care.¹⁹ Although the VA has worked to address this issue, the data hint at the missed opportunities for prevention of complications and the challenges of ensuring that a large at-risk veteran population has systematic and routine screening with access to specialist foot care.

Given the large proportion of veterans at high risk of chronic wound formation and the challenges of ensuring that this cohort receives good preventive foot care, expanding telemedicine has been suggested. Telemedicine solutions have the potential to reduce the impact of chronic wounds on overburdened clinic resources, schedules, and local and federal budgets.²⁰ Interestingly, the only preventive practice for the diabetic foot that has been proven effective through multiple randomized controlled trials and national and international clinical guidance documents is once-daily foot temperature monitoring.^21-26 Daily monitoring has the potential to reduce the burden of DFUs to veterans, improve veteran access to needed preventive care, and reduce costs incurred by the VHA treating diabetic foot complications. Yet despite a recent national guidance document detailing its appropriate use in PAVE 3 veterans, it remains underutilized.²⁷

The purpose of this review is to: (1) discuss the evidence supporting once-daily remote temperature monitoring (RTM), a telemedicine approach critical to improving both veteran access to care and diabetic foot outcomes; (2) summarize a 2017 study that presented an advanced clinical understanding of RTM use among veterans; (3) provide previously unpublished data from this study comparing high-risk VA and non-VA cohorts, highlighting the opportunity for additional focus on foot ulcer prevention within the VA; and (4) report on recent VA utilization of a RTM technology based on this research, emphasizing lessons learned and best practices.

Remote Temperature Monitoring

The objective of daily foot temperature monitoring is to identify impending inflammatory foot conditions, such as DFUs, infection, and acute Charcot neuroarthropathy episodes. The patient and care team then act to resolve the cause of detected inflammation before clinical presentation (prevention) and begin treatment earlier than would otherwise be possible to avoid expensive complications, such as infection (early detection). Preventive therapies are low risk to the patient and inexpensive.

RTM is recommended by multiple clinical practice guidelines, including those of the International Working Group on the Diabetic Foot, the American College of Foot and Ankle Surgeons, and the Wound Healing Society.^24-26 Its use is supported by evidence from 3 National Institutes of Health-funded and well-designed randomized controlled trials, 1 of which was additionally supported by a VA Health Services Research and Development Service Merit Award.^21-23,28 Conducted between 2004 and 2007, these studies demonstrated the potential to reduce foot ulcer incidence by as much as 85% using a dermal thermometer to identify inflammation and prompt decreased ambulation. Investigators established a clinical monitoring protocol comparing the temperatures between 6 matched locations on the left and right feet. Persistent differences in contralateral temperatures exceeding 2.2°C (4.0°F) were used as a marker for elevated risk and to initiate preventive care. Based on the encouraging results from these studies, a 2017 effectiveness review prepared for the Agency for Healthcare Research and Quality concluded that “home monitoring of foot skin temperature is effective for reducing foot ulcer incidence and recurrence.”²⁹

Accuracy of RTM

A 2017 longitudinal study (NCT02647346) has provided novel data to advance understanding of RTM for the prediction and prevention of DFUs.³⁰ This study was the first to systematically analyze the accuracy of RTM over different monitoring thresholds. The results enable practitioners to deliver risk-stratified preventive care. Policy makers can use the data from this study to weigh the cost and benefits of RTM for population health.

The multicenter trials had 129 participants from 4 VA health care systems: VA Long Beach Healthcare System in California, Miami VA Healthcare System in Florida, Phoenix VA Healthcare System in Arizona, and VA West Los Angeles Healthcare System in California. Each participant was followed for 34 weeks under standard preventive foot care and was instructed to step on a telemedicine SmartMat (Podimetrics, Inc) RTM mat for 20 seconds daily. Participants and investigators were blinded to the temperature data so that the accuracy of temperature monitoring could be assessed. All participants had a history of T2DM and healed DFU. Principal exclusion criteria included unhealed plantar wound, history of proximal lower extremity amputation (ie, above ankle), active Charcot foot disease, and comorbidities that could potentially inhibit an inflammatory response, such as end-stage renal disease, active malignancy, and immunosuppressive diseases.

The investigators reported that RTM with the study mat detected 97% of nonacute plantar DFUs using the most commonly studied threshold (sustained 2.2°C temperature difference). The lead time averaged 37 days before clinical identification of the wound under standard care. Although the false-positive rate of 57% was high, corresponding to approximately 3.0 notifications per patient per year on average in the research setting, it is important to note that this study only considered the prediction of plantar DFUs. Thus, detection of foot inflammation secondary to other conditions, such as preulcerative lesion, dorsal wound, Charcot neuroarthropathy, or foot infection, were reported as a false positive per the study’s definitions. Further, Crisologo and Lavery noted in a translational medicine summary of this research, because the intervention is noninvasive and minimally impactful to the patient and the health care system, “the potential to arrest re-ulceration is worth the perceived inconvenience to the patient.”³¹

Secondary outcomes related to adherence and ease of use were encouraging. Eighty-eight percent of participants reported that the mat was “very easy to use,” the highest possible score, and 98% were able to set up the mat for home use without difficulty. At the end of the 34-week study, more than 74% of participants remained engaged in routine use of the mat under a per-protocol assessment of adherence. These results are especially impressive given the documented poor adherence of at-risk patients to routine use of therapeutic footwear, which has been reported to be as low as 15%.³²

New Research

The data collected during this study has led to new research and advancements in RTM. A recent publication by Gordon and colleagues investigated whether RTM is less accurate in cohorts with perceived challenges.³³ They include patients with recently healed wounds and those with a history of partial foot amputation. There was no difference in the accuracy or lead time for either cohort relative to the entire cohort, suggesting that RTM is appropriate for monitoring patients with recently healed DFUs or partial foot amputations.

In another recent study, the data were used to derive a novel approach to monitor a single at-risk foot.³⁴ The practice of RTM has traditionally required comparing temperatures between contralaterally matched plantar locations on the feet, thus limiting its use in patients with a history of major lower extremity amputation and patients being treated for a wound, which may be bandaged or in an off-loading cast or boot. Because the risk factors for DFUs exist in both limbs, these patients are at high risk for developing complications to the contralateral foot and may benefit from preventive once-daily foot temperature monitoring. The investigators empirically derived a novel monitoring approach for patients without a contralateral control. This approach was found to predict 91% of impending plantar DFUs on average 41 days before clinical presentation with a false positive rate of 54%.

Additional Focus on Prevention

Table 2 shows previously unpublished data from a subgroup analysis between veteran and nonveteran participants in the study.²⁵ These descriptive statistics reinforce some widely held assumptions regarding the high-risk veteran population and challenge others. For example, compared with the nonveteran participants, the veteran cohort unsurprisingly had a larger ratio of male participants (P < .01), had a higher rate of cigarette use (P < .01), and was more likely to live alone (although not at a statistically significant level). Veterans in the study had body mass index, rates of alcohol use, frequency of exercise, and glucose control comparable to that of nonveterans.

The potential impact of the PAVE program is clear in several of these comparisons. Although as few as 15% of patients use therapeutic shoes routinely, PAVE ensures that the majority of veterans receive them. Nearly 95% of veterans have therapeutic shoes compared with about 80% of nonveteran participants (P < .05). Veterans also had higher ankle-brachial index results (P < .05), although on average both cohorts were within normal clinical parameters. Veterans had a significantly longer duration since healing from the most recent wound, and fewer veteran participants had a wound that healed in the 3 months prior to the study. Despite this, during the study veterans had annualized DFU incidence equal to that of nonveterans. Furthermore, veterans also had significantly higher rates of amputation prior to participation. That these critical outcomes for veterans are no better than those observed in other care environments despite PAVE suggests that approaches recommended via PAVE alone are insufficient to significantly arrest DFU recurrence, and even more focus on prevention in the VA may be warranted.

From Research to Practice

Since the publication of the 2017 study, the VHA has been at the vanguard of translating the evidence and research underlying RTM into clinical practice. A clinical guidance document governing appropriate use of RTM with the study mat was recently published by the VA Prosthetic and Sensory Aids Service in collaboration with the National Podiatry Program office.²⁷ This guidance document recommends once-daily RTM for at-risk veterans designated PAVE level 3. It defines roles and responsibilities required for the successful implementation of a RTM program with the study device. The document additionally presents various clinical monitoring protocols for veterans, although the protocol and thresholds used are at the discretion of the prescribing clinician and should reflect the risk profile of the veteran in question.

A staged response to inflammation has proven popular, whereby an initial high-sensitivity threshold is chosen for monitoring. The initial response is telephone outreach by a designee supplied by the clinic or device manufacturer, typically a trained registered nurse, to the veteran to collect subjective history and instruct off-loading and reduced ambulation, with a target of 50% baseline reduction in step count. Should the inflammation persist despite off-loading, an examination may be necessary to identify and resolve its cause. For recalcitrant inflammation, more targeted pressure off-loading of the affected area may be accomplished with custom orthotics, accommodative insoles, removable cast walkers, and total contact casting. After 2 to 4 weeks without signs of inflammation, the cause is deemed to have been resolved and lowered the acute risk for developing further diabetic foot complications.

More than 600 veterans have been monitored for > 1,000 patient-years—13 VA medical centers are practicing RTM with the study mat as of this writing. The monitoring program has been integrated into many veteran daily routines as evidenced by > 70% retaining full engagement after having been monitored for > 1 year. The total number of alerts/patient-years across these veterans has been 1.4, significantly lower than the 3.0 alerts/patient-year observed in the study. This is potentially due to successful interventions in response to detected inflammation, resolving inflammation, and avoiding unnecessary alerts occurring in the research setting, which did not employ interventions that resolved inflammation episodes. In the past 6 months, 68% of all inflammation detected resolved via off-loading alone without requiring further clinical intervention. In the cases that required an examination, 76% of patients reported clinically meaningful preventive care (eg, preulcerative callus was debrided, a subungual hemorrhage was treated, a foot ulcer was identified).

Organizational Best Practices

Several best practices have been cultivated related to initiating a RTM program at a new site, for promoting the success of a RTM program, and provisioning excellent preventive care to support the RTM program. Although we advise adhering to the recommendations in the VA guidance document,²⁷ the authors have observed several additional organizational best practices that are not explicitly addressed.

Partnering with PACT. Collaboration between PAVE and PACT has the potential not only to improve outcomes for patients at risk for diabetic foot complications, but also can help identify appropriate high-risk veteran candidates for preventive care with RTM who may not be followed for routine care from a specialty provider, such as a podiatrist, as highlighted by the 2013 OIG report.

Prescreening eligible patients. Several programs have used PAVE data or appointment schedules to identify and target high-risk veterans proactively. This approach has several benefits. It simplifies clinical coordination and streamlines workflow for patient identification and onboarding. It also allows those veterans at highest risk to receive needed and recommended preventive care at their next scheduled appointment. Finally, if PAVE data are used to identify eligible patients, it has the added benefit of ensuring a baseline level of telemedicine preventive foot care for veterans who have become lost to follow-up and have not been seen recently for a routine foot examination.

Implementing foot monitoring during wound treatment. Recent research has expanded the reach of once-daily RTM with the mat to patients being treated for a wound to only 1 foot. This practice has 2 benefits: The patient is able to establish a preventive routine before healing, an important advantage because research strongly suggests that recurrence is most likely in the first months after healing. Second, 48% of patients with a history of DFUs will develop new wounds to the contralateral foot because risk factors, such as neuropathy and peripheral arterial disease, exist in both limbs.³⁵ Furthermore, ongoing treatment for a wound to 1 foot may result in gait deviation and elevated pressure to the sound foot, additionally predisposing the veteran to complications, resulting in a high rate of wounds occurring to the unwounded foot during treatment (0.2 DFU/DFU-year).³⁴ Thus, there is potential benefit in monitoring the sound foot while undergoing treatment for a wound; further, the patient will have immediate access to the device for prevention of recurrence once the wound has resolved.

Utilizing foot monitoring as an extension of telemedicine. Many VA facilities have large geographic catchment areas, making routine follow-up difficult for veterans living in rural areas. RTM serves as an extension of the patient’s daily self-examination and the clinician’s ability to monitor patients with objective information daily. The veterans using the system become more invested and feel as though they are taking an active role in their health care.

Investing in ongoing medical education. Multidisciplinary education sessions reviewing supporting clinical data and resultant clinical practice guidelines raise awareness for those providers and trainees unaware of preventive best practices for the diabetic foot, including those related to foot RTM. These sessions also are helpful for those familiar with foot temperature monitoring or who are responsible for administration of an ongoing program to remain current with contemporary best practices and to discuss improvements for patient care. Familiarity also can help address clinical inertia when benefits and evidence are clearly communicated with health care providers (HCPs).

Clinical Best Practices

Treating preulcerative lesions urgently and aggressively. Callus and other preulcerative lesions often cause progressive tissue damage and poor outcomes. When identified, these lesions should be promptly treated to ensure best outcomes.²⁴

Recognizing the limits of patient self-examinations. Comorbidities such as visual impairment and reduced joint mobility often preclude patients from completing rigorous self-examinations of the foot, which is especially critical while collecting subjective history from the patient during triage of inflammation. A caregiver or spouse can help inspect the foot during outreach and provide additional context.³⁶

Interpreting a benign foot on examination. Because RTM has been demonstrated to detect inflammation preceding a foot ulcer as many as 5 weeks before presentation to the clinic, some veterans may have few signs or symptoms of acute risk during examination. Often, the damage is to subcutaneous tissue resulting from repetitive microtrauma. Research suggests that clinical examination in these cases is often unreliable for identifying the earliest signs of risk, such as palpation to identify subtle temperature changes secondary to inflammation.³⁷ If a patient has refractory inflammation requiring examination and presents with an otherwise unremarkable foot, it is an opportunity to evaluate whether the patient’s shoewear remains appropriate or has worn out, to communicate the veteran’s ongoing elevated risk, and to educate on the importance of diligence in daily foot self-examinations, daily use of the foot temperature monitoring, and continued off-loading until the inflammation resolves.

Communicating the distinction between healing and remission. Although healing is the goal of wound care, patients should be educated that the underlying disease remains after epithelialization. In some cases, tissue deep to the skin has not completed remodeling, and the patient is at acute risk of recurrence. Remission is a powerful metaphor that better describes the patient’s ongoing risk to encourage continued healthy routines and diligent self-care.³⁸Considering the entirety of both feet for recurrence. Critical risk factors for diabetic foot complications, such as peripheral neuropathy and PAD, exist in both limbs, and patients with a history of wounds often develop new complications to different ipsilateral locations, or in as many as 48% of cases, to the contralateral foot.³⁵ For best outcomes, detected inflammation should be treated aggressively independent of whether the location coincides with an area of previous concern.

Encouraging adherence, routine, and empowerment. Advanced diabetes mellitus and neuropathy may impact a patient’s executive function, and multiple studies have reported that patients at risk for inflammatory foot diseases exhibit fatalism toward their foot care and outcomes.^39-41 Consistent education, encouragement, empowerment, and establishment of positive routines are needed to ensure high adherence with all preventive care regimens, including RTM.

Case Presentations

The following case series illustrates many of these clinical best practices and characterizes the potential benefits of RTM to veterans within the VA.

Case 1: Prevention After Healing

A veteran underwent a Chopart amputation and was recommended to use the mat after healing was perceived. Immediately on use of the study mat, the patient was found to have inflammation to the surgical incision (Figure 1). Clinical staff was alerted to the findings, and the patient was instructed to limit further walking and continue off-loading in his removable cast walker, per protocol. The inflammation of the operative foot quickly reduced, and the patient continued healing successfully, potentially avoiding incisional dehiscence and possible postoperative infection.

This case illustrates that patients’ wounds or surgical incisions may not be completely healed on epithelialization. In the immediate phase after closure, HCPs should consider additional protection to avoid complications. This case demonstrates that RTM can provide objective data to help guide care in that critical period.

Case 2: Identifying Preulcerative Lesions

An 88-year-old veteran had a chronic callus under the second metatarsal head. In addition to routine foot care and therapeutic shoes, he was followed with once-daily RTM. Inflammation was noted, and the veteran was seen in the podiatry clinic where debridement of the callus was performed. The difference in temperatures between feet detected by thermography prior to the clinic visits rapidly resolved after callus debridement, indicating that the underlying inflammation had subsided. RTM was used by the clinical staff to determine the appropriate time interval between clinic visits to avoid callus breakdown and subsequent ulceration.

Case 3: Extending the Clinic Into the Home

An 80-year-old veteran with T2DM and neuropathy was deemed a high-risk patient due to recurrent ulcerations to the left great toe. He was issued a RTM mat and was adherent with routine use. After nearly a year without hot-spot development, inflammation was noted (Figure 2).

Unfortunately, the patient had missed several routine foot care visits and likely that was the reason for the noted inflammation. The patient was called and became reengaged in regular visits for routine foot care. On debridement of his callus, a superficial, noninfected ulceration was discovered. Had remote monitoring not detected the inflammation and impending ulceration, the patient likely would not have been seen in the regular clinic and may have developed a wound infection, potentially resulting in a worse and more costly outcome.

Paradigm Shift to Prevention

Given the exceedingly high burden of diabetic foot complications in the VA, a paradigm shift is needed among HCPs from a culture of treatment to one of prevention. Bus and colleagues reported that in Europe, for every euro spent on ulcer prevention, 10 are spent on ulcer healing, and for every randomized clinical trial conducted on prevention, 10 are conducted on treatment.^42-44 Hicks and colleagues showed that the cost of curative care for DFUs is 5 to 30 times greater than the cost of preventive care.⁴⁵ For RTM in high-risk cohorts (ie, PAVE level 3), the number-needed-to-treat for DFU prevention may be as low as 6, assuming that a 70% reduction in incidence is possible, consistent with previous research. In the year following a DFU, costs exceed $44,000.⁹ Thus, it seems natural that future direction in diabetic foot care should emphasize prevention strategies.

Foot ulcers that become infected often lead to hospitalization and result in an increased burden to an already overburdened VA health care system. Research suggests that about two-thirds of all diabetic foot costs are attributable to inpatient management.⁴⁶ The impact of diabetic foot complications on hospital resource utilization is staggering. A 2017 study by Skrepnik analyzed the risk of hospitalization for various diseases.⁴⁷ The investigators found that the inpatient admission odds ratio (OR) for congestive heart failure was 2.6, surpassed only by DFUs (OR, 3.4) and diabetic foot infection (OR, 6.7). A 2019 point-prevalence study found that > 10% of hospital admissions have a foot-related condition as the primary or secondary reason, and the majority of these are due to foot diseases, such as ulcers, infections, and Charcot neuroarthropathy.⁴⁸

It is therefore incumbent on VA HCPs to avert wound recurrence in the interest of avoiding veteran hospitalizations and for administrators to encourage and incentivize best practices for managing the diabetic foot, with an emphasis on prevention therapies. In evaluating the financial impact of prevention with foot RTM, administrators should consider that the cost benefit is likely to be realized across the medical center, with budgets related to inpatient management likely to receive the largest returns.

Prevention has the potential to rein in costs as well as reduce strain on the hospital and clinic by preventing outcomes that require frequent visits for treatment or hospitalization. Wound treatment is very burdensome to the clinic; patients require frequent (in many cases, weekly) examinations, and chronic wounds often require hospitalization, necessitating rounding and additional coordination in care. Thus, preventing wounds or reducing their severity at presentation substantially reduces burden on the clinic, even after accounting for the modest clinical resources needed to administer preventative care. For example, a brief examination may be necessary if the inflammation detected by the study mat is secondary to a callus that must be debrided. However, if the patient was not seen until the callus had progressed to a wound, weekly follow-up and substantial clinical and budgetary resources may be required to heal the wound. Preventive care allows for substantially better patient outcomes, and the minimal time invested prevents the clinical burden of extensive wound treatment.

The success of preventive efforts relies on multidisciplinary management of this high-risk patient cohort. Often, it is the responsibility of the primary care provider to follow diabetic foot clinical reminders and appropriately refer to specialty care. Successful, open communication between PACT, PAVE, and the Podiatry Service has been shown to reduce poor outcomes, including lower extremity amputations. Traditionally, the model of preventive care has included podiatrist-driven interventions, including integrated routine foot care and comprehensive diabetic foot education. Collaboration between routine evaluation and prompt referral of at-risk patients for specialist foot care, therapeutic footwear recommendations, daily self-foot examinations, and in-home temperature monitoring are critically effective when performed consistently.

When trying to translate research science to effective clinical practice for preventing lower extremity complication, there are several important concepts. First, given the frequency of examination for patients being treated for a wound, provision of good preventive care, such as RTM, can reduce overall burden to resource-constrained clinics and improve access for patients needing to be seen. Additionally, preventive efforts extend clinical practice into the home and may reduce the need for in-clinic examinations and routine follow-up visits. Finally, there may be a sense of trust established between the clinician and patient with a positive record of adherence with preventive practices. This may translate into more productive communication and less frequent routine visits to better accommodate urgent visits and ensure podiatric care is accessible to veterans.

Conclusions

There is a significant opportunity to shift diabetic foot care from treatment to prevention, improving veteran outcomes and reducing resource utilization. RTM is an evidence-based and recommended but underused telemedicine solution that can catalyze this needed paradigm shift. The VA has been at the forefront of preventive foot care through the PAVE program and more recently through research and clinical application of RTM for veterans. However, as the data presented suggest, more can be done to improve veteran outcomes. More widespread adoption of evidence-based preventive technologies for the diabetic foot, such as RTM, has the potential to dramatically improve the quality of and access to care and reduce costs and burden on resource-constrained clinics.

Diabetic foot ulcers (DFUs) are devastating, common, and costly. This burden is borne disproportionately by veterans who have high prevalence of type 2 diabetes mellitus (T2DM) and other precipitating risk factors.¹ The mortality of veterans following a DFU is sobering, and ulceration is recognized as a significant marker of disease severity.

A 2017 study by Brennan and colleagues reported a 19% mortality rate within 1 year, and only 29% survive past 5 years.² DFUs are often complicated by peripheral arterial disease (PAD) and diabetic immune dysfunction, contributing to chronic wounds and infection.^3,4 About 60% of all foot ulcers become infected, and > 20% of patients with a diabetic foot infection require amputation.^5,6

A 2010 retrospective study reports that > 3,400 veterans have a diabetes-related lower extremity amputation annually, vastly surpassing the rate of amputation secondary to trauma in the Veterans Health Administration (VHA).^7,8 The inpatient costs for each amputation exceeded $60,000 in fiscal year 2010, and these amputation-related costs represent only 1 component of the total expense to the VHA attributable to diabetic foot complications.⁷ A recent systematic review by Chan and colleagues estimated mean annual costs in the year following a foot ulcer to be $44,200 to the public payer.⁹ This implies that direct expenditures for treatment of DFUs within the VHA exceeds $3 billion annually.

Diabetic Foot Ulcer Prevention

Given the dramatic impact of diabetic foot complications to the veteran and the US health care system, the VHA has long recognized the importance of preventive care for those at risk. In 2017 US Department of Veterans Affairs (VA) and Department of Defense issued a clinical practice guideline for the management of T2DM that recommended prophylactic foot care for early identification of any deformity or skin breakdown.¹⁰ The guidelines note that a “person who has had a foot ulcer is at lifelong risk of further ulceration,” reflecting the high rate of recurrence among all patients, including veterans. Multiple studies suggest that as many as 40% of patients experience recidivism in the first year after healing from a wound.^11-16

The VA is well equipped to deliver quality preventive care because of its innovative and long-standing PAVE (Prevention of Amputations for Veterans Everywhere) program.¹⁷ PAVE provides screening, education, appropriate footwear, and stratified care guidelines for veterans at risk for diabetes-related foot complications (Table 1). The practices encouraged by PAVE are evidence-based and synergistic with the objectives of the VA’s patient aligned care team (PACT) delivery approach.¹⁸ The granular data collected through PAVE are used to guide best practices and provide benchmarks for diabetic foot outcomes.

Unfortunately, despite PAVE guidelines requiring annual specialist foot care for at-risk veterans, a 2013 report by the VA Office of the Inspector General (OIG) found that one-third of all patients had no documentation of this minimal requirement of preventive foot care.¹⁹ Although the VA has worked to address this issue, the data hint at the missed opportunities for prevention of complications and the challenges of ensuring that a large at-risk veteran population has systematic and routine screening with access to specialist foot care.

Given the large proportion of veterans at high risk of chronic wound formation and the challenges of ensuring that this cohort receives good preventive foot care, expanding telemedicine has been suggested. Telemedicine solutions have the potential to reduce the impact of chronic wounds on overburdened clinic resources, schedules, and local and federal budgets.²⁰ Interestingly, the only preventive practice for the diabetic foot that has been proven effective through multiple randomized controlled trials and national and international clinical guidance documents is once-daily foot temperature monitoring.^21-26 Daily monitoring has the potential to reduce the burden of DFUs to veterans, improve veteran access to needed preventive care, and reduce costs incurred by the VHA treating diabetic foot complications. Yet despite a recent national guidance document detailing its appropriate use in PAVE 3 veterans, it remains underutilized.²⁷

The purpose of this review is to: (1) discuss the evidence supporting once-daily remote temperature monitoring (RTM), a telemedicine approach critical to improving both veteran access to care and diabetic foot outcomes; (2) summarize a 2017 study that presented an advanced clinical understanding of RTM use among veterans; (3) provide previously unpublished data from this study comparing high-risk VA and non-VA cohorts, highlighting the opportunity for additional focus on foot ulcer prevention within the VA; and (4) report on recent VA utilization of a RTM technology based on this research, emphasizing lessons learned and best practices.

Remote Temperature Monitoring

The objective of daily foot temperature monitoring is to identify impending inflammatory foot conditions, such as DFUs, infection, and acute Charcot neuroarthropathy episodes. The patient and care team then act to resolve the cause of detected inflammation before clinical presentation (prevention) and begin treatment earlier than would otherwise be possible to avoid expensive complications, such as infection (early detection). Preventive therapies are low risk to the patient and inexpensive.

RTM is recommended by multiple clinical practice guidelines, including those of the International Working Group on the Diabetic Foot, the American College of Foot and Ankle Surgeons, and the Wound Healing Society.^24-26 Its use is supported by evidence from 3 National Institutes of Health-funded and well-designed randomized controlled trials, 1 of which was additionally supported by a VA Health Services Research and Development Service Merit Award.^21-23,28 Conducted between 2004 and 2007, these studies demonstrated the potential to reduce foot ulcer incidence by as much as 85% using a dermal thermometer to identify inflammation and prompt decreased ambulation. Investigators established a clinical monitoring protocol comparing the temperatures between 6 matched locations on the left and right feet. Persistent differences in contralateral temperatures exceeding 2.2°C (4.0°F) were used as a marker for elevated risk and to initiate preventive care. Based on the encouraging results from these studies, a 2017 effectiveness review prepared for the Agency for Healthcare Research and Quality concluded that “home monitoring of foot skin temperature is effective for reducing foot ulcer incidence and recurrence.”²⁹

Accuracy of RTM

A 2017 longitudinal study (NCT02647346) has provided novel data to advance understanding of RTM for the prediction and prevention of DFUs.³⁰ This study was the first to systematically analyze the accuracy of RTM over different monitoring thresholds. The results enable practitioners to deliver risk-stratified preventive care. Policy makers can use the data from this study to weigh the cost and benefits of RTM for population health.

The multicenter trials had 129 participants from 4 VA health care systems: VA Long Beach Healthcare System in California, Miami VA Healthcare System in Florida, Phoenix VA Healthcare System in Arizona, and VA West Los Angeles Healthcare System in California. Each participant was followed for 34 weeks under standard preventive foot care and was instructed to step on a telemedicine SmartMat (Podimetrics, Inc) RTM mat for 20 seconds daily. Participants and investigators were blinded to the temperature data so that the accuracy of temperature monitoring could be assessed. All participants had a history of T2DM and healed DFU. Principal exclusion criteria included unhealed plantar wound, history of proximal lower extremity amputation (ie, above ankle), active Charcot foot disease, and comorbidities that could potentially inhibit an inflammatory response, such as end-stage renal disease, active malignancy, and immunosuppressive diseases.

The investigators reported that RTM with the study mat detected 97% of nonacute plantar DFUs using the most commonly studied threshold (sustained 2.2°C temperature difference). The lead time averaged 37 days before clinical identification of the wound under standard care. Although the false-positive rate of 57% was high, corresponding to approximately 3.0 notifications per patient per year on average in the research setting, it is important to note that this study only considered the prediction of plantar DFUs. Thus, detection of foot inflammation secondary to other conditions, such as preulcerative lesion, dorsal wound, Charcot neuroarthropathy, or foot infection, were reported as a false positive per the study’s definitions. Further, Crisologo and Lavery noted in a translational medicine summary of this research, because the intervention is noninvasive and minimally impactful to the patient and the health care system, “the potential to arrest re-ulceration is worth the perceived inconvenience to the patient.”³¹

Secondary outcomes related to adherence and ease of use were encouraging. Eighty-eight percent of participants reported that the mat was “very easy to use,” the highest possible score, and 98% were able to set up the mat for home use without difficulty. At the end of the 34-week study, more than 74% of participants remained engaged in routine use of the mat under a per-protocol assessment of adherence. These results are especially impressive given the documented poor adherence of at-risk patients to routine use of therapeutic footwear, which has been reported to be as low as 15%.³²

New Research

The data collected during this study has led to new research and advancements in RTM. A recent publication by Gordon and colleagues investigated whether RTM is less accurate in cohorts with perceived challenges.³³ They include patients with recently healed wounds and those with a history of partial foot amputation. There was no difference in the accuracy or lead time for either cohort relative to the entire cohort, suggesting that RTM is appropriate for monitoring patients with recently healed DFUs or partial foot amputations.

In another recent study, the data were used to derive a novel approach to monitor a single at-risk foot.³⁴ The practice of RTM has traditionally required comparing temperatures between contralaterally matched plantar locations on the feet, thus limiting its use in patients with a history of major lower extremity amputation and patients being treated for a wound, which may be bandaged or in an off-loading cast or boot. Because the risk factors for DFUs exist in both limbs, these patients are at high risk for developing complications to the contralateral foot and may benefit from preventive once-daily foot temperature monitoring. The investigators empirically derived a novel monitoring approach for patients without a contralateral control. This approach was found to predict 91% of impending plantar DFUs on average 41 days before clinical presentation with a false positive rate of 54%.

Additional Focus on Prevention

Table 2 shows previously unpublished data from a subgroup analysis between veteran and nonveteran participants in the study.²⁵ These descriptive statistics reinforce some widely held assumptions regarding the high-risk veteran population and challenge others. For example, compared with the nonveteran participants, the veteran cohort unsurprisingly had a larger ratio of male participants (P < .01), had a higher rate of cigarette use (P < .01), and was more likely to live alone (although not at a statistically significant level). Veterans in the study had body mass index, rates of alcohol use, frequency of exercise, and glucose control comparable to that of nonveterans.

The potential impact of the PAVE program is clear in several of these comparisons. Although as few as 15% of patients use therapeutic shoes routinely, PAVE ensures that the majority of veterans receive them. Nearly 95% of veterans have therapeutic shoes compared with about 80% of nonveteran participants (P < .05). Veterans also had higher ankle-brachial index results (P < .05), although on average both cohorts were within normal clinical parameters. Veterans had a significantly longer duration since healing from the most recent wound, and fewer veteran participants had a wound that healed in the 3 months prior to the study. Despite this, during the study veterans had annualized DFU incidence equal to that of nonveterans. Furthermore, veterans also had significantly higher rates of amputation prior to participation. That these critical outcomes for veterans are no better than those observed in other care environments despite PAVE suggests that approaches recommended via PAVE alone are insufficient to significantly arrest DFU recurrence, and even more focus on prevention in the VA may be warranted.

From Research to Practice

Since the publication of the 2017 study, the VHA has been at the vanguard of translating the evidence and research underlying RTM into clinical practice. A clinical guidance document governing appropriate use of RTM with the study mat was recently published by the VA Prosthetic and Sensory Aids Service in collaboration with the National Podiatry Program office.²⁷ This guidance document recommends once-daily RTM for at-risk veterans designated PAVE level 3. It defines roles and responsibilities required for the successful implementation of a RTM program with the study device. The document additionally presents various clinical monitoring protocols for veterans, although the protocol and thresholds used are at the discretion of the prescribing clinician and should reflect the risk profile of the veteran in question.

A staged response to inflammation has proven popular, whereby an initial high-sensitivity threshold is chosen for monitoring. The initial response is telephone outreach by a designee supplied by the clinic or device manufacturer, typically a trained registered nurse, to the veteran to collect subjective history and instruct off-loading and reduced ambulation, with a target of 50% baseline reduction in step count. Should the inflammation persist despite off-loading, an examination may be necessary to identify and resolve its cause. For recalcitrant inflammation, more targeted pressure off-loading of the affected area may be accomplished with custom orthotics, accommodative insoles, removable cast walkers, and total contact casting. After 2 to 4 weeks without signs of inflammation, the cause is deemed to have been resolved and lowered the acute risk for developing further diabetic foot complications.

More than 600 veterans have been monitored for > 1,000 patient-years—13 VA medical centers are practicing RTM with the study mat as of this writing. The monitoring program has been integrated into many veteran daily routines as evidenced by > 70% retaining full engagement after having been monitored for > 1 year. The total number of alerts/patient-years across these veterans has been 1.4, significantly lower than the 3.0 alerts/patient-year observed in the study. This is potentially due to successful interventions in response to detected inflammation, resolving inflammation, and avoiding unnecessary alerts occurring in the research setting, which did not employ interventions that resolved inflammation episodes. In the past 6 months, 68% of all inflammation detected resolved via off-loading alone without requiring further clinical intervention. In the cases that required an examination, 76% of patients reported clinically meaningful preventive care (eg, preulcerative callus was debrided, a subungual hemorrhage was treated, a foot ulcer was identified).

Organizational Best Practices

Several best practices have been cultivated related to initiating a RTM program at a new site, for promoting the success of a RTM program, and provisioning excellent preventive care to support the RTM program. Although we advise adhering to the recommendations in the VA guidance document,²⁷ the authors have observed several additional organizational best practices that are not explicitly addressed.

Partnering with PACT. Collaboration between PAVE and PACT has the potential not only to improve outcomes for patients at risk for diabetic foot complications, but also can help identify appropriate high-risk veteran candidates for preventive care with RTM who may not be followed for routine care from a specialty provider, such as a podiatrist, as highlighted by the 2013 OIG report.

Prescreening eligible patients. Several programs have used PAVE data or appointment schedules to identify and target high-risk veterans proactively. This approach has several benefits. It simplifies clinical coordination and streamlines workflow for patient identification and onboarding. It also allows those veterans at highest risk to receive needed and recommended preventive care at their next scheduled appointment. Finally, if PAVE data are used to identify eligible patients, it has the added benefit of ensuring a baseline level of telemedicine preventive foot care for veterans who have become lost to follow-up and have not been seen recently for a routine foot examination.

Implementing foot monitoring during wound treatment. Recent research has expanded the reach of once-daily RTM with the mat to patients being treated for a wound to only 1 foot. This practice has 2 benefits: The patient is able to establish a preventive routine before healing, an important advantage because research strongly suggests that recurrence is most likely in the first months after healing. Second, 48% of patients with a history of DFUs will develop new wounds to the contralateral foot because risk factors, such as neuropathy and peripheral arterial disease, exist in both limbs.³⁵ Furthermore, ongoing treatment for a wound to 1 foot may result in gait deviation and elevated pressure to the sound foot, additionally predisposing the veteran to complications, resulting in a high rate of wounds occurring to the unwounded foot during treatment (0.2 DFU/DFU-year).³⁴ Thus, there is potential benefit in monitoring the sound foot while undergoing treatment for a wound; further, the patient will have immediate access to the device for prevention of recurrence once the wound has resolved.

Utilizing foot monitoring as an extension of telemedicine. Many VA facilities have large geographic catchment areas, making routine follow-up difficult for veterans living in rural areas. RTM serves as an extension of the patient’s daily self-examination and the clinician’s ability to monitor patients with objective information daily. The veterans using the system become more invested and feel as though they are taking an active role in their health care.

Investing in ongoing medical education. Multidisciplinary education sessions reviewing supporting clinical data and resultant clinical practice guidelines raise awareness for those providers and trainees unaware of preventive best practices for the diabetic foot, including those related to foot RTM. These sessions also are helpful for those familiar with foot temperature monitoring or who are responsible for administration of an ongoing program to remain current with contemporary best practices and to discuss improvements for patient care. Familiarity also can help address clinical inertia when benefits and evidence are clearly communicated with health care providers (HCPs).

Clinical Best Practices

Treating preulcerative lesions urgently and aggressively. Callus and other preulcerative lesions often cause progressive tissue damage and poor outcomes. When identified, these lesions should be promptly treated to ensure best outcomes.²⁴

Recognizing the limits of patient self-examinations. Comorbidities such as visual impairment and reduced joint mobility often preclude patients from completing rigorous self-examinations of the foot, which is especially critical while collecting subjective history from the patient during triage of inflammation. A caregiver or spouse can help inspect the foot during outreach and provide additional context.³⁶

Interpreting a benign foot on examination. Because RTM has been demonstrated to detect inflammation preceding a foot ulcer as many as 5 weeks before presentation to the clinic, some veterans may have few signs or symptoms of acute risk during examination. Often, the damage is to subcutaneous tissue resulting from repetitive microtrauma. Research suggests that clinical examination in these cases is often unreliable for identifying the earliest signs of risk, such as palpation to identify subtle temperature changes secondary to inflammation.³⁷ If a patient has refractory inflammation requiring examination and presents with an otherwise unremarkable foot, it is an opportunity to evaluate whether the patient’s shoewear remains appropriate or has worn out, to communicate the veteran’s ongoing elevated risk, and to educate on the importance of diligence in daily foot self-examinations, daily use of the foot temperature monitoring, and continued off-loading until the inflammation resolves.

Communicating the distinction between healing and remission. Although healing is the goal of wound care, patients should be educated that the underlying disease remains after epithelialization. In some cases, tissue deep to the skin has not completed remodeling, and the patient is at acute risk of recurrence. Remission is a powerful metaphor that better describes the patient’s ongoing risk to encourage continued healthy routines and diligent self-care.³⁸Considering the entirety of both feet for recurrence. Critical risk factors for diabetic foot complications, such as peripheral neuropathy and PAD, exist in both limbs, and patients with a history of wounds often develop new complications to different ipsilateral locations, or in as many as 48% of cases, to the contralateral foot.³⁵ For best outcomes, detected inflammation should be treated aggressively independent of whether the location coincides with an area of previous concern.

Encouraging adherence, routine, and empowerment. Advanced diabetes mellitus and neuropathy may impact a patient’s executive function, and multiple studies have reported that patients at risk for inflammatory foot diseases exhibit fatalism toward their foot care and outcomes.^39-41 Consistent education, encouragement, empowerment, and establishment of positive routines are needed to ensure high adherence with all preventive care regimens, including RTM.

Case Presentations

The following case series illustrates many of these clinical best practices and characterizes the potential benefits of RTM to veterans within the VA.

Case 1: Prevention After Healing

A veteran underwent a Chopart amputation and was recommended to use the mat after healing was perceived. Immediately on use of the study mat, the patient was found to have inflammation to the surgical incision (Figure 1). Clinical staff was alerted to the findings, and the patient was instructed to limit further walking and continue off-loading in his removable cast walker, per protocol. The inflammation of the operative foot quickly reduced, and the patient continued healing successfully, potentially avoiding incisional dehiscence and possible postoperative infection.

This case illustrates that patients’ wounds or surgical incisions may not be completely healed on epithelialization. In the immediate phase after closure, HCPs should consider additional protection to avoid complications. This case demonstrates that RTM can provide objective data to help guide care in that critical period.

Case 2: Identifying Preulcerative Lesions

An 88-year-old veteran had a chronic callus under the second metatarsal head. In addition to routine foot care and therapeutic shoes, he was followed with once-daily RTM. Inflammation was noted, and the veteran was seen in the podiatry clinic where debridement of the callus was performed. The difference in temperatures between feet detected by thermography prior to the clinic visits rapidly resolved after callus debridement, indicating that the underlying inflammation had subsided. RTM was used by the clinical staff to determine the appropriate time interval between clinic visits to avoid callus breakdown and subsequent ulceration.

Case 3: Extending the Clinic Into the Home

An 80-year-old veteran with T2DM and neuropathy was deemed a high-risk patient due to recurrent ulcerations to the left great toe. He was issued a RTM mat and was adherent with routine use. After nearly a year without hot-spot development, inflammation was noted (Figure 2).

Unfortunately, the patient had missed several routine foot care visits and likely that was the reason for the noted inflammation. The patient was called and became reengaged in regular visits for routine foot care. On debridement of his callus, a superficial, noninfected ulceration was discovered. Had remote monitoring not detected the inflammation and impending ulceration, the patient likely would not have been seen in the regular clinic and may have developed a wound infection, potentially resulting in a worse and more costly outcome.

Paradigm Shift to Prevention

Given the exceedingly high burden of diabetic foot complications in the VA, a paradigm shift is needed among HCPs from a culture of treatment to one of prevention. Bus and colleagues reported that in Europe, for every euro spent on ulcer prevention, 10 are spent on ulcer healing, and for every randomized clinical trial conducted on prevention, 10 are conducted on treatment.^42-44 Hicks and colleagues showed that the cost of curative care for DFUs is 5 to 30 times greater than the cost of preventive care.⁴⁵ For RTM in high-risk cohorts (ie, PAVE level 3), the number-needed-to-treat for DFU prevention may be as low as 6, assuming that a 70% reduction in incidence is possible, consistent with previous research. In the year following a DFU, costs exceed $44,000.⁹ Thus, it seems natural that future direction in diabetic foot care should emphasize prevention strategies.

Foot ulcers that become infected often lead to hospitalization and result in an increased burden to an already overburdened VA health care system. Research suggests that about two-thirds of all diabetic foot costs are attributable to inpatient management.⁴⁶ The impact of diabetic foot complications on hospital resource utilization is staggering. A 2017 study by Skrepnik analyzed the risk of hospitalization for various diseases.⁴⁷ The investigators found that the inpatient admission odds ratio (OR) for congestive heart failure was 2.6, surpassed only by DFUs (OR, 3.4) and diabetic foot infection (OR, 6.7). A 2019 point-prevalence study found that > 10% of hospital admissions have a foot-related condition as the primary or secondary reason, and the majority of these are due to foot diseases, such as ulcers, infections, and Charcot neuroarthropathy.⁴⁸

It is therefore incumbent on VA HCPs to avert wound recurrence in the interest of avoiding veteran hospitalizations and for administrators to encourage and incentivize best practices for managing the diabetic foot, with an emphasis on prevention therapies. In evaluating the financial impact of prevention with foot RTM, administrators should consider that the cost benefit is likely to be realized across the medical center, with budgets related to inpatient management likely to receive the largest returns.

Prevention has the potential to rein in costs as well as reduce strain on the hospital and clinic by preventing outcomes that require frequent visits for treatment or hospitalization. Wound treatment is very burdensome to the clinic; patients require frequent (in many cases, weekly) examinations, and chronic wounds often require hospitalization, necessitating rounding and additional coordination in care. Thus, preventing wounds or reducing their severity at presentation substantially reduces burden on the clinic, even after accounting for the modest clinical resources needed to administer preventative care. For example, a brief examination may be necessary if the inflammation detected by the study mat is secondary to a callus that must be debrided. However, if the patient was not seen until the callus had progressed to a wound, weekly follow-up and substantial clinical and budgetary resources may be required to heal the wound. Preventive care allows for substantially better patient outcomes, and the minimal time invested prevents the clinical burden of extensive wound treatment.

The success of preventive efforts relies on multidisciplinary management of this high-risk patient cohort. Often, it is the responsibility of the primary care provider to follow diabetic foot clinical reminders and appropriately refer to specialty care. Successful, open communication between PACT, PAVE, and the Podiatry Service has been shown to reduce poor outcomes, including lower extremity amputations. Traditionally, the model of preventive care has included podiatrist-driven interventions, including integrated routine foot care and comprehensive diabetic foot education. Collaboration between routine evaluation and prompt referral of at-risk patients for specialist foot care, therapeutic footwear recommendations, daily self-foot examinations, and in-home temperature monitoring are critically effective when performed consistently.

When trying to translate research science to effective clinical practice for preventing lower extremity complication, there are several important concepts. First, given the frequency of examination for patients being treated for a wound, provision of good preventive care, such as RTM, can reduce overall burden to resource-constrained clinics and improve access for patients needing to be seen. Additionally, preventive efforts extend clinical practice into the home and may reduce the need for in-clinic examinations and routine follow-up visits. Finally, there may be a sense of trust established between the clinician and patient with a positive record of adherence with preventive practices. This may translate into more productive communication and less frequent routine visits to better accommodate urgent visits and ensure podiatric care is accessible to veterans.

Conclusions

There is a significant opportunity to shift diabetic foot care from treatment to prevention, improving veteran outcomes and reducing resource utilization. RTM is an evidence-based and recommended but underused telemedicine solution that can catalyze this needed paradigm shift. The VA has been at the forefront of preventive foot care through the PAVE program and more recently through research and clinical application of RTM for veterans. However, as the data presented suggest, more can be done to improve veteran outcomes. More widespread adoption of evidence-based preventive technologies for the diabetic foot, such as RTM, has the potential to dramatically improve the quality of and access to care and reduce costs and burden on resource-constrained clinics.

Empagliflozin and dulaglutide became the most-prescribed drugs in their respective classes for treating type 2 diabetes in the United States from July 2013 to June 2018, new research shows.

The findings, from U.S.-based administrative claims data, were published online in Diabetes Care by Chintan V. Dave, PharmD, PhD, and colleagues.

Among patients initiating oral sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) over the 5-year period, empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) became the most commonly prescribed glucose-lowering drug, primarily driven by an increasing proportion of patients with diabetes who had a diagnosis of myocardial infarction, stroke, or heart failure (collectively called cardiovascular disease-heart failure [CVD-HF]).

And within the subcutaneous injectable glucagonlike peptide–1 receptor (GLP-1) agonist class, initiations of dulaglutide (Trulicity, Lilly) surpassed liraglutide in 2013-2018, although patients starting liraglutide (Victoza, Novo Nordisk) were more likely to have a CVD-HF diagnosis.

“This study shows that by preferring empagliflozin, prescribers have largely reacted in accordance with the available evidence and drug labels, while other factors such as lower price, frequency of administration [dulaglutide is given weekly and liraglutide is given daily], or prior authorizations may have led prescribers to select dulaglutide over liraglutide,” Dr. Dave, of the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, and colleagues wrote.

Internists and endocrinologists were the most frequent prescribers of both drug classes, but cardiologists rarely prescribed them, even for patients with established CVD-HF. “As patients with co-occurring diabetes and CVD are likely to see their cardiologist, these encounters may provide an additional opportunity to optimize their treatment,” the authors emphasized.

SGLT2 inhibitors and label changes

Over the study period, the proportion of patients who had CVD-HF and who received SGLT2 inhibitors rose by 3.4 percentage points, from 8.8% to 12.2% (P trend < .001).

The proportion of overall prescriptions for SGLT2 inhibitors written by endocrinologists dropped by 12.0%, although the absolute number of SGLT2-inhibitor prescriptions written by endocrinologists increased (P < .001).

The proportion written by internists did not change (P = .58), whereas it increased slightly among cardiologists but still barely exceeded 1% (P < .001). The findings were similar for the subgroup of patients with CVD-HF who initiated SGLT2 inhibitors.

By individual agents, canagliflozin (Invokana, Janssen) prescriptions dropped by 75.1 percentage points over the study period, from 100% in 2013 to just 24.9% by 2018 (P < .001), whereas empagliflozin initiation rose by 51.7 percentage points, from 13.9% to 65.6% of all SGLT2 inhibitor initiations (P < .001).

Among those initiating empagliflozin, the proportion with CVD-HF rose by 5.3 percentage points, from 8.8% to 14.1% (P < .001), mostly after the additional indication for reducing CV events and death was added to the U.S. label in December 2016.

In contrast, there were no significant changes in the proportions of those with CVD-HF who initiated canagliflozin (P = 065), dapagliflozin (P = .87), or other medications (P = .060).

“Changes in the drug label for canagliflozin (boxed warning for amputation) and empagliflozin (for reduction in CV events and death) in 2016 likely contributed to a rapid change in prescribing preference for empagliflozin,” Dr. Dave and colleagues wrote.
 

GLP-1 agonists and frequency

Among the patients starting GLP-1 agonists, the proportion with CVD-HF increased by 3.9 percentage points, from 10.5% to 14.4% (P < .001) during the study period.

Prescriptions by endocrinologists declined as a proportion, but rose in absolute numbers (P < .001), and remained consistent for internists (> 55%; P = .12).

Prescribing of GLP-1 agonists by cardiologists remained low (< 0.5%) and was not higher for individuals with CVD-HF.

By individual GLP-1 agonist, liraglutide initiation declined by 32.1 percentage points, from 72.4% to 40.3% of GLP-1 agonist initiations (P < .001), whereas dulaglutide initiation rose by 43.8 percentage points, from 5.0% to 48.8% (P < .001). Again, these trends were similar in the subgroup of patients with CVD-HF.

The proportion of patients with CVD-HF in liraglutide initiators increased by 5.1 percentage points, from 10.5% to 15.6% (P = .018), and in exenatide initiators by 2.1 percentage points, from 10.3% to 13.8% (P = .77).

“Due to the reduced frequency of administration and possible formulary preferences, dulaglutide initiations surpassed liraglutide, the only GLP-1 agonist with evidence of CV benefit at the time,” Dr. Dave and colleagues noted.

Dulaglutide has just been granted an additional approval by the Food and Drug Administration for reducing the risk of major adverse cardiovascular events in adults with type 2 diabetes with and without established CVD or multiple CV risk factors. That makes it the first and only type 2 diabetes medicine approved to reduce the risk of CV events for both primary and secondary prevention populations.

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston. Dr. Dave has reported receiving support from the New Jersey Alliance for Clinical and Translational Science.
 

This article first appeared on Medscape.com.

Empagliflozin and dulaglutide became the most-prescribed drugs in their respective classes for treating type 2 diabetes in the United States from July 2013 to June 2018, new research shows.

The findings, from U.S.-based administrative claims data, were published online in Diabetes Care by Chintan V. Dave, PharmD, PhD, and colleagues.

Among patients initiating oral sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) over the 5-year period, empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) became the most commonly prescribed glucose-lowering drug, primarily driven by an increasing proportion of patients with diabetes who had a diagnosis of myocardial infarction, stroke, or heart failure (collectively called cardiovascular disease-heart failure [CVD-HF]).

And within the subcutaneous injectable glucagonlike peptide–1 receptor (GLP-1) agonist class, initiations of dulaglutide (Trulicity, Lilly) surpassed liraglutide in 2013-2018, although patients starting liraglutide (Victoza, Novo Nordisk) were more likely to have a CVD-HF diagnosis.

“This study shows that by preferring empagliflozin, prescribers have largely reacted in accordance with the available evidence and drug labels, while other factors such as lower price, frequency of administration [dulaglutide is given weekly and liraglutide is given daily], or prior authorizations may have led prescribers to select dulaglutide over liraglutide,” Dr. Dave, of the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, and colleagues wrote.

Internists and endocrinologists were the most frequent prescribers of both drug classes, but cardiologists rarely prescribed them, even for patients with established CVD-HF. “As patients with co-occurring diabetes and CVD are likely to see their cardiologist, these encounters may provide an additional opportunity to optimize their treatment,” the authors emphasized.

SGLT2 inhibitors and label changes

Over the study period, the proportion of patients who had CVD-HF and who received SGLT2 inhibitors rose by 3.4 percentage points, from 8.8% to 12.2% (P trend < .001).

The proportion of overall prescriptions for SGLT2 inhibitors written by endocrinologists dropped by 12.0%, although the absolute number of SGLT2-inhibitor prescriptions written by endocrinologists increased (P < .001).

The proportion written by internists did not change (P = .58), whereas it increased slightly among cardiologists but still barely exceeded 1% (P < .001). The findings were similar for the subgroup of patients with CVD-HF who initiated SGLT2 inhibitors.

By individual agents, canagliflozin (Invokana, Janssen) prescriptions dropped by 75.1 percentage points over the study period, from 100% in 2013 to just 24.9% by 2018 (P < .001), whereas empagliflozin initiation rose by 51.7 percentage points, from 13.9% to 65.6% of all SGLT2 inhibitor initiations (P < .001).

Among those initiating empagliflozin, the proportion with CVD-HF rose by 5.3 percentage points, from 8.8% to 14.1% (P < .001), mostly after the additional indication for reducing CV events and death was added to the U.S. label in December 2016.

In contrast, there were no significant changes in the proportions of those with CVD-HF who initiated canagliflozin (P = 065), dapagliflozin (P = .87), or other medications (P = .060).

“Changes in the drug label for canagliflozin (boxed warning for amputation) and empagliflozin (for reduction in CV events and death) in 2016 likely contributed to a rapid change in prescribing preference for empagliflozin,” Dr. Dave and colleagues wrote.
 

GLP-1 agonists and frequency

Among the patients starting GLP-1 agonists, the proportion with CVD-HF increased by 3.9 percentage points, from 10.5% to 14.4% (P < .001) during the study period.

Prescriptions by endocrinologists declined as a proportion, but rose in absolute numbers (P < .001), and remained consistent for internists (> 55%; P = .12).

Prescribing of GLP-1 agonists by cardiologists remained low (< 0.5%) and was not higher for individuals with CVD-HF.

By individual GLP-1 agonist, liraglutide initiation declined by 32.1 percentage points, from 72.4% to 40.3% of GLP-1 agonist initiations (P < .001), whereas dulaglutide initiation rose by 43.8 percentage points, from 5.0% to 48.8% (P < .001). Again, these trends were similar in the subgroup of patients with CVD-HF.

The proportion of patients with CVD-HF in liraglutide initiators increased by 5.1 percentage points, from 10.5% to 15.6% (P = .018), and in exenatide initiators by 2.1 percentage points, from 10.3% to 13.8% (P = .77).

“Due to the reduced frequency of administration and possible formulary preferences, dulaglutide initiations surpassed liraglutide, the only GLP-1 agonist with evidence of CV benefit at the time,” Dr. Dave and colleagues noted.

Dulaglutide has just been granted an additional approval by the Food and Drug Administration for reducing the risk of major adverse cardiovascular events in adults with type 2 diabetes with and without established CVD or multiple CV risk factors. That makes it the first and only type 2 diabetes medicine approved to reduce the risk of CV events for both primary and secondary prevention populations.

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston. Dr. Dave has reported receiving support from the New Jersey Alliance for Clinical and Translational Science.
 

This article first appeared on Medscape.com.

Empagliflozin and dulaglutide became the most-prescribed drugs in their respective classes for treating type 2 diabetes in the United States from July 2013 to June 2018, new research shows.

The findings, from U.S.-based administrative claims data, were published online in Diabetes Care by Chintan V. Dave, PharmD, PhD, and colleagues.

Among patients initiating oral sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) over the 5-year period, empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) became the most commonly prescribed glucose-lowering drug, primarily driven by an increasing proportion of patients with diabetes who had a diagnosis of myocardial infarction, stroke, or heart failure (collectively called cardiovascular disease-heart failure [CVD-HF]).

And within the subcutaneous injectable glucagonlike peptide–1 receptor (GLP-1) agonist class, initiations of dulaglutide (Trulicity, Lilly) surpassed liraglutide in 2013-2018, although patients starting liraglutide (Victoza, Novo Nordisk) were more likely to have a CVD-HF diagnosis.

“This study shows that by preferring empagliflozin, prescribers have largely reacted in accordance with the available evidence and drug labels, while other factors such as lower price, frequency of administration [dulaglutide is given weekly and liraglutide is given daily], or prior authorizations may have led prescribers to select dulaglutide over liraglutide,” Dr. Dave, of the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, and colleagues wrote.

Internists and endocrinologists were the most frequent prescribers of both drug classes, but cardiologists rarely prescribed them, even for patients with established CVD-HF. “As patients with co-occurring diabetes and CVD are likely to see their cardiologist, these encounters may provide an additional opportunity to optimize their treatment,” the authors emphasized.

SGLT2 inhibitors and label changes

Over the study period, the proportion of patients who had CVD-HF and who received SGLT2 inhibitors rose by 3.4 percentage points, from 8.8% to 12.2% (P trend < .001).

The proportion of overall prescriptions for SGLT2 inhibitors written by endocrinologists dropped by 12.0%, although the absolute number of SGLT2-inhibitor prescriptions written by endocrinologists increased (P < .001).

The proportion written by internists did not change (P = .58), whereas it increased slightly among cardiologists but still barely exceeded 1% (P < .001). The findings were similar for the subgroup of patients with CVD-HF who initiated SGLT2 inhibitors.

By individual agents, canagliflozin (Invokana, Janssen) prescriptions dropped by 75.1 percentage points over the study period, from 100% in 2013 to just 24.9% by 2018 (P < .001), whereas empagliflozin initiation rose by 51.7 percentage points, from 13.9% to 65.6% of all SGLT2 inhibitor initiations (P < .001).

Among those initiating empagliflozin, the proportion with CVD-HF rose by 5.3 percentage points, from 8.8% to 14.1% (P < .001), mostly after the additional indication for reducing CV events and death was added to the U.S. label in December 2016.

In contrast, there were no significant changes in the proportions of those with CVD-HF who initiated canagliflozin (P = 065), dapagliflozin (P = .87), or other medications (P = .060).

“Changes in the drug label for canagliflozin (boxed warning for amputation) and empagliflozin (for reduction in CV events and death) in 2016 likely contributed to a rapid change in prescribing preference for empagliflozin,” Dr. Dave and colleagues wrote.
 

GLP-1 agonists and frequency

Among the patients starting GLP-1 agonists, the proportion with CVD-HF increased by 3.9 percentage points, from 10.5% to 14.4% (P < .001) during the study period.

Prescriptions by endocrinologists declined as a proportion, but rose in absolute numbers (P < .001), and remained consistent for internists (> 55%; P = .12).

Prescribing of GLP-1 agonists by cardiologists remained low (< 0.5%) and was not higher for individuals with CVD-HF.

By individual GLP-1 agonist, liraglutide initiation declined by 32.1 percentage points, from 72.4% to 40.3% of GLP-1 agonist initiations (P < .001), whereas dulaglutide initiation rose by 43.8 percentage points, from 5.0% to 48.8% (P < .001). Again, these trends were similar in the subgroup of patients with CVD-HF.

The proportion of patients with CVD-HF in liraglutide initiators increased by 5.1 percentage points, from 10.5% to 15.6% (P = .018), and in exenatide initiators by 2.1 percentage points, from 10.3% to 13.8% (P = .77).

“Due to the reduced frequency of administration and possible formulary preferences, dulaglutide initiations surpassed liraglutide, the only GLP-1 agonist with evidence of CV benefit at the time,” Dr. Dave and colleagues noted.

Dulaglutide has just been granted an additional approval by the Food and Drug Administration for reducing the risk of major adverse cardiovascular events in adults with type 2 diabetes with and without established CVD or multiple CV risk factors. That makes it the first and only type 2 diabetes medicine approved to reduce the risk of CV events for both primary and secondary prevention populations.

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston. Dr. Dave has reported receiving support from the New Jersey Alliance for Clinical and Translational Science.
 

This article first appeared on Medscape.com.

Valisure, an online pharmacy and analytical laboratory based in New Haven, Conn., has asked the U.S. Food and Drug Administration to request recalls of the diabetes drug metformin from 11 companies after its own testing found levels of the probable carcinogen N-nitrosodimethylamine (NDMA) exceeded those recognized by the agency as being safe, according to a petition filed with the FDA.

Several of the batches tested from a total of 22 companies contained more than 10 times the accepted 96-ng daily limit for NDMA set by the agency.

“The presence of this probable carcinogen in a medication that is taken daily by adults and adolescents for a chronic condition like diabetes, makes [these findings] particularly troubling,” the pharmacy said in the petition. It noted that NDMA is classified by the World Health Organization and the International Agency for Research on Cancer as a Group 2A compound, meaning that it is “probably carcinogenic to humans.”

The Valisure findings are in contrast to those from the FDA’s own testing of metformin from eight companies. In results released Feb. 2, the agency found no NDMA in metformin from seven of the companies, and elevations within the safe limit in metformin from the remaining company. Based on those results, the FDA did not issue a recall.

The FDA declined to comment on the petition, pending a formal written response, a spokesman said.

Valisure said in its petition that one reason it found NDMA at concerning levels, and the FDA did not, could be that the pharmacy’s testing was more thorough than the agency’s because it had used its proprietary analytical technologies in addition to FDA standard assays. The pharmacy said it also cast a wider net, testing samples from 22 companies instead of 8, as the FDA had.

“At least one company that consistently displayed high levels of NDMA in all Valisure-tested batches was a company whose metformin products, to Valisure’s knowledge, were not tested by FDA,” Valisure said in the petition.

The pharmacy tested 38 batches of metformin from 22 companies, and found 16 contaminated batches from 11 companies. Results from one company were confirmed by an independent laboratory in California.

In addition, “there was significant variability from batch to batch, even within a single company, underscoring the importance of batch-level chemical analysis and the necessity of overall increased quality surveillance of medications,” the pharmacy stated in the petition.

David Light, Valisure founder and CEO, said in a press release that the results “indicate that contaminated batches of drugs are scattered and intermixed with clean [batches] throughout the American pharmaceutical supply chain. This strongly suggests that neither the limited testing FDA is able to conduct nor the pharmaceutical companies’ self-reporting of analytical results is sufficient to protect American consumers.”

He explained in an interview that metformin contamination probably comes from poor manufacturing, as NDMA can form during the manufacturing process. Companies are supposed to have processes in place to limit its formation and to check for and remove it before products are shipped. The contaminated batches might have come from China, which makes the bulk of U.S. active pharmaceutical ingredients, he said.

Recently, Apotex and Ranbaxy Pharmaceuticals recalled specific metformin lots in Canada after Canadian health authorities requested NDMA testing. Metformin versions have also been recalled in Singapore. European health authorities are also looking into the issue, according to a Mar. 3 press release from the European Medicines Agency.

Over the past 2 years, NDMA contamination has led to recalls of angiotensin receptor blockers, such as valsartan and losartan, because of NDMA in excess of the daily limit, and ranitidine-containing products such as Zantac. Valisure said it hopes the FDA will avoid the “year-long rolling recalls” that have occurred for angiotensin receptor blockers.

Metformin, which is used to treat type 2 diabetes, is the fourth-most prescribed drug in the United States. About 80 million prescriptions were written for it during 2019, according to the press release.

Valisure launched its investigation after it found NDMA in metformin a client asked it to check.

[email protected]

Valisure, an online pharmacy and analytical laboratory based in New Haven, Conn., has asked the U.S. Food and Drug Administration to request recalls of the diabetes drug metformin from 11 companies after its own testing found levels of the probable carcinogen N-nitrosodimethylamine (NDMA) exceeded those recognized by the agency as being safe, according to a petition filed with the FDA.

Several of the batches tested from a total of 22 companies contained more than 10 times the accepted 96-ng daily limit for NDMA set by the agency.

“The presence of this probable carcinogen in a medication that is taken daily by adults and adolescents for a chronic condition like diabetes, makes [these findings] particularly troubling,” the pharmacy said in the petition. It noted that NDMA is classified by the World Health Organization and the International Agency for Research on Cancer as a Group 2A compound, meaning that it is “probably carcinogenic to humans.”

The Valisure findings are in contrast to those from the FDA’s own testing of metformin from eight companies. In results released Feb. 2, the agency found no NDMA in metformin from seven of the companies, and elevations within the safe limit in metformin from the remaining company. Based on those results, the FDA did not issue a recall.

The FDA declined to comment on the petition, pending a formal written response, a spokesman said.

Valisure said in its petition that one reason it found NDMA at concerning levels, and the FDA did not, could be that the pharmacy’s testing was more thorough than the agency’s because it had used its proprietary analytical technologies in addition to FDA standard assays. The pharmacy said it also cast a wider net, testing samples from 22 companies instead of 8, as the FDA had.

“At least one company that consistently displayed high levels of NDMA in all Valisure-tested batches was a company whose metformin products, to Valisure’s knowledge, were not tested by FDA,” Valisure said in the petition.

The pharmacy tested 38 batches of metformin from 22 companies, and found 16 contaminated batches from 11 companies. Results from one company were confirmed by an independent laboratory in California.

In addition, “there was significant variability from batch to batch, even within a single company, underscoring the importance of batch-level chemical analysis and the necessity of overall increased quality surveillance of medications,” the pharmacy stated in the petition.

David Light, Valisure founder and CEO, said in a press release that the results “indicate that contaminated batches of drugs are scattered and intermixed with clean [batches] throughout the American pharmaceutical supply chain. This strongly suggests that neither the limited testing FDA is able to conduct nor the pharmaceutical companies’ self-reporting of analytical results is sufficient to protect American consumers.”

He explained in an interview that metformin contamination probably comes from poor manufacturing, as NDMA can form during the manufacturing process. Companies are supposed to have processes in place to limit its formation and to check for and remove it before products are shipped. The contaminated batches might have come from China, which makes the bulk of U.S. active pharmaceutical ingredients, he said.

Recently, Apotex and Ranbaxy Pharmaceuticals recalled specific metformin lots in Canada after Canadian health authorities requested NDMA testing. Metformin versions have also been recalled in Singapore. European health authorities are also looking into the issue, according to a Mar. 3 press release from the European Medicines Agency.

Over the past 2 years, NDMA contamination has led to recalls of angiotensin receptor blockers, such as valsartan and losartan, because of NDMA in excess of the daily limit, and ranitidine-containing products such as Zantac. Valisure said it hopes the FDA will avoid the “year-long rolling recalls” that have occurred for angiotensin receptor blockers.

Metformin, which is used to treat type 2 diabetes, is the fourth-most prescribed drug in the United States. About 80 million prescriptions were written for it during 2019, according to the press release.

Valisure launched its investigation after it found NDMA in metformin a client asked it to check.

[email protected]

Valisure, an online pharmacy and analytical laboratory based in New Haven, Conn., has asked the U.S. Food and Drug Administration to request recalls of the diabetes drug metformin from 11 companies after its own testing found levels of the probable carcinogen N-nitrosodimethylamine (NDMA) exceeded those recognized by the agency as being safe, according to a petition filed with the FDA.

Several of the batches tested from a total of 22 companies contained more than 10 times the accepted 96-ng daily limit for NDMA set by the agency.

“The presence of this probable carcinogen in a medication that is taken daily by adults and adolescents for a chronic condition like diabetes, makes [these findings] particularly troubling,” the pharmacy said in the petition. It noted that NDMA is classified by the World Health Organization and the International Agency for Research on Cancer as a Group 2A compound, meaning that it is “probably carcinogenic to humans.”

The Valisure findings are in contrast to those from the FDA’s own testing of metformin from eight companies. In results released Feb. 2, the agency found no NDMA in metformin from seven of the companies, and elevations within the safe limit in metformin from the remaining company. Based on those results, the FDA did not issue a recall.

The FDA declined to comment on the petition, pending a formal written response, a spokesman said.

Valisure said in its petition that one reason it found NDMA at concerning levels, and the FDA did not, could be that the pharmacy’s testing was more thorough than the agency’s because it had used its proprietary analytical technologies in addition to FDA standard assays. The pharmacy said it also cast a wider net, testing samples from 22 companies instead of 8, as the FDA had.

“At least one company that consistently displayed high levels of NDMA in all Valisure-tested batches was a company whose metformin products, to Valisure’s knowledge, were not tested by FDA,” Valisure said in the petition.

The pharmacy tested 38 batches of metformin from 22 companies, and found 16 contaminated batches from 11 companies. Results from one company were confirmed by an independent laboratory in California.

In addition, “there was significant variability from batch to batch, even within a single company, underscoring the importance of batch-level chemical analysis and the necessity of overall increased quality surveillance of medications,” the pharmacy stated in the petition.

David Light, Valisure founder and CEO, said in a press release that the results “indicate that contaminated batches of drugs are scattered and intermixed with clean [batches] throughout the American pharmaceutical supply chain. This strongly suggests that neither the limited testing FDA is able to conduct nor the pharmaceutical companies’ self-reporting of analytical results is sufficient to protect American consumers.”

He explained in an interview that metformin contamination probably comes from poor manufacturing, as NDMA can form during the manufacturing process. Companies are supposed to have processes in place to limit its formation and to check for and remove it before products are shipped. The contaminated batches might have come from China, which makes the bulk of U.S. active pharmaceutical ingredients, he said.

Recently, Apotex and Ranbaxy Pharmaceuticals recalled specific metformin lots in Canada after Canadian health authorities requested NDMA testing. Metformin versions have also been recalled in Singapore. European health authorities are also looking into the issue, according to a Mar. 3 press release from the European Medicines Agency.

Over the past 2 years, NDMA contamination has led to recalls of angiotensin receptor blockers, such as valsartan and losartan, because of NDMA in excess of the daily limit, and ranitidine-containing products such as Zantac. Valisure said it hopes the FDA will avoid the “year-long rolling recalls” that have occurred for angiotensin receptor blockers.

Metformin, which is used to treat type 2 diabetes, is the fourth-most prescribed drug in the United States. About 80 million prescriptions were written for it during 2019, according to the press release.

Valisure launched its investigation after it found NDMA in metformin a client asked it to check.

[email protected]

Treatment with the sodium-glucose transporter 2 inhibitor dapagliflozin reduced the risk for cardiovascular disease or hospitalization for heart failure (CVD/HHF) in patients with diabetes, regardless of the duration of the disease, but had a greater protective benefit against major adverse cardiovascular events (MACE) and renal events in patients with longer disease duration, according to new findings from a post hoc analysis of the DECLARE-TIMI 58 trial.

The positive effect of dapagliflozin in patients with MACE – which includes myocardial infarction (MI), CVD, and ischemic stroke – may have been driven by lower rates of MI and ischemic stroke with the drug, compared with placebo, in patients with longer disease duration, wrote Harpreet S. Bajaj, MD, and colleagues. Their report is in Diabetes, Obesity and Metabolism (2020 Feb 23. doi: 10.1111/dom.14011).

It has been previously reported that the risk for complications in diabetes increases with increasing duration of the disease. Recent studies with SGLT-2 inhibitors have shown that the drugs improve cardiovascular and renal outcomes in diabetes, and they are recommended by the American Diabetes Association as second-line therapy in patients with atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure. The European Society of Cardiology and the European Association for the Study of Diabetes recommend that patients with diabetes patients who have three or more risk factors, or those with a disease duration of more than 20 years, should be deemed very high risk and be considered for early treatment with SGLT2 inhibitors.

“The MACE benefit observed with dapagliflozin in this study in patients with diabetes duration of [more than] 20 years, clearly supports that notion,” the authors wrote.

In DECLARE-TIMI 58, 17,160 patients with type 2 diabetes received dapagliflozin or placebo and were followed for a median of 4.2 years. Of those patients, 22.4% had a disease duration of fewer than 5 years; 27.6%, a duration of 5-10 years; 23.0%, 10-15 years; 14.2%, 10-15 years; and 12.9%, more than 20 years. The median duration of disease was 11 years.

Patients in all the age groups had similar reductions in CVD/HHF, compared with placebo, with hazard ratios of 0.79 (disease duration of 5 or fewer years), 0.86, 0.92, 0.81, and 0.75 (duration of 20 years), respectively (interaction trend P = .760).

Treatment with dapagliflozin reduced the incidence of MACE, but the benefit was more apparent in patients with longer-term disease: HR, 1.08; 1.02; 0.94; 0.92; and 0.67, respectively (interaction trend P = .004). Similar trends were seen with MI (interaction trend P = .019) and ischemic stroke (interaction trend P = .015).

The researchers also reported improved benefits in renal-specific outcome with increasing disease duration, with HRs ranging from 0.79 in patients with diabetes duration of fewer than 5 years, to 0.42 in those with a duration of more than 20 years (interaction trend P = .084).

Limitations of the study include the fact that the information about diabetes duration relied on patient reports, and that the original trial was not powered for all subgroup interactions. This authors emphasized that this was a post hoc analysis and as such, should be considered hypothesis generating.

All but two of the authors reported relationships with Astra Zeneca, which funded the study, and other drug companies.

SOURCE: Bajaj HS et al. Diabetes Obes Metab. 2020 Feb 23. doi: 10.1111/dom.14011.

Treatment with the sodium-glucose transporter 2 inhibitor dapagliflozin reduced the risk for cardiovascular disease or hospitalization for heart failure (CVD/HHF) in patients with diabetes, regardless of the duration of the disease, but had a greater protective benefit against major adverse cardiovascular events (MACE) and renal events in patients with longer disease duration, according to new findings from a post hoc analysis of the DECLARE-TIMI 58 trial.

The positive effect of dapagliflozin in patients with MACE – which includes myocardial infarction (MI), CVD, and ischemic stroke – may have been driven by lower rates of MI and ischemic stroke with the drug, compared with placebo, in patients with longer disease duration, wrote Harpreet S. Bajaj, MD, and colleagues. Their report is in Diabetes, Obesity and Metabolism (2020 Feb 23. doi: 10.1111/dom.14011).

It has been previously reported that the risk for complications in diabetes increases with increasing duration of the disease. Recent studies with SGLT-2 inhibitors have shown that the drugs improve cardiovascular and renal outcomes in diabetes, and they are recommended by the American Diabetes Association as second-line therapy in patients with atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure. The European Society of Cardiology and the European Association for the Study of Diabetes recommend that patients with diabetes patients who have three or more risk factors, or those with a disease duration of more than 20 years, should be deemed very high risk and be considered for early treatment with SGLT2 inhibitors.

“The MACE benefit observed with dapagliflozin in this study in patients with diabetes duration of [more than] 20 years, clearly supports that notion,” the authors wrote.

In DECLARE-TIMI 58, 17,160 patients with type 2 diabetes received dapagliflozin or placebo and were followed for a median of 4.2 years. Of those patients, 22.4% had a disease duration of fewer than 5 years; 27.6%, a duration of 5-10 years; 23.0%, 10-15 years; 14.2%, 10-15 years; and 12.9%, more than 20 years. The median duration of disease was 11 years.

Patients in all the age groups had similar reductions in CVD/HHF, compared with placebo, with hazard ratios of 0.79 (disease duration of 5 or fewer years), 0.86, 0.92, 0.81, and 0.75 (duration of 20 years), respectively (interaction trend P = .760).

Treatment with dapagliflozin reduced the incidence of MACE, but the benefit was more apparent in patients with longer-term disease: HR, 1.08; 1.02; 0.94; 0.92; and 0.67, respectively (interaction trend P = .004). Similar trends were seen with MI (interaction trend P = .019) and ischemic stroke (interaction trend P = .015).

The researchers also reported improved benefits in renal-specific outcome with increasing disease duration, with HRs ranging from 0.79 in patients with diabetes duration of fewer than 5 years, to 0.42 in those with a duration of more than 20 years (interaction trend P = .084).

Limitations of the study include the fact that the information about diabetes duration relied on patient reports, and that the original trial was not powered for all subgroup interactions. This authors emphasized that this was a post hoc analysis and as such, should be considered hypothesis generating.

All but two of the authors reported relationships with Astra Zeneca, which funded the study, and other drug companies.

SOURCE: Bajaj HS et al. Diabetes Obes Metab. 2020 Feb 23. doi: 10.1111/dom.14011.

Treatment with the sodium-glucose transporter 2 inhibitor dapagliflozin reduced the risk for cardiovascular disease or hospitalization for heart failure (CVD/HHF) in patients with diabetes, regardless of the duration of the disease, but had a greater protective benefit against major adverse cardiovascular events (MACE) and renal events in patients with longer disease duration, according to new findings from a post hoc analysis of the DECLARE-TIMI 58 trial.

The positive effect of dapagliflozin in patients with MACE – which includes myocardial infarction (MI), CVD, and ischemic stroke – may have been driven by lower rates of MI and ischemic stroke with the drug, compared with placebo, in patients with longer disease duration, wrote Harpreet S. Bajaj, MD, and colleagues. Their report is in Diabetes, Obesity and Metabolism (2020 Feb 23. doi: 10.1111/dom.14011).

It has been previously reported that the risk for complications in diabetes increases with increasing duration of the disease. Recent studies with SGLT-2 inhibitors have shown that the drugs improve cardiovascular and renal outcomes in diabetes, and they are recommended by the American Diabetes Association as second-line therapy in patients with atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure. The European Society of Cardiology and the European Association for the Study of Diabetes recommend that patients with diabetes patients who have three or more risk factors, or those with a disease duration of more than 20 years, should be deemed very high risk and be considered for early treatment with SGLT2 inhibitors.

“The MACE benefit observed with dapagliflozin in this study in patients with diabetes duration of [more than] 20 years, clearly supports that notion,” the authors wrote.

In DECLARE-TIMI 58, 17,160 patients with type 2 diabetes received dapagliflozin or placebo and were followed for a median of 4.2 years. Of those patients, 22.4% had a disease duration of fewer than 5 years; 27.6%, a duration of 5-10 years; 23.0%, 10-15 years; 14.2%, 10-15 years; and 12.9%, more than 20 years. The median duration of disease was 11 years.

Patients in all the age groups had similar reductions in CVD/HHF, compared with placebo, with hazard ratios of 0.79 (disease duration of 5 or fewer years), 0.86, 0.92, 0.81, and 0.75 (duration of 20 years), respectively (interaction trend P = .760).

Treatment with dapagliflozin reduced the incidence of MACE, but the benefit was more apparent in patients with longer-term disease: HR, 1.08; 1.02; 0.94; 0.92; and 0.67, respectively (interaction trend P = .004). Similar trends were seen with MI (interaction trend P = .019) and ischemic stroke (interaction trend P = .015).

The researchers also reported improved benefits in renal-specific outcome with increasing disease duration, with HRs ranging from 0.79 in patients with diabetes duration of fewer than 5 years, to 0.42 in those with a duration of more than 20 years (interaction trend P = .084).

Limitations of the study include the fact that the information about diabetes duration relied on patient reports, and that the original trial was not powered for all subgroup interactions. This authors emphasized that this was a post hoc analysis and as such, should be considered hypothesis generating.

All but two of the authors reported relationships with Astra Zeneca, which funded the study, and other drug companies.

SOURCE: Bajaj HS et al. Diabetes Obes Metab. 2020 Feb 23. doi: 10.1111/dom.14011.

The risk for microvascular complications in adults with latent autoimmune diabetes increases the longer they have the disease, according a post hoc analysis of a large European database.

However, Ernesto Maddaloni, MD, of Sapienza University of Rome and University of Oxford (England), and colleagues noted that the risk is less than half that in patients with type 2 disease during the first several years after diagnosis but that, after 9 years, the risk curves cross over, and patients with latent autoimmune diabetes of adulthood (LADA) matriculate to a 25% greater risk microvascular complications than do their type 2 counterparts.

The results point to a need for tighter glycemic control in patients with latent autoimmune disease and “might have relevant implications for the understanding of the differential risk of complications between type 2 diabetes and autoimmune diabetes in general,” the researchers wrote online in The Lancet Diabetes & Endocrinology. They emphasized that the study represents the largest population of patients with latent autoimmune diabetes with the longest follow-up in a randomized controlled trial so far.

Diabetic microvascular complications are a major cause of end-stage renal disease and blindness in LADA, therefore, “implementing strict glycemic control from the time of diagnosis could reduce the later risk of microvascular complications in [these patients],” the authors wrote.

The researchers analyzed 30 years of data from the United Kingdom Prospective Diabetes Study, focusing on 564 patients with LADA and 4,464 adults with type 2 diabetes. The primary outcome was first occurrence of renal failure, death from renal disease, blindness in one eye, vitreous hemorrhage, or retinal laser treatment.

With a median follow-up of 17.3 years, 21% of all patients (1,041) developed microvascular complications, of which there were 65 renal events and 976 retinopathy events. Secondary outcomes were nephropathy and retinopathy.

The study measured incidence in 1,000 person-years and found that the incidence for the overall primary composite microvascular outcome was 5.3% for LADA and 10% for type 2 diabetes in the first 9 years after diagnosis (P = .0020), but 13.6% and 9.2%, respectively, after that (P less than .0001). That translated into adjusted hazard ratios of 0.45 for LADA, compared with type 2 diabetes, in the first 9 years (P less than .0001) and 1.25 beyond 9 years (P = .047). The incidence of retinopathy events was 5.3% for LADA and 9.6% for type 2 diabetes up to 9 years (P = .003), and 12.5% and 8.6% thereafter (P = .001). Nephropathy rates were similar in both groups at 1.3% or less.

“The lower risk of microvascular complications during the first years after the diagnosis of latent autoimmune diabetes needs further examination,” Dr. Maddaloni and colleagues wrote.

They cautioned that LADA is often misdiagnosed as a form of type 1 diabetes. “Therefore, latent autoimmune diabetes could be the right bench test for studying differences between autoimmune diabetes and type 2 diabetes, because of fewer disparities in age and disease duration than with the comparison of type 1 diabetes and type 2 diabetes,” they wrote.

In an accompanying editorial, Didac Mauricio, MD, of the Autonomous University of Barcelona, credited Dr. Maddaloni and colleagues with presenting evidence “of major relevance” in an adequately powered study that provided “a robust conclusion” about the risk of microvascular complications in latent autoimmune diabetes.

Dr. Mauricio noted that the study adds to the literature that different subgroups of type 2 diabetes patients exist and highlights the distinct characteristics of latent autoimmune diabetes. In addition, it builds on a previous study by Dr. Maddaloni and coauthors that found cardiovascular disease outcomes did not differ between latent autoimmune and type 2 diabetes (Diabetes Obes Metab. 2019;21:2115-22), he wrote. The research team’s most recent findings “emphasize the need for early identification of latent autoimmune disease,” he stated.

The findings also raise important questions about screening all patients for antibodies upon diagnosis of diabetes, he said. “I firmly believe that it is time to take action,” first, because antibody testing is likely cost-effective and cost-saving because it facilitates better-informed, more timely decisions early in the disease trajectory, and second, it has already been well documented that patients with latent autoimmune diabetes have a higher glycemic burden.

An alternative to early universal screening for antibodies would be to raise awareness, especially among general practitioners, about the importance of timely diagnosis of LADA, Dr. Mauricio added.

The study received funding from the European Foundation for the Study of Diabetes Mentorship Program, supported by AstraZeneca. Dr. Maddaloni disclosed financial relationships with Sanofi, Eli Lilly, Abbott, and AstraZeneca. Another author disclosed financial relationships with Boehringer Ingelheim, Merck, Bayer, AstraZeneca, Novartis, and Novo Nordisk. All the other authors had no relevant financial relationships to disclose. Dr. Mauricio disclosed financial relationships with AstraZeneca, Eli Lilly, Merck Sharp & Dohme, NovoNordisk, Sanofi, Almirall, Boehringer Ingelheim, Eli Lilly, Ferrer, Janssen, Menarini, and URGO.
 

SOURCE: Maddaloni E et al. Lancet Diabetes Endocrinol. 2020 Feb 4. doi: 0.1016/S2213-8587(20)30003-6.

The risk for microvascular complications in adults with latent autoimmune diabetes increases the longer they have the disease, according a post hoc analysis of a large European database.

However, Ernesto Maddaloni, MD, of Sapienza University of Rome and University of Oxford (England), and colleagues noted that the risk is less than half that in patients with type 2 disease during the first several years after diagnosis but that, after 9 years, the risk curves cross over, and patients with latent autoimmune diabetes of adulthood (LADA) matriculate to a 25% greater risk microvascular complications than do their type 2 counterparts.

The results point to a need for tighter glycemic control in patients with latent autoimmune disease and “might have relevant implications for the understanding of the differential risk of complications between type 2 diabetes and autoimmune diabetes in general,” the researchers wrote online in The Lancet Diabetes & Endocrinology. They emphasized that the study represents the largest population of patients with latent autoimmune diabetes with the longest follow-up in a randomized controlled trial so far.

Diabetic microvascular complications are a major cause of end-stage renal disease and blindness in LADA, therefore, “implementing strict glycemic control from the time of diagnosis could reduce the later risk of microvascular complications in [these patients],” the authors wrote.

The researchers analyzed 30 years of data from the United Kingdom Prospective Diabetes Study, focusing on 564 patients with LADA and 4,464 adults with type 2 diabetes. The primary outcome was first occurrence of renal failure, death from renal disease, blindness in one eye, vitreous hemorrhage, or retinal laser treatment.

With a median follow-up of 17.3 years, 21% of all patients (1,041) developed microvascular complications, of which there were 65 renal events and 976 retinopathy events. Secondary outcomes were nephropathy and retinopathy.

The study measured incidence in 1,000 person-years and found that the incidence for the overall primary composite microvascular outcome was 5.3% for LADA and 10% for type 2 diabetes in the first 9 years after diagnosis (P = .0020), but 13.6% and 9.2%, respectively, after that (P less than .0001). That translated into adjusted hazard ratios of 0.45 for LADA, compared with type 2 diabetes, in the first 9 years (P less than .0001) and 1.25 beyond 9 years (P = .047). The incidence of retinopathy events was 5.3% for LADA and 9.6% for type 2 diabetes up to 9 years (P = .003), and 12.5% and 8.6% thereafter (P = .001). Nephropathy rates were similar in both groups at 1.3% or less.

“The lower risk of microvascular complications during the first years after the diagnosis of latent autoimmune diabetes needs further examination,” Dr. Maddaloni and colleagues wrote.

They cautioned that LADA is often misdiagnosed as a form of type 1 diabetes. “Therefore, latent autoimmune diabetes could be the right bench test for studying differences between autoimmune diabetes and type 2 diabetes, because of fewer disparities in age and disease duration than with the comparison of type 1 diabetes and type 2 diabetes,” they wrote.

In an accompanying editorial, Didac Mauricio, MD, of the Autonomous University of Barcelona, credited Dr. Maddaloni and colleagues with presenting evidence “of major relevance” in an adequately powered study that provided “a robust conclusion” about the risk of microvascular complications in latent autoimmune diabetes.

Dr. Mauricio noted that the study adds to the literature that different subgroups of type 2 diabetes patients exist and highlights the distinct characteristics of latent autoimmune diabetes. In addition, it builds on a previous study by Dr. Maddaloni and coauthors that found cardiovascular disease outcomes did not differ between latent autoimmune and type 2 diabetes (Diabetes Obes Metab. 2019;21:2115-22), he wrote. The research team’s most recent findings “emphasize the need for early identification of latent autoimmune disease,” he stated.

The findings also raise important questions about screening all patients for antibodies upon diagnosis of diabetes, he said. “I firmly believe that it is time to take action,” first, because antibody testing is likely cost-effective and cost-saving because it facilitates better-informed, more timely decisions early in the disease trajectory, and second, it has already been well documented that patients with latent autoimmune diabetes have a higher glycemic burden.

An alternative to early universal screening for antibodies would be to raise awareness, especially among general practitioners, about the importance of timely diagnosis of LADA, Dr. Mauricio added.

The study received funding from the European Foundation for the Study of Diabetes Mentorship Program, supported by AstraZeneca. Dr. Maddaloni disclosed financial relationships with Sanofi, Eli Lilly, Abbott, and AstraZeneca. Another author disclosed financial relationships with Boehringer Ingelheim, Merck, Bayer, AstraZeneca, Novartis, and Novo Nordisk. All the other authors had no relevant financial relationships to disclose. Dr. Mauricio disclosed financial relationships with AstraZeneca, Eli Lilly, Merck Sharp & Dohme, NovoNordisk, Sanofi, Almirall, Boehringer Ingelheim, Eli Lilly, Ferrer, Janssen, Menarini, and URGO.
 

SOURCE: Maddaloni E et al. Lancet Diabetes Endocrinol. 2020 Feb 4. doi: 0.1016/S2213-8587(20)30003-6.

The risk for microvascular complications in adults with latent autoimmune diabetes increases the longer they have the disease, according a post hoc analysis of a large European database.

However, Ernesto Maddaloni, MD, of Sapienza University of Rome and University of Oxford (England), and colleagues noted that the risk is less than half that in patients with type 2 disease during the first several years after diagnosis but that, after 9 years, the risk curves cross over, and patients with latent autoimmune diabetes of adulthood (LADA) matriculate to a 25% greater risk microvascular complications than do their type 2 counterparts.

The results point to a need for tighter glycemic control in patients with latent autoimmune disease and “might have relevant implications for the understanding of the differential risk of complications between type 2 diabetes and autoimmune diabetes in general,” the researchers wrote online in The Lancet Diabetes & Endocrinology. They emphasized that the study represents the largest population of patients with latent autoimmune diabetes with the longest follow-up in a randomized controlled trial so far.

Diabetic microvascular complications are a major cause of end-stage renal disease and blindness in LADA, therefore, “implementing strict glycemic control from the time of diagnosis could reduce the later risk of microvascular complications in [these patients],” the authors wrote.

The researchers analyzed 30 years of data from the United Kingdom Prospective Diabetes Study, focusing on 564 patients with LADA and 4,464 adults with type 2 diabetes. The primary outcome was first occurrence of renal failure, death from renal disease, blindness in one eye, vitreous hemorrhage, or retinal laser treatment.

With a median follow-up of 17.3 years, 21% of all patients (1,041) developed microvascular complications, of which there were 65 renal events and 976 retinopathy events. Secondary outcomes were nephropathy and retinopathy.

The study measured incidence in 1,000 person-years and found that the incidence for the overall primary composite microvascular outcome was 5.3% for LADA and 10% for type 2 diabetes in the first 9 years after diagnosis (P = .0020), but 13.6% and 9.2%, respectively, after that (P less than .0001). That translated into adjusted hazard ratios of 0.45 for LADA, compared with type 2 diabetes, in the first 9 years (P less than .0001) and 1.25 beyond 9 years (P = .047). The incidence of retinopathy events was 5.3% for LADA and 9.6% for type 2 diabetes up to 9 years (P = .003), and 12.5% and 8.6% thereafter (P = .001). Nephropathy rates were similar in both groups at 1.3% or less.

“The lower risk of microvascular complications during the first years after the diagnosis of latent autoimmune diabetes needs further examination,” Dr. Maddaloni and colleagues wrote.

They cautioned that LADA is often misdiagnosed as a form of type 1 diabetes. “Therefore, latent autoimmune diabetes could be the right bench test for studying differences between autoimmune diabetes and type 2 diabetes, because of fewer disparities in age and disease duration than with the comparison of type 1 diabetes and type 2 diabetes,” they wrote.

In an accompanying editorial, Didac Mauricio, MD, of the Autonomous University of Barcelona, credited Dr. Maddaloni and colleagues with presenting evidence “of major relevance” in an adequately powered study that provided “a robust conclusion” about the risk of microvascular complications in latent autoimmune diabetes.

Dr. Mauricio noted that the study adds to the literature that different subgroups of type 2 diabetes patients exist and highlights the distinct characteristics of latent autoimmune diabetes. In addition, it builds on a previous study by Dr. Maddaloni and coauthors that found cardiovascular disease outcomes did not differ between latent autoimmune and type 2 diabetes (Diabetes Obes Metab. 2019;21:2115-22), he wrote. The research team’s most recent findings “emphasize the need for early identification of latent autoimmune disease,” he stated.

The findings also raise important questions about screening all patients for antibodies upon diagnosis of diabetes, he said. “I firmly believe that it is time to take action,” first, because antibody testing is likely cost-effective and cost-saving because it facilitates better-informed, more timely decisions early in the disease trajectory, and second, it has already been well documented that patients with latent autoimmune diabetes have a higher glycemic burden.

An alternative to early universal screening for antibodies would be to raise awareness, especially among general practitioners, about the importance of timely diagnosis of LADA, Dr. Mauricio added.

The study received funding from the European Foundation for the Study of Diabetes Mentorship Program, supported by AstraZeneca. Dr. Maddaloni disclosed financial relationships with Sanofi, Eli Lilly, Abbott, and AstraZeneca. Another author disclosed financial relationships with Boehringer Ingelheim, Merck, Bayer, AstraZeneca, Novartis, and Novo Nordisk. All the other authors had no relevant financial relationships to disclose. Dr. Mauricio disclosed financial relationships with AstraZeneca, Eli Lilly, Merck Sharp & Dohme, NovoNordisk, Sanofi, Almirall, Boehringer Ingelheim, Eli Lilly, Ferrer, Janssen, Menarini, and URGO.
 

SOURCE: Maddaloni E et al. Lancet Diabetes Endocrinol. 2020 Feb 4. doi: 0.1016/S2213-8587(20)30003-6.

ILLUSTRATIVE CASE

Blanche is a 54-year-old overweight woman who has had type 2 diabetes mellitus (T2DM) for 5 years. She has been optimized on both metformin (1000 mg bid) and exenatide (2 mg weekly). While taking these medications, her hemoglobin A1C (HbA1C) has dropped from 11.2 to 8.4, and her body mass index (BMI) has declined from 35 to 31. However, she is still not at goal. You decide to start her on long-acting basal insulin. She has limited income, and she currently spends $75/month for her metformin, exenatide, atorvastatin, and lisinopril. What insulin do you prescribe?

The Centers for Disease Control and Prevention (CDC) reported that the prevalence of diabetes in the United States was 9.4% (30.3 million people) in 2015.² Among those affected, approximately 95.8% had T2DM.² The same report estimated that 1.5 million new cases of diabetes (6.7 per 1000 persons) were diagnosed annually among US adults ≥ 18 years of age, and that about $7900 of annual medical expenses for patients diagnosed with diabetes was directly attributable to diabetes.²

In the United States, neutral protamine Hagedorn (NPH) insulin was the most commonly used intermediate- to long-acting insulin until the introduction of the long-acting insulin analogs (insulin glargine in 2000 and insulin detemir in 2005).³ Despite being considerably more expensive than NPH insulin, long-acting insulin analogs had captured more than 80% of the total long-acting insulin market by 2010.⁴ The market share for NPH insulin dropped from 81.9% in 2001 to 16.2% in 2010.⁴

While the newer insulin analogs are significantly more expensive than NPH insulin, with higher corresponding out-of-pocket costs to patients, researchers have had a difficult time demonstrating greater effectiveness or any definitive differences in any long-term outcomes between NPH and the insulin analogs. A 2007 Cochrane review comparing NPH insulin to both glargine and detemir showed little difference in metabolic control (as measured by HbA1C) or in the rate of severe hypoglycemia. However, the rates of symptomatic, overall, and nocturnal hypoglycemia were statistically lower with the insulin analogs.⁵

A 2015 retrospective observational study from the Veterans Health Administration (N = 142,940) covering a 10-year period from 2000 to 2010 found no consistent differences in long-term health outcomes when comparing the use of long-acting insulin analogs to that of NPH insulin.^3,6

STUDY SUMMARY

Study compares performance of basal insulin analogs to that of NPH

This retrospective, observational study included 25,489 adult patients with T2DM who were enrolled in Kaiser Permanente of Northern California, had full medical and prescription coverage, and initiated basal insulin therapy with either NPH or an insulin analog between 2006 and 2015.

This study makes a strong case for a different approach to initial basal insulin therapy for patients with T2DM who need insulin for glucose control.

The primary outcome was the time from basal insulin therapy initiation to a hypoglycemia-related emergency department (ED) visit or hospital admission. The secondary outcome was the change in HbA1C level within 1 year of initiation of basal insulin therapy.

Continue to: Per 1000 person-years...

Per 1000 person-years, there was no significant difference in hypoglycemia-related ED visits or hospital admissions between the analog and NPH groups (11.9 events vs 8.8 events, respectively; between-group difference, 3.1 events; 95% confidence interval [CI], –1.5 to 7.7). HbA1C reduction was statistically greater with NPH, but most likely not clinically significant between insulin analogs and NPH (1.26 vs 1.48 percentage points; between group difference, –0.22%; 95% CI, –0.09% to –0.37%).

WHAT’S NEW?

No clinically relevant differences between insulin analogs and NPH

This study revealed that there is no clinically relevant difference in HbA1C levels and no difference in patient-focused outcomes of hypoglycemia-related ED visits or hospital admissions between NPH insulin and the more expensive insulin analogs. This makes a strong case for a different approach to initial basal insulin therapy for patients with T2DM who need insulin for glucose control.

CAVEATS

Demographics and less severe hypoglycemia might be at issue

This retrospective, observational study has broad demographics (but moderate under-representation of African-Americans), minimal patient health care disparities, and good access to medications. But generalizability outside of an integrated health delivery system may be limited. The study design also is subject to confounding, as not all potential impacts on the results can be corrected for or controlled in an observational study. Also, less profound hypoglycemia that did not require an ED visit or hospital admission was not captured.

CHALLENGES TO IMPLEMENTATION

Convenience and marketing factors may hinder change

Insulin analogs may have a number of convenience and marketing factors that may make it hard for providers and systems to change and use more NPH. However, the easy-to-use insulin analog pens are matched in availability and convenience by the much less advertised NPH insulin pens produced by at least 3 major pharmaceutical companies. In addition, while the overall cost for the insulin analogs continues to be 2 to 3 times that of non-human NPH insulin, insurance often covers up to, or more than, 80% of the cost of the insulin analogs, making the difference in the patient’s copay between the 2 not as severe. For example, patients may pay $30 to $40 per month for insulin analogs vs $10 to $25 per month for cheaper versions of NPH.^7,8

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Blanche is a 54-year-old overweight woman who has had type 2 diabetes mellitus (T2DM) for 5 years. She has been optimized on both metformin (1000 mg bid) and exenatide (2 mg weekly). While taking these medications, her hemoglobin A1C (HbA1C) has dropped from 11.2 to 8.4, and her body mass index (BMI) has declined from 35 to 31. However, she is still not at goal. You decide to start her on long-acting basal insulin. She has limited income, and she currently spends $75/month for her metformin, exenatide, atorvastatin, and lisinopril. What insulin do you prescribe?

The Centers for Disease Control and Prevention (CDC) reported that the prevalence of diabetes in the United States was 9.4% (30.3 million people) in 2015.² Among those affected, approximately 95.8% had T2DM.² The same report estimated that 1.5 million new cases of diabetes (6.7 per 1000 persons) were diagnosed annually among US adults ≥ 18 years of age, and that about $7900 of annual medical expenses for patients diagnosed with diabetes was directly attributable to diabetes.²

In the United States, neutral protamine Hagedorn (NPH) insulin was the most commonly used intermediate- to long-acting insulin until the introduction of the long-acting insulin analogs (insulin glargine in 2000 and insulin detemir in 2005).³ Despite being considerably more expensive than NPH insulin, long-acting insulin analogs had captured more than 80% of the total long-acting insulin market by 2010.⁴ The market share for NPH insulin dropped from 81.9% in 2001 to 16.2% in 2010.⁴

While the newer insulin analogs are significantly more expensive than NPH insulin, with higher corresponding out-of-pocket costs to patients, researchers have had a difficult time demonstrating greater effectiveness or any definitive differences in any long-term outcomes between NPH and the insulin analogs. A 2007 Cochrane review comparing NPH insulin to both glargine and detemir showed little difference in metabolic control (as measured by HbA1C) or in the rate of severe hypoglycemia. However, the rates of symptomatic, overall, and nocturnal hypoglycemia were statistically lower with the insulin analogs.⁵

A 2015 retrospective observational study from the Veterans Health Administration (N = 142,940) covering a 10-year period from 2000 to 2010 found no consistent differences in long-term health outcomes when comparing the use of long-acting insulin analogs to that of NPH insulin.^3,6

STUDY SUMMARY

Study compares performance of basal insulin analogs to that of NPH

This retrospective, observational study included 25,489 adult patients with T2DM who were enrolled in Kaiser Permanente of Northern California, had full medical and prescription coverage, and initiated basal insulin therapy with either NPH or an insulin analog between 2006 and 2015.

This study makes a strong case for a different approach to initial basal insulin therapy for patients with T2DM who need insulin for glucose control.

The primary outcome was the time from basal insulin therapy initiation to a hypoglycemia-related emergency department (ED) visit or hospital admission. The secondary outcome was the change in HbA1C level within 1 year of initiation of basal insulin therapy.

Continue to: Per 1000 person-years...

Per 1000 person-years, there was no significant difference in hypoglycemia-related ED visits or hospital admissions between the analog and NPH groups (11.9 events vs 8.8 events, respectively; between-group difference, 3.1 events; 95% confidence interval [CI], –1.5 to 7.7). HbA1C reduction was statistically greater with NPH, but most likely not clinically significant between insulin analogs and NPH (1.26 vs 1.48 percentage points; between group difference, –0.22%; 95% CI, –0.09% to –0.37%).

WHAT’S NEW?

No clinically relevant differences between insulin analogs and NPH

This study revealed that there is no clinically relevant difference in HbA1C levels and no difference in patient-focused outcomes of hypoglycemia-related ED visits or hospital admissions between NPH insulin and the more expensive insulin analogs. This makes a strong case for a different approach to initial basal insulin therapy for patients with T2DM who need insulin for glucose control.

CAVEATS

Demographics and less severe hypoglycemia might be at issue

This retrospective, observational study has broad demographics (but moderate under-representation of African-Americans), minimal patient health care disparities, and good access to medications. But generalizability outside of an integrated health delivery system may be limited. The study design also is subject to confounding, as not all potential impacts on the results can be corrected for or controlled in an observational study. Also, less profound hypoglycemia that did not require an ED visit or hospital admission was not captured.

CHALLENGES TO IMPLEMENTATION

Convenience and marketing factors may hinder change

Insulin analogs may have a number of convenience and marketing factors that may make it hard for providers and systems to change and use more NPH. However, the easy-to-use insulin analog pens are matched in availability and convenience by the much less advertised NPH insulin pens produced by at least 3 major pharmaceutical companies. In addition, while the overall cost for the insulin analogs continues to be 2 to 3 times that of non-human NPH insulin, insurance often covers up to, or more than, 80% of the cost of the insulin analogs, making the difference in the patient’s copay between the 2 not as severe. For example, patients may pay $30 to $40 per month for insulin analogs vs $10 to $25 per month for cheaper versions of NPH.^7,8

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Blanche is a 54-year-old overweight woman who has had type 2 diabetes mellitus (T2DM) for 5 years. She has been optimized on both metformin (1000 mg bid) and exenatide (2 mg weekly). While taking these medications, her hemoglobin A1C (HbA1C) has dropped from 11.2 to 8.4, and her body mass index (BMI) has declined from 35 to 31. However, she is still not at goal. You decide to start her on long-acting basal insulin. She has limited income, and she currently spends $75/month for her metformin, exenatide, atorvastatin, and lisinopril. What insulin do you prescribe?

The Centers for Disease Control and Prevention (CDC) reported that the prevalence of diabetes in the United States was 9.4% (30.3 million people) in 2015.² Among those affected, approximately 95.8% had T2DM.² The same report estimated that 1.5 million new cases of diabetes (6.7 per 1000 persons) were diagnosed annually among US adults ≥ 18 years of age, and that about $7900 of annual medical expenses for patients diagnosed with diabetes was directly attributable to diabetes.²

In the United States, neutral protamine Hagedorn (NPH) insulin was the most commonly used intermediate- to long-acting insulin until the introduction of the long-acting insulin analogs (insulin glargine in 2000 and insulin detemir in 2005).³ Despite being considerably more expensive than NPH insulin, long-acting insulin analogs had captured more than 80% of the total long-acting insulin market by 2010.⁴ The market share for NPH insulin dropped from 81.9% in 2001 to 16.2% in 2010.⁴

While the newer insulin analogs are significantly more expensive than NPH insulin, with higher corresponding out-of-pocket costs to patients, researchers have had a difficult time demonstrating greater effectiveness or any definitive differences in any long-term outcomes between NPH and the insulin analogs. A 2007 Cochrane review comparing NPH insulin to both glargine and detemir showed little difference in metabolic control (as measured by HbA1C) or in the rate of severe hypoglycemia. However, the rates of symptomatic, overall, and nocturnal hypoglycemia were statistically lower with the insulin analogs.⁵

A 2015 retrospective observational study from the Veterans Health Administration (N = 142,940) covering a 10-year period from 2000 to 2010 found no consistent differences in long-term health outcomes when comparing the use of long-acting insulin analogs to that of NPH insulin.^3,6

STUDY SUMMARY

Study compares performance of basal insulin analogs to that of NPH

This retrospective, observational study included 25,489 adult patients with T2DM who were enrolled in Kaiser Permanente of Northern California, had full medical and prescription coverage, and initiated basal insulin therapy with either NPH or an insulin analog between 2006 and 2015.

This study makes a strong case for a different approach to initial basal insulin therapy for patients with T2DM who need insulin for glucose control.

The primary outcome was the time from basal insulin therapy initiation to a hypoglycemia-related emergency department (ED) visit or hospital admission. The secondary outcome was the change in HbA1C level within 1 year of initiation of basal insulin therapy.

Continue to: Per 1000 person-years...

Per 1000 person-years, there was no significant difference in hypoglycemia-related ED visits or hospital admissions between the analog and NPH groups (11.9 events vs 8.8 events, respectively; between-group difference, 3.1 events; 95% confidence interval [CI], –1.5 to 7.7). HbA1C reduction was statistically greater with NPH, but most likely not clinically significant between insulin analogs and NPH (1.26 vs 1.48 percentage points; between group difference, –0.22%; 95% CI, –0.09% to –0.37%).

WHAT’S NEW?

No clinically relevant differences between insulin analogs and NPH

This study revealed that there is no clinically relevant difference in HbA1C levels and no difference in patient-focused outcomes of hypoglycemia-related ED visits or hospital admissions between NPH insulin and the more expensive insulin analogs. This makes a strong case for a different approach to initial basal insulin therapy for patients with T2DM who need insulin for glucose control.

CAVEATS

Demographics and less severe hypoglycemia might be at issue

This retrospective, observational study has broad demographics (but moderate under-representation of African-Americans), minimal patient health care disparities, and good access to medications. But generalizability outside of an integrated health delivery system may be limited. The study design also is subject to confounding, as not all potential impacts on the results can be corrected for or controlled in an observational study. Also, less profound hypoglycemia that did not require an ED visit or hospital admission was not captured.

CHALLENGES TO IMPLEMENTATION

Convenience and marketing factors may hinder change

Insulin analogs may have a number of convenience and marketing factors that may make it hard for providers and systems to change and use more NPH. However, the easy-to-use insulin analog pens are matched in availability and convenience by the much less advertised NPH insulin pens produced by at least 3 major pharmaceutical companies. In addition, while the overall cost for the insulin analogs continues to be 2 to 3 times that of non-human NPH insulin, insurance often covers up to, or more than, 80% of the cost of the insulin analogs, making the difference in the patient’s copay between the 2 not as severe. For example, patients may pay $30 to $40 per month for insulin analogs vs $10 to $25 per month for cheaper versions of NPH.^7,8

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Glucocorticoid use is associated with greater mortality and cardiovascular risk in RA patients, and the associated risk is greater still in patients with RA and comorbid diabetes. The findings come from a new retrospective analysis derived from U.K. primary care records.

Although patients with diabetes actually had a lower relative risk for mortality than the nondiabetes cohort, they had a greater mortality difference because of a greater baseline risk. Ultimately, glucocorticoid (GC) use was associated with an additional 44.9 deaths per 1,000 person-years in the diabetes group, compared with 34.4 per 1,000 person-years in the RA-only group.

The study, led by Ruth Costello and William Dixon, MBBS, PhD of the University of Manchester (England), was published in BMC Rheumatology.

The findings aren’t particularly surprising, given that steroid use and diabetes have associated cardiovascular risks, and physicians generally try to reduce or eliminate their use. “There’s a group [of physicians] saying that we don’t need to use steroids at all in rheumatoid arthritis, except maybe for [a] short time at diagnosis to bridge to other therapies, or during flares,” Gordon Starkebaum, MD, professor emeritus of rheumatology at the University of Washington, Seattle, said in an interview. He recounted a session at last year’s annual meeting of the American College of Rheumatology that advocated for only injectable steroid use during flare-ups. “That was provocative,” Dr. Starkebaum said.

“It’s a retrospective study, so it has some limitations, but it provides good insight, and some substantiation to what we already think,” added Brett Smith, DO, a rheumatologist practicing in Knoxville, Tenn.

Dr. Smith suggested that the study further underscores the need to follow treat-to-target protocols in RA. He emphasized that lifetime exposure to steroids is likely the greatest concern, and that steady accumulating doses are a sign of trouble. “If you need that much steroids, you need to go up on your medication – your methotrexate, or sulfasalazine, or your biologic,” said Dr. Smith. “At least 50% of people will need a biologic to [achieve] disease control, and if you get them on it, they’re going to have better disease control, compliance is typically better, and they’re going to have less steroid exposure.”

Dr. Smith also noted that comorbid diabetes shouldn’t affect treat-to-target strategies. In fact, in such patients “you should probably be following it more tightly to reduce the cardiovascular outcomes,” he said.

The retrospective analysis included 9,085 patients with RA and with or without type 2 diabetes, with a mean follow-up of 5.2 years. They were recruited to the study between 1998 and 2011. Among patients with comorbid diabetes, those exposed to GC had a mortality of 67.4 per 1,000 person-years, compared with 22.5 among those not exposed to GC. Among those with RA alone, mortality was 44.6 versus 10.2 with and without GC exposure, respectively. Those with diabetes had a lower risk ratio for mortality (2.99 vs. 4.37), but a higher mortality difference (44.9 vs. 34.4 per 1,000 person-years).

“The increased absolute hazard for all-cause mortality indicates the greater public health impact of people with RA using GCs if they have [diabetes],” the researchers wrote. “Rheumatologists should consider [diabetes] status when prescribing GCs to patients with RA given this potential impact of GC therapy on glucose control and mortality.”

The study was limited by a lack of information on GC dose and cumulative exposure. Given its retrospective nature, the study could have been affected by confounding by indication, as well as unknown confounders.

The study was funded by the Centre for Epidemiology Versus Arthritis and the National Institute for Health Research Biomedical Research Centre. Dr. Starkebaum has no relevant financial disclosures. Dr. Smith is on the speaker’s bureau for AbbVie and serves on the company’s advisory board. He is also on the advisory boards of Regeneron and Sanofi Genzyme.

SOURCE: Costello R et al. BMC Rheumatol. 2020 Feb 19. doi: 10.1186/s41927-019-0105-4.

Glucocorticoid use is associated with greater mortality and cardiovascular risk in RA patients, and the associated risk is greater still in patients with RA and comorbid diabetes. The findings come from a new retrospective analysis derived from U.K. primary care records.

Although patients with diabetes actually had a lower relative risk for mortality than the nondiabetes cohort, they had a greater mortality difference because of a greater baseline risk. Ultimately, glucocorticoid (GC) use was associated with an additional 44.9 deaths per 1,000 person-years in the diabetes group, compared with 34.4 per 1,000 person-years in the RA-only group.

The study, led by Ruth Costello and William Dixon, MBBS, PhD of the University of Manchester (England), was published in BMC Rheumatology.

The findings aren’t particularly surprising, given that steroid use and diabetes have associated cardiovascular risks, and physicians generally try to reduce or eliminate their use. “There’s a group [of physicians] saying that we don’t need to use steroids at all in rheumatoid arthritis, except maybe for [a] short time at diagnosis to bridge to other therapies, or during flares,” Gordon Starkebaum, MD, professor emeritus of rheumatology at the University of Washington, Seattle, said in an interview. He recounted a session at last year’s annual meeting of the American College of Rheumatology that advocated for only injectable steroid use during flare-ups. “That was provocative,” Dr. Starkebaum said.

“It’s a retrospective study, so it has some limitations, but it provides good insight, and some substantiation to what we already think,” added Brett Smith, DO, a rheumatologist practicing in Knoxville, Tenn.

Dr. Smith suggested that the study further underscores the need to follow treat-to-target protocols in RA. He emphasized that lifetime exposure to steroids is likely the greatest concern, and that steady accumulating doses are a sign of trouble. “If you need that much steroids, you need to go up on your medication – your methotrexate, or sulfasalazine, or your biologic,” said Dr. Smith. “At least 50% of people will need a biologic to [achieve] disease control, and if you get them on it, they’re going to have better disease control, compliance is typically better, and they’re going to have less steroid exposure.”

Dr. Smith also noted that comorbid diabetes shouldn’t affect treat-to-target strategies. In fact, in such patients “you should probably be following it more tightly to reduce the cardiovascular outcomes,” he said.

The retrospective analysis included 9,085 patients with RA and with or without type 2 diabetes, with a mean follow-up of 5.2 years. They were recruited to the study between 1998 and 2011. Among patients with comorbid diabetes, those exposed to GC had a mortality of 67.4 per 1,000 person-years, compared with 22.5 among those not exposed to GC. Among those with RA alone, mortality was 44.6 versus 10.2 with and without GC exposure, respectively. Those with diabetes had a lower risk ratio for mortality (2.99 vs. 4.37), but a higher mortality difference (44.9 vs. 34.4 per 1,000 person-years).

“The increased absolute hazard for all-cause mortality indicates the greater public health impact of people with RA using GCs if they have [diabetes],” the researchers wrote. “Rheumatologists should consider [diabetes] status when prescribing GCs to patients with RA given this potential impact of GC therapy on glucose control and mortality.”

The study was limited by a lack of information on GC dose and cumulative exposure. Given its retrospective nature, the study could have been affected by confounding by indication, as well as unknown confounders.

The study was funded by the Centre for Epidemiology Versus Arthritis and the National Institute for Health Research Biomedical Research Centre. Dr. Starkebaum has no relevant financial disclosures. Dr. Smith is on the speaker’s bureau for AbbVie and serves on the company’s advisory board. He is also on the advisory boards of Regeneron and Sanofi Genzyme.

SOURCE: Costello R et al. BMC Rheumatol. 2020 Feb 19. doi: 10.1186/s41927-019-0105-4.

Glucocorticoid use is associated with greater mortality and cardiovascular risk in RA patients, and the associated risk is greater still in patients with RA and comorbid diabetes. The findings come from a new retrospective analysis derived from U.K. primary care records.

Although patients with diabetes actually had a lower relative risk for mortality than the nondiabetes cohort, they had a greater mortality difference because of a greater baseline risk. Ultimately, glucocorticoid (GC) use was associated with an additional 44.9 deaths per 1,000 person-years in the diabetes group, compared with 34.4 per 1,000 person-years in the RA-only group.

The study, led by Ruth Costello and William Dixon, MBBS, PhD of the University of Manchester (England), was published in BMC Rheumatology.

The findings aren’t particularly surprising, given that steroid use and diabetes have associated cardiovascular risks, and physicians generally try to reduce or eliminate their use. “There’s a group [of physicians] saying that we don’t need to use steroids at all in rheumatoid arthritis, except maybe for [a] short time at diagnosis to bridge to other therapies, or during flares,” Gordon Starkebaum, MD, professor emeritus of rheumatology at the University of Washington, Seattle, said in an interview. He recounted a session at last year’s annual meeting of the American College of Rheumatology that advocated for only injectable steroid use during flare-ups. “That was provocative,” Dr. Starkebaum said.

“It’s a retrospective study, so it has some limitations, but it provides good insight, and some substantiation to what we already think,” added Brett Smith, DO, a rheumatologist practicing in Knoxville, Tenn.

Dr. Smith suggested that the study further underscores the need to follow treat-to-target protocols in RA. He emphasized that lifetime exposure to steroids is likely the greatest concern, and that steady accumulating doses are a sign of trouble. “If you need that much steroids, you need to go up on your medication – your methotrexate, or sulfasalazine, or your biologic,” said Dr. Smith. “At least 50% of people will need a biologic to [achieve] disease control, and if you get them on it, they’re going to have better disease control, compliance is typically better, and they’re going to have less steroid exposure.”

Dr. Smith also noted that comorbid diabetes shouldn’t affect treat-to-target strategies. In fact, in such patients “you should probably be following it more tightly to reduce the cardiovascular outcomes,” he said.

The retrospective analysis included 9,085 patients with RA and with or without type 2 diabetes, with a mean follow-up of 5.2 years. They were recruited to the study between 1998 and 2011. Among patients with comorbid diabetes, those exposed to GC had a mortality of 67.4 per 1,000 person-years, compared with 22.5 among those not exposed to GC. Among those with RA alone, mortality was 44.6 versus 10.2 with and without GC exposure, respectively. Those with diabetes had a lower risk ratio for mortality (2.99 vs. 4.37), but a higher mortality difference (44.9 vs. 34.4 per 1,000 person-years).

“The increased absolute hazard for all-cause mortality indicates the greater public health impact of people with RA using GCs if they have [diabetes],” the researchers wrote. “Rheumatologists should consider [diabetes] status when prescribing GCs to patients with RA given this potential impact of GC therapy on glucose control and mortality.”

The study was limited by a lack of information on GC dose and cumulative exposure. Given its retrospective nature, the study could have been affected by confounding by indication, as well as unknown confounders.

The study was funded by the Centre for Epidemiology Versus Arthritis and the National Institute for Health Research Biomedical Research Centre. Dr. Starkebaum has no relevant financial disclosures. Dr. Smith is on the speaker’s bureau for AbbVie and serves on the company’s advisory board. He is also on the advisory boards of Regeneron and Sanofi Genzyme.

SOURCE: Costello R et al. BMC Rheumatol. 2020 Feb 19. doi: 10.1186/s41927-019-0105-4.