Q1. Correct Answer: B

Rationale

The leading cause of death in patients with NASH is cardiovascular disease. Death from liver-related causes is much more common in NASH than in the general population, but is not the leading cause of death. Cancer-related death is among the top three causes of death in patients with NASH, but is not the most common.

References

1. Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129:113-21.

2. Chalasani N, Younossi Z, Lavine JE, et al. The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance from the American Association for the Study of Liver Disease. Hepatology 2018;67:328-57.

Q1. Correct Answer: B

Rationale

The leading cause of death in patients with NASH is cardiovascular disease. Death from liver-related causes is much more common in NASH than in the general population, but is not the leading cause of death. Cancer-related death is among the top three causes of death in patients with NASH, but is not the most common.

References

1. Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129:113-21.

2. Chalasani N, Younossi Z, Lavine JE, et al. The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance from the American Association for the Study of Liver Disease. Hepatology 2018;67:328-57.

Q1. Correct Answer: B

Rationale

The leading cause of death in patients with NASH is cardiovascular disease. Death from liver-related causes is much more common in NASH than in the general population, but is not the leading cause of death. Cancer-related death is among the top three causes of death in patients with NASH, but is not the most common.

References

1. Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129:113-21.

2. Chalasani N, Younossi Z, Lavine JE, et al. The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance from the American Association for the Study of Liver Disease. Hepatology 2018;67:328-57.

The 2019 Novel Coronavirus (2019-nCoV) outbreak has unfolded so rapidly that many clinicians are scrambling to stay on top of it. Here are the answers to some frequently asked questions about how to prepare your clinic to respond to this outbreak.

Keep in mind that the outbreak is moving rapidly. Though scientific and epidemiologic knowledge has increased at unprecedented speed, there is much we don’t know, and some of what we think we know will change. Follow the links for the most up-to-date information.

What should our clinic do first?

Plan ahead with the following:

• Develop a plan for office staff to take travel histories from anyone with a respiratory illness and provide training for those who need it. Travel history at present should include asking about travel to China in the past 14 days, specifically Wuhan city or Hubei province.
• Review up-to-date infection control practices with all office staff and provide training for those who need it.
• Take an inventory of supplies of personal protective equipment (PPE), such as gowns, gloves, masks, eye protection, and N95 respirators or powered air-purifying respirators (PAPRs), and order items that are missing or low in stock.
• Fit-test users of N95 masks for maximal effectiveness.
• Plan where a potential patient would be isolated while obtaining expert advice.
• Know whom to contact at the state or local health department if you have a patient with the appropriate travel history.

The Centers for Disease Control and Prevention has prepared a toolkit to help frontline health care professionals prepare for this virus. Providers need to stay up to date on the latest recommendations, as the situation is changing rapidly.

When should I suspect 2019-nCoV illness, and what should I do?

Take the following steps to assess the concern and respond:

• If a patient with respiratory illness has traveled to China in the past 14 days, immediately put a mask on the patient and move the individual to a private room. Use a negative-pressure room if available.
• Put on appropriate PPE (including gloves, gown, eye protection, and mask) for contact, droplet, and airborne precautions. CDC recommends an N95 respirator mask if available, although we don’t know yet if there is true airborne spread.
• Obtain an accurate travel history, including dates and cities. (Tip: Get the correct spelling, as the English spelling of cities in China can cause confusion.)
• If the patient meets the current CDC definition of “person under investigation” or PUI, or if you need guidance on how to proceed, notify infection control (if you are in a facility that has it) and call your state or local health department immediately.
• Contact public health authorities who can help decide whether the patient should be admitted to airborne isolation or monitored at home with appropriate precautions.

What is the definition of a PUI?

The current definition of a PUI is a person who has fever and symptoms of a respiratory infection (cough, shortness of breath) AND who has EITHER been in Wuhan city or Hubei province in the past 14 days OR had close contact with a person either under investigation for 2019-nCoV infection or with confirmed infection. The definition of a PUI will change over time, so check this link.

How can I test for 2019-nCoV?

As of Jan. 30, 2020, testing is by polymerase chain reaction (PCR) and is available in the United States only through the CDC in Atlanta. Testing should soon be available in state health department laboratories. If public health authorities decide that your patient should be tested, they will instruct you on which samples to obtain.

The full sequence of 2019-nCoV has been shared, so some reference laboratories may develop and validate tests, ideally with assistance from CDC. If testing becomes available, make certain that it is a reputable lab that has carefully validated the test.

Should I test for other viruses?

Because the symptoms of 2019-nCoV infection overlap with those of influenza and other respiratory viruses, PCR testing for other viruses should be considered if it will change management (i.e., change the decision to provide influenza antivirals). Use appropriate PPE while collecting specimens, including eye protection. If 2019-nCoV is a consideration, you may want to send the specimen to a hospital lab for testing, where the sample will be processed under a biosafety hood, rather than doing point-of-care testing in the office.

How dangerous is 2019-nCoV?

The current estimated mortality rate is 2%-3%. That is probably an overestimate, as those with severe disease and those who die are more likely to be tested and reported early in an epidemic.

Our current knowledge is based on preliminary reports from hospitalized patients and will probably change. From the speed of spread and a single family cluster, it seems likely that there are milder cases and perhaps asymptomatic infection.

What else do I need to know about coronaviruses?

Coronaviruses are a large and diverse group of viruses, many of which are animal viruses. Before the discovery of the 2019-nCoV, six coronaviruses were known to infect humans. Four of these (HKU1, NL63, OC43, and 229E) predominantly caused mild to moderate upper respiratory illness, and they are thought to be responsible for 10%-30% of colds. They occasionally cause viral pneumonia and can be detected by some commercial multiplex panels.

Two other coronaviruses have caused outbreaks of severe respiratory illness in people: SARS, which emerged in Southern China in 2002, and MERS in the Middle East, in 2012. Unlike SARS, sporadic cases of MERS continue to occur.

The current outbreak is caused by 2019-nCoV, a previously unknown beta coronavirus. It is most closely related (~96%) to a bat virus and shares about 80% sequence homology with SARS CoV.

Andrew T. Pavia, MD, is the George and Esther Gross Presidential Professor and chief of the division of pediatric infectious disease in the department of pediatrics at the University of Utah, Salt Lake City. He is also director of hospital epidemiology and associate director of antimicrobial stewardship at Primary Children’s Hospital, Salt Lake City. Dr. Pavia has disclosed that he has served as a consultant for Genentech, Merck, and Seqirus and that he has served as associate editor for The Sanford Guide.

This article first appeared on Medscape.com.

The 2019 Novel Coronavirus (2019-nCoV) outbreak has unfolded so rapidly that many clinicians are scrambling to stay on top of it. Here are the answers to some frequently asked questions about how to prepare your clinic to respond to this outbreak.

Keep in mind that the outbreak is moving rapidly. Though scientific and epidemiologic knowledge has increased at unprecedented speed, there is much we don’t know, and some of what we think we know will change. Follow the links for the most up-to-date information.

What should our clinic do first?

Plan ahead with the following:

• Develop a plan for office staff to take travel histories from anyone with a respiratory illness and provide training for those who need it. Travel history at present should include asking about travel to China in the past 14 days, specifically Wuhan city or Hubei province.
• Review up-to-date infection control practices with all office staff and provide training for those who need it.
• Take an inventory of supplies of personal protective equipment (PPE), such as gowns, gloves, masks, eye protection, and N95 respirators or powered air-purifying respirators (PAPRs), and order items that are missing or low in stock.
• Fit-test users of N95 masks for maximal effectiveness.
• Plan where a potential patient would be isolated while obtaining expert advice.
• Know whom to contact at the state or local health department if you have a patient with the appropriate travel history.

The Centers for Disease Control and Prevention has prepared a toolkit to help frontline health care professionals prepare for this virus. Providers need to stay up to date on the latest recommendations, as the situation is changing rapidly.

When should I suspect 2019-nCoV illness, and what should I do?

Take the following steps to assess the concern and respond:

• If a patient with respiratory illness has traveled to China in the past 14 days, immediately put a mask on the patient and move the individual to a private room. Use a negative-pressure room if available.
• Put on appropriate PPE (including gloves, gown, eye protection, and mask) for contact, droplet, and airborne precautions. CDC recommends an N95 respirator mask if available, although we don’t know yet if there is true airborne spread.
• Obtain an accurate travel history, including dates and cities. (Tip: Get the correct spelling, as the English spelling of cities in China can cause confusion.)
• If the patient meets the current CDC definition of “person under investigation” or PUI, or if you need guidance on how to proceed, notify infection control (if you are in a facility that has it) and call your state or local health department immediately.
• Contact public health authorities who can help decide whether the patient should be admitted to airborne isolation or monitored at home with appropriate precautions.

What is the definition of a PUI?

The current definition of a PUI is a person who has fever and symptoms of a respiratory infection (cough, shortness of breath) AND who has EITHER been in Wuhan city or Hubei province in the past 14 days OR had close contact with a person either under investigation for 2019-nCoV infection or with confirmed infection. The definition of a PUI will change over time, so check this link.

How can I test for 2019-nCoV?

As of Jan. 30, 2020, testing is by polymerase chain reaction (PCR) and is available in the United States only through the CDC in Atlanta. Testing should soon be available in state health department laboratories. If public health authorities decide that your patient should be tested, they will instruct you on which samples to obtain.

The full sequence of 2019-nCoV has been shared, so some reference laboratories may develop and validate tests, ideally with assistance from CDC. If testing becomes available, make certain that it is a reputable lab that has carefully validated the test.

Should I test for other viruses?

Because the symptoms of 2019-nCoV infection overlap with those of influenza and other respiratory viruses, PCR testing for other viruses should be considered if it will change management (i.e., change the decision to provide influenza antivirals). Use appropriate PPE while collecting specimens, including eye protection. If 2019-nCoV is a consideration, you may want to send the specimen to a hospital lab for testing, where the sample will be processed under a biosafety hood, rather than doing point-of-care testing in the office.

How dangerous is 2019-nCoV?

The current estimated mortality rate is 2%-3%. That is probably an overestimate, as those with severe disease and those who die are more likely to be tested and reported early in an epidemic.

Our current knowledge is based on preliminary reports from hospitalized patients and will probably change. From the speed of spread and a single family cluster, it seems likely that there are milder cases and perhaps asymptomatic infection.

What else do I need to know about coronaviruses?

Coronaviruses are a large and diverse group of viruses, many of which are animal viruses. Before the discovery of the 2019-nCoV, six coronaviruses were known to infect humans. Four of these (HKU1, NL63, OC43, and 229E) predominantly caused mild to moderate upper respiratory illness, and they are thought to be responsible for 10%-30% of colds. They occasionally cause viral pneumonia and can be detected by some commercial multiplex panels.

Two other coronaviruses have caused outbreaks of severe respiratory illness in people: SARS, which emerged in Southern China in 2002, and MERS in the Middle East, in 2012. Unlike SARS, sporadic cases of MERS continue to occur.

The current outbreak is caused by 2019-nCoV, a previously unknown beta coronavirus. It is most closely related (~96%) to a bat virus and shares about 80% sequence homology with SARS CoV.

Andrew T. Pavia, MD, is the George and Esther Gross Presidential Professor and chief of the division of pediatric infectious disease in the department of pediatrics at the University of Utah, Salt Lake City. He is also director of hospital epidemiology and associate director of antimicrobial stewardship at Primary Children’s Hospital, Salt Lake City. Dr. Pavia has disclosed that he has served as a consultant for Genentech, Merck, and Seqirus and that he has served as associate editor for The Sanford Guide.

This article first appeared on Medscape.com.

The 2019 Novel Coronavirus (2019-nCoV) outbreak has unfolded so rapidly that many clinicians are scrambling to stay on top of it. Here are the answers to some frequently asked questions about how to prepare your clinic to respond to this outbreak.

Keep in mind that the outbreak is moving rapidly. Though scientific and epidemiologic knowledge has increased at unprecedented speed, there is much we don’t know, and some of what we think we know will change. Follow the links for the most up-to-date information.

What should our clinic do first?

Plan ahead with the following:

• Develop a plan for office staff to take travel histories from anyone with a respiratory illness and provide training for those who need it. Travel history at present should include asking about travel to China in the past 14 days, specifically Wuhan city or Hubei province.
• Review up-to-date infection control practices with all office staff and provide training for those who need it.
• Take an inventory of supplies of personal protective equipment (PPE), such as gowns, gloves, masks, eye protection, and N95 respirators or powered air-purifying respirators (PAPRs), and order items that are missing or low in stock.
• Fit-test users of N95 masks for maximal effectiveness.
• Plan where a potential patient would be isolated while obtaining expert advice.
• Know whom to contact at the state or local health department if you have a patient with the appropriate travel history.

The Centers for Disease Control and Prevention has prepared a toolkit to help frontline health care professionals prepare for this virus. Providers need to stay up to date on the latest recommendations, as the situation is changing rapidly.

When should I suspect 2019-nCoV illness, and what should I do?

Take the following steps to assess the concern and respond:

• If a patient with respiratory illness has traveled to China in the past 14 days, immediately put a mask on the patient and move the individual to a private room. Use a negative-pressure room if available.
• Put on appropriate PPE (including gloves, gown, eye protection, and mask) for contact, droplet, and airborne precautions. CDC recommends an N95 respirator mask if available, although we don’t know yet if there is true airborne spread.
• Obtain an accurate travel history, including dates and cities. (Tip: Get the correct spelling, as the English spelling of cities in China can cause confusion.)
• If the patient meets the current CDC definition of “person under investigation” or PUI, or if you need guidance on how to proceed, notify infection control (if you are in a facility that has it) and call your state or local health department immediately.
• Contact public health authorities who can help decide whether the patient should be admitted to airborne isolation or monitored at home with appropriate precautions.

What is the definition of a PUI?

The current definition of a PUI is a person who has fever and symptoms of a respiratory infection (cough, shortness of breath) AND who has EITHER been in Wuhan city or Hubei province in the past 14 days OR had close contact with a person either under investigation for 2019-nCoV infection or with confirmed infection. The definition of a PUI will change over time, so check this link.

How can I test for 2019-nCoV?

As of Jan. 30, 2020, testing is by polymerase chain reaction (PCR) and is available in the United States only through the CDC in Atlanta. Testing should soon be available in state health department laboratories. If public health authorities decide that your patient should be tested, they will instruct you on which samples to obtain.

The full sequence of 2019-nCoV has been shared, so some reference laboratories may develop and validate tests, ideally with assistance from CDC. If testing becomes available, make certain that it is a reputable lab that has carefully validated the test.

Should I test for other viruses?

Because the symptoms of 2019-nCoV infection overlap with those of influenza and other respiratory viruses, PCR testing for other viruses should be considered if it will change management (i.e., change the decision to provide influenza antivirals). Use appropriate PPE while collecting specimens, including eye protection. If 2019-nCoV is a consideration, you may want to send the specimen to a hospital lab for testing, where the sample will be processed under a biosafety hood, rather than doing point-of-care testing in the office.

How dangerous is 2019-nCoV?

The current estimated mortality rate is 2%-3%. That is probably an overestimate, as those with severe disease and those who die are more likely to be tested and reported early in an epidemic.

Our current knowledge is based on preliminary reports from hospitalized patients and will probably change. From the speed of spread and a single family cluster, it seems likely that there are milder cases and perhaps asymptomatic infection.

What else do I need to know about coronaviruses?

Coronaviruses are a large and diverse group of viruses, many of which are animal viruses. Before the discovery of the 2019-nCoV, six coronaviruses were known to infect humans. Four of these (HKU1, NL63, OC43, and 229E) predominantly caused mild to moderate upper respiratory illness, and they are thought to be responsible for 10%-30% of colds. They occasionally cause viral pneumonia and can be detected by some commercial multiplex panels.

Two other coronaviruses have caused outbreaks of severe respiratory illness in people: SARS, which emerged in Southern China in 2002, and MERS in the Middle East, in 2012. Unlike SARS, sporadic cases of MERS continue to occur.

The current outbreak is caused by 2019-nCoV, a previously unknown beta coronavirus. It is most closely related (~96%) to a bat virus and shares about 80% sequence homology with SARS CoV.

Andrew T. Pavia, MD, is the George and Esther Gross Presidential Professor and chief of the division of pediatric infectious disease in the department of pediatrics at the University of Utah, Salt Lake City. He is also director of hospital epidemiology and associate director of antimicrobial stewardship at Primary Children’s Hospital, Salt Lake City. Dr. Pavia has disclosed that he has served as a consultant for Genentech, Merck, and Seqirus and that he has served as associate editor for The Sanford Guide.

This article first appeared on Medscape.com.

LOS ANGELES – Although menopausal hormone therapy is not approved for the prevention of type 2 diabetes because of its complex balance of risks and benefits, it should not be withheld from women with increased risk of type 2 diabetes who seek treatment for menopausal symptoms, according to Franck Mauvais-Jarvis, MD.

Doug Brunk/MDedge News

“During the menopause transition, women accumulate metabolic disturbances, including visceral obesity, systemic inflammation, insulin resistance, dyslipidemia, and hypertension,” Dr. Mauvais-Jarvis, director of the Tulane Diabetes Research Program at Tulane University Health Sciences Center, New Orleans, said at the Annual World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “They also lose muscle mass. Some of these abnormalities are partially explained by chronological aging, but they are also caused by estrogen deficiency. There’s a synergism between aging and estrogen deficiency.”

The best evidence of this synergy comes from older trials. Nearly 30 years ago, researchers examined the association between postmenopausal hormone use and the subsequent incidence of non–insulin dependent diabetes in a prospective cohort of 21,028 postmenopausal U.S. women aged 30-55 years, who were enrolled in the Nurse’s Health Study and followed for 12 years (Ann Epidemiol. 1992;2[5]:665-73). They found that study participants on hormone therapy experienced a 20% reduction in the incidence of type 2 diabetes. In a more recent trial, researchers examined the association between use of hormone therapy and new-onset diabetes in 63,624 postmenopausal women who were enrolled in the prospective French cohort of the Etude Epidemiologique de Femmes de la Mutuelle Générale de l’Education Nationale (E3N) and followed for 15 years (Diabetologia. 2009;52[10]:2092-100). It found that study participants on hormone therapy experienced a 20% reduction in the incidence of type 2 diabetes.

In the Heart and Estrogen/Progestin Replacement Study, researchers evaluated the effect of hormone therapy on fasting glucose level and incident diabetes in 2,763 postmenopausal women with coronary heart disease (Ann Intern Med. 2003;138[1]:1-9). At 20 U.S. centers, the study participants received 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone, or placebo, and were followed for 4 years. The researchers found that the use of hormone therapy reduced the incidence of diabetes by 35%.

According to Dr. Mauvais-Jarvis, the strongest data come from the Women’s Health Initiative (WHI), a randomized, double-blind trial that compared the effect of daily 0.625 mg conjugated estrogen plus 2.5 mg medroxyprogesterone acetate with that of placebo during 5.6 years of follow-up (Diabetologia. 2004; 47[7]:1175-87). It showed a 20% decrease in the incidence of diabetes at 5 years. More recently, researchers found that, whether WHI participants took estrogen plus medroxyprogesterone or estrogen alone, the protection from diabetes was present (N Engl J Med. 2016;374:803-6).

In 2006, researchers published results from a meta-analysis of 107 trials in an effort to quantify the effects of hormone therapy on components of metabolic syndrome in postmenopausal women (Diabetes Obes Metab. 2006;8[5]:538-54). In women without diabetes, hormone therapy reduced the HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) score by 13% and incidence of type 2 diabetes by 30%. In women with diabetes, hormone therapy reduced fasting glucose by 11% and HOMA-IR by 36%.

The mechanisms by which estrogens improve glucose homeostasis are yet to be fully understood. “One of the most important [mechanisms] is a decrease in abdominal fat, which improves insulin resistance and systemic inflammation,” Dr. Mauvais-Jarvis said. “However, in the WHI, it was clear that the improvement in HOMA-IR was independent from the body weight and fat. Estrogen has also been found to increase insulin clearance and sensitivity, increase glucose disposal and effectiveness and decrease sarcopenia. There are fewer than 20 studies looking at beta-cell function. Half of them have shown that estrogen improves insulin secretion.”

Route of estrogen administration also comes into play. For example, oral estrogens increase liver exposure to estrogen, increase triglycerides, and increase clotting factors. “That is why oral estrogens are not indicated in women with risk of deep venous thrombosis,” Dr. Mauvais-Jarvis said. “They also increase inflammatory factors like C-reactive protein. Advantages are that they decrease LDL cholesterol levels and increase HDL cholesterol levels more than transdermal estrogen does.”

The main advantage with transdermal delivery of estrogen, he continued, is that it does not raise triglycerides, clotting factors, or inflammatory factors, and it confers less exposure to the liver. “That’s why it’s the preferred way of administration in women who are obese, who have a risk of DVT, or who have cardiovascular risk factors,” he said. “It has a lower suppression of hepatic glucose production, it increases circulating estradiol, and the delivery to nonhepatic tissue is increased. The oral form of estrogen is cheaper, compared with the transdermal form, though. This is a factor that is always taken into account.”

Dr. Mauvais-Jarvis and colleagues were first to evaluate the effect of conjugated estrogens plus bazedoxifene in mice (Mol Metab. 2014;3[2]:177-90). “The idea was that by combining estrogen and bazedoxifene, you have the beneficial effect of estrogen in the tissues but you block estrogen in the breast and in the uterus, and therefore, you prevent the risk of cancer,” he said. “We found that tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice. It increased energy expenditure and decreased fatty liver.”

In a subsequent pilot study, he and his colleagues assessed the effect of 12 weeks’ treatment with bazedoxifene/conjugated estrogens, compared with placebo, on glucose homeostasis and body composition in 12 postmenopausal women (NCT02237079). “We did not find any significant alterations in the IVGTT [Intravenous Glucose Tolerance Test] but we observed improved fasting beta-cell function and serum glucose in menopausal women with obesity,” Dr. Mauvais-Jarvis said (J Endocr Soc. 2019;3[8]:1583-94).

In a separate, randomized, double-blind, placebo-controlled, crossover trial that he and his colleagues performed in eight postmenopausal women with obesity, the primary endpoint was insulin action as measured by a two-step hyperinsulinemic-euglycemic clamp. Secondary endpoints were body composition, basal metabolic rate, ectopic fat, and metabolome. “We did not find any difference in systemic insulin action, ectopic fat, or energy expenditure,” he said. “But we found something very interesting. We did a metabolic analysis and found that oral estrogens increase hepatic de novo lipogenesis and liver triacylglycerol production. In other words, the oral estrogens were increasing [triacylglycerol] synthesis from glucose, but it does not accumulate in the liver.”

Dr. Mauvais-Jarvis disclosed that he has received research support from the National Institutes of Health, the American Diabetes Association, the Department of Veterans Affairs, and Pfizer.
 

[email protected]

LOS ANGELES – Although menopausal hormone therapy is not approved for the prevention of type 2 diabetes because of its complex balance of risks and benefits, it should not be withheld from women with increased risk of type 2 diabetes who seek treatment for menopausal symptoms, according to Franck Mauvais-Jarvis, MD.

Doug Brunk/MDedge News

“During the menopause transition, women accumulate metabolic disturbances, including visceral obesity, systemic inflammation, insulin resistance, dyslipidemia, and hypertension,” Dr. Mauvais-Jarvis, director of the Tulane Diabetes Research Program at Tulane University Health Sciences Center, New Orleans, said at the Annual World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “They also lose muscle mass. Some of these abnormalities are partially explained by chronological aging, but they are also caused by estrogen deficiency. There’s a synergism between aging and estrogen deficiency.”

The best evidence of this synergy comes from older trials. Nearly 30 years ago, researchers examined the association between postmenopausal hormone use and the subsequent incidence of non–insulin dependent diabetes in a prospective cohort of 21,028 postmenopausal U.S. women aged 30-55 years, who were enrolled in the Nurse’s Health Study and followed for 12 years (Ann Epidemiol. 1992;2[5]:665-73). They found that study participants on hormone therapy experienced a 20% reduction in the incidence of type 2 diabetes. In a more recent trial, researchers examined the association between use of hormone therapy and new-onset diabetes in 63,624 postmenopausal women who were enrolled in the prospective French cohort of the Etude Epidemiologique de Femmes de la Mutuelle Générale de l’Education Nationale (E3N) and followed for 15 years (Diabetologia. 2009;52[10]:2092-100). It found that study participants on hormone therapy experienced a 20% reduction in the incidence of type 2 diabetes.

In the Heart and Estrogen/Progestin Replacement Study, researchers evaluated the effect of hormone therapy on fasting glucose level and incident diabetes in 2,763 postmenopausal women with coronary heart disease (Ann Intern Med. 2003;138[1]:1-9). At 20 U.S. centers, the study participants received 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone, or placebo, and were followed for 4 years. The researchers found that the use of hormone therapy reduced the incidence of diabetes by 35%.

According to Dr. Mauvais-Jarvis, the strongest data come from the Women’s Health Initiative (WHI), a randomized, double-blind trial that compared the effect of daily 0.625 mg conjugated estrogen plus 2.5 mg medroxyprogesterone acetate with that of placebo during 5.6 years of follow-up (Diabetologia. 2004; 47[7]:1175-87). It showed a 20% decrease in the incidence of diabetes at 5 years. More recently, researchers found that, whether WHI participants took estrogen plus medroxyprogesterone or estrogen alone, the protection from diabetes was present (N Engl J Med. 2016;374:803-6).

In 2006, researchers published results from a meta-analysis of 107 trials in an effort to quantify the effects of hormone therapy on components of metabolic syndrome in postmenopausal women (Diabetes Obes Metab. 2006;8[5]:538-54). In women without diabetes, hormone therapy reduced the HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) score by 13% and incidence of type 2 diabetes by 30%. In women with diabetes, hormone therapy reduced fasting glucose by 11% and HOMA-IR by 36%.

The mechanisms by which estrogens improve glucose homeostasis are yet to be fully understood. “One of the most important [mechanisms] is a decrease in abdominal fat, which improves insulin resistance and systemic inflammation,” Dr. Mauvais-Jarvis said. “However, in the WHI, it was clear that the improvement in HOMA-IR was independent from the body weight and fat. Estrogen has also been found to increase insulin clearance and sensitivity, increase glucose disposal and effectiveness and decrease sarcopenia. There are fewer than 20 studies looking at beta-cell function. Half of them have shown that estrogen improves insulin secretion.”

Route of estrogen administration also comes into play. For example, oral estrogens increase liver exposure to estrogen, increase triglycerides, and increase clotting factors. “That is why oral estrogens are not indicated in women with risk of deep venous thrombosis,” Dr. Mauvais-Jarvis said. “They also increase inflammatory factors like C-reactive protein. Advantages are that they decrease LDL cholesterol levels and increase HDL cholesterol levels more than transdermal estrogen does.”

The main advantage with transdermal delivery of estrogen, he continued, is that it does not raise triglycerides, clotting factors, or inflammatory factors, and it confers less exposure to the liver. “That’s why it’s the preferred way of administration in women who are obese, who have a risk of DVT, or who have cardiovascular risk factors,” he said. “It has a lower suppression of hepatic glucose production, it increases circulating estradiol, and the delivery to nonhepatic tissue is increased. The oral form of estrogen is cheaper, compared with the transdermal form, though. This is a factor that is always taken into account.”

Dr. Mauvais-Jarvis and colleagues were first to evaluate the effect of conjugated estrogens plus bazedoxifene in mice (Mol Metab. 2014;3[2]:177-90). “The idea was that by combining estrogen and bazedoxifene, you have the beneficial effect of estrogen in the tissues but you block estrogen in the breast and in the uterus, and therefore, you prevent the risk of cancer,” he said. “We found that tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice. It increased energy expenditure and decreased fatty liver.”

In a subsequent pilot study, he and his colleagues assessed the effect of 12 weeks’ treatment with bazedoxifene/conjugated estrogens, compared with placebo, on glucose homeostasis and body composition in 12 postmenopausal women (NCT02237079). “We did not find any significant alterations in the IVGTT [Intravenous Glucose Tolerance Test] but we observed improved fasting beta-cell function and serum glucose in menopausal women with obesity,” Dr. Mauvais-Jarvis said (J Endocr Soc. 2019;3[8]:1583-94).

In a separate, randomized, double-blind, placebo-controlled, crossover trial that he and his colleagues performed in eight postmenopausal women with obesity, the primary endpoint was insulin action as measured by a two-step hyperinsulinemic-euglycemic clamp. Secondary endpoints were body composition, basal metabolic rate, ectopic fat, and metabolome. “We did not find any difference in systemic insulin action, ectopic fat, or energy expenditure,” he said. “But we found something very interesting. We did a metabolic analysis and found that oral estrogens increase hepatic de novo lipogenesis and liver triacylglycerol production. In other words, the oral estrogens were increasing [triacylglycerol] synthesis from glucose, but it does not accumulate in the liver.”

Dr. Mauvais-Jarvis disclosed that he has received research support from the National Institutes of Health, the American Diabetes Association, the Department of Veterans Affairs, and Pfizer.
 

[email protected]

LOS ANGELES – Although menopausal hormone therapy is not approved for the prevention of type 2 diabetes because of its complex balance of risks and benefits, it should not be withheld from women with increased risk of type 2 diabetes who seek treatment for menopausal symptoms, according to Franck Mauvais-Jarvis, MD.

Doug Brunk/MDedge News

“During the menopause transition, women accumulate metabolic disturbances, including visceral obesity, systemic inflammation, insulin resistance, dyslipidemia, and hypertension,” Dr. Mauvais-Jarvis, director of the Tulane Diabetes Research Program at Tulane University Health Sciences Center, New Orleans, said at the Annual World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “They also lose muscle mass. Some of these abnormalities are partially explained by chronological aging, but they are also caused by estrogen deficiency. There’s a synergism between aging and estrogen deficiency.”

The best evidence of this synergy comes from older trials. Nearly 30 years ago, researchers examined the association between postmenopausal hormone use and the subsequent incidence of non–insulin dependent diabetes in a prospective cohort of 21,028 postmenopausal U.S. women aged 30-55 years, who were enrolled in the Nurse’s Health Study and followed for 12 years (Ann Epidemiol. 1992;2[5]:665-73). They found that study participants on hormone therapy experienced a 20% reduction in the incidence of type 2 diabetes. In a more recent trial, researchers examined the association between use of hormone therapy and new-onset diabetes in 63,624 postmenopausal women who were enrolled in the prospective French cohort of the Etude Epidemiologique de Femmes de la Mutuelle Générale de l’Education Nationale (E3N) and followed for 15 years (Diabetologia. 2009;52[10]:2092-100). It found that study participants on hormone therapy experienced a 20% reduction in the incidence of type 2 diabetes.

In the Heart and Estrogen/Progestin Replacement Study, researchers evaluated the effect of hormone therapy on fasting glucose level and incident diabetes in 2,763 postmenopausal women with coronary heart disease (Ann Intern Med. 2003;138[1]:1-9). At 20 U.S. centers, the study participants received 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone, or placebo, and were followed for 4 years. The researchers found that the use of hormone therapy reduced the incidence of diabetes by 35%.

According to Dr. Mauvais-Jarvis, the strongest data come from the Women’s Health Initiative (WHI), a randomized, double-blind trial that compared the effect of daily 0.625 mg conjugated estrogen plus 2.5 mg medroxyprogesterone acetate with that of placebo during 5.6 years of follow-up (Diabetologia. 2004; 47[7]:1175-87). It showed a 20% decrease in the incidence of diabetes at 5 years. More recently, researchers found that, whether WHI participants took estrogen plus medroxyprogesterone or estrogen alone, the protection from diabetes was present (N Engl J Med. 2016;374:803-6).

In 2006, researchers published results from a meta-analysis of 107 trials in an effort to quantify the effects of hormone therapy on components of metabolic syndrome in postmenopausal women (Diabetes Obes Metab. 2006;8[5]:538-54). In women without diabetes, hormone therapy reduced the HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) score by 13% and incidence of type 2 diabetes by 30%. In women with diabetes, hormone therapy reduced fasting glucose by 11% and HOMA-IR by 36%.

The mechanisms by which estrogens improve glucose homeostasis are yet to be fully understood. “One of the most important [mechanisms] is a decrease in abdominal fat, which improves insulin resistance and systemic inflammation,” Dr. Mauvais-Jarvis said. “However, in the WHI, it was clear that the improvement in HOMA-IR was independent from the body weight and fat. Estrogen has also been found to increase insulin clearance and sensitivity, increase glucose disposal and effectiveness and decrease sarcopenia. There are fewer than 20 studies looking at beta-cell function. Half of them have shown that estrogen improves insulin secretion.”

Route of estrogen administration also comes into play. For example, oral estrogens increase liver exposure to estrogen, increase triglycerides, and increase clotting factors. “That is why oral estrogens are not indicated in women with risk of deep venous thrombosis,” Dr. Mauvais-Jarvis said. “They also increase inflammatory factors like C-reactive protein. Advantages are that they decrease LDL cholesterol levels and increase HDL cholesterol levels more than transdermal estrogen does.”

The main advantage with transdermal delivery of estrogen, he continued, is that it does not raise triglycerides, clotting factors, or inflammatory factors, and it confers less exposure to the liver. “That’s why it’s the preferred way of administration in women who are obese, who have a risk of DVT, or who have cardiovascular risk factors,” he said. “It has a lower suppression of hepatic glucose production, it increases circulating estradiol, and the delivery to nonhepatic tissue is increased. The oral form of estrogen is cheaper, compared with the transdermal form, though. This is a factor that is always taken into account.”

Dr. Mauvais-Jarvis and colleagues were first to evaluate the effect of conjugated estrogens plus bazedoxifene in mice (Mol Metab. 2014;3[2]:177-90). “The idea was that by combining estrogen and bazedoxifene, you have the beneficial effect of estrogen in the tissues but you block estrogen in the breast and in the uterus, and therefore, you prevent the risk of cancer,” he said. “We found that tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice. It increased energy expenditure and decreased fatty liver.”

In a subsequent pilot study, he and his colleagues assessed the effect of 12 weeks’ treatment with bazedoxifene/conjugated estrogens, compared with placebo, on glucose homeostasis and body composition in 12 postmenopausal women (NCT02237079). “We did not find any significant alterations in the IVGTT [Intravenous Glucose Tolerance Test] but we observed improved fasting beta-cell function and serum glucose in menopausal women with obesity,” Dr. Mauvais-Jarvis said (J Endocr Soc. 2019;3[8]:1583-94).

In a separate, randomized, double-blind, placebo-controlled, crossover trial that he and his colleagues performed in eight postmenopausal women with obesity, the primary endpoint was insulin action as measured by a two-step hyperinsulinemic-euglycemic clamp. Secondary endpoints were body composition, basal metabolic rate, ectopic fat, and metabolome. “We did not find any difference in systemic insulin action, ectopic fat, or energy expenditure,” he said. “But we found something very interesting. We did a metabolic analysis and found that oral estrogens increase hepatic de novo lipogenesis and liver triacylglycerol production. In other words, the oral estrogens were increasing [triacylglycerol] synthesis from glucose, but it does not accumulate in the liver.”

Dr. Mauvais-Jarvis disclosed that he has received research support from the National Institutes of Health, the American Diabetes Association, the Department of Veterans Affairs, and Pfizer.
 

[email protected]

A Chicago woman in her 60s who tested positive for the 2019 Novel Coronavirus (2019-nCoV) after returning from Wuhan, China, earlier this month has infected her husband, becoming the first known instance of person-to-person transmission of the 2019-nCoV in the United States.

James Gathany/Centers for Disease Control and Prevention

“Limited person-to-person spread of this new virus outside of China has already been seen in nine close contacts, where travelers were infected and transmitted the virus to someone else,” Robert R. Redfield, MD, director of the Centers for Disease Control and Prevention, said during a press briefing on Jan. 30, 2020. “However, the full picture of how easy and how sustainable this virus can spread is unclear. Today’s news underscores the important risk-dependent exposure. The vast majority of Americans have not had recent travel to China, where sustained human-to-human transmission is occurring. Individuals who are close personal contacts of cases, though, could have a risk.”

The affected man, also in his 60s, is the spouse of the first confirmed travel-associated case of 2019-nCoV to be reported in the state of Illinois, according to Ngozi O. Ezike, MD, director of the Illinois Department of Public Health. The man had no history of recent travel to China. “This person-to-person spread was between two very close contacts: a wife and husband,” said Dr. Ezike, who added that 21 individuals in the state are under investigation for 2019-nCoV. “The virus is not spreading widely across the community. At this time, we are not recommending that people in the general public take additional precautions such as canceling activities or avoiding going out. While there is concern with this second case, public health officials are actively monitoring close contacts, including health care workers, and we believe that people in Illinois are at low risk.”

Jennifer Layden, MD, state epidemiologist at the Illinois Department of Public Health, said that the infected Chicago woman returned from Wuhan, China on Jan. 13, 2020. She is hospitalized in stable condition “and continues to do well,” Dr. Layden said. “Public health officials have been actively and closely monitoring individuals who had contacts with her, including her husband, who had close contact for symptoms. He recently began reporting symptoms and was immediately admitted to the hospital and placed in an isolation room, where he is in stable condition. We are actively monitoring individuals such as health care workers, household contacts, and others who were in contact with either of the confirmed cases in the goal to contain and reduce the risk of additional transmission.”

Nancy Messonnier, MD, director, National Center for Immunization and Respiratory Diseases, expects that more cases of 2019-nCoV will transpire in the United States.

“More cases means the potential for more person-to-person spread,” Dr. Messonnier said. “We’re trying to strike a balance in our response right now. We want to be aggressive, but we want our actions to be evidence-based and appropriate for the current circumstance. For example, CDC does not currently recommend use of face masks for the general public. The virus is not spreading in the general community.”

[email protected]

A Chicago woman in her 60s who tested positive for the 2019 Novel Coronavirus (2019-nCoV) after returning from Wuhan, China, earlier this month has infected her husband, becoming the first known instance of person-to-person transmission of the 2019-nCoV in the United States.

James Gathany/Centers for Disease Control and Prevention

“Limited person-to-person spread of this new virus outside of China has already been seen in nine close contacts, where travelers were infected and transmitted the virus to someone else,” Robert R. Redfield, MD, director of the Centers for Disease Control and Prevention, said during a press briefing on Jan. 30, 2020. “However, the full picture of how easy and how sustainable this virus can spread is unclear. Today’s news underscores the important risk-dependent exposure. The vast majority of Americans have not had recent travel to China, where sustained human-to-human transmission is occurring. Individuals who are close personal contacts of cases, though, could have a risk.”

The affected man, also in his 60s, is the spouse of the first confirmed travel-associated case of 2019-nCoV to be reported in the state of Illinois, according to Ngozi O. Ezike, MD, director of the Illinois Department of Public Health. The man had no history of recent travel to China. “This person-to-person spread was between two very close contacts: a wife and husband,” said Dr. Ezike, who added that 21 individuals in the state are under investigation for 2019-nCoV. “The virus is not spreading widely across the community. At this time, we are not recommending that people in the general public take additional precautions such as canceling activities or avoiding going out. While there is concern with this second case, public health officials are actively monitoring close contacts, including health care workers, and we believe that people in Illinois are at low risk.”

Jennifer Layden, MD, state epidemiologist at the Illinois Department of Public Health, said that the infected Chicago woman returned from Wuhan, China on Jan. 13, 2020. She is hospitalized in stable condition “and continues to do well,” Dr. Layden said. “Public health officials have been actively and closely monitoring individuals who had contacts with her, including her husband, who had close contact for symptoms. He recently began reporting symptoms and was immediately admitted to the hospital and placed in an isolation room, where he is in stable condition. We are actively monitoring individuals such as health care workers, household contacts, and others who were in contact with either of the confirmed cases in the goal to contain and reduce the risk of additional transmission.”

Nancy Messonnier, MD, director, National Center for Immunization and Respiratory Diseases, expects that more cases of 2019-nCoV will transpire in the United States.

“More cases means the potential for more person-to-person spread,” Dr. Messonnier said. “We’re trying to strike a balance in our response right now. We want to be aggressive, but we want our actions to be evidence-based and appropriate for the current circumstance. For example, CDC does not currently recommend use of face masks for the general public. The virus is not spreading in the general community.”

[email protected]

A Chicago woman in her 60s who tested positive for the 2019 Novel Coronavirus (2019-nCoV) after returning from Wuhan, China, earlier this month has infected her husband, becoming the first known instance of person-to-person transmission of the 2019-nCoV in the United States.

James Gathany/Centers for Disease Control and Prevention

“Limited person-to-person spread of this new virus outside of China has already been seen in nine close contacts, where travelers were infected and transmitted the virus to someone else,” Robert R. Redfield, MD, director of the Centers for Disease Control and Prevention, said during a press briefing on Jan. 30, 2020. “However, the full picture of how easy and how sustainable this virus can spread is unclear. Today’s news underscores the important risk-dependent exposure. The vast majority of Americans have not had recent travel to China, where sustained human-to-human transmission is occurring. Individuals who are close personal contacts of cases, though, could have a risk.”

The affected man, also in his 60s, is the spouse of the first confirmed travel-associated case of 2019-nCoV to be reported in the state of Illinois, according to Ngozi O. Ezike, MD, director of the Illinois Department of Public Health. The man had no history of recent travel to China. “This person-to-person spread was between two very close contacts: a wife and husband,” said Dr. Ezike, who added that 21 individuals in the state are under investigation for 2019-nCoV. “The virus is not spreading widely across the community. At this time, we are not recommending that people in the general public take additional precautions such as canceling activities or avoiding going out. While there is concern with this second case, public health officials are actively monitoring close contacts, including health care workers, and we believe that people in Illinois are at low risk.”

Jennifer Layden, MD, state epidemiologist at the Illinois Department of Public Health, said that the infected Chicago woman returned from Wuhan, China on Jan. 13, 2020. She is hospitalized in stable condition “and continues to do well,” Dr. Layden said. “Public health officials have been actively and closely monitoring individuals who had contacts with her, including her husband, who had close contact for symptoms. He recently began reporting symptoms and was immediately admitted to the hospital and placed in an isolation room, where he is in stable condition. We are actively monitoring individuals such as health care workers, household contacts, and others who were in contact with either of the confirmed cases in the goal to contain and reduce the risk of additional transmission.”

Nancy Messonnier, MD, director, National Center for Immunization and Respiratory Diseases, expects that more cases of 2019-nCoV will transpire in the United States.

“More cases means the potential for more person-to-person spread,” Dr. Messonnier said. “We’re trying to strike a balance in our response right now. We want to be aggressive, but we want our actions to be evidence-based and appropriate for the current circumstance. For example, CDC does not currently recommend use of face masks for the general public. The virus is not spreading in the general community.”

[email protected]

England’s ban on smoking in cars carrying children led to a 72% relative reduction in the percentage of children self-reporting exposure to tobacco smoke in cars.

“Given children’s known vulnerability to secondhand smoke, reductions in exposure will probably result in improved health,” wrote Anthony A. Laverty, PhD, of Imperial College London and coauthors. Their findings were published in Thorax.

To determine the impact of a 2015 ban on smoking in cars carrying children in England and a 2016 ban in Scotland, the researchers analyzed survey data from 2012, 2014, and 2016 for each of the two countries. In England, children aged 13-15 years were asked, “In the past year, how often were you in a car with somebody smoking?” In Scotland, they were asked, “Are you regularly exposed to other people’s tobacco smoke in any of these places?” with cars/vehicles being one of the options.

Overall, 15,318 responses were received in England and 822 were received in Scotland. In England, self-reported regular exposure to smoke in cars was 6% in 2012, 6% in 2014 and 2% in 2016. In Scotland, it was 3% in 2012, 2% in 2014 and 1% in 2016. From 2014-2016 in England, implementation of the smoke-free policy was associated with a 4% absolute reduction – or a 72% relative reduction – in the percentage of children self-reporting exposure.

The authors acknowledged their study’s limitations, including exposure being based on self-reporting alone and the analyses using only three data points. “Future analyses with more data are recommended,” they wrote, “and may provide discrepant results.”

The study was funded by the National Institute for Health Research School for Public Health Research. One author was funded by the Medical Research Council on a clinician scientist fellowship. The others reported no potential conflicts of interest.

SOURCE: Laverty AA et al. Thorax. 2020 Jan 27. doi: 10.1136/thoraxjnl-2019-213998.

England’s ban on smoking in cars carrying children led to a 72% relative reduction in the percentage of children self-reporting exposure to tobacco smoke in cars.

“Given children’s known vulnerability to secondhand smoke, reductions in exposure will probably result in improved health,” wrote Anthony A. Laverty, PhD, of Imperial College London and coauthors. Their findings were published in Thorax.

To determine the impact of a 2015 ban on smoking in cars carrying children in England and a 2016 ban in Scotland, the researchers analyzed survey data from 2012, 2014, and 2016 for each of the two countries. In England, children aged 13-15 years were asked, “In the past year, how often were you in a car with somebody smoking?” In Scotland, they were asked, “Are you regularly exposed to other people’s tobacco smoke in any of these places?” with cars/vehicles being one of the options.

Overall, 15,318 responses were received in England and 822 were received in Scotland. In England, self-reported regular exposure to smoke in cars was 6% in 2012, 6% in 2014 and 2% in 2016. In Scotland, it was 3% in 2012, 2% in 2014 and 1% in 2016. From 2014-2016 in England, implementation of the smoke-free policy was associated with a 4% absolute reduction – or a 72% relative reduction – in the percentage of children self-reporting exposure.

The authors acknowledged their study’s limitations, including exposure being based on self-reporting alone and the analyses using only three data points. “Future analyses with more data are recommended,” they wrote, “and may provide discrepant results.”

The study was funded by the National Institute for Health Research School for Public Health Research. One author was funded by the Medical Research Council on a clinician scientist fellowship. The others reported no potential conflicts of interest.

SOURCE: Laverty AA et al. Thorax. 2020 Jan 27. doi: 10.1136/thoraxjnl-2019-213998.

England’s ban on smoking in cars carrying children led to a 72% relative reduction in the percentage of children self-reporting exposure to tobacco smoke in cars.

“Given children’s known vulnerability to secondhand smoke, reductions in exposure will probably result in improved health,” wrote Anthony A. Laverty, PhD, of Imperial College London and coauthors. Their findings were published in Thorax.

To determine the impact of a 2015 ban on smoking in cars carrying children in England and a 2016 ban in Scotland, the researchers analyzed survey data from 2012, 2014, and 2016 for each of the two countries. In England, children aged 13-15 years were asked, “In the past year, how often were you in a car with somebody smoking?” In Scotland, they were asked, “Are you regularly exposed to other people’s tobacco smoke in any of these places?” with cars/vehicles being one of the options.

Overall, 15,318 responses were received in England and 822 were received in Scotland. In England, self-reported regular exposure to smoke in cars was 6% in 2012, 6% in 2014 and 2% in 2016. In Scotland, it was 3% in 2012, 2% in 2014 and 1% in 2016. From 2014-2016 in England, implementation of the smoke-free policy was associated with a 4% absolute reduction – or a 72% relative reduction – in the percentage of children self-reporting exposure.

The authors acknowledged their study’s limitations, including exposure being based on self-reporting alone and the analyses using only three data points. “Future analyses with more data are recommended,” they wrote, “and may provide discrepant results.”

The study was funded by the National Institute for Health Research School for Public Health Research. One author was funded by the Medical Research Council on a clinician scientist fellowship. The others reported no potential conflicts of interest.

SOURCE: Laverty AA et al. Thorax. 2020 Jan 27. doi: 10.1136/thoraxjnl-2019-213998.

In new guidelines, the American Society of Clinical Oncology recommends offering germline genetic testing for BRCA1, BRCA2, and other ovarian cancer susceptibility genes to all women diagnosed with epithelial ovarian cancer, regardless of their clinical features or family history.

Testing should be offered at diagnosis or as soon as possible after that, Panagiotis A. Konstantinopoulos, MD, PhD, of the Dana-Farber Cancer Institute in Boston, and colleagues wrote in the Journal of Clinical Oncology.

For patients who do not carry a germline pathogenic or likely pathogenic BRCA1/2 variant, the guidelines recommend offering somatic tumor testing for BRCA1/2 pathogenic or likely pathogenic variants. This testing can be offered at the time of disease recurrence after up-front therapy.

The guidelines also recommend somatic tumor testing for mismatch repair deficiency in patients diagnosed with clear cell, endometrioid, or mucinous ovarian cancer. This testing may be offered to patients with other histologic types of epithelial ovarian cancer as well.

Genetic testing, as well as genetic risk evaluation and counseling, should be offered to first- or second-degree blood relatives of a patient with ovarian cancer and a known germline pathogenic cancer susceptibility gene variant, according to the guidelines.

According to the guidelines, genetic evaluations should be conducted in cooperation with other health care providers who are “familiar with the diagnosis and management of hereditary cancer syndromes to determine the most appropriate testing strategy and discuss implications of the findings.”

Patients with identified germline or somatic pathogenic or likely pathogenic BRCA1/2 variants should receive treatments approved for them by the Food and Drug Administration, according to the guidelines. The authors note that patients with these variants have responded well to FDA-approved poly (ADP-ribose) polymerase inhibitors, including niraparib (Zejula), olaparib (Lynparza), and rucaparib (Rubraca).

The guidelines also state that mismatch repair deficiency qualifies for FDA-approved treatment, so patients with recurrent epithelial ovarian cancer and mismatch repair deficiency should receive FDA-approved treatments under their labeled indications.

The guidelines note that clinical decisions should not be based on a variant of uncertain significance. When a patient has such a variant, “clinical features and family history should inform clinical decision making,” according to the guidelines.

Dr. Konstantinopoulos and colleagues formulated the guidelines after reviewing data from 19 studies, including 6 meta-analyses; 11 randomized, controlled trials; and 2 observational studies.

The authors reported relationships with a range of pharmaceutical companies, including those that market drugs for epithelial ovarian cancer.

SOURCE: Konstantinopoulos PA et al. J Clin Oncol. 2020 Jan 27. doi: 10.1200/JCO.19.02960.

In new guidelines, the American Society of Clinical Oncology recommends offering germline genetic testing for BRCA1, BRCA2, and other ovarian cancer susceptibility genes to all women diagnosed with epithelial ovarian cancer, regardless of their clinical features or family history.

Testing should be offered at diagnosis or as soon as possible after that, Panagiotis A. Konstantinopoulos, MD, PhD, of the Dana-Farber Cancer Institute in Boston, and colleagues wrote in the Journal of Clinical Oncology.

For patients who do not carry a germline pathogenic or likely pathogenic BRCA1/2 variant, the guidelines recommend offering somatic tumor testing for BRCA1/2 pathogenic or likely pathogenic variants. This testing can be offered at the time of disease recurrence after up-front therapy.

The guidelines also recommend somatic tumor testing for mismatch repair deficiency in patients diagnosed with clear cell, endometrioid, or mucinous ovarian cancer. This testing may be offered to patients with other histologic types of epithelial ovarian cancer as well.

Genetic testing, as well as genetic risk evaluation and counseling, should be offered to first- or second-degree blood relatives of a patient with ovarian cancer and a known germline pathogenic cancer susceptibility gene variant, according to the guidelines.

According to the guidelines, genetic evaluations should be conducted in cooperation with other health care providers who are “familiar with the diagnosis and management of hereditary cancer syndromes to determine the most appropriate testing strategy and discuss implications of the findings.”

Patients with identified germline or somatic pathogenic or likely pathogenic BRCA1/2 variants should receive treatments approved for them by the Food and Drug Administration, according to the guidelines. The authors note that patients with these variants have responded well to FDA-approved poly (ADP-ribose) polymerase inhibitors, including niraparib (Zejula), olaparib (Lynparza), and rucaparib (Rubraca).

The guidelines also state that mismatch repair deficiency qualifies for FDA-approved treatment, so patients with recurrent epithelial ovarian cancer and mismatch repair deficiency should receive FDA-approved treatments under their labeled indications.

The guidelines note that clinical decisions should not be based on a variant of uncertain significance. When a patient has such a variant, “clinical features and family history should inform clinical decision making,” according to the guidelines.

Dr. Konstantinopoulos and colleagues formulated the guidelines after reviewing data from 19 studies, including 6 meta-analyses; 11 randomized, controlled trials; and 2 observational studies.

The authors reported relationships with a range of pharmaceutical companies, including those that market drugs for epithelial ovarian cancer.

SOURCE: Konstantinopoulos PA et al. J Clin Oncol. 2020 Jan 27. doi: 10.1200/JCO.19.02960.

In new guidelines, the American Society of Clinical Oncology recommends offering germline genetic testing for BRCA1, BRCA2, and other ovarian cancer susceptibility genes to all women diagnosed with epithelial ovarian cancer, regardless of their clinical features or family history.

Testing should be offered at diagnosis or as soon as possible after that, Panagiotis A. Konstantinopoulos, MD, PhD, of the Dana-Farber Cancer Institute in Boston, and colleagues wrote in the Journal of Clinical Oncology.

For patients who do not carry a germline pathogenic or likely pathogenic BRCA1/2 variant, the guidelines recommend offering somatic tumor testing for BRCA1/2 pathogenic or likely pathogenic variants. This testing can be offered at the time of disease recurrence after up-front therapy.

The guidelines also recommend somatic tumor testing for mismatch repair deficiency in patients diagnosed with clear cell, endometrioid, or mucinous ovarian cancer. This testing may be offered to patients with other histologic types of epithelial ovarian cancer as well.

Genetic testing, as well as genetic risk evaluation and counseling, should be offered to first- or second-degree blood relatives of a patient with ovarian cancer and a known germline pathogenic cancer susceptibility gene variant, according to the guidelines.

According to the guidelines, genetic evaluations should be conducted in cooperation with other health care providers who are “familiar with the diagnosis and management of hereditary cancer syndromes to determine the most appropriate testing strategy and discuss implications of the findings.”

Patients with identified germline or somatic pathogenic or likely pathogenic BRCA1/2 variants should receive treatments approved for them by the Food and Drug Administration, according to the guidelines. The authors note that patients with these variants have responded well to FDA-approved poly (ADP-ribose) polymerase inhibitors, including niraparib (Zejula), olaparib (Lynparza), and rucaparib (Rubraca).

The guidelines also state that mismatch repair deficiency qualifies for FDA-approved treatment, so patients with recurrent epithelial ovarian cancer and mismatch repair deficiency should receive FDA-approved treatments under their labeled indications.

The guidelines note that clinical decisions should not be based on a variant of uncertain significance. When a patient has such a variant, “clinical features and family history should inform clinical decision making,” according to the guidelines.

Dr. Konstantinopoulos and colleagues formulated the guidelines after reviewing data from 19 studies, including 6 meta-analyses; 11 randomized, controlled trials; and 2 observational studies.

The authors reported relationships with a range of pharmaceutical companies, including those that market drugs for epithelial ovarian cancer.

SOURCE: Konstantinopoulos PA et al. J Clin Oncol. 2020 Jan 27. doi: 10.1200/JCO.19.02960.

WASHINGTON – Pharmacologic treatment of gestational diabetes remains controversial, with the American College of Obstetricians and Gynecologists and the American Diabetes Association firmly recommending insulin as the preferred first-line pharmacologic therapy, and the Society of Maternal-Fetal Medicine more accepting of metformin as a “reasonable and safe first-line” alternative to insulin and stating that there are no strong data supporting metformin over the sulfonylurea glyburide.

If there’s one main take-away, Mark B. Landon, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America, it was that “the primary concern” about the use of oral agents for treating gestational diabetes mellitus (GDM) is that there is limited long-term follow-up of exposed offspring.

“The claim that long-term safety data are not available for any oral agent is probably the most valid warning [of any of the concerns voiced by professional organizations],” said Dr. Landon, Richard L. Meiling professor and chair of the department of obstetrics and gynecology at The Ohio State University Wexner Medical Center, Columbus.

Otherwise, he said, there are not enough data to firmly prioritize the drugs most commonly used for GDM, and “the superiority of insulin over oral agents simply remains questionable.”

ACOG’s 2017 level A recommendation for insulin as the first-line option when pharmacologic treatment is needed for treating GDM (Obstet Gynecol. 2017;130[1]:e17-37) was followed in 2018 by another updated practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64) that considered several meta-analyses published in 2017 and reiterated a preference for insulin.

Those recent meta-analyses of pharmacologic treatment of GDM show that the available literature is generally of “poor trial quality,” and that studies are small and not designed to assess equivalence or noninferiority, Mark Turrentine, MD, chair of ACOG’s committee on practice bulletins, said in an interview. “Taking that into account and [considering] that oral antidiabetic medications are not approved by the Food and Drug Administration [for the treatment of GDM], that they cross the placenta, and that we currently lack long-term neonatal safety data ... we felt that insulin is the preferred treatment.”

In its 2017 and 2018 bulletins, ACOG said that metformin is a “reasonable alternative choice” for women who decline insulin therapy or who may be unable to safely administer it (a level B recommendation). The 2018 practice bulletin mentions one additional factor: affordability. “Insurance companies aren’t always covering [insulin],” said Dr. Turrentine, of the department of obstetrics and gynecology, Baylor College of Medicine, Houston. “It’s a challenge – no question.”

ACOG says glyburide should not be recommended as a first-line pharmacologic treatment, “because, in most studies, it does not yield outcomes equivalent to insulin or metformin,” Dr. Turrentine emphasized.
 

Glyburide’s role

Dr. Landon took issue with ACOG’s stance on the sulfonylurea. “Frankly, I think this [conclusion] is debatable,” he said. The trend in the United States – “at least after the 2017 ACOG document came out”– has been toward use of metformin over glyburide when an oral agent is [used], but “I think glyburide has been unfairly trashed. It probably still has a place.”

As Dr. Landon sees it, research published in 2015 put a damper on the use of glyburide, which “had become the number one agent” after an earlier, seminal trial, led by Oded Langer, MD, had shown equivalent glycemic control in about 400 women with GDM who were randomized to receive either insulin or glyburide (N Engl J Med. 2000;343;1134-8). The trial was not powered to evaluate other outcomes, but there were no significant differences in neonatal complications, Dr. Landon said.

One of the 2015 studies – a large, retrospective, population-based study of more than 9,000 women with GDM treated with glyburide or insulin – showed a higher risk of admission to the neonatal intensive care unit (relative risk, 1.41), hypoglycemia in the newborn (RR, 1.40), and large-for-gestational age (RR, 1.43) with glyburide, compared with insulin (JAMA Pediatr. 2015;169[5]:452-8).

A meta-analysis of glyburide, metformin, and insulin showed significant differences between glyburide and insulin in birth weight, macrosomia (RR, 2.62), and neonatal hypoglycemia (RR, 2.04; BMJ. 2015;350;h102). However, “this was basically a conglomeration of studies with about 50 [individuals] in each arm, and in which entry criteria for the diagnosis of GDM were rather heterogeneous,” said Dr. Landon. “There are real problems with this and other meta-analyses.”

The authors of a 2018 multicenter, noninferiority, randomized, controlled trial of about 900 women concluded that their study failed to show that the use of glyburide, compared with insulin, does not result in a greater frequency of perinatal complications. The authors also wrote, however, that the “increase in perinatal complications [with glyburide] may be no more than 10.5%, compared with insulin” (JAMA. 2018;319[17]:1773-80).

That increase, Dr. Landon said, was “not an absolute 10%, but 10% of the complication rate, which probably translates to about 2%.” The only component of a composite outcome (including macrosomia, hypoglycemia, and hyperbilirubinemia) that was significantly different, he noted, was hypoglycemia, which affected 12.2% of neonates in the glyburide group and 7.2% in the insulin group.

Glyburide’s role may well be substantiated in the future, Dr. Landon said during a discussion period at the meeting, through research underway at the University of Pittsburgh aimed at tailoring treatment to the underlying pathophysiology of a patient’s GDM.

The MATCh-GDM study (Metabolic Analysis for Treatment Choice in GDM) is randomizing women to receive usual, unmatched treatment or treatment matched to GDM mechanism – metformin for predominant insulin resistance, glyburide or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. The study’s principal investigator, Maisa Feghali, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh, stressed in a presentation on the study that GDM is a heterogeneous condition and that research is needed to understand the impact of GDM subtypes on treatment response.
 

Metformin outcomes

Concerns about the impact of metformin on short-term perinatal outcomes focus on preterm birth, Dr. Landon said. The only study to date that has shown an increased rate of prematurity, however, is the “seminal” Metformin in Gestational Diabetes (MiG) trial led by Janet A. Rowan, MBChB, that randomized 751 women with GDM in Australia and New Zealand to treatment with metformin or insulin. The researchers found no significant differences between a composite of neonatal complications but did establish that severe hypoglycemia was less common in the metformin group and preterm birth was more common (N Engl J Med. 2008;358:2003-15).

A 2016 systematic review and meta-analysis of short- and long-term outcomes of metformin, compared with insulin, found that metformin did not increase preterm delivery (Diabet Med. 2017;34[1]:27-36). And while the 2015 BMJ meta-analysis found that metformin was associated with higher rates of preterm birth (RR, 1.50), the increased risk “was all driven by the Rowan study,” Dr. Landon said. The 2015 meta-analysis also found that metformin was associated with less maternal weight gain and fewer infants who were large for gestational age.

Metformin is also tainted by high rates of failure in GDM. In the 2008 Rowan study, 46% of patients on metformin failed to achieve glycemic control. “But this is a classic half-full, half-empty [phenomena],” Dr. Landon said. “Some people say this isn’t good, but on the other hand, 54% avoided insulin.”

Indeed, the Society of Maternal-Fetal Medicine (SMFM), in its 2018 statement on the pharmacologic treatment of GDM, said that oral hypoglycemic agents that are used as monotherapy work in “more than half” of GDM pregnancies. The need for adjunctive insulin to achieve glycemic control ranges between 26% and 46% for women using metformin, and 4% and 16% for women using glyburide, it says.

In the society’s view, recent meta-analyses and systemic reviews “support the efficacy and safety of oral agents,” and “although concerns have been raised for more frequent adverse neonatal outcomes with glyburide, including macrosomia and hypoglycemia, the evidence of benefit of one oral agent over the other remains limited.”

The society says that the difference between its statement and the ACOG recommendations is “based on the values placed by different experts and providers on the available evidence,” and it adds that more long-term data are needed.

But as Dr. Landon said, the SMFM is “a little more forgiving” in its interpretation of a limited body of literature. And clinicians, in the meantime, have to navigate the controversy. “The professional organizations don’t make it easy for [us],” he said. At this point, “insulin does not cross the placenta, and the oral agents do cross it. Informed consent is absolutely necessary when choosing oral agents for treating GDM.”
 

Offspring well-being

Of greater concern than neonatal outcomes are the potential long-term issues for offspring, Dr. Landon said. On the one hand, it is theorized that metformin may protect beta-cell function in offspring and thereby reduce the cross-generational effects of obesity and type 2 diabetes. On the other hand, it is theorized that the drug may cause a decrease in cell-cycle proliferation, which could have “unknown fetal programming effects,” and it may inhibit the mTOR signaling pathway, thus restricting the transport of glucose and amino acids across the placenta, he said. (Findings from in vitro research have suggested that glyburide treatment in GDM might be associated with enhanced transport across the placenta, he noted.)

Long-term follow-up studies of offspring are “clearly needed,” Dr. Landon said. At this point, in regard to long-term safety, he and other experts are concerned primarily about the potential for obesity and metabolic dysfunction in offspring who are exposed to metformin in utero. They are watching follow-up from Dr. Rowan’s MiG trial, as well as elsewhere in the literature, on metformin-exposed offspring from mothers with polycystic ovary syndrome.

A follow-up analysis of offspring from the MiG trial found that children of women with GDM who were exposed to metformin had larger measures of subcutaneous fat at age 2 years, compared with children of mothers treated with insulin alone, but that overall body fat was the same, Dr. Landon noted. The investigators postulated that these children may have less visceral fat and a more favorable pattern of fat distribution (Diab Care. 2011;34:2279-84).

A recently published follow-up analysis of two randomized, controlled trials of women with polycystic ovary syndrome is cause for more concern, he said. That analysis showed that offspring exposed to metformin in utero had a higher body mass index and an increased prevalence of obesity or overweight at age 4 years, compared with placebo groups (J Clin Endocrinol Metab. 2018;103[4]:1612-21).

That analysis of metformin-exposed offspring in the context of polycystic ovary syndrome was published after the SMFM statement, as was another follow-up analysis of MiG trial offspring – this one, at ages 7-9 years – that showed an increase in weight, size, and fat mass in one of two subsets analyzed, despite no difference in large-for-gestational age rates between the metformin- and insulin-exposed offspring (BMJ Open Diabetes Res Care. 2018;6[1]: e000456).

In 2018, a group of 17 prominent diabetes and maternal-fetal medicine researchers cited these findings in a response to the SMFM statement and cautioned against the widespread adoption of metformin use during pregnancy, writing that, based on “both pharmacologic and randomized trial evidence that metformin may create an atypical intrauterine environment ... we believe it is premature to embrace metformin as equivalent to insulin or as superior to glyburide, and that patients should be counseled on the limited long-term safety data and potential for adverse childhood metabolic effects” (Am J Obstet Gynecol. 2018;219[4]:367.e1-7).

WASHINGTON – Pharmacologic treatment of gestational diabetes remains controversial, with the American College of Obstetricians and Gynecologists and the American Diabetes Association firmly recommending insulin as the preferred first-line pharmacologic therapy, and the Society of Maternal-Fetal Medicine more accepting of metformin as a “reasonable and safe first-line” alternative to insulin and stating that there are no strong data supporting metformin over the sulfonylurea glyburide.

If there’s one main take-away, Mark B. Landon, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America, it was that “the primary concern” about the use of oral agents for treating gestational diabetes mellitus (GDM) is that there is limited long-term follow-up of exposed offspring.

“The claim that long-term safety data are not available for any oral agent is probably the most valid warning [of any of the concerns voiced by professional organizations],” said Dr. Landon, Richard L. Meiling professor and chair of the department of obstetrics and gynecology at The Ohio State University Wexner Medical Center, Columbus.

Otherwise, he said, there are not enough data to firmly prioritize the drugs most commonly used for GDM, and “the superiority of insulin over oral agents simply remains questionable.”

ACOG’s 2017 level A recommendation for insulin as the first-line option when pharmacologic treatment is needed for treating GDM (Obstet Gynecol. 2017;130[1]:e17-37) was followed in 2018 by another updated practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64) that considered several meta-analyses published in 2017 and reiterated a preference for insulin.

Those recent meta-analyses of pharmacologic treatment of GDM show that the available literature is generally of “poor trial quality,” and that studies are small and not designed to assess equivalence or noninferiority, Mark Turrentine, MD, chair of ACOG’s committee on practice bulletins, said in an interview. “Taking that into account and [considering] that oral antidiabetic medications are not approved by the Food and Drug Administration [for the treatment of GDM], that they cross the placenta, and that we currently lack long-term neonatal safety data ... we felt that insulin is the preferred treatment.”

In its 2017 and 2018 bulletins, ACOG said that metformin is a “reasonable alternative choice” for women who decline insulin therapy or who may be unable to safely administer it (a level B recommendation). The 2018 practice bulletin mentions one additional factor: affordability. “Insurance companies aren’t always covering [insulin],” said Dr. Turrentine, of the department of obstetrics and gynecology, Baylor College of Medicine, Houston. “It’s a challenge – no question.”

ACOG says glyburide should not be recommended as a first-line pharmacologic treatment, “because, in most studies, it does not yield outcomes equivalent to insulin or metformin,” Dr. Turrentine emphasized.
 

Glyburide’s role

Dr. Landon took issue with ACOG’s stance on the sulfonylurea. “Frankly, I think this [conclusion] is debatable,” he said. The trend in the United States – “at least after the 2017 ACOG document came out”– has been toward use of metformin over glyburide when an oral agent is [used], but “I think glyburide has been unfairly trashed. It probably still has a place.”

As Dr. Landon sees it, research published in 2015 put a damper on the use of glyburide, which “had become the number one agent” after an earlier, seminal trial, led by Oded Langer, MD, had shown equivalent glycemic control in about 400 women with GDM who were randomized to receive either insulin or glyburide (N Engl J Med. 2000;343;1134-8). The trial was not powered to evaluate other outcomes, but there were no significant differences in neonatal complications, Dr. Landon said.

One of the 2015 studies – a large, retrospective, population-based study of more than 9,000 women with GDM treated with glyburide or insulin – showed a higher risk of admission to the neonatal intensive care unit (relative risk, 1.41), hypoglycemia in the newborn (RR, 1.40), and large-for-gestational age (RR, 1.43) with glyburide, compared with insulin (JAMA Pediatr. 2015;169[5]:452-8).

A meta-analysis of glyburide, metformin, and insulin showed significant differences between glyburide and insulin in birth weight, macrosomia (RR, 2.62), and neonatal hypoglycemia (RR, 2.04; BMJ. 2015;350;h102). However, “this was basically a conglomeration of studies with about 50 [individuals] in each arm, and in which entry criteria for the diagnosis of GDM were rather heterogeneous,” said Dr. Landon. “There are real problems with this and other meta-analyses.”

The authors of a 2018 multicenter, noninferiority, randomized, controlled trial of about 900 women concluded that their study failed to show that the use of glyburide, compared with insulin, does not result in a greater frequency of perinatal complications. The authors also wrote, however, that the “increase in perinatal complications [with glyburide] may be no more than 10.5%, compared with insulin” (JAMA. 2018;319[17]:1773-80).

That increase, Dr. Landon said, was “not an absolute 10%, but 10% of the complication rate, which probably translates to about 2%.” The only component of a composite outcome (including macrosomia, hypoglycemia, and hyperbilirubinemia) that was significantly different, he noted, was hypoglycemia, which affected 12.2% of neonates in the glyburide group and 7.2% in the insulin group.

Glyburide’s role may well be substantiated in the future, Dr. Landon said during a discussion period at the meeting, through research underway at the University of Pittsburgh aimed at tailoring treatment to the underlying pathophysiology of a patient’s GDM.

The MATCh-GDM study (Metabolic Analysis for Treatment Choice in GDM) is randomizing women to receive usual, unmatched treatment or treatment matched to GDM mechanism – metformin for predominant insulin resistance, glyburide or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. The study’s principal investigator, Maisa Feghali, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh, stressed in a presentation on the study that GDM is a heterogeneous condition and that research is needed to understand the impact of GDM subtypes on treatment response.
 

Metformin outcomes

Concerns about the impact of metformin on short-term perinatal outcomes focus on preterm birth, Dr. Landon said. The only study to date that has shown an increased rate of prematurity, however, is the “seminal” Metformin in Gestational Diabetes (MiG) trial led by Janet A. Rowan, MBChB, that randomized 751 women with GDM in Australia and New Zealand to treatment with metformin or insulin. The researchers found no significant differences between a composite of neonatal complications but did establish that severe hypoglycemia was less common in the metformin group and preterm birth was more common (N Engl J Med. 2008;358:2003-15).

A 2016 systematic review and meta-analysis of short- and long-term outcomes of metformin, compared with insulin, found that metformin did not increase preterm delivery (Diabet Med. 2017;34[1]:27-36). And while the 2015 BMJ meta-analysis found that metformin was associated with higher rates of preterm birth (RR, 1.50), the increased risk “was all driven by the Rowan study,” Dr. Landon said. The 2015 meta-analysis also found that metformin was associated with less maternal weight gain and fewer infants who were large for gestational age.

Metformin is also tainted by high rates of failure in GDM. In the 2008 Rowan study, 46% of patients on metformin failed to achieve glycemic control. “But this is a classic half-full, half-empty [phenomena],” Dr. Landon said. “Some people say this isn’t good, but on the other hand, 54% avoided insulin.”

Indeed, the Society of Maternal-Fetal Medicine (SMFM), in its 2018 statement on the pharmacologic treatment of GDM, said that oral hypoglycemic agents that are used as monotherapy work in “more than half” of GDM pregnancies. The need for adjunctive insulin to achieve glycemic control ranges between 26% and 46% for women using metformin, and 4% and 16% for women using glyburide, it says.

In the society’s view, recent meta-analyses and systemic reviews “support the efficacy and safety of oral agents,” and “although concerns have been raised for more frequent adverse neonatal outcomes with glyburide, including macrosomia and hypoglycemia, the evidence of benefit of one oral agent over the other remains limited.”

The society says that the difference between its statement and the ACOG recommendations is “based on the values placed by different experts and providers on the available evidence,” and it adds that more long-term data are needed.

But as Dr. Landon said, the SMFM is “a little more forgiving” in its interpretation of a limited body of literature. And clinicians, in the meantime, have to navigate the controversy. “The professional organizations don’t make it easy for [us],” he said. At this point, “insulin does not cross the placenta, and the oral agents do cross it. Informed consent is absolutely necessary when choosing oral agents for treating GDM.”
 

Offspring well-being

Of greater concern than neonatal outcomes are the potential long-term issues for offspring, Dr. Landon said. On the one hand, it is theorized that metformin may protect beta-cell function in offspring and thereby reduce the cross-generational effects of obesity and type 2 diabetes. On the other hand, it is theorized that the drug may cause a decrease in cell-cycle proliferation, which could have “unknown fetal programming effects,” and it may inhibit the mTOR signaling pathway, thus restricting the transport of glucose and amino acids across the placenta, he said. (Findings from in vitro research have suggested that glyburide treatment in GDM might be associated with enhanced transport across the placenta, he noted.)

Long-term follow-up studies of offspring are “clearly needed,” Dr. Landon said. At this point, in regard to long-term safety, he and other experts are concerned primarily about the potential for obesity and metabolic dysfunction in offspring who are exposed to metformin in utero. They are watching follow-up from Dr. Rowan’s MiG trial, as well as elsewhere in the literature, on metformin-exposed offspring from mothers with polycystic ovary syndrome.

A follow-up analysis of offspring from the MiG trial found that children of women with GDM who were exposed to metformin had larger measures of subcutaneous fat at age 2 years, compared with children of mothers treated with insulin alone, but that overall body fat was the same, Dr. Landon noted. The investigators postulated that these children may have less visceral fat and a more favorable pattern of fat distribution (Diab Care. 2011;34:2279-84).

A recently published follow-up analysis of two randomized, controlled trials of women with polycystic ovary syndrome is cause for more concern, he said. That analysis showed that offspring exposed to metformin in utero had a higher body mass index and an increased prevalence of obesity or overweight at age 4 years, compared with placebo groups (J Clin Endocrinol Metab. 2018;103[4]:1612-21).

That analysis of metformin-exposed offspring in the context of polycystic ovary syndrome was published after the SMFM statement, as was another follow-up analysis of MiG trial offspring – this one, at ages 7-9 years – that showed an increase in weight, size, and fat mass in one of two subsets analyzed, despite no difference in large-for-gestational age rates between the metformin- and insulin-exposed offspring (BMJ Open Diabetes Res Care. 2018;6[1]: e000456).

In 2018, a group of 17 prominent diabetes and maternal-fetal medicine researchers cited these findings in a response to the SMFM statement and cautioned against the widespread adoption of metformin use during pregnancy, writing that, based on “both pharmacologic and randomized trial evidence that metformin may create an atypical intrauterine environment ... we believe it is premature to embrace metformin as equivalent to insulin or as superior to glyburide, and that patients should be counseled on the limited long-term safety data and potential for adverse childhood metabolic effects” (Am J Obstet Gynecol. 2018;219[4]:367.e1-7).

WASHINGTON – Pharmacologic treatment of gestational diabetes remains controversial, with the American College of Obstetricians and Gynecologists and the American Diabetes Association firmly recommending insulin as the preferred first-line pharmacologic therapy, and the Society of Maternal-Fetal Medicine more accepting of metformin as a “reasonable and safe first-line” alternative to insulin and stating that there are no strong data supporting metformin over the sulfonylurea glyburide.

If there’s one main take-away, Mark B. Landon, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America, it was that “the primary concern” about the use of oral agents for treating gestational diabetes mellitus (GDM) is that there is limited long-term follow-up of exposed offspring.

“The claim that long-term safety data are not available for any oral agent is probably the most valid warning [of any of the concerns voiced by professional organizations],” said Dr. Landon, Richard L. Meiling professor and chair of the department of obstetrics and gynecology at The Ohio State University Wexner Medical Center, Columbus.

Otherwise, he said, there are not enough data to firmly prioritize the drugs most commonly used for GDM, and “the superiority of insulin over oral agents simply remains questionable.”

ACOG’s 2017 level A recommendation for insulin as the first-line option when pharmacologic treatment is needed for treating GDM (Obstet Gynecol. 2017;130[1]:e17-37) was followed in 2018 by another updated practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64) that considered several meta-analyses published in 2017 and reiterated a preference for insulin.

Those recent meta-analyses of pharmacologic treatment of GDM show that the available literature is generally of “poor trial quality,” and that studies are small and not designed to assess equivalence or noninferiority, Mark Turrentine, MD, chair of ACOG’s committee on practice bulletins, said in an interview. “Taking that into account and [considering] that oral antidiabetic medications are not approved by the Food and Drug Administration [for the treatment of GDM], that they cross the placenta, and that we currently lack long-term neonatal safety data ... we felt that insulin is the preferred treatment.”

In its 2017 and 2018 bulletins, ACOG said that metformin is a “reasonable alternative choice” for women who decline insulin therapy or who may be unable to safely administer it (a level B recommendation). The 2018 practice bulletin mentions one additional factor: affordability. “Insurance companies aren’t always covering [insulin],” said Dr. Turrentine, of the department of obstetrics and gynecology, Baylor College of Medicine, Houston. “It’s a challenge – no question.”

ACOG says glyburide should not be recommended as a first-line pharmacologic treatment, “because, in most studies, it does not yield outcomes equivalent to insulin or metformin,” Dr. Turrentine emphasized.
 

Glyburide’s role

Dr. Landon took issue with ACOG’s stance on the sulfonylurea. “Frankly, I think this [conclusion] is debatable,” he said. The trend in the United States – “at least after the 2017 ACOG document came out”– has been toward use of metformin over glyburide when an oral agent is [used], but “I think glyburide has been unfairly trashed. It probably still has a place.”

As Dr. Landon sees it, research published in 2015 put a damper on the use of glyburide, which “had become the number one agent” after an earlier, seminal trial, led by Oded Langer, MD, had shown equivalent glycemic control in about 400 women with GDM who were randomized to receive either insulin or glyburide (N Engl J Med. 2000;343;1134-8). The trial was not powered to evaluate other outcomes, but there were no significant differences in neonatal complications, Dr. Landon said.

One of the 2015 studies – a large, retrospective, population-based study of more than 9,000 women with GDM treated with glyburide or insulin – showed a higher risk of admission to the neonatal intensive care unit (relative risk, 1.41), hypoglycemia in the newborn (RR, 1.40), and large-for-gestational age (RR, 1.43) with glyburide, compared with insulin (JAMA Pediatr. 2015;169[5]:452-8).

A meta-analysis of glyburide, metformin, and insulin showed significant differences between glyburide and insulin in birth weight, macrosomia (RR, 2.62), and neonatal hypoglycemia (RR, 2.04; BMJ. 2015;350;h102). However, “this was basically a conglomeration of studies with about 50 [individuals] in each arm, and in which entry criteria for the diagnosis of GDM were rather heterogeneous,” said Dr. Landon. “There are real problems with this and other meta-analyses.”

The authors of a 2018 multicenter, noninferiority, randomized, controlled trial of about 900 women concluded that their study failed to show that the use of glyburide, compared with insulin, does not result in a greater frequency of perinatal complications. The authors also wrote, however, that the “increase in perinatal complications [with glyburide] may be no more than 10.5%, compared with insulin” (JAMA. 2018;319[17]:1773-80).

That increase, Dr. Landon said, was “not an absolute 10%, but 10% of the complication rate, which probably translates to about 2%.” The only component of a composite outcome (including macrosomia, hypoglycemia, and hyperbilirubinemia) that was significantly different, he noted, was hypoglycemia, which affected 12.2% of neonates in the glyburide group and 7.2% in the insulin group.

Glyburide’s role may well be substantiated in the future, Dr. Landon said during a discussion period at the meeting, through research underway at the University of Pittsburgh aimed at tailoring treatment to the underlying pathophysiology of a patient’s GDM.

The MATCh-GDM study (Metabolic Analysis for Treatment Choice in GDM) is randomizing women to receive usual, unmatched treatment or treatment matched to GDM mechanism – metformin for predominant insulin resistance, glyburide or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. The study’s principal investigator, Maisa Feghali, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh, stressed in a presentation on the study that GDM is a heterogeneous condition and that research is needed to understand the impact of GDM subtypes on treatment response.
 

Metformin outcomes

Concerns about the impact of metformin on short-term perinatal outcomes focus on preterm birth, Dr. Landon said. The only study to date that has shown an increased rate of prematurity, however, is the “seminal” Metformin in Gestational Diabetes (MiG) trial led by Janet A. Rowan, MBChB, that randomized 751 women with GDM in Australia and New Zealand to treatment with metformin or insulin. The researchers found no significant differences between a composite of neonatal complications but did establish that severe hypoglycemia was less common in the metformin group and preterm birth was more common (N Engl J Med. 2008;358:2003-15).

A 2016 systematic review and meta-analysis of short- and long-term outcomes of metformin, compared with insulin, found that metformin did not increase preterm delivery (Diabet Med. 2017;34[1]:27-36). And while the 2015 BMJ meta-analysis found that metformin was associated with higher rates of preterm birth (RR, 1.50), the increased risk “was all driven by the Rowan study,” Dr. Landon said. The 2015 meta-analysis also found that metformin was associated with less maternal weight gain and fewer infants who were large for gestational age.

Metformin is also tainted by high rates of failure in GDM. In the 2008 Rowan study, 46% of patients on metformin failed to achieve glycemic control. “But this is a classic half-full, half-empty [phenomena],” Dr. Landon said. “Some people say this isn’t good, but on the other hand, 54% avoided insulin.”

Indeed, the Society of Maternal-Fetal Medicine (SMFM), in its 2018 statement on the pharmacologic treatment of GDM, said that oral hypoglycemic agents that are used as monotherapy work in “more than half” of GDM pregnancies. The need for adjunctive insulin to achieve glycemic control ranges between 26% and 46% for women using metformin, and 4% and 16% for women using glyburide, it says.

In the society’s view, recent meta-analyses and systemic reviews “support the efficacy and safety of oral agents,” and “although concerns have been raised for more frequent adverse neonatal outcomes with glyburide, including macrosomia and hypoglycemia, the evidence of benefit of one oral agent over the other remains limited.”

The society says that the difference between its statement and the ACOG recommendations is “based on the values placed by different experts and providers on the available evidence,” and it adds that more long-term data are needed.

But as Dr. Landon said, the SMFM is “a little more forgiving” in its interpretation of a limited body of literature. And clinicians, in the meantime, have to navigate the controversy. “The professional organizations don’t make it easy for [us],” he said. At this point, “insulin does not cross the placenta, and the oral agents do cross it. Informed consent is absolutely necessary when choosing oral agents for treating GDM.”
 

Offspring well-being

Of greater concern than neonatal outcomes are the potential long-term issues for offspring, Dr. Landon said. On the one hand, it is theorized that metformin may protect beta-cell function in offspring and thereby reduce the cross-generational effects of obesity and type 2 diabetes. On the other hand, it is theorized that the drug may cause a decrease in cell-cycle proliferation, which could have “unknown fetal programming effects,” and it may inhibit the mTOR signaling pathway, thus restricting the transport of glucose and amino acids across the placenta, he said. (Findings from in vitro research have suggested that glyburide treatment in GDM might be associated with enhanced transport across the placenta, he noted.)

Long-term follow-up studies of offspring are “clearly needed,” Dr. Landon said. At this point, in regard to long-term safety, he and other experts are concerned primarily about the potential for obesity and metabolic dysfunction in offspring who are exposed to metformin in utero. They are watching follow-up from Dr. Rowan’s MiG trial, as well as elsewhere in the literature, on metformin-exposed offspring from mothers with polycystic ovary syndrome.

A follow-up analysis of offspring from the MiG trial found that children of women with GDM who were exposed to metformin had larger measures of subcutaneous fat at age 2 years, compared with children of mothers treated with insulin alone, but that overall body fat was the same, Dr. Landon noted. The investigators postulated that these children may have less visceral fat and a more favorable pattern of fat distribution (Diab Care. 2011;34:2279-84).

A recently published follow-up analysis of two randomized, controlled trials of women with polycystic ovary syndrome is cause for more concern, he said. That analysis showed that offspring exposed to metformin in utero had a higher body mass index and an increased prevalence of obesity or overweight at age 4 years, compared with placebo groups (J Clin Endocrinol Metab. 2018;103[4]:1612-21).

That analysis of metformin-exposed offspring in the context of polycystic ovary syndrome was published after the SMFM statement, as was another follow-up analysis of MiG trial offspring – this one, at ages 7-9 years – that showed an increase in weight, size, and fat mass in one of two subsets analyzed, despite no difference in large-for-gestational age rates between the metformin- and insulin-exposed offspring (BMJ Open Diabetes Res Care. 2018;6[1]: e000456).

In 2018, a group of 17 prominent diabetes and maternal-fetal medicine researchers cited these findings in a response to the SMFM statement and cautioned against the widespread adoption of metformin use during pregnancy, writing that, based on “both pharmacologic and randomized trial evidence that metformin may create an atypical intrauterine environment ... we believe it is premature to embrace metformin as equivalent to insulin or as superior to glyburide, and that patients should be counseled on the limited long-term safety data and potential for adverse childhood metabolic effects” (Am J Obstet Gynecol. 2018;219[4]:367.e1-7).

The presence of occult hepatitis C virus infection is determined by finding HCV RNA in the liver and peripheral blood mononuclear cells, with no HCV RNA in the serum. Researchers have shown that the presence of occult HCV infection (OCI) was correlated with unfavorable polymorphisms near interferon lambda-3/4 (IFNL3/4), which has been associated with spontaneous HCV clearance.

This study was conducted to assess the frequency of OCI in 450 hemophilia patients in Iran with negative HCV markers, and to evaluate the association of three IFNL3 single nucleotide polymorphisms (rs8099917, rs12979860, and rs12980275) and the IFNL4 ss469415590 SNP with OCI positivity.

The estimated OCI rate was 10.2%. Among the 46 OCI patients, 56.5%, 23.9%, and 19.6% were infected with HCV-1b, HCV-1a, and HCV-3a, respectively. The researchers found that, compared with patients without OCI, unfavorable IFNL3 rs12979860, IFNL3 rs8099917, IFNL3 rs12980275, and IFNL4 ss469415590 genotypes were more frequently found in OCI patients. Multivariate analysis showed that ALT, cholesterol, triglyceride, as well as the aforementioned unfavorable interferon SNP geneotypes were associated with OCI positivity.

“10.2% of anti-HCV seronegative Iranian patients with hemophilia had OCI in our study; therefore, risk of this infection should be taken into consideration. We also showed that patients with unfavorable IFNL3 SNPs and IFNL4 ss469415590 genotypes were exposed to a higher risk of OCI, compared to hemophilia patients with other genotypes,” the researchers concluded.

The authors reported that they had no disclosures.

[email protected]

SOURCE: Nafari AH et al. Infect Genet Evol. 2019 Dec 13. doi: 10.1016/j.meegid.2019.104144.

The presence of occult hepatitis C virus infection is determined by finding HCV RNA in the liver and peripheral blood mononuclear cells, with no HCV RNA in the serum. Researchers have shown that the presence of occult HCV infection (OCI) was correlated with unfavorable polymorphisms near interferon lambda-3/4 (IFNL3/4), which has been associated with spontaneous HCV clearance.

This study was conducted to assess the frequency of OCI in 450 hemophilia patients in Iran with negative HCV markers, and to evaluate the association of three IFNL3 single nucleotide polymorphisms (rs8099917, rs12979860, and rs12980275) and the IFNL4 ss469415590 SNP with OCI positivity.

The estimated OCI rate was 10.2%. Among the 46 OCI patients, 56.5%, 23.9%, and 19.6% were infected with HCV-1b, HCV-1a, and HCV-3a, respectively. The researchers found that, compared with patients without OCI, unfavorable IFNL3 rs12979860, IFNL3 rs8099917, IFNL3 rs12980275, and IFNL4 ss469415590 genotypes were more frequently found in OCI patients. Multivariate analysis showed that ALT, cholesterol, triglyceride, as well as the aforementioned unfavorable interferon SNP geneotypes were associated with OCI positivity.

“10.2% of anti-HCV seronegative Iranian patients with hemophilia had OCI in our study; therefore, risk of this infection should be taken into consideration. We also showed that patients with unfavorable IFNL3 SNPs and IFNL4 ss469415590 genotypes were exposed to a higher risk of OCI, compared to hemophilia patients with other genotypes,” the researchers concluded.

The authors reported that they had no disclosures.

[email protected]

SOURCE: Nafari AH et al. Infect Genet Evol. 2019 Dec 13. doi: 10.1016/j.meegid.2019.104144.

The presence of occult hepatitis C virus infection is determined by finding HCV RNA in the liver and peripheral blood mononuclear cells, with no HCV RNA in the serum. Researchers have shown that the presence of occult HCV infection (OCI) was correlated with unfavorable polymorphisms near interferon lambda-3/4 (IFNL3/4), which has been associated with spontaneous HCV clearance.

This study was conducted to assess the frequency of OCI in 450 hemophilia patients in Iran with negative HCV markers, and to evaluate the association of three IFNL3 single nucleotide polymorphisms (rs8099917, rs12979860, and rs12980275) and the IFNL4 ss469415590 SNP with OCI positivity.

The estimated OCI rate was 10.2%. Among the 46 OCI patients, 56.5%, 23.9%, and 19.6% were infected with HCV-1b, HCV-1a, and HCV-3a, respectively. The researchers found that, compared with patients without OCI, unfavorable IFNL3 rs12979860, IFNL3 rs8099917, IFNL3 rs12980275, and IFNL4 ss469415590 genotypes were more frequently found in OCI patients. Multivariate analysis showed that ALT, cholesterol, triglyceride, as well as the aforementioned unfavorable interferon SNP geneotypes were associated with OCI positivity.

“10.2% of anti-HCV seronegative Iranian patients with hemophilia had OCI in our study; therefore, risk of this infection should be taken into consideration. We also showed that patients with unfavorable IFNL3 SNPs and IFNL4 ss469415590 genotypes were exposed to a higher risk of OCI, compared to hemophilia patients with other genotypes,” the researchers concluded.

The authors reported that they had no disclosures.

[email protected]

SOURCE: Nafari AH et al. Infect Genet Evol. 2019 Dec 13. doi: 10.1016/j.meegid.2019.104144.

The plant compounds known as flavonols that are found in many fruits and vegetables may reduce risk of developing Alzheimer’s disease, results of a recent observational study suggest.

Chalffy/Getty Images

Onset of Alzheimer’s disease (AD) was inversely associated with intake of flavonols, a subclass of flavonoids with antioxidant and anti-inflammatory properties, according to the study authors.

The rate of developing AD was reduced by 50% among individuals reporting high intake of kaempferol, a flavonol plentiful in leafy green vegetables, and by 38% for high intake of the flavonols myricetin and isorhamnetin, researchers said in a report published in Neurology.

The findings are from the Rush Memory and Aging Project (MAP), a large, prospective study of older individuals in retirement communities and public housing in the Chicago area that has been ongoing since 1997.

“Although there is more work to be done, the associations that we observed are promising and deserve further study,” said Thomas M. Holland, MD, of the Rush Institute for Healthy Aging in Chicago, and coauthors.

Those associations between flavonol intake and AD help set the stage for U.S. POINTER and other randomized, controlled trials that seek to evaluate the effects of dietary interventions in a more rigorous way, according to Laura D. Baker, PhD, associate professor of internal medicine at Wake Forest University, Winston-Salem, N.C.

Michele G. Sullivan/MDedge News

“This kind of data helps us feel like we are looking in the right direction in the randomized, controlled trials,” Dr. Baker said in an interview.

Dr. Baker is an investigator in the U.S. POINTER study, which will in part evaluate the impact of the MIND diet, which has been shown to slow cognitive decline with age in a previously published MAP study.

However, in the absence of randomized, controlled trial data, Dr. Baker cautioned against “prematurely advocating” for specific dietary approaches when speaking to patients and caregivers now.

“What I say is, we know for sure that the standard American Heart Association diet has been shown in clinical trials to reduce the risk of heart disease, and in terms of brain health, if you can reduce risk of heart disease, you are protecting your brain,” she said in the interview.

The present MAP study linking a reduced rate of AD to flavonol consumption is believed to be the first of its kind, though two previous studies from the early 2000s did find inverse associations between incident AD and intake of flavonoids, of which flavonoids are just one subclass, said Dr. Holland and coinvestigators in their report.

Moreover, in a MAP study published in 2018, Martha Clare Morris, ScD, and coauthors concluded that consuming about a serving per day of green leafy vegetables and foods rich in kaempferol, among other nutrients and bioactive compounds, may help slow cognitive decline associated with aging.

To more specifically study the relationship between kaempferol and other flavonols and the development of AD, Dr. Holland and colleagues evaluated data for MAP participants who had completed a comprehensive food frequency questionnaire and underwent at least two evaluations to assess incidence of disease.

The mean age of the 921 individuals in the present analysis was 81 years, three-quarters were female, and over approximately 6 years of follow-up, 220 developed AD.

The rate of developing AD was 48% lower among participants reporting the highest total dietary intake of flavonols, compared with those reporting the lowest intake, Dr. Holland and coauthors reported.

Intake of the specific flavonols kaempferol, myricetin, and isorhamnetin were associated with incident AD reductions of 50%, 38%, and 38%, respectively. Another flavonol, quercetin, was by contrast not inversely associated with incident AD, according to the report.

Kaempferol was independently associated with AD in subsequent analyses, while there was no such independent association for myricetin, isorhamnetin, or quercetin, according to Dr. Holland and coinvestigators.

Further analyses of the data suggested the linkages between flavonols and AD were independent of lifestyle factors, dietary intakes, or cardiovascular conditions, they said in their report.

“Confirmation of these findings is warranted through other longitudinal epidemiologic studies and clinical trials, in addition to further elucidation of the biologic mechanisms,” they concluded.

The study was funded by grants from the National Institutes of Health and the USDA Agricultural Research Service. Dr. Holland and coauthors said that they had no disclosures relevant to their report.

SOURCE: Holland TM et al. Neurology. 2020 Jan 29. doi: 10.1212/WNL.0000000000008981.

The plant compounds known as flavonols that are found in many fruits and vegetables may reduce risk of developing Alzheimer’s disease, results of a recent observational study suggest.

Chalffy/Getty Images

Onset of Alzheimer’s disease (AD) was inversely associated with intake of flavonols, a subclass of flavonoids with antioxidant and anti-inflammatory properties, according to the study authors.

The rate of developing AD was reduced by 50% among individuals reporting high intake of kaempferol, a flavonol plentiful in leafy green vegetables, and by 38% for high intake of the flavonols myricetin and isorhamnetin, researchers said in a report published in Neurology.

The findings are from the Rush Memory and Aging Project (MAP), a large, prospective study of older individuals in retirement communities and public housing in the Chicago area that has been ongoing since 1997.

“Although there is more work to be done, the associations that we observed are promising and deserve further study,” said Thomas M. Holland, MD, of the Rush Institute for Healthy Aging in Chicago, and coauthors.

Those associations between flavonol intake and AD help set the stage for U.S. POINTER and other randomized, controlled trials that seek to evaluate the effects of dietary interventions in a more rigorous way, according to Laura D. Baker, PhD, associate professor of internal medicine at Wake Forest University, Winston-Salem, N.C.

Michele G. Sullivan/MDedge News

“This kind of data helps us feel like we are looking in the right direction in the randomized, controlled trials,” Dr. Baker said in an interview.

Dr. Baker is an investigator in the U.S. POINTER study, which will in part evaluate the impact of the MIND diet, which has been shown to slow cognitive decline with age in a previously published MAP study.

However, in the absence of randomized, controlled trial data, Dr. Baker cautioned against “prematurely advocating” for specific dietary approaches when speaking to patients and caregivers now.

“What I say is, we know for sure that the standard American Heart Association diet has been shown in clinical trials to reduce the risk of heart disease, and in terms of brain health, if you can reduce risk of heart disease, you are protecting your brain,” she said in the interview.

The present MAP study linking a reduced rate of AD to flavonol consumption is believed to be the first of its kind, though two previous studies from the early 2000s did find inverse associations between incident AD and intake of flavonoids, of which flavonoids are just one subclass, said Dr. Holland and coinvestigators in their report.

Moreover, in a MAP study published in 2018, Martha Clare Morris, ScD, and coauthors concluded that consuming about a serving per day of green leafy vegetables and foods rich in kaempferol, among other nutrients and bioactive compounds, may help slow cognitive decline associated with aging.

To more specifically study the relationship between kaempferol and other flavonols and the development of AD, Dr. Holland and colleagues evaluated data for MAP participants who had completed a comprehensive food frequency questionnaire and underwent at least two evaluations to assess incidence of disease.

The mean age of the 921 individuals in the present analysis was 81 years, three-quarters were female, and over approximately 6 years of follow-up, 220 developed AD.

The rate of developing AD was 48% lower among participants reporting the highest total dietary intake of flavonols, compared with those reporting the lowest intake, Dr. Holland and coauthors reported.

Intake of the specific flavonols kaempferol, myricetin, and isorhamnetin were associated with incident AD reductions of 50%, 38%, and 38%, respectively. Another flavonol, quercetin, was by contrast not inversely associated with incident AD, according to the report.

Kaempferol was independently associated with AD in subsequent analyses, while there was no such independent association for myricetin, isorhamnetin, or quercetin, according to Dr. Holland and coinvestigators.

Further analyses of the data suggested the linkages between flavonols and AD were independent of lifestyle factors, dietary intakes, or cardiovascular conditions, they said in their report.

“Confirmation of these findings is warranted through other longitudinal epidemiologic studies and clinical trials, in addition to further elucidation of the biologic mechanisms,” they concluded.

The study was funded by grants from the National Institutes of Health and the USDA Agricultural Research Service. Dr. Holland and coauthors said that they had no disclosures relevant to their report.

SOURCE: Holland TM et al. Neurology. 2020 Jan 29. doi: 10.1212/WNL.0000000000008981.

The plant compounds known as flavonols that are found in many fruits and vegetables may reduce risk of developing Alzheimer’s disease, results of a recent observational study suggest.

Chalffy/Getty Images

Onset of Alzheimer’s disease (AD) was inversely associated with intake of flavonols, a subclass of flavonoids with antioxidant and anti-inflammatory properties, according to the study authors.

The rate of developing AD was reduced by 50% among individuals reporting high intake of kaempferol, a flavonol plentiful in leafy green vegetables, and by 38% for high intake of the flavonols myricetin and isorhamnetin, researchers said in a report published in Neurology.

The findings are from the Rush Memory and Aging Project (MAP), a large, prospective study of older individuals in retirement communities and public housing in the Chicago area that has been ongoing since 1997.

“Although there is more work to be done, the associations that we observed are promising and deserve further study,” said Thomas M. Holland, MD, of the Rush Institute for Healthy Aging in Chicago, and coauthors.

Those associations between flavonol intake and AD help set the stage for U.S. POINTER and other randomized, controlled trials that seek to evaluate the effects of dietary interventions in a more rigorous way, according to Laura D. Baker, PhD, associate professor of internal medicine at Wake Forest University, Winston-Salem, N.C.

Michele G. Sullivan/MDedge News

“This kind of data helps us feel like we are looking in the right direction in the randomized, controlled trials,” Dr. Baker said in an interview.

Dr. Baker is an investigator in the U.S. POINTER study, which will in part evaluate the impact of the MIND diet, which has been shown to slow cognitive decline with age in a previously published MAP study.

However, in the absence of randomized, controlled trial data, Dr. Baker cautioned against “prematurely advocating” for specific dietary approaches when speaking to patients and caregivers now.

“What I say is, we know for sure that the standard American Heart Association diet has been shown in clinical trials to reduce the risk of heart disease, and in terms of brain health, if you can reduce risk of heart disease, you are protecting your brain,” she said in the interview.

The present MAP study linking a reduced rate of AD to flavonol consumption is believed to be the first of its kind, though two previous studies from the early 2000s did find inverse associations between incident AD and intake of flavonoids, of which flavonoids are just one subclass, said Dr. Holland and coinvestigators in their report.

Moreover, in a MAP study published in 2018, Martha Clare Morris, ScD, and coauthors concluded that consuming about a serving per day of green leafy vegetables and foods rich in kaempferol, among other nutrients and bioactive compounds, may help slow cognitive decline associated with aging.

To more specifically study the relationship between kaempferol and other flavonols and the development of AD, Dr. Holland and colleagues evaluated data for MAP participants who had completed a comprehensive food frequency questionnaire and underwent at least two evaluations to assess incidence of disease.

The mean age of the 921 individuals in the present analysis was 81 years, three-quarters were female, and over approximately 6 years of follow-up, 220 developed AD.

The rate of developing AD was 48% lower among participants reporting the highest total dietary intake of flavonols, compared with those reporting the lowest intake, Dr. Holland and coauthors reported.

Intake of the specific flavonols kaempferol, myricetin, and isorhamnetin were associated with incident AD reductions of 50%, 38%, and 38%, respectively. Another flavonol, quercetin, was by contrast not inversely associated with incident AD, according to the report.

Kaempferol was independently associated with AD in subsequent analyses, while there was no such independent association for myricetin, isorhamnetin, or quercetin, according to Dr. Holland and coinvestigators.

Further analyses of the data suggested the linkages between flavonols and AD were independent of lifestyle factors, dietary intakes, or cardiovascular conditions, they said in their report.

“Confirmation of these findings is warranted through other longitudinal epidemiologic studies and clinical trials, in addition to further elucidation of the biologic mechanisms,” they concluded.

The study was funded by grants from the National Institutes of Health and the USDA Agricultural Research Service. Dr. Holland and coauthors said that they had no disclosures relevant to their report.

SOURCE: Holland TM et al. Neurology. 2020 Jan 29. doi: 10.1212/WNL.0000000000008981.

Traditionally, U.S. health care has operated under a fee-for-service payment model, in which health care providers (such as physicians, hospitals, and health care systems) receive a fee for services such as office visits, hospital stays, procedures, and tests. However, reimbursement discussions are increasingly moving from fee-for-service to value-based, in which payments are tied to managing population health and total cost of care.

Because these changes will impact the entire system all the way down to individual providers, in the upcoming Population Management article series in The Hospitalist, we will discuss the nuances and implications that physicians, executives, and hospitals should be aware of. In this first article, we will examine the impetus for the shift toward population management and introduce common terminology to lay the foundation for the future content.
 

The traditional model: Fee for service

Under the traditional fee-for-service payment system, health care providers are paid per unit of service. For example, hospitals receive diagnosis-related group (DRG) payments for inpatient stays, and physicians are paid per patient visit. The more services that hospitals or physicians provide, the more money both get paid, without financial consequences for quality outcomes or total cost of care. Total cost of care includes clinic visits, outpatient procedures and tests, hospital and ED visits, home health, skilled nursing facilities, durable medical equipment, and sometimes drugs during an episode of care (for example, a hospital stay plus 90 days after discharge) or over a period of time (for example, a month or a year).

As a result of the fee-for-service payment system, the United States spends more money on health care than other wealthy countries, yet it lags behind other countries on many quality measures, such as disease burden, overall mortality, premature death, and preventable death.^1,2

In 2007, the Institute for Healthcare Improvement (IHI) developed the Triple Aim framework that focused on the following:

• Improving the patient experience of care (including quality and satisfaction).
• Improving the health of populations.
• Reducing per capita cost of care.

Both public payers like Medicare and Medicaid, as well as private payers, embraced the Triple Aim to reform how health care is delivered and paid for. As such, health care delivery focus and financial incentives are shifting from managing discrete patient encounters for acute illness to managing population health and total cost of care.
 

A new approach: Population management

Before diving into population management, it is important to first understand the terms “population” and “population health.” A population can be defined geographically or may include employees of an organization, members of a health plan, or patients receiving care from a specific physician group or health care system. David A. Kindig, MD, PhD, professor emeritus of population health sciences at the University of Wisconsin–Madison, defined population health as “the health outcomes of a group of individuals, including the distribution of such outcomes within the group.”³ Dr. Kindig noted that population health outcomes have many determinants, such as the following:⁴

• Health care (access, cost, quantity, and quality of health care services).
• Individual behavior (including diet, exercise, and substance abuse).
• Genetics.
• The social environment (education, income, occupation, class, and social support).
• Physical environment (air and water quality, lead exposure, and the design of neighborhoods).

IHI operationally defines population health by measures such as life expectancy, mortality rates, health and functional status, the incidence and/or prevalence of chronic disease, and behavioral and physiological factors such as smoking, physical activity, diet, blood pressure, body mass index, and cholesterol.⁵

On the other hand, population management is primarily concerned with health care determinants of health and, according to IHI, should be clearly distinguished from population health, which focuses on the broader determinants of health.⁵

According to Ron Greeno, MD, MHM, one of the founding members and a past-president of the Society of Hospital Medicine, population management is a “global approach of caring for an entire patient population to deliver safe and equitable care and to more intelligently allocate resources to keep people well.”

Population management requires understanding the patient population, which includes risk stratification and redesigning and delivering services that are guided by integrated clinical and administrative data and enabled by information technology.
 

Cost-sharing payment models

The cornerstone of population management is provider accountability for the cost of care, which can be accomplished through shared-risk models or population-based payments. Let’s take a closer look at each.

Under shared-risk models, providers receive payment based on their performance against cost targets. The goal is to generate cost savings by improving care coordination, engaging patients in shared decision making based on their health goals, and reducing utilization of care that provides little to no value for patients (for example, preventable hospital admissions or unnecessary imaging or procedures).

Cost targets and actual spending are reconciled retrospectively. If providers beat cost targets, they are eligible to keep a share of generated savings based on their performance on selected quality measures. However, if providers’ actual spending exceeds cost targets, they will compensate payers for a portion of the losses. Under one-sided risk models, providers are eligible for shared savings but not financially responsible for losses. Under two-sided risk models, providers are accountable for both savings and losses.

With prospective population-based payments, also known as capitation, providers receive in advance a fixed amount of money per patient per unit of time (for example, per month) that creates a budget to cover the cost of agreed-upon health care services. The prospective payments are risk adjusted and typically tied to performance on selected quality, effectiveness, and patient experience measures.

Professional services capitation arrangements between physician groups and payers cover the cost of physician services including primary care, specialty care, and related laboratory and radiology services. Under global capitation or global payment arrangements, health care systems receive payments that cover the total cost of care for the patient population for a defined period.

Population-based payments create incentives to provide high-quality and efficient care within a set budget.⁶ If actual cost of delivering services to the defined patient population comes under the budget, the providers will realize savings, but otherwise will encounter losses.
 

What is next?

Now that we have explained the impetus for population management and the terminology, in the next article in this series we will discuss the current state of population management. We will also delve into a hospitalist’s role and participation so you can be aware of impending changes and ensure you are set up for success, no matter how the payment models evolve.
 

Dr. Farah is a hospitalist, physician adviser, and Lean Six Sigma Black Belt. She is a performance improvement consultant based in Corvallis, Ore., and a member of The Hospitalist’s editorial advisory board.

References

1. Source: https://www.healthsystemtracker.org/chart-collection/health-spending-u-s-compare-countries/#item-start

2. Source: https://www.healthsystemtracker.org/brief/on-several-indicators-of-healthcare-quality the-u-s-falls-short/

3. Kindig D, Asada Y, Booske B. (2008). A Population Health Framework for Setting National and State Health Goals. JAMA, 299, 2081-2083.

4. Source: https://improvingpopulationhealth.typepad.com/blog/what-are-health-factorsdeterminants.html

5. Source: http://www.ihi.org/communities/blogs/population-health-population-management-terminology-in-us-health-care

6. Source: http://hcp-lan.org/workproducts/apm-refresh-whitepaper-final.pdf

Traditionally, U.S. health care has operated under a fee-for-service payment model, in which health care providers (such as physicians, hospitals, and health care systems) receive a fee for services such as office visits, hospital stays, procedures, and tests. However, reimbursement discussions are increasingly moving from fee-for-service to value-based, in which payments are tied to managing population health and total cost of care.

Because these changes will impact the entire system all the way down to individual providers, in the upcoming Population Management article series in The Hospitalist, we will discuss the nuances and implications that physicians, executives, and hospitals should be aware of. In this first article, we will examine the impetus for the shift toward population management and introduce common terminology to lay the foundation for the future content.
 

The traditional model: Fee for service

Under the traditional fee-for-service payment system, health care providers are paid per unit of service. For example, hospitals receive diagnosis-related group (DRG) payments for inpatient stays, and physicians are paid per patient visit. The more services that hospitals or physicians provide, the more money both get paid, without financial consequences for quality outcomes or total cost of care. Total cost of care includes clinic visits, outpatient procedures and tests, hospital and ED visits, home health, skilled nursing facilities, durable medical equipment, and sometimes drugs during an episode of care (for example, a hospital stay plus 90 days after discharge) or over a period of time (for example, a month or a year).

As a result of the fee-for-service payment system, the United States spends more money on health care than other wealthy countries, yet it lags behind other countries on many quality measures, such as disease burden, overall mortality, premature death, and preventable death.^1,2

In 2007, the Institute for Healthcare Improvement (IHI) developed the Triple Aim framework that focused on the following:

• Improving the patient experience of care (including quality and satisfaction).
• Improving the health of populations.
• Reducing per capita cost of care.

Both public payers like Medicare and Medicaid, as well as private payers, embraced the Triple Aim to reform how health care is delivered and paid for. As such, health care delivery focus and financial incentives are shifting from managing discrete patient encounters for acute illness to managing population health and total cost of care.
 

A new approach: Population management

Before diving into population management, it is important to first understand the terms “population” and “population health.” A population can be defined geographically or may include employees of an organization, members of a health plan, or patients receiving care from a specific physician group or health care system. David A. Kindig, MD, PhD, professor emeritus of population health sciences at the University of Wisconsin–Madison, defined population health as “the health outcomes of a group of individuals, including the distribution of such outcomes within the group.”³ Dr. Kindig noted that population health outcomes have many determinants, such as the following:⁴

• Health care (access, cost, quantity, and quality of health care services).
• Individual behavior (including diet, exercise, and substance abuse).
• Genetics.
• The social environment (education, income, occupation, class, and social support).
• Physical environment (air and water quality, lead exposure, and the design of neighborhoods).

IHI operationally defines population health by measures such as life expectancy, mortality rates, health and functional status, the incidence and/or prevalence of chronic disease, and behavioral and physiological factors such as smoking, physical activity, diet, blood pressure, body mass index, and cholesterol.⁵

On the other hand, population management is primarily concerned with health care determinants of health and, according to IHI, should be clearly distinguished from population health, which focuses on the broader determinants of health.⁵

According to Ron Greeno, MD, MHM, one of the founding members and a past-president of the Society of Hospital Medicine, population management is a “global approach of caring for an entire patient population to deliver safe and equitable care and to more intelligently allocate resources to keep people well.”

Population management requires understanding the patient population, which includes risk stratification and redesigning and delivering services that are guided by integrated clinical and administrative data and enabled by information technology.
 

Cost-sharing payment models

The cornerstone of population management is provider accountability for the cost of care, which can be accomplished through shared-risk models or population-based payments. Let’s take a closer look at each.

Under shared-risk models, providers receive payment based on their performance against cost targets. The goal is to generate cost savings by improving care coordination, engaging patients in shared decision making based on their health goals, and reducing utilization of care that provides little to no value for patients (for example, preventable hospital admissions or unnecessary imaging or procedures).

Cost targets and actual spending are reconciled retrospectively. If providers beat cost targets, they are eligible to keep a share of generated savings based on their performance on selected quality measures. However, if providers’ actual spending exceeds cost targets, they will compensate payers for a portion of the losses. Under one-sided risk models, providers are eligible for shared savings but not financially responsible for losses. Under two-sided risk models, providers are accountable for both savings and losses.

With prospective population-based payments, also known as capitation, providers receive in advance a fixed amount of money per patient per unit of time (for example, per month) that creates a budget to cover the cost of agreed-upon health care services. The prospective payments are risk adjusted and typically tied to performance on selected quality, effectiveness, and patient experience measures.

Professional services capitation arrangements between physician groups and payers cover the cost of physician services including primary care, specialty care, and related laboratory and radiology services. Under global capitation or global payment arrangements, health care systems receive payments that cover the total cost of care for the patient population for a defined period.

Population-based payments create incentives to provide high-quality and efficient care within a set budget.⁶ If actual cost of delivering services to the defined patient population comes under the budget, the providers will realize savings, but otherwise will encounter losses.
 

What is next?

Now that we have explained the impetus for population management and the terminology, in the next article in this series we will discuss the current state of population management. We will also delve into a hospitalist’s role and participation so you can be aware of impending changes and ensure you are set up for success, no matter how the payment models evolve.
 

Dr. Farah is a hospitalist, physician adviser, and Lean Six Sigma Black Belt. She is a performance improvement consultant based in Corvallis, Ore., and a member of The Hospitalist’s editorial advisory board.

References

1. Source: https://www.healthsystemtracker.org/chart-collection/health-spending-u-s-compare-countries/#item-start

2. Source: https://www.healthsystemtracker.org/brief/on-several-indicators-of-healthcare-quality the-u-s-falls-short/

3. Kindig D, Asada Y, Booske B. (2008). A Population Health Framework for Setting National and State Health Goals. JAMA, 299, 2081-2083.

4. Source: https://improvingpopulationhealth.typepad.com/blog/what-are-health-factorsdeterminants.html

5. Source: http://www.ihi.org/communities/blogs/population-health-population-management-terminology-in-us-health-care

6. Source: http://hcp-lan.org/workproducts/apm-refresh-whitepaper-final.pdf

Traditionally, U.S. health care has operated under a fee-for-service payment model, in which health care providers (such as physicians, hospitals, and health care systems) receive a fee for services such as office visits, hospital stays, procedures, and tests. However, reimbursement discussions are increasingly moving from fee-for-service to value-based, in which payments are tied to managing population health and total cost of care.

Because these changes will impact the entire system all the way down to individual providers, in the upcoming Population Management article series in The Hospitalist, we will discuss the nuances and implications that physicians, executives, and hospitals should be aware of. In this first article, we will examine the impetus for the shift toward population management and introduce common terminology to lay the foundation for the future content.
 

The traditional model: Fee for service

Under the traditional fee-for-service payment system, health care providers are paid per unit of service. For example, hospitals receive diagnosis-related group (DRG) payments for inpatient stays, and physicians are paid per patient visit. The more services that hospitals or physicians provide, the more money both get paid, without financial consequences for quality outcomes or total cost of care. Total cost of care includes clinic visits, outpatient procedures and tests, hospital and ED visits, home health, skilled nursing facilities, durable medical equipment, and sometimes drugs during an episode of care (for example, a hospital stay plus 90 days after discharge) or over a period of time (for example, a month or a year).

As a result of the fee-for-service payment system, the United States spends more money on health care than other wealthy countries, yet it lags behind other countries on many quality measures, such as disease burden, overall mortality, premature death, and preventable death.^1,2

In 2007, the Institute for Healthcare Improvement (IHI) developed the Triple Aim framework that focused on the following:

• Improving the patient experience of care (including quality and satisfaction).
• Improving the health of populations.
• Reducing per capita cost of care.

Both public payers like Medicare and Medicaid, as well as private payers, embraced the Triple Aim to reform how health care is delivered and paid for. As such, health care delivery focus and financial incentives are shifting from managing discrete patient encounters for acute illness to managing population health and total cost of care.
 

A new approach: Population management

Before diving into population management, it is important to first understand the terms “population” and “population health.” A population can be defined geographically or may include employees of an organization, members of a health plan, or patients receiving care from a specific physician group or health care system. David A. Kindig, MD, PhD, professor emeritus of population health sciences at the University of Wisconsin–Madison, defined population health as “the health outcomes of a group of individuals, including the distribution of such outcomes within the group.”³ Dr. Kindig noted that population health outcomes have many determinants, such as the following:⁴

• Health care (access, cost, quantity, and quality of health care services).
• Individual behavior (including diet, exercise, and substance abuse).
• Genetics.
• The social environment (education, income, occupation, class, and social support).
• Physical environment (air and water quality, lead exposure, and the design of neighborhoods).

IHI operationally defines population health by measures such as life expectancy, mortality rates, health and functional status, the incidence and/or prevalence of chronic disease, and behavioral and physiological factors such as smoking, physical activity, diet, blood pressure, body mass index, and cholesterol.⁵

On the other hand, population management is primarily concerned with health care determinants of health and, according to IHI, should be clearly distinguished from population health, which focuses on the broader determinants of health.⁵

According to Ron Greeno, MD, MHM, one of the founding members and a past-president of the Society of Hospital Medicine, population management is a “global approach of caring for an entire patient population to deliver safe and equitable care and to more intelligently allocate resources to keep people well.”

Population management requires understanding the patient population, which includes risk stratification and redesigning and delivering services that are guided by integrated clinical and administrative data and enabled by information technology.
 

Cost-sharing payment models

The cornerstone of population management is provider accountability for the cost of care, which can be accomplished through shared-risk models or population-based payments. Let’s take a closer look at each.

Under shared-risk models, providers receive payment based on their performance against cost targets. The goal is to generate cost savings by improving care coordination, engaging patients in shared decision making based on their health goals, and reducing utilization of care that provides little to no value for patients (for example, preventable hospital admissions or unnecessary imaging or procedures).

Cost targets and actual spending are reconciled retrospectively. If providers beat cost targets, they are eligible to keep a share of generated savings based on their performance on selected quality measures. However, if providers’ actual spending exceeds cost targets, they will compensate payers for a portion of the losses. Under one-sided risk models, providers are eligible for shared savings but not financially responsible for losses. Under two-sided risk models, providers are accountable for both savings and losses.

With prospective population-based payments, also known as capitation, providers receive in advance a fixed amount of money per patient per unit of time (for example, per month) that creates a budget to cover the cost of agreed-upon health care services. The prospective payments are risk adjusted and typically tied to performance on selected quality, effectiveness, and patient experience measures.

Professional services capitation arrangements between physician groups and payers cover the cost of physician services including primary care, specialty care, and related laboratory and radiology services. Under global capitation or global payment arrangements, health care systems receive payments that cover the total cost of care for the patient population for a defined period.

Population-based payments create incentives to provide high-quality and efficient care within a set budget.⁶ If actual cost of delivering services to the defined patient population comes under the budget, the providers will realize savings, but otherwise will encounter losses.
 

What is next?

Now that we have explained the impetus for population management and the terminology, in the next article in this series we will discuss the current state of population management. We will also delve into a hospitalist’s role and participation so you can be aware of impending changes and ensure you are set up for success, no matter how the payment models evolve.
 

Dr. Farah is a hospitalist, physician adviser, and Lean Six Sigma Black Belt. She is a performance improvement consultant based in Corvallis, Ore., and a member of The Hospitalist’s editorial advisory board.

References

1. Source: https://www.healthsystemtracker.org/chart-collection/health-spending-u-s-compare-countries/#item-start

2. Source: https://www.healthsystemtracker.org/brief/on-several-indicators-of-healthcare-quality the-u-s-falls-short/

3. Kindig D, Asada Y, Booske B. (2008). A Population Health Framework for Setting National and State Health Goals. JAMA, 299, 2081-2083.

4. Source: https://improvingpopulationhealth.typepad.com/blog/what-are-health-factorsdeterminants.html

5. Source: http://www.ihi.org/communities/blogs/population-health-population-management-terminology-in-us-health-care

6. Source: http://hcp-lan.org/workproducts/apm-refresh-whitepaper-final.pdf