The number of states at the highest level of flu activity jumped from 7 to 19 during the week ending Feb. 4, 2017, according to the Centers for Disease Control and Prevention.

The 19 states at level 10 on the CDC’s 1-10 scale of influenza-like illness (ILI) activity were largely concentrated in the South and lower Midwest, with another grouping mainly in the Mid-Atlantic. They were joined in the “high” range of ILI activity by four other states: Indiana and Minnesota at level 9 and New Mexico and Virginia at level 8, the CDC reported.

[email protected]

The number of states at the highest level of flu activity jumped from 7 to 19 during the week ending Feb. 4, 2017, according to the Centers for Disease Control and Prevention.

The 19 states at level 10 on the CDC’s 1-10 scale of influenza-like illness (ILI) activity were largely concentrated in the South and lower Midwest, with another grouping mainly in the Mid-Atlantic. They were joined in the “high” range of ILI activity by four other states: Indiana and Minnesota at level 9 and New Mexico and Virginia at level 8, the CDC reported.

[email protected]

The number of states at the highest level of flu activity jumped from 7 to 19 during the week ending Feb. 4, 2017, according to the Centers for Disease Control and Prevention.

The 19 states at level 10 on the CDC’s 1-10 scale of influenza-like illness (ILI) activity were largely concentrated in the South and lower Midwest, with another grouping mainly in the Mid-Atlantic. They were joined in the “high” range of ILI activity by four other states: Indiana and Minnesota at level 9 and New Mexico and Virginia at level 8, the CDC reported.

[email protected]

Modern medicine is truly blessed. Dermatology is no exception. With the development of more precise medications, our patients with severe psoriasis and atopic dermatitis no longer have to suffer in misery and social isolation. There is new hope for patients with metastatic melanoma. I recently watched President Jimmy Carter – a man with melanoma in his brain, certainly dead except for the advent of new drugs that are truly miraculous – release a rehabilitated sea turtle.

What is the drawback to such miracles? Cost! The cost of these medications can be extraordinary (hundreds of thousands of dollars a year); and guess what, everyone wants and needs their insurance plans to foot the bill for them. Biosimilars are not going to solve the cost issue, since biologic drugs are difficult to manufacture and get approved. The biosimilars are pricing in at only 5%-10% less than costs of the original biologic.

Dr. Coldiron is past president of the American Academy of Dermatology. He is currently in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. Write to him at [email protected].

Modern medicine is truly blessed. Dermatology is no exception. With the development of more precise medications, our patients with severe psoriasis and atopic dermatitis no longer have to suffer in misery and social isolation. There is new hope for patients with metastatic melanoma. I recently watched President Jimmy Carter – a man with melanoma in his brain, certainly dead except for the advent of new drugs that are truly miraculous – release a rehabilitated sea turtle.

What is the drawback to such miracles? Cost! The cost of these medications can be extraordinary (hundreds of thousands of dollars a year); and guess what, everyone wants and needs their insurance plans to foot the bill for them. Biosimilars are not going to solve the cost issue, since biologic drugs are difficult to manufacture and get approved. The biosimilars are pricing in at only 5%-10% less than costs of the original biologic.

Dr. Coldiron is past president of the American Academy of Dermatology. He is currently in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. Write to him at [email protected].

Modern medicine is truly blessed. Dermatology is no exception. With the development of more precise medications, our patients with severe psoriasis and atopic dermatitis no longer have to suffer in misery and social isolation. There is new hope for patients with metastatic melanoma. I recently watched President Jimmy Carter – a man with melanoma in his brain, certainly dead except for the advent of new drugs that are truly miraculous – release a rehabilitated sea turtle.

What is the drawback to such miracles? Cost! The cost of these medications can be extraordinary (hundreds of thousands of dollars a year); and guess what, everyone wants and needs their insurance plans to foot the bill for them. Biosimilars are not going to solve the cost issue, since biologic drugs are difficult to manufacture and get approved. The biosimilars are pricing in at only 5%-10% less than costs of the original biologic.

Dr. Coldiron is past president of the American Academy of Dermatology. He is currently in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. Write to him at [email protected].

For patients with chronic low-back pain, the benefits of cognitive-behavioral therapy and mindfulness-based stress reduction that were reported at 6 months and 1 year largely disappeared by 2-year follow-up, according to a Research Letter to the Editor published Feb 14 in JAMA.

In a clinical trial involving 342 affected patients aged 20-70 years, participants were randomly assigned to receive CBT (113 patients), mindfulness-based stress reduction (MBSR, 116 patients), or usual care (113 patients) and followed up at 26 weeks. The two psychological interventions were delivered in 2-hour group sessions every week for 8 weeks. As previously reported, both CBT and MBSR reduced functional limitations and decreased the “bothersomeness” of the pain, as measured by scores on the modified Roland Disability Questionnaire, compared with usual care, said Daniel C. Cherkin, PhD of the Group Health Research Institute, Seattle, and his associates.

©Rocky89/Thinkstock

For patients with chronic low-back pain, the benefits of cognitive-behavioral therapy and mindfulness-based stress reduction that were reported at 6 months and 1 year largely disappeared by 2-year follow-up, according to a Research Letter to the Editor published Feb 14 in JAMA.

In a clinical trial involving 342 affected patients aged 20-70 years, participants were randomly assigned to receive CBT (113 patients), mindfulness-based stress reduction (MBSR, 116 patients), or usual care (113 patients) and followed up at 26 weeks. The two psychological interventions were delivered in 2-hour group sessions every week for 8 weeks. As previously reported, both CBT and MBSR reduced functional limitations and decreased the “bothersomeness” of the pain, as measured by scores on the modified Roland Disability Questionnaire, compared with usual care, said Daniel C. Cherkin, PhD of the Group Health Research Institute, Seattle, and his associates.

©Rocky89/Thinkstock

For patients with chronic low-back pain, the benefits of cognitive-behavioral therapy and mindfulness-based stress reduction that were reported at 6 months and 1 year largely disappeared by 2-year follow-up, according to a Research Letter to the Editor published Feb 14 in JAMA.

In a clinical trial involving 342 affected patients aged 20-70 years, participants were randomly assigned to receive CBT (113 patients), mindfulness-based stress reduction (MBSR, 116 patients), or usual care (113 patients) and followed up at 26 weeks. The two psychological interventions were delivered in 2-hour group sessions every week for 8 weeks. As previously reported, both CBT and MBSR reduced functional limitations and decreased the “bothersomeness” of the pain, as measured by scores on the modified Roland Disability Questionnaire, compared with usual care, said Daniel C. Cherkin, PhD of the Group Health Research Institute, Seattle, and his associates.

©Rocky89/Thinkstock

Researchers have developed a
portable technology, Seq-Well, that
can prepare the RNA of many cells
for simultaneous sequencing.
Photo courtesy of Alex K. Shalek
and his colleagues

Researchers say they have developed a portable, low-cost platform for high-throughput, single-cell RNA sequencing.

The

team believes the technology, known as Seq-Well, could allow

scientists to more easily identify different cell types in blood and tissue

samples, helping them study how cancer cells respond to treatment, among other applications.

“Rather than trying to pick one marker that defines a cell type, using single-cell RNA sequencing, we can go in and look at everything a cell is expressing at a given moment,” said Alex K. Shalek, PhD, of the Massachusetts Institute of Technology in Cambridge.

“By finding common patterns across cells, we can figure out who those cells are.”

Dr Shalek and his colleagues have spent the past several years developing single-cell RNA sequencing strategies.

Now, they’ve created a new version of the technology that, they say, can rapidly analyze large numbers of cells using simple equipment.

“We’ve combined [Dr Shalek’s] technologies with some of ours in a way that makes it really accessible for researchers who want to do this type of sequencing on a range of different clinical samples and settings,” said J. Christopher Love, PhD, also of the Massachusetts Institute of Technology.

“It overcomes some of the barriers that are facing the adoption of these techniques more broadly.”

Drs Love and Shalek are the senior authors of a paper describing Seq-Well in Nature Methods.

Improving analysis

Key to sequencing RNA from large populations of cells is keeping track of which RNA transcripts came from which cell. The earliest techniques for this required sorting the cells into individual tubes or compartments of multiwell plates and then separately transforming each into a sequencing library.

That process works well but can’t handle large samples containing thousands of cells, such as blood samples or tissue biopsies, and costs between $25 and $35 per cell.

Dr Shalek and others have recently developed microfluidic techniques to help automate and parallelize the process considerably, but the amount of equipment required makes it impossible to be easily transported.

Drs Shalek and Love realized that technology Dr Love had previously developed to analyze protein secretions from single cells could be adapted to do single-cell RNA sequencing rapidly and inexpensively using a portable device.

Over the past several years, Dr Love’s lab has developed a microscale system that can isolate individual cells and measure the antibodies and other proteins that each cell secretes. The device resembles a tiny ice cube tray, with individual compartments for each cell.

Dr Love also developed a process known as microengraving that uses these trays, which can hold tens of thousands of cells, to measure each cell’s protein secretions.

To use this approach for sequencing RNA, the researchers created arrays of nanowells that each capture a single cell plus a barcoded bead to capture the RNA fragments.

The nanowells are sealed with a semipermeable membrane that allows the passage of chemicals needed to break the cells apart, while the RNA stays contained.

After the RNA binds to the beads, it is removed and sequenced. Using this process, the cost per cell is less than $1.

Uncovering unknowns

Similar to previous single-cell RNA sequencing techniques, the Seq-Well process captures and analyzes about 10% to 15% of the total number of RNA transcripts per cell.

“That is still a very rich set of information that maps to several thousand genes,” Dr Love said. “If you look at sets of these genes, you can start to understand the identity of those cells based on the sets of genes that are expressed in common.”

The researchers used Seq-Well to analyze macrophages infected with tuberculosis, allowing them to identify different pre-existing populations and responses to infection.

Dr Shalek and members of his lab also brought the technology to South Africa and analyzed tissue samples from tuberculosis- and HIV-infected patients there.

“Having a simple system that can go everywhere, I think, is going to be incredibly empowering,” Dr Shalek said.

Dr Love’s lab is now using this approach to analyze immune cells from people with food allergies, which could help researchers determine why some people are more likely to respond well to therapies designed to treat their allergies.

“There are still a lot of unknowns in chronic diseases, and these types of tools help you uncover new insights,” Dr Love said.

The research team has also joined forces with clinical investigators at Dana-Farber/Harvard Cancer Center to apply this technology toward the discovery of new combination immunotherapies for cancers.

Researchers have developed a
portable technology, Seq-Well, that
can prepare the RNA of many cells
for simultaneous sequencing.
Photo courtesy of Alex K. Shalek
and his colleagues

Researchers say they have developed a portable, low-cost platform for high-throughput, single-cell RNA sequencing.

The

team believes the technology, known as Seq-Well, could allow

scientists to more easily identify different cell types in blood and tissue

samples, helping them study how cancer cells respond to treatment, among other applications.

“Rather than trying to pick one marker that defines a cell type, using single-cell RNA sequencing, we can go in and look at everything a cell is expressing at a given moment,” said Alex K. Shalek, PhD, of the Massachusetts Institute of Technology in Cambridge.

“By finding common patterns across cells, we can figure out who those cells are.”

Dr Shalek and his colleagues have spent the past several years developing single-cell RNA sequencing strategies.

Now, they’ve created a new version of the technology that, they say, can rapidly analyze large numbers of cells using simple equipment.

“We’ve combined [Dr Shalek’s] technologies with some of ours in a way that makes it really accessible for researchers who want to do this type of sequencing on a range of different clinical samples and settings,” said J. Christopher Love, PhD, also of the Massachusetts Institute of Technology.

“It overcomes some of the barriers that are facing the adoption of these techniques more broadly.”

Drs Love and Shalek are the senior authors of a paper describing Seq-Well in Nature Methods.

Improving analysis

Key to sequencing RNA from large populations of cells is keeping track of which RNA transcripts came from which cell. The earliest techniques for this required sorting the cells into individual tubes or compartments of multiwell plates and then separately transforming each into a sequencing library.

That process works well but can’t handle large samples containing thousands of cells, such as blood samples or tissue biopsies, and costs between $25 and $35 per cell.

Dr Shalek and others have recently developed microfluidic techniques to help automate and parallelize the process considerably, but the amount of equipment required makes it impossible to be easily transported.

Drs Shalek and Love realized that technology Dr Love had previously developed to analyze protein secretions from single cells could be adapted to do single-cell RNA sequencing rapidly and inexpensively using a portable device.

Over the past several years, Dr Love’s lab has developed a microscale system that can isolate individual cells and measure the antibodies and other proteins that each cell secretes. The device resembles a tiny ice cube tray, with individual compartments for each cell.

Dr Love also developed a process known as microengraving that uses these trays, which can hold tens of thousands of cells, to measure each cell’s protein secretions.

To use this approach for sequencing RNA, the researchers created arrays of nanowells that each capture a single cell plus a barcoded bead to capture the RNA fragments.

The nanowells are sealed with a semipermeable membrane that allows the passage of chemicals needed to break the cells apart, while the RNA stays contained.

After the RNA binds to the beads, it is removed and sequenced. Using this process, the cost per cell is less than $1.

Uncovering unknowns

Similar to previous single-cell RNA sequencing techniques, the Seq-Well process captures and analyzes about 10% to 15% of the total number of RNA transcripts per cell.

“That is still a very rich set of information that maps to several thousand genes,” Dr Love said. “If you look at sets of these genes, you can start to understand the identity of those cells based on the sets of genes that are expressed in common.”

The researchers used Seq-Well to analyze macrophages infected with tuberculosis, allowing them to identify different pre-existing populations and responses to infection.

Dr Shalek and members of his lab also brought the technology to South Africa and analyzed tissue samples from tuberculosis- and HIV-infected patients there.

“Having a simple system that can go everywhere, I think, is going to be incredibly empowering,” Dr Shalek said.

Dr Love’s lab is now using this approach to analyze immune cells from people with food allergies, which could help researchers determine why some people are more likely to respond well to therapies designed to treat their allergies.

“There are still a lot of unknowns in chronic diseases, and these types of tools help you uncover new insights,” Dr Love said.

The research team has also joined forces with clinical investigators at Dana-Farber/Harvard Cancer Center to apply this technology toward the discovery of new combination immunotherapies for cancers.

Researchers have developed a
portable technology, Seq-Well, that
can prepare the RNA of many cells
for simultaneous sequencing.
Photo courtesy of Alex K. Shalek
and his colleagues

Researchers say they have developed a portable, low-cost platform for high-throughput, single-cell RNA sequencing.

The

team believes the technology, known as Seq-Well, could allow

scientists to more easily identify different cell types in blood and tissue

samples, helping them study how cancer cells respond to treatment, among other applications.

“Rather than trying to pick one marker that defines a cell type, using single-cell RNA sequencing, we can go in and look at everything a cell is expressing at a given moment,” said Alex K. Shalek, PhD, of the Massachusetts Institute of Technology in Cambridge.

“By finding common patterns across cells, we can figure out who those cells are.”

Dr Shalek and his colleagues have spent the past several years developing single-cell RNA sequencing strategies.

Now, they’ve created a new version of the technology that, they say, can rapidly analyze large numbers of cells using simple equipment.

“We’ve combined [Dr Shalek’s] technologies with some of ours in a way that makes it really accessible for researchers who want to do this type of sequencing on a range of different clinical samples and settings,” said J. Christopher Love, PhD, also of the Massachusetts Institute of Technology.

“It overcomes some of the barriers that are facing the adoption of these techniques more broadly.”

Drs Love and Shalek are the senior authors of a paper describing Seq-Well in Nature Methods.

Improving analysis

Key to sequencing RNA from large populations of cells is keeping track of which RNA transcripts came from which cell. The earliest techniques for this required sorting the cells into individual tubes or compartments of multiwell plates and then separately transforming each into a sequencing library.

That process works well but can’t handle large samples containing thousands of cells, such as blood samples or tissue biopsies, and costs between $25 and $35 per cell.

Dr Shalek and others have recently developed microfluidic techniques to help automate and parallelize the process considerably, but the amount of equipment required makes it impossible to be easily transported.

Drs Shalek and Love realized that technology Dr Love had previously developed to analyze protein secretions from single cells could be adapted to do single-cell RNA sequencing rapidly and inexpensively using a portable device.

Over the past several years, Dr Love’s lab has developed a microscale system that can isolate individual cells and measure the antibodies and other proteins that each cell secretes. The device resembles a tiny ice cube tray, with individual compartments for each cell.

Dr Love also developed a process known as microengraving that uses these trays, which can hold tens of thousands of cells, to measure each cell’s protein secretions.

To use this approach for sequencing RNA, the researchers created arrays of nanowells that each capture a single cell plus a barcoded bead to capture the RNA fragments.

The nanowells are sealed with a semipermeable membrane that allows the passage of chemicals needed to break the cells apart, while the RNA stays contained.

After the RNA binds to the beads, it is removed and sequenced. Using this process, the cost per cell is less than $1.

Uncovering unknowns

Similar to previous single-cell RNA sequencing techniques, the Seq-Well process captures and analyzes about 10% to 15% of the total number of RNA transcripts per cell.

“That is still a very rich set of information that maps to several thousand genes,” Dr Love said. “If you look at sets of these genes, you can start to understand the identity of those cells based on the sets of genes that are expressed in common.”

The researchers used Seq-Well to analyze macrophages infected with tuberculosis, allowing them to identify different pre-existing populations and responses to infection.

Dr Shalek and members of his lab also brought the technology to South Africa and analyzed tissue samples from tuberculosis- and HIV-infected patients there.

“Having a simple system that can go everywhere, I think, is going to be incredibly empowering,” Dr Shalek said.

Dr Love’s lab is now using this approach to analyze immune cells from people with food allergies, which could help researchers determine why some people are more likely to respond well to therapies designed to treat their allergies.

“There are still a lot of unknowns in chronic diseases, and these types of tools help you uncover new insights,” Dr Love said.

The research team has also joined forces with clinical investigators at Dana-Farber/Harvard Cancer Center to apply this technology toward the discovery of new combination immunotherapies for cancers.

EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of

Benjamin Chaigne-Delalande

New research published in Nature Communications appears to explain how Epstein-Barr virus (EBV) reprograms cells into cancer cells.

Investigators said they discovered a mechanism by which EBV particles induce chromosomal instability without establishing a chronic infection, thereby conferring a risk for the development of tumors that do not necessarily carry the viral genome.

“The contribution of the viral infection to cancer development in patients with a weakened immune system is well understood,” said study author Henri-Jacques Delecluse, MD, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

“But in the majority of cases, it remains unclear how an EBV infection leads to cancer development.”

With their research, Dr Delecluse and his colleagues found that BNRF1, a protein component of EBV, promotes the development of cancer. They said BNRF1 induces centrosome amplification, which is associated with chromosomal instability.

When a dividing cell comes in contact with EBV, BNRF1 frequently prompts the formation of an excessive number of centrosomes. As a result, chromosomes are no longer divided equally and accurately between daughter cells—a known cancer risk factor.

In contrast, when the investigators studied EBV deficient of BNRF1, they found the virus did not interfere with chromosome distribution to daughter cells.

The team noted that EBV normally remains silent in a few infected cells, but, occasionally, it reactivates to produce viral offspring that infects nearby cells. As a consequence, these cells come in close contact with BNRF1, thus increasing their risk of transforming into cancer cells.

“The novelty of our work is that we have uncovered a component of the viral particle as a cancer driver,” Dr Delecluse said. “All human-tumors viruses that have been studied so far cause cancer in a completely different manner.”

“Usually, the genetic material of the viruses needs to be permanently present in the infected cell, thus causing the activation of one or several viral genes that cause cancer development. However, these gene products are not present in the infectious particle itself.”

Dr Delecluse and his colleagues therefore suspect that EBV could cause cancers other than those that have already been linked to EBV. Certain cancers might not have been linked to the virus because they do not carry the viral genetic material.

“We must push forward with the development of a vaccine against EBV infection,” Dr Delecluse said. “This would be the most direct strategy to prevent an infection with the virus.”

“Our latest results show that the first infection could already be a cancer risk, and this fits with earlier work that showed an increase in the incidence of Hodgkin’s lymphoma in people who underwent an episode of infectious mononucleosis.”

EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of

Benjamin Chaigne-Delalande

New research published in Nature Communications appears to explain how Epstein-Barr virus (EBV) reprograms cells into cancer cells.

Investigators said they discovered a mechanism by which EBV particles induce chromosomal instability without establishing a chronic infection, thereby conferring a risk for the development of tumors that do not necessarily carry the viral genome.

“The contribution of the viral infection to cancer development in patients with a weakened immune system is well understood,” said study author Henri-Jacques Delecluse, MD, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

“But in the majority of cases, it remains unclear how an EBV infection leads to cancer development.”

With their research, Dr Delecluse and his colleagues found that BNRF1, a protein component of EBV, promotes the development of cancer. They said BNRF1 induces centrosome amplification, which is associated with chromosomal instability.

When a dividing cell comes in contact with EBV, BNRF1 frequently prompts the formation of an excessive number of centrosomes. As a result, chromosomes are no longer divided equally and accurately between daughter cells—a known cancer risk factor.

In contrast, when the investigators studied EBV deficient of BNRF1, they found the virus did not interfere with chromosome distribution to daughter cells.

The team noted that EBV normally remains silent in a few infected cells, but, occasionally, it reactivates to produce viral offspring that infects nearby cells. As a consequence, these cells come in close contact with BNRF1, thus increasing their risk of transforming into cancer cells.

“The novelty of our work is that we have uncovered a component of the viral particle as a cancer driver,” Dr Delecluse said. “All human-tumors viruses that have been studied so far cause cancer in a completely different manner.”

“Usually, the genetic material of the viruses needs to be permanently present in the infected cell, thus causing the activation of one or several viral genes that cause cancer development. However, these gene products are not present in the infectious particle itself.”

Dr Delecluse and his colleagues therefore suspect that EBV could cause cancers other than those that have already been linked to EBV. Certain cancers might not have been linked to the virus because they do not carry the viral genetic material.

“We must push forward with the development of a vaccine against EBV infection,” Dr Delecluse said. “This would be the most direct strategy to prevent an infection with the virus.”

“Our latest results show that the first infection could already be a cancer risk, and this fits with earlier work that showed an increase in the incidence of Hodgkin’s lymphoma in people who underwent an episode of infectious mononucleosis.”

EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of

Benjamin Chaigne-Delalande

New research published in Nature Communications appears to explain how Epstein-Barr virus (EBV) reprograms cells into cancer cells.

Investigators said they discovered a mechanism by which EBV particles induce chromosomal instability without establishing a chronic infection, thereby conferring a risk for the development of tumors that do not necessarily carry the viral genome.

“The contribution of the viral infection to cancer development in patients with a weakened immune system is well understood,” said study author Henri-Jacques Delecluse, MD, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

“But in the majority of cases, it remains unclear how an EBV infection leads to cancer development.”

With their research, Dr Delecluse and his colleagues found that BNRF1, a protein component of EBV, promotes the development of cancer. They said BNRF1 induces centrosome amplification, which is associated with chromosomal instability.

When a dividing cell comes in contact with EBV, BNRF1 frequently prompts the formation of an excessive number of centrosomes. As a result, chromosomes are no longer divided equally and accurately between daughter cells—a known cancer risk factor.

In contrast, when the investigators studied EBV deficient of BNRF1, they found the virus did not interfere with chromosome distribution to daughter cells.

The team noted that EBV normally remains silent in a few infected cells, but, occasionally, it reactivates to produce viral offspring that infects nearby cells. As a consequence, these cells come in close contact with BNRF1, thus increasing their risk of transforming into cancer cells.

“The novelty of our work is that we have uncovered a component of the viral particle as a cancer driver,” Dr Delecluse said. “All human-tumors viruses that have been studied so far cause cancer in a completely different manner.”

“Usually, the genetic material of the viruses needs to be permanently present in the infected cell, thus causing the activation of one or several viral genes that cause cancer development. However, these gene products are not present in the infectious particle itself.”

Dr Delecluse and his colleagues therefore suspect that EBV could cause cancers other than those that have already been linked to EBV. Certain cancers might not have been linked to the virus because they do not carry the viral genetic material.

“We must push forward with the development of a vaccine against EBV infection,” Dr Delecluse said. “This would be the most direct strategy to prevent an infection with the virus.”

“Our latest results show that the first infection could already be a cancer risk, and this fits with earlier work that showed an increase in the incidence of Hodgkin’s lymphoma in people who underwent an episode of infectious mononucleosis.”

Lab mouse

Granulocyte colony-stimulating factor (G-CSF) could prevent infertility in male cancer patients, according to preclinical research published in Reproductive Biology and Endocrinology.

Researchers said they found that G-CSF protects spermatogenesis after alkylating chemotherapy by stimulating the proliferation of surviving spermatogonia.

The team also found evidence to suggest that G-CSF may be useful as a fertility-restoring treatment.

The researchers have been pursuing initiatives to restore fertility in men who have lost their ability to have children as a result of cancer treatments they received as children.

While working on methods to restart sperm production, the team discovered a link between G-CSF and the absence of normal damage to reproductive ability.

“We were using G-CSF to prevent infections in our research experiments,” said study author Brian Hermann, PhD, of The University of Texas at San Antonio.

“It turned out that the drug also had the unexpected impact of guarding against male infertility.”

To test the fertility-related impact of G-CSF, the researchers treated male mice with G-CSF before and/or after treatment with busulfan.

The team then evaluated effects on spermatogenesis in these mice and control mice that only received busulfan.

G-CSF had a protective effect on spermatogenesis that was stable for at least 19 weeks after chemotherapy.

And mice treated with G-CSF for 4 days after busulfan showed modestly enhanced spermatogenic recovery compared to controls.

The researchers said these results suggest G-CSF promotes spermatogonial proliferation, leading to enhanced spermatogenic regeneration from surviving spermatogonial stem cells.

Lab mouse

Granulocyte colony-stimulating factor (G-CSF) could prevent infertility in male cancer patients, according to preclinical research published in Reproductive Biology and Endocrinology.

Researchers said they found that G-CSF protects spermatogenesis after alkylating chemotherapy by stimulating the proliferation of surviving spermatogonia.

The team also found evidence to suggest that G-CSF may be useful as a fertility-restoring treatment.

The researchers have been pursuing initiatives to restore fertility in men who have lost their ability to have children as a result of cancer treatments they received as children.

While working on methods to restart sperm production, the team discovered a link between G-CSF and the absence of normal damage to reproductive ability.

“We were using G-CSF to prevent infections in our research experiments,” said study author Brian Hermann, PhD, of The University of Texas at San Antonio.

“It turned out that the drug also had the unexpected impact of guarding against male infertility.”

To test the fertility-related impact of G-CSF, the researchers treated male mice with G-CSF before and/or after treatment with busulfan.

The team then evaluated effects on spermatogenesis in these mice and control mice that only received busulfan.

G-CSF had a protective effect on spermatogenesis that was stable for at least 19 weeks after chemotherapy.

And mice treated with G-CSF for 4 days after busulfan showed modestly enhanced spermatogenic recovery compared to controls.

The researchers said these results suggest G-CSF promotes spermatogonial proliferation, leading to enhanced spermatogenic regeneration from surviving spermatogonial stem cells.

Lab mouse

Granulocyte colony-stimulating factor (G-CSF) could prevent infertility in male cancer patients, according to preclinical research published in Reproductive Biology and Endocrinology.

Researchers said they found that G-CSF protects spermatogenesis after alkylating chemotherapy by stimulating the proliferation of surviving spermatogonia.

The team also found evidence to suggest that G-CSF may be useful as a fertility-restoring treatment.

The researchers have been pursuing initiatives to restore fertility in men who have lost their ability to have children as a result of cancer treatments they received as children.

While working on methods to restart sperm production, the team discovered a link between G-CSF and the absence of normal damage to reproductive ability.

“We were using G-CSF to prevent infections in our research experiments,” said study author Brian Hermann, PhD, of The University of Texas at San Antonio.

“It turned out that the drug also had the unexpected impact of guarding against male infertility.”

To test the fertility-related impact of G-CSF, the researchers treated male mice with G-CSF before and/or after treatment with busulfan.

The team then evaluated effects on spermatogenesis in these mice and control mice that only received busulfan.

G-CSF had a protective effect on spermatogenesis that was stable for at least 19 weeks after chemotherapy.

And mice treated with G-CSF for 4 days after busulfan showed modestly enhanced spermatogenic recovery compared to controls.

The researchers said these results suggest G-CSF promotes spermatogonial proliferation, leading to enhanced spermatogenic regeneration from surviving spermatogonial stem cells.

Irish setter, a breed of dog

that can develop hemophilia B

A plant-made therapy has demonstrated safety and efficacy in dogs with hemophilia B, according to research published in Molecular Therapy.

Previously, researchers found they could produce freeze-dried lettuce cells expressing human coagulation factor IX (FIX) fused with cholera toxin B subunit (CTB).

These cells were able to prevent inhibitor formation and allergic reactions to intravenous FIX therapy in mice with hemophilia B.

With the current study, the researchers showed that lettuce cells expressing CTB-FIX were safe and could prevent anaphylaxis and inhibitor formation in dogs receiving intravenous FIX to treat hemophilia B.

“The results were quite dramatic,” said study author Henry Daniell, PhD, of the University of Pennsylvania in Philadelphia.

“We corrected blood clotting time in each of the dogs and were able to suppress antibody formation as well. All signs point to this material being ready for the clinic.”

This study made use of Dr Daniell’s patented plant-based drug-production platform, in which genetic modifications enable the growth of plants that have specified human proteins in their leaves.

The researchers grew lettuce that had been modified to produce a fusion protein of human FIX and CTB. CTB helps the fused protein cross the intestinal lining as the lettuce cells are digested by gut microbes, while the plant cell walls protect FIX from digestion.

The researchers said they were able to achieve commercial-scale production of CTB-FIX fusions expressed in lettuce chloroplasts by growing the plants in a hydroponic facility.

The team first tested their product in 2 dogs with hemophilia B. Twice a week for 10 months, the dogs consumed the freeze-dried lettuce material, which was spiked with bacon flavor and sprinkled on their food.

Observing no negative effects of the treatment, the researchers went on to a more robust study, including 4 dogs that were fed the lettuce material and 4 that served as controls.

The 4 dogs in the experimental group were fed the lettuce material for 4 weeks. At that point, they also began receiving weekly injections of FIX, which continued for 8 weeks. The control dogs only received the FIX injections.

All 4 dogs in the control group developed significant levels of antibodies against FIX, and 2 had visible anaphylactic reactions that required the administration of antihistamine.

In contrast, 3 of the 4 dogs in the experimental group had only minimal levels of one type of antibody, IgG2, and no detectable levels of IgG1 or IgE.

The fourth dog in the experimental group had only a partial response to the lettuce cells expressing CTB-FIX. The researchers believe this was due to a pre-existing antibody to human FIX.

Overall, levels of IgG2 were 32 times lower in the experimental group than in the controls.

In addition, the dogs showed no negative side effects from ingesting the lettuce material, and blood samples taken throughout the experiment revealed no signs of toxicity.

“Looking at the dogs that were fed the lettuce material, you can see it’s quite effective,” Dr Daniell said. “They either developed no antibodies to factor IX, or their antibodies went up just a little bit and then came down.”

The next steps for the researchers include additional toxicology and pharmacokinetics studies before applying for an investigational new drug application with the US Food and Drug Administration, a step they hope to take before the end of the year.

Irish setter, a breed of dog

that can develop hemophilia B

A plant-made therapy has demonstrated safety and efficacy in dogs with hemophilia B, according to research published in Molecular Therapy.

Previously, researchers found they could produce freeze-dried lettuce cells expressing human coagulation factor IX (FIX) fused with cholera toxin B subunit (CTB).

These cells were able to prevent inhibitor formation and allergic reactions to intravenous FIX therapy in mice with hemophilia B.

With the current study, the researchers showed that lettuce cells expressing CTB-FIX were safe and could prevent anaphylaxis and inhibitor formation in dogs receiving intravenous FIX to treat hemophilia B.

“The results were quite dramatic,” said study author Henry Daniell, PhD, of the University of Pennsylvania in Philadelphia.

“We corrected blood clotting time in each of the dogs and were able to suppress antibody formation as well. All signs point to this material being ready for the clinic.”

This study made use of Dr Daniell’s patented plant-based drug-production platform, in which genetic modifications enable the growth of plants that have specified human proteins in their leaves.

The researchers grew lettuce that had been modified to produce a fusion protein of human FIX and CTB. CTB helps the fused protein cross the intestinal lining as the lettuce cells are digested by gut microbes, while the plant cell walls protect FIX from digestion.

The researchers said they were able to achieve commercial-scale production of CTB-FIX fusions expressed in lettuce chloroplasts by growing the plants in a hydroponic facility.

The team first tested their product in 2 dogs with hemophilia B. Twice a week for 10 months, the dogs consumed the freeze-dried lettuce material, which was spiked with bacon flavor and sprinkled on their food.

Observing no negative effects of the treatment, the researchers went on to a more robust study, including 4 dogs that were fed the lettuce material and 4 that served as controls.

The 4 dogs in the experimental group were fed the lettuce material for 4 weeks. At that point, they also began receiving weekly injections of FIX, which continued for 8 weeks. The control dogs only received the FIX injections.

All 4 dogs in the control group developed significant levels of antibodies against FIX, and 2 had visible anaphylactic reactions that required the administration of antihistamine.

In contrast, 3 of the 4 dogs in the experimental group had only minimal levels of one type of antibody, IgG2, and no detectable levels of IgG1 or IgE.

The fourth dog in the experimental group had only a partial response to the lettuce cells expressing CTB-FIX. The researchers believe this was due to a pre-existing antibody to human FIX.

Overall, levels of IgG2 were 32 times lower in the experimental group than in the controls.

In addition, the dogs showed no negative side effects from ingesting the lettuce material, and blood samples taken throughout the experiment revealed no signs of toxicity.

“Looking at the dogs that were fed the lettuce material, you can see it’s quite effective,” Dr Daniell said. “They either developed no antibodies to factor IX, or their antibodies went up just a little bit and then came down.”

The next steps for the researchers include additional toxicology and pharmacokinetics studies before applying for an investigational new drug application with the US Food and Drug Administration, a step they hope to take before the end of the year.

Irish setter, a breed of dog

that can develop hemophilia B

A plant-made therapy has demonstrated safety and efficacy in dogs with hemophilia B, according to research published in Molecular Therapy.

Previously, researchers found they could produce freeze-dried lettuce cells expressing human coagulation factor IX (FIX) fused with cholera toxin B subunit (CTB).

These cells were able to prevent inhibitor formation and allergic reactions to intravenous FIX therapy in mice with hemophilia B.

With the current study, the researchers showed that lettuce cells expressing CTB-FIX were safe and could prevent anaphylaxis and inhibitor formation in dogs receiving intravenous FIX to treat hemophilia B.

“The results were quite dramatic,” said study author Henry Daniell, PhD, of the University of Pennsylvania in Philadelphia.

“We corrected blood clotting time in each of the dogs and were able to suppress antibody formation as well. All signs point to this material being ready for the clinic.”

This study made use of Dr Daniell’s patented plant-based drug-production platform, in which genetic modifications enable the growth of plants that have specified human proteins in their leaves.

The researchers grew lettuce that had been modified to produce a fusion protein of human FIX and CTB. CTB helps the fused protein cross the intestinal lining as the lettuce cells are digested by gut microbes, while the plant cell walls protect FIX from digestion.

The researchers said they were able to achieve commercial-scale production of CTB-FIX fusions expressed in lettuce chloroplasts by growing the plants in a hydroponic facility.

The team first tested their product in 2 dogs with hemophilia B. Twice a week for 10 months, the dogs consumed the freeze-dried lettuce material, which was spiked with bacon flavor and sprinkled on their food.

Observing no negative effects of the treatment, the researchers went on to a more robust study, including 4 dogs that were fed the lettuce material and 4 that served as controls.

The 4 dogs in the experimental group were fed the lettuce material for 4 weeks. At that point, they also began receiving weekly injections of FIX, which continued for 8 weeks. The control dogs only received the FIX injections.

All 4 dogs in the control group developed significant levels of antibodies against FIX, and 2 had visible anaphylactic reactions that required the administration of antihistamine.

In contrast, 3 of the 4 dogs in the experimental group had only minimal levels of one type of antibody, IgG2, and no detectable levels of IgG1 or IgE.

The fourth dog in the experimental group had only a partial response to the lettuce cells expressing CTB-FIX. The researchers believe this was due to a pre-existing antibody to human FIX.

Overall, levels of IgG2 were 32 times lower in the experimental group than in the controls.

In addition, the dogs showed no negative side effects from ingesting the lettuce material, and blood samples taken throughout the experiment revealed no signs of toxicity.

“Looking at the dogs that were fed the lettuce material, you can see it’s quite effective,” Dr Daniell said. “They either developed no antibodies to factor IX, or their antibodies went up just a little bit and then came down.”

The next steps for the researchers include additional toxicology and pharmacokinetics studies before applying for an investigational new drug application with the US Food and Drug Administration, a step they hope to take before the end of the year.

Normally, negotiations to use drugs in preclinical studies and clinical trials can take as long as 18 months. But the National Cancer Institute’s (NCI) new drug formulary will allow investigators at NCI-designated cancer centers quicker access to approved and investigational agents, helping make more effective treatments available sooner.

The NCI Formulary, a public-private partnership between NCI and pharmaceutical and biotechnology companies, is one of NCI’s efforts in support of the Cancer Moonshot (ex-Vice President Biden’s call for greater collaboration and faster development of new therapies). The formulary enables NCI to act as an intermediary between investigators at cancer centers and participating pharmaceutical companies, streamlining arrangements for access to and use of drugs.

The formulary launched with 15 targeted agents from 6 pharmaceutical companies: Bristol-Myers Squibb, Eli Lilly and Company, Genentech, Kyowa Hakko Kirin, Loxo Oncology, and Xcovery Holding Company LLC.

Normally, negotiations to use drugs in preclinical studies and clinical trials can take as long as 18 months. But the National Cancer Institute’s (NCI) new drug formulary will allow investigators at NCI-designated cancer centers quicker access to approved and investigational agents, helping make more effective treatments available sooner.

The NCI Formulary, a public-private partnership between NCI and pharmaceutical and biotechnology companies, is one of NCI’s efforts in support of the Cancer Moonshot (ex-Vice President Biden’s call for greater collaboration and faster development of new therapies). The formulary enables NCI to act as an intermediary between investigators at cancer centers and participating pharmaceutical companies, streamlining arrangements for access to and use of drugs.

The formulary launched with 15 targeted agents from 6 pharmaceutical companies: Bristol-Myers Squibb, Eli Lilly and Company, Genentech, Kyowa Hakko Kirin, Loxo Oncology, and Xcovery Holding Company LLC.

Normally, negotiations to use drugs in preclinical studies and clinical trials can take as long as 18 months. But the National Cancer Institute’s (NCI) new drug formulary will allow investigators at NCI-designated cancer centers quicker access to approved and investigational agents, helping make more effective treatments available sooner.

The NCI Formulary, a public-private partnership between NCI and pharmaceutical and biotechnology companies, is one of NCI’s efforts in support of the Cancer Moonshot (ex-Vice President Biden’s call for greater collaboration and faster development of new therapies). The formulary enables NCI to act as an intermediary between investigators at cancer centers and participating pharmaceutical companies, streamlining arrangements for access to and use of drugs.

The formulary launched with 15 targeted agents from 6 pharmaceutical companies: Bristol-Myers Squibb, Eli Lilly and Company, Genentech, Kyowa Hakko Kirin, Loxo Oncology, and Xcovery Holding Company LLC.

Ginsenosides are pharmacologically active components of ginseng, which often is used to relieve coughs and colds. They also have been found to have antineoplastic, antioxidant, antimicrobial, and antifungal properties; other studies suggest neuroprotective properties as well. Ginsenosides may act against coxsackievirus B3, enterovirus 71, human rhinovirus 3, and hemagglutinating virus of Japan (HVJ) infection. But do they have an antiviral effect on influenza?

Related: A New Kind of Flu Drug

Researchers from University Health Network & Shantou University Medical College and Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, both in China, and University of Toronto in Canada conducted a study in mice of the anti-influenza properties of ginseng and ginseng-derived compounds both in vitro and in vivo. They found that ginsenosides exerted “strong antiviral activity” to 2009 pandemic H1N1 virus. Ginsenoside protected the animals from infection and lowered viral titers in their lungs.

Sugars were the key to the effectiveness of the ginsenosides, which are composed of a steroid skeleton with various sugar groups attached. The researchers note that previous studies have shown that ginsenosides’ anticancer activity and antioxidant activity are related to the type and position of sugar moieties.

Related: How Common is Flu Without Fever?

The pilot experiment did not have negative or toxic effects on the animals or in cell proliferation in vitro, thus “defining the nontoxic nature and therapeutic value of these compounds,” the researchers say. They also point out that in phase 2 randomized clinical trials in children, oral consumption of ginseng extract as an alternative influenza treatment did not result in severe adverse effects. They suggest that their findings could spur other research into a novel antiviral drug for influenza.

Source:

Dong W, Farooqui A, Leon AJ, Kelvin DJ. PloS One. 2017;12(2):e0171936.
doi: 10.1371/journal.pone.0171936.

Ginsenosides are pharmacologically active components of ginseng, which often is used to relieve coughs and colds. They also have been found to have antineoplastic, antioxidant, antimicrobial, and antifungal properties; other studies suggest neuroprotective properties as well. Ginsenosides may act against coxsackievirus B3, enterovirus 71, human rhinovirus 3, and hemagglutinating virus of Japan (HVJ) infection. But do they have an antiviral effect on influenza?

Related: A New Kind of Flu Drug

Researchers from University Health Network & Shantou University Medical College and Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, both in China, and University of Toronto in Canada conducted a study in mice of the anti-influenza properties of ginseng and ginseng-derived compounds both in vitro and in vivo. They found that ginsenosides exerted “strong antiviral activity” to 2009 pandemic H1N1 virus. Ginsenoside protected the animals from infection and lowered viral titers in their lungs.

Sugars were the key to the effectiveness of the ginsenosides, which are composed of a steroid skeleton with various sugar groups attached. The researchers note that previous studies have shown that ginsenosides’ anticancer activity and antioxidant activity are related to the type and position of sugar moieties.

Related: How Common is Flu Without Fever?

The pilot experiment did not have negative or toxic effects on the animals or in cell proliferation in vitro, thus “defining the nontoxic nature and therapeutic value of these compounds,” the researchers say. They also point out that in phase 2 randomized clinical trials in children, oral consumption of ginseng extract as an alternative influenza treatment did not result in severe adverse effects. They suggest that their findings could spur other research into a novel antiviral drug for influenza.

Source:

Dong W, Farooqui A, Leon AJ, Kelvin DJ. PloS One. 2017;12(2):e0171936.
doi: 10.1371/journal.pone.0171936.

Ginsenosides are pharmacologically active components of ginseng, which often is used to relieve coughs and colds. They also have been found to have antineoplastic, antioxidant, antimicrobial, and antifungal properties; other studies suggest neuroprotective properties as well. Ginsenosides may act against coxsackievirus B3, enterovirus 71, human rhinovirus 3, and hemagglutinating virus of Japan (HVJ) infection. But do they have an antiviral effect on influenza?

Related: A New Kind of Flu Drug

Researchers from University Health Network & Shantou University Medical College and Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, both in China, and University of Toronto in Canada conducted a study in mice of the anti-influenza properties of ginseng and ginseng-derived compounds both in vitro and in vivo. They found that ginsenosides exerted “strong antiviral activity” to 2009 pandemic H1N1 virus. Ginsenoside protected the animals from infection and lowered viral titers in their lungs.

Sugars were the key to the effectiveness of the ginsenosides, which are composed of a steroid skeleton with various sugar groups attached. The researchers note that previous studies have shown that ginsenosides’ anticancer activity and antioxidant activity are related to the type and position of sugar moieties.

Related: How Common is Flu Without Fever?

The pilot experiment did not have negative or toxic effects on the animals or in cell proliferation in vitro, thus “defining the nontoxic nature and therapeutic value of these compounds,” the researchers say. They also point out that in phase 2 randomized clinical trials in children, oral consumption of ginseng extract as an alternative influenza treatment did not result in severe adverse effects. They suggest that their findings could spur other research into a novel antiviral drug for influenza.

Source:

Dong W, Farooqui A, Leon AJ, Kelvin DJ. PloS One. 2017;12(2):e0171936.
doi: 10.1371/journal.pone.0171936.

A 58-year-old woman with T2DM and heart failure returns to your office for follow-up. She has been on the maximum dose of metformin alone for the past six months, but her A1C is now 7.8%. She wants to avoid injections. What do you recommend?

There is surprisingly little consensus about what to add to metformin for patients with T2DM who require a second agent to achieve their glycemic goal. Attaining glycemic control earlier in the course of the disease may lead to reduced overall cardiovascular (CV) risk, so the choice of a second drug is an important one.² While the proven mortality benefit, wide availability, and low cost of metformin make it well-established as initial pharmacotherapy, no second-choice drug has amassed enough evidence of benefit to become the add-on therapy of choice.

The professional societies are of little assistance; dual-therapy recommendations from the American Diabetes Association and the European Association for the Study of Diabetes do not specify a preference.³ Although the American Association of Clinical Endocrinologists/American College of Endocrinology suggest a hierarchy of choices, it is based on expert consensus recommendations.⁴

A look at the options

Options for add-on therapy include sulfonylureas, thiazolidines, DPP-4 inhibitors, sodium glucose cotransporter 2 inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and insulin. Providers frequently prescribe sulfonylureas after metformin because they are low in cost, have long-term safety data, and are effective at lowering A1C. They work by directly stimulating insulin secretion via pancreatic ß-cells in a glucose-independent manner. But as a 2010 meta-analysis revealed, sulfonylureas carry significant risk for hypoglycemia (relative risk [RR], 4.57) and weight gain (average, 2.06 kg), compared to placebo.⁵

DPP-4 inhibitors, on the other hand, induce insulin secretion in a glucose-dependent manner through an incretin mechanism. Combined with metformin, they provide glucose control similar to that achieved with the combination of a sulfonylurea and metformin.⁶ DPP-4 inhibitors were initially found to be associated with fewer CV events and less hypoglycemia than sulfonylureas but were subsequently linked to an increased risk for heart failure–related hospitalization.⁷

A recent study provides more data on the effects of DPP-4s added to metformin.¹

STUDY SUMMARY

DPP-4s as effective, less risky

This observational cohort study compared DPP-4 inhibitors and sulfonylureas when combined with metformin for the treatment of T2DM.¹ Outcomes were all-cause mortality, major adverse CV events (defined as hospitalization for ischemic stroke or myocardial infarction [MI]), and hospitalizations for either heart failure or hypoglycemia. The study included data from the National Health Insurance Research Database in Taiwan on more than 70,000 patients (ages 20 and older) with diagnosed T2DM. Individuals adherent to metformin were considered to be enrolled in the cohort on the day they began using either a DPP-4 inhibitor or a sulfonylurea, in addition to metformin.

The researchers collected additional data on socioeconomic factors, urbanization, robustness of the local health care system, Charlson Comorbidity Index, adapted Diabetes Complications Severity Index, and other comorbidities and medications that could affect the outcomes of interest. Participants were then matched by propensity score into 10,089 pairs, each consisting of one DPP-4 inhibitor user and one sulfonylurea user.

After mean follow-up of 2.8 years, the investigators used Cox regression analysis to evaluate the relative hazards of the outcomes. Subgroup analysis stratified by age, sex, Charlson Comorbidity Index, hypertension, chronic kidney disease, hospitalization for heart failure, MI, and cerebrovascular disease yielded results similar to those of the primary analysis for each outcome. Similar results were also obtained when the data were analyzed without propensity-score matching.

The researchers found that users of DPP-4 inhibitors—compared with those who used sulfonylureas—had a lower risk for all-cause mortality (366 vs 488 deaths; hazard ratio [HR], 0.63; number needed to treat [NNT], 117), major cardiac events (209 vs 282 events; HR, 0.68; NNT, 191), ischemic stroke (144 vs 203 strokes; HR, 0.64; NNT, 246), and hypoglycemia (89 vs 170 events; HR, 0.43; NNT, 201). There were no significant differences in the occurrence of MIs (69 vs 88 MIs; HR, 0.75) or the number of hospitalizations for heart failure (100 vs 100 events; HR, 0.78) between the two groups.

WHAT’S NEW

Lower risks for death, CV events, and hypoglycemia

This study found that when added to metformin, DPP-4 inhibitors were associated with lower risks for all-cause mortality, CV events, and hypoglycemia when compared to sulfonylureas. Additionally, DPP-4 inhibitors did not increase the risk for heart failure hospitalization. A recent multicenter observational study of nearly 1.5 million patients on the effects of incretin-based treatments (including DPP-4 inhibitors and GLP-1 agonists) found no increased risk for heart failure hospitalization with DPP-4 inhibitors, compared to other combinations of oral T2DM agents.⁸

CAVEATS

Did unmeasured confounders play a role?

Unmeasured confounders potentially bias all observational population cohort results. In this particular study, there may have been unmeasured but significant patient factors that providers used to choose diabetes medications. Also, the study did not evaluate diabetes control, although previous studies have shown similar glucose control between sulfonylureas and DPP-4 inhibitors when added to metformin.⁶

Another caveat is that the results from this study group may not be generalizable to other populations due to physiologic differences. People of Asian ancestry are at risk for T2DM at a lower BMI than people of European ancestry, which could affect the outcomes of interest.⁹

Furthermore, the study did not evaluate outcomes based on whether patients were taking first-, second-, or third-generation sulfonylureas. Some sulfonylureas (eg, glyburide) carry a higher risk for hypoglycemia, which could bias the results.¹⁰

Lastly, the study only provides guidance when choosing between a sulfonylurea and a DPP-4 inhibitor for secondline pharmacotherapy. The GRADE trial, due to be completed in 2023, is comparing sulfonylureas, DPP-4 inhibitors, GLP-1 agonists, and insulin as add-on medications to metformin; it may provide more data on which to base treatment decisions.¹¹

CHALLENGES TO IMPLEMENTATION

DPP-4s are more expensive

Sulfonylureas and DPP-4 inhibitors are both available as generic medications, but the cost of DPP-4 inhibitors remains significantly higher.¹² Higher copays and deductibles could affect patient preference. For patients without health insurance, sulfonylureas are available on the discounted drug lists of many major retailers, while DPP-4 inhibitors are not.

ACKNOWLEDGEMENT

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.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2017;66(1):42-44.

A 58-year-old woman with T2DM and heart failure returns to your office for follow-up. She has been on the maximum dose of metformin alone for the past six months, but her A1C is now 7.8%. She wants to avoid injections. What do you recommend?

There is surprisingly little consensus about what to add to metformin for patients with T2DM who require a second agent to achieve their glycemic goal. Attaining glycemic control earlier in the course of the disease may lead to reduced overall cardiovascular (CV) risk, so the choice of a second drug is an important one.² While the proven mortality benefit, wide availability, and low cost of metformin make it well-established as initial pharmacotherapy, no second-choice drug has amassed enough evidence of benefit to become the add-on therapy of choice.

The professional societies are of little assistance; dual-therapy recommendations from the American Diabetes Association and the European Association for the Study of Diabetes do not specify a preference.³ Although the American Association of Clinical Endocrinologists/American College of Endocrinology suggest a hierarchy of choices, it is based on expert consensus recommendations.⁴

A look at the options

Options for add-on therapy include sulfonylureas, thiazolidines, DPP-4 inhibitors, sodium glucose cotransporter 2 inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and insulin. Providers frequently prescribe sulfonylureas after metformin because they are low in cost, have long-term safety data, and are effective at lowering A1C. They work by directly stimulating insulin secretion via pancreatic ß-cells in a glucose-independent manner. But as a 2010 meta-analysis revealed, sulfonylureas carry significant risk for hypoglycemia (relative risk [RR], 4.57) and weight gain (average, 2.06 kg), compared to placebo.⁵

DPP-4 inhibitors, on the other hand, induce insulin secretion in a glucose-dependent manner through an incretin mechanism. Combined with metformin, they provide glucose control similar to that achieved with the combination of a sulfonylurea and metformin.⁶ DPP-4 inhibitors were initially found to be associated with fewer CV events and less hypoglycemia than sulfonylureas but were subsequently linked to an increased risk for heart failure–related hospitalization.⁷

A recent study provides more data on the effects of DPP-4s added to metformin.¹

STUDY SUMMARY

DPP-4s as effective, less risky

This observational cohort study compared DPP-4 inhibitors and sulfonylureas when combined with metformin for the treatment of T2DM.¹ Outcomes were all-cause mortality, major adverse CV events (defined as hospitalization for ischemic stroke or myocardial infarction [MI]), and hospitalizations for either heart failure or hypoglycemia. The study included data from the National Health Insurance Research Database in Taiwan on more than 70,000 patients (ages 20 and older) with diagnosed T2DM. Individuals adherent to metformin were considered to be enrolled in the cohort on the day they began using either a DPP-4 inhibitor or a sulfonylurea, in addition to metformin.

The researchers collected additional data on socioeconomic factors, urbanization, robustness of the local health care system, Charlson Comorbidity Index, adapted Diabetes Complications Severity Index, and other comorbidities and medications that could affect the outcomes of interest. Participants were then matched by propensity score into 10,089 pairs, each consisting of one DPP-4 inhibitor user and one sulfonylurea user.

After mean follow-up of 2.8 years, the investigators used Cox regression analysis to evaluate the relative hazards of the outcomes. Subgroup analysis stratified by age, sex, Charlson Comorbidity Index, hypertension, chronic kidney disease, hospitalization for heart failure, MI, and cerebrovascular disease yielded results similar to those of the primary analysis for each outcome. Similar results were also obtained when the data were analyzed without propensity-score matching.

The researchers found that users of DPP-4 inhibitors—compared with those who used sulfonylureas—had a lower risk for all-cause mortality (366 vs 488 deaths; hazard ratio [HR], 0.63; number needed to treat [NNT], 117), major cardiac events (209 vs 282 events; HR, 0.68; NNT, 191), ischemic stroke (144 vs 203 strokes; HR, 0.64; NNT, 246), and hypoglycemia (89 vs 170 events; HR, 0.43; NNT, 201). There were no significant differences in the occurrence of MIs (69 vs 88 MIs; HR, 0.75) or the number of hospitalizations for heart failure (100 vs 100 events; HR, 0.78) between the two groups.

WHAT’S NEW

Lower risks for death, CV events, and hypoglycemia

This study found that when added to metformin, DPP-4 inhibitors were associated with lower risks for all-cause mortality, CV events, and hypoglycemia when compared to sulfonylureas. Additionally, DPP-4 inhibitors did not increase the risk for heart failure hospitalization. A recent multicenter observational study of nearly 1.5 million patients on the effects of incretin-based treatments (including DPP-4 inhibitors and GLP-1 agonists) found no increased risk for heart failure hospitalization with DPP-4 inhibitors, compared to other combinations of oral T2DM agents.⁸

CAVEATS

Did unmeasured confounders play a role?

Unmeasured confounders potentially bias all observational population cohort results. In this particular study, there may have been unmeasured but significant patient factors that providers used to choose diabetes medications. Also, the study did not evaluate diabetes control, although previous studies have shown similar glucose control between sulfonylureas and DPP-4 inhibitors when added to metformin.⁶

Another caveat is that the results from this study group may not be generalizable to other populations due to physiologic differences. People of Asian ancestry are at risk for T2DM at a lower BMI than people of European ancestry, which could affect the outcomes of interest.⁹

Furthermore, the study did not evaluate outcomes based on whether patients were taking first-, second-, or third-generation sulfonylureas. Some sulfonylureas (eg, glyburide) carry a higher risk for hypoglycemia, which could bias the results.¹⁰

Lastly, the study only provides guidance when choosing between a sulfonylurea and a DPP-4 inhibitor for secondline pharmacotherapy. The GRADE trial, due to be completed in 2023, is comparing sulfonylureas, DPP-4 inhibitors, GLP-1 agonists, and insulin as add-on medications to metformin; it may provide more data on which to base treatment decisions.¹¹

CHALLENGES TO IMPLEMENTATION

DPP-4s are more expensive

Sulfonylureas and DPP-4 inhibitors are both available as generic medications, but the cost of DPP-4 inhibitors remains significantly higher.¹² Higher copays and deductibles could affect patient preference. For patients without health insurance, sulfonylureas are available on the discounted drug lists of many major retailers, while DPP-4 inhibitors are not.

ACKNOWLEDGEMENT

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.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2017;66(1):42-44.

A 58-year-old woman with T2DM and heart failure returns to your office for follow-up. She has been on the maximum dose of metformin alone for the past six months, but her A1C is now 7.8%. She wants to avoid injections. What do you recommend?

There is surprisingly little consensus about what to add to metformin for patients with T2DM who require a second agent to achieve their glycemic goal. Attaining glycemic control earlier in the course of the disease may lead to reduced overall cardiovascular (CV) risk, so the choice of a second drug is an important one.² While the proven mortality benefit, wide availability, and low cost of metformin make it well-established as initial pharmacotherapy, no second-choice drug has amassed enough evidence of benefit to become the add-on therapy of choice.

The professional societies are of little assistance; dual-therapy recommendations from the American Diabetes Association and the European Association for the Study of Diabetes do not specify a preference.³ Although the American Association of Clinical Endocrinologists/American College of Endocrinology suggest a hierarchy of choices, it is based on expert consensus recommendations.⁴

A look at the options

Options for add-on therapy include sulfonylureas, thiazolidines, DPP-4 inhibitors, sodium glucose cotransporter 2 inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and insulin. Providers frequently prescribe sulfonylureas after metformin because they are low in cost, have long-term safety data, and are effective at lowering A1C. They work by directly stimulating insulin secretion via pancreatic ß-cells in a glucose-independent manner. But as a 2010 meta-analysis revealed, sulfonylureas carry significant risk for hypoglycemia (relative risk [RR], 4.57) and weight gain (average, 2.06 kg), compared to placebo.⁵

DPP-4 inhibitors, on the other hand, induce insulin secretion in a glucose-dependent manner through an incretin mechanism. Combined with metformin, they provide glucose control similar to that achieved with the combination of a sulfonylurea and metformin.⁶ DPP-4 inhibitors were initially found to be associated with fewer CV events and less hypoglycemia than sulfonylureas but were subsequently linked to an increased risk for heart failure–related hospitalization.⁷

A recent study provides more data on the effects of DPP-4s added to metformin.¹

STUDY SUMMARY

DPP-4s as effective, less risky

This observational cohort study compared DPP-4 inhibitors and sulfonylureas when combined with metformin for the treatment of T2DM.¹ Outcomes were all-cause mortality, major adverse CV events (defined as hospitalization for ischemic stroke or myocardial infarction [MI]), and hospitalizations for either heart failure or hypoglycemia. The study included data from the National Health Insurance Research Database in Taiwan on more than 70,000 patients (ages 20 and older) with diagnosed T2DM. Individuals adherent to metformin were considered to be enrolled in the cohort on the day they began using either a DPP-4 inhibitor or a sulfonylurea, in addition to metformin.

The researchers collected additional data on socioeconomic factors, urbanization, robustness of the local health care system, Charlson Comorbidity Index, adapted Diabetes Complications Severity Index, and other comorbidities and medications that could affect the outcomes of interest. Participants were then matched by propensity score into 10,089 pairs, each consisting of one DPP-4 inhibitor user and one sulfonylurea user.

After mean follow-up of 2.8 years, the investigators used Cox regression analysis to evaluate the relative hazards of the outcomes. Subgroup analysis stratified by age, sex, Charlson Comorbidity Index, hypertension, chronic kidney disease, hospitalization for heart failure, MI, and cerebrovascular disease yielded results similar to those of the primary analysis for each outcome. Similar results were also obtained when the data were analyzed without propensity-score matching.

The researchers found that users of DPP-4 inhibitors—compared with those who used sulfonylureas—had a lower risk for all-cause mortality (366 vs 488 deaths; hazard ratio [HR], 0.63; number needed to treat [NNT], 117), major cardiac events (209 vs 282 events; HR, 0.68; NNT, 191), ischemic stroke (144 vs 203 strokes; HR, 0.64; NNT, 246), and hypoglycemia (89 vs 170 events; HR, 0.43; NNT, 201). There were no significant differences in the occurrence of MIs (69 vs 88 MIs; HR, 0.75) or the number of hospitalizations for heart failure (100 vs 100 events; HR, 0.78) between the two groups.

WHAT’S NEW

Lower risks for death, CV events, and hypoglycemia

This study found that when added to metformin, DPP-4 inhibitors were associated with lower risks for all-cause mortality, CV events, and hypoglycemia when compared to sulfonylureas. Additionally, DPP-4 inhibitors did not increase the risk for heart failure hospitalization. A recent multicenter observational study of nearly 1.5 million patients on the effects of incretin-based treatments (including DPP-4 inhibitors and GLP-1 agonists) found no increased risk for heart failure hospitalization with DPP-4 inhibitors, compared to other combinations of oral T2DM agents.⁸

CAVEATS

Did unmeasured confounders play a role?

Unmeasured confounders potentially bias all observational population cohort results. In this particular study, there may have been unmeasured but significant patient factors that providers used to choose diabetes medications. Also, the study did not evaluate diabetes control, although previous studies have shown similar glucose control between sulfonylureas and DPP-4 inhibitors when added to metformin.⁶

Another caveat is that the results from this study group may not be generalizable to other populations due to physiologic differences. People of Asian ancestry are at risk for T2DM at a lower BMI than people of European ancestry, which could affect the outcomes of interest.⁹

Furthermore, the study did not evaluate outcomes based on whether patients were taking first-, second-, or third-generation sulfonylureas. Some sulfonylureas (eg, glyburide) carry a higher risk for hypoglycemia, which could bias the results.¹⁰

Lastly, the study only provides guidance when choosing between a sulfonylurea and a DPP-4 inhibitor for secondline pharmacotherapy. The GRADE trial, due to be completed in 2023, is comparing sulfonylureas, DPP-4 inhibitors, GLP-1 agonists, and insulin as add-on medications to metformin; it may provide more data on which to base treatment decisions.¹¹

CHALLENGES TO IMPLEMENTATION

DPP-4s are more expensive

Sulfonylureas and DPP-4 inhibitors are both available as generic medications, but the cost of DPP-4 inhibitors remains significantly higher.¹² Higher copays and deductibles could affect patient preference. For patients without health insurance, sulfonylureas are available on the discounted drug lists of many major retailers, while DPP-4 inhibitors are not.

ACKNOWLEDGEMENT

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.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2017;66(1):42-44.